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WO2025235034A1 - 3-fluoro-5-(((ls,2ar)-1,3,3,4, 4-pentafluoro-2a-hydroxy-2,2a, 3,4-tetrahydro-lh-cyclopenta[cd]inden-7- yl)oxy)- benzonitrile dosing regimen for use in the treatment of cancer - Google Patents

3-fluoro-5-(((ls,2ar)-1,3,3,4, 4-pentafluoro-2a-hydroxy-2,2a, 3,4-tetrahydro-lh-cyclopenta[cd]inden-7- yl)oxy)- benzonitrile dosing regimen for use in the treatment of cancer

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Publication number
WO2025235034A1
WO2025235034A1 PCT/US2024/056721 US2024056721W WO2025235034A1 WO 2025235034 A1 WO2025235034 A1 WO 2025235034A1 US 2024056721 W US2024056721 W US 2024056721W WO 2025235034 A1 WO2025235034 A1 WO 2025235034A1
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WO
WIPO (PCT)
Prior art keywords
compound
dose
patients
study
patient
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2024/056721
Other languages
French (fr)
Inventor
Keshi Wang
Jim Xiao
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nikang Therapeutics Inc
Original Assignee
Nikang Therapeutics Inc
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Filing date
Publication date
Application filed by Nikang Therapeutics Inc filed Critical Nikang Therapeutics Inc
Priority to PCT/US2025/027249 priority Critical patent/WO2025235290A1/en
Publication of WO2025235034A1 publication Critical patent/WO2025235034A1/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Definitions

  • Compound (I) and a crystalline form of Compound (I), referred to as Compound (I) Form A, having an X-ray powder diffraction (XRPD) pattern comprising peaks at angular positions 15.8 and 18.6, wherein the angular positions may vary by + 0.2 o 2 ⁇ as measured by X-ray powder diffraction using (Cu K ⁇ ) an X-ray wavelength of 1.5418 ⁇ are disclosed in PCT Application Publication No. WO 2020/214853, filed on April 16, 2020, the entire content of which is incorporated herein by reference. Attorney Docket No.16036.0005-00304 Ref. No.
  • NKT-24-007PCT Compound (I) Form A is currently in a Phase 1/2 open label dose-escalation and expansion trial (Study) in patients with clear cell renal cell carcinoma (ccRCC) as a monotherapy. Multiple oral doses of Compound (I) Form A, formulated as immediate-release capsules, are being used in the Study to evaluate the safety, tolerability, PK, PD, and anti-tumor activity.
  • Phase 1 to identify the maximum tolerated dose (MTD) and/or the recommended doses for expansion (RDEs) of Compound (I) Form A in patients with relapsed or refractory ccRCC
  • Phase 2 to evaluate the antitumor activity of Compound (I) Form A by objective response rate (ORR) at the RDEs in patients with ccRCC and determine the recommended Phase 2 dose (RP2D).
  • ORR objective response rate
  • R2D Phase 2 dose
  • Compound (I) Form A could be administered at different sequential loading and maintenance dosing schedules to rapidly achieve and then maintain a potential therapeutic plasma level of Compound (I) in patients.
  • the model described the PK data of Compound (I) after administration of both a single dose and multiple doses of Compound (I) Form A, as well as after dose reductions and dose holds.
  • NKT-24-007PCT distribution of Compound (I) were, generally, 0.684 h -1 , 0.512 L/h, 24.4 L/h, 153 L, and 624 L, respectively. Higher body weight appeared to correlate with higher Vc/F and Vp/F values but not CL/F.
  • the model-estimated median terminal t 1/2 of Compound (I) was 38 days. Between-patient variability was moderate on CL/F (49%), Vc/F (37%), Vp/F (34%), and Ka (81%).
  • the PK modeling analysis suggested no time- or concentration-dependent PK nonlinearity.
  • Q2W or Q4W may offer similar efficacy as maintenance QW or maintenance QD dosing, better safety and tolerability, and/or a reduction in drug-drug interaction risks with Compound (I) as a CYP3A4 inducer, especially in the gut. Accordingly, amongst the various aspects of the present disclosure, provided herein are dosing regimens for Compound (I) or Compound (I) Form A.
  • a method of treating cancer comprising administering to a patient in need thereof: (a) a loading dose during a loading period, wherein each loading dose comprises from about 20 mg to about 300 mg of Compound (I) or Compound (I) Form A having an X-ray powder diffraction (XRPD) pattern comprising peaks at angular positions 15.8 and 18.6, wherein the angular positions may vary by + 0.2 o 2 ⁇ as measured by X-ray powder diffraction using (Cu K ⁇ ) an X-ray wavelength of 1.5418 ⁇ ; and (b) a maintenance dose during a maintenance period, wherein each maintenance dose comprises less than or the same amount of the Compound (I) or Compound (I) Form A present in the loading dose in (a), provided that, when the amount of Compound (I) or Compound (I) Form A in the maintenance dose is the same as the loading dose in (a), the maintenance dose is administered to the patient less frequently than the loading dose is administered during the loading period.
  • XRPD X-ray
  • Compound (I) or Compound (I) Form A having an X-ray powder diffraction pattern comprising peaks at angular positions 15.8 and 18.6, wherein the angular positions may vary by + 0.2 o 2 ⁇ as measured by X-ray powder diffraction using (Cu K ⁇ ) an X-ray wavelength of 1.5418 ⁇ , for use in the manufacture of a medicament for the treatment of cancer in a patient which medicament is administered as: (a) a loading dose during a loading period, wherein each loading dose comprises from about 20 mg to about 300 mg of the Compound (I) or Compound (I) Form A; and Attorney Docket No.16036.0005-00304 Ref. No.
  • NKT-24-007PCT (b) a maintenance dose during a maintenance period, wherein each maintenance dose comprises less than or the same amount of the Compound (I) or Compound (I) Form A present in the loading dose in (a), provided that, when the amount of Compound (I) or Compound (I) Form A in the maintenance dose is the same as the loading dose in (a), the maintenance dose is administered to the patient less frequently than the loading dose is administered during the loading period.
  • Compound (I) or Compound (I) Form A having an X-ray powder diffraction pattern comprising peaks at angular positions 15.8 and 18.6, wherein the angular positions may vary by + 0.2 o 2 ⁇ as measured by X-ray powder diffraction using (Cu K ⁇ ) an X-ray wavelength of 1.5418 ⁇ , for use in the the treatment of cancer comprising administering to a patient in need thereof: (a) a loading dose during a loading period, wherein each loading dose comprises from about 20 mg to about 300 mg of the Compound (I) or Compound (I) Form A; and (b) a maintenance dose during a maintenance period, wherein each maintenance dose comprises less than or the same amount of the Compound (I) or Compound (I) Form A present in the loading dose in (a), provided that, when the amount of Compound (I) or Compound (I) Form A in the maintenance dose is the same as the loading dose in (a), the maintenance dose is administered to the patient less frequently than the
  • a method of treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of a Compound (I) or Compound (I) Form A having an X-ray powder diffraction (XRPD) pattern comprising peaks at angular positions 15.8 and 18.6, wherein the angular positions may vary by + 0.2 o 2 ⁇ as measured by X- ray powder diffraction using (Cu K ⁇ ) an X-ray wavelength of 1.5418 ⁇ in a dosing regimen comprising: (a) administering a loading dose during a loading period, wherein each loading dose comprises the Compound (I) or Compound (I) Form A; and (b) administering a maintenance dose during a maintenance period, wherein each maintenance dose comprises less than or the same amount of Compound (I) or Compound (I) Form A present in the loading dose in (a), provided that, when the amount of Compound (I) or the Compound (I) Form A in the maintenance dose is the same as the loading dose
  • XRPD
  • the therapeutically effective amount of Compound (I) or Compound (I) Form A is the amount of Compound (I) or Compound (I) Form A Attorney Docket No.16036.0005-00304 Ref. No.
  • NKT-24-007PCT used in the dosing regimen that yields a median trough plasma concentration of Compound (I) (Ctrough) in the patient ofabout 936 ng/mL (with 90% prediction interval of 265 to 2220 ng/mL) and about 3460 ng/mL (with 90% prediction interval of 1170 to about 8120 ng/mL) at RDE-w and RDE-d, respectively, after the first maintenance dose is administered to the patient (for sake of clarity after the loading dosage and first maintaince dose are administered to the patient).
  • the therapeutically effective amount of Compound (I) or Compound (I) Form A is the amount of Compound (I) or Compound (I) Form A used in the dosing regimen that yields a weekly area under the plasma concentration-time curve (AUC 0-168h ) value of Compound (I) in the patient of about 177000 and about 624000 ng•hr/ml at RDE-w and RDE-d, respectively, for the first week of maintenance treatment (for sake of clarity after the loading dosage and RDE-w or RDE-d are administered to the patient).
  • AUC 0-168h plasma concentration-time curve
  • the therapeutically effective amount of Compound (I) or Compound (I) Form A is the amount of Compound (I) or Compound (I) Form A used in the dosing regimen that yields a maximum plasma concentration (Cmax) of Compound (I) in the patient of about 1420 and about 3870 ng/ml at RDE-w and RDE-d, respectively, for the first week of maintenance treatment.
  • the therapeutically effective amount of Compound (I) or Compound (I) Form A is the amount of Compound (I) or Compound (I) Form A used in the dosing regimen that yields a minimum plasma concentration (Cmin) of Compound (I) in the patient of about 973 and about 3650 ng/ml at RDE-w and RDE-d, respectively, for the first week of maintenance treatment.
  • Cmin minimum plasma concentration
  • Figs.1A and 1B depict plots of mean (+SE) plasma Compound (I) concentration-time profiles by dosage on linear scale as of the 5 October 2023 analysis in Example 3.
  • Fig.1A depicts cohorts with 50 mg, 100 mg, 200 mg, or 300 mg QD dosing schedules of Compound (I) Form A and Fig.1B depicts cohorts with sequential loading and maintenance treatments of Compound (I) Form A.
  • Figs.2A and 2B depicts plot of mean (+SE) percent serum erythropoietin concentration change from baseline-time profiles by cohort as of the 5 October 2023 analysis in Example 3.
  • Fig. 2A depicts cohorts with 50 mg, 100 mg, 200 mg, or 300 ng QD dosing schedules of Compound (I) Form A and Fig.2B depicts cohorts with sequential loading and maintenance treatments of Compound (I) Form A.
  • Fig.3 depicts model-simulated typical PK profiles of Compound (I) at the proposed RDE- w and RDE-d dosages of Compound (I) Form A.
  • Fig.4 depicts a representative XRPD diffractogram of Form A polymorph of 3-fluoro-5- (((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7- yl)oxy)-benzonitrile, Compound (I), crystallized from pentanol and hexane according to the method described in Example 25 in WO 2020/214853.
  • Fig.5 depicts model-simulated typical PK profiles of Compound (I) at the depicted RDE- w and RDE-d dosages of Compound (I) Form A.
  • Fig.6 depicts a Phase 2 Mono-expansion study design involving a first cohort administered a Compound (I) Form A dosage, a second cohort administered a RDE-w dosage of Compound (I) Form A, and a third cohort pre-treated with belzutifan.
  • Fig.7 depicts a study design, wherein patients are administered a regimen comprising 200 mg QD x 7 days of Compound (I) Form A (W1D1 to W1D7) followed by 200 mg QW of Compound (I) Form A starting at W2D1.
  • Fig.8 depicts a study design, wherein patients are administered a regimen comprising 200 mg QD x 14 days of Compound (I) Form A (W1 and W2) followed by 50 mg QD of Compound (I) Form A starting at W3.
  • Fig.9 depicts a population PK model comprising simulated PK profiles of Compound (I) for dosages with sequential loading and maintenance dosing regimens of Compound (I) Form A.
  • Fig.10 depicts simulated Compound (I) PK profiles for Q4W maintenance treatments of 100 mg, 200 mg, and 300 mg of Compound (I) Form A compared to 100 mg QW of Compound (I) Form A following loading doses of 100 mg QD x 7 of Compound (I) Form A.
  • Fig.11 depicts simulated Compound (I) PK profiles for Q3W maintenance treatments of 50 mg, 100 mg, 200 mg, and 300 mg of Compound (I) Form A compared to 100 mg QW of Compound (I) Form A following loading doses of 100 mg QD x 7 of Compound (I) Form A.
  • Fig.12 depicts simulated Compound (I) PK profiles for Q2W maintenance treatments of 50 mg, 100 mg, 200 mg, and 300 mg of Compound (I) Form A compared to 100 mg QW of Compound (I) Form A following loading doses of 100 mg QD x 7 of Compound (I) Form A.
  • Fig.13 depicts simulated PK profiles for tested Compound (I) Form A dosages.
  • Fig.14 depicts simulated Compound (I) PK profiles for 2 days-on/26 days-off maintenance treatments of Compound (I) Form A compared to 100 mg QW following loading doses of 100 mg QD x 7 of Compound (I) Form A.
  • Fig.15 depicts simulated Compound (I) PK profiles for 4 days-on/24 days-off maintenance treatments of Compound (I) Form A compared to 100 mg QW following loading doses of 100 mg QD x 7 of Compound (I) Form A.
  • Fig.16 depicts simulated Compound (I) PK profiles for 7 days-on/21 days-off maintenance treatments of Compound (I) Form A compared to 100 mg QW following loading doses of 100 mg QD x 7 of Compound (I) Form A.
  • Fig.17 depicts the study design for the Compound (I) Form A Phase 1/2 open label dose- escalation and expansion trial.
  • Fig.18 depicts the patient demographics for the Compound (I) Form A Phase 1/2 open label dose-escalation and expansion trial, as of the 16 June 2024 analysis in Example 4.
  • Fig.19 depicts PK profiles of Compound (I) following treatment with Compound (I) Form A in the dose escalation portion of the Study, as of the 16 June 2024 analysis in Example 4.
  • Fig.20 depicts EPO levels in patients treated with Compound (I) Form A in the dose escalation portion of the Study, as of the 16 June 2024 analysis in Example 4.
  • Fig.21 depicts the response rate and confidence interval in various categories of patients treated with Compound (I) Form A in the dose escalation portion of the Study, as of the 16 June 2024 analysis in Example 4.
  • Fig.22 depicts the number of target lesions in patients treated with Compound (I) Form A categorized by prognosis in the dose escalation portion of the Study, as of the 16 June 2024 analysis in Example 4.
  • Fig.23 depicts the number of target lesions in patients treated with Compound (I) Form A categorized by objective response in the dose escalation portion of the Study, as of the 16 June 2024 analysis in Example 4.
  • Fig.24 depicts time to disease progression or death of any cause in months in patients treated with Compound (I) Form A in the dose escalation portion of the Study, as of the 16 June 2024 analysis in Example 4.
  • Fig.25 depicts the median progression-free survival (PFS) in months and confidence interval in various categories of patients treated with Compound (I) Form A in the dose escalation portion of the Study. Median and 95% confidence interval were estimated based on Loglog transformation and methods by Breslow, Brookmeyer, and Crowley, as of the 16 June 2024 analysis in Example 4.
  • Fig.26 depicts adverse events reported by > 10% of patients treated with Compound (I) Form A in the dose escalation portion of the Study, as of the 16 June 2024 analysis in Example 4.
  • NKT-24-007PCT As used herein, “a” and “an,” mean one or more, unless the context clearly dictates otherwise. As used herein, “about” means + 10%, in one embodiment + 5% of listed value. For example, a reaction carried out at about 10 °C includes 9 °C and 11 °C, and all temperatures contained in between 9 °C and 11 °C. As used herein, “AUC” means area under the concentration-time curve and is the definite integral of the concentration of an administered compound (e.g, Compound (I)) found in blood plasma, after a dose is given, as a function of time, as measured using liquid chromatography– mass spectrometry.
  • an administered compound e.g, Compound (I)
  • AUClast means area under the concentration-time curve up to the last measurable concentration after a dose is given.
  • Cmax means the maximum (peak) concentration of an adminstered compound (e.g, Compound (I)) found in blood plasma, after a dose is given and reflects the rate and extent of absorption, as measured using liquid chromatography–mass spectrometry.
  • Cmin means the minimum concentration of an adminstered compound (e.g, Compound (I)) found in blood plasma, before a dose is given, as measured using liquid chromatography–mass spectrometry.
  • a “loading” dose is an initial dose of a drug (e.g., Compound (I) or Compound (I) Form A) that is given to a patient at the beginning of a course of treatment during the loading period before initiation of a maintenance dose of the drug.
  • the loading dose can be administered QD, twice a day (BID), or three times a day (TID).
  • “loading period” means a number of days on which a loading dose is administered to a patient.
  • a “maintenance” dose is a dose of a drug (e.g., Compound (I) or Compound (I) Form A) administered to maintain therapeutic drug concentrations after administration of a loading dosage.
  • maintenance period means a number of days on which a maintenance dose is administered to a patient.
  • QD means once a day e.g., 20 mg QD means 20 mg administered once a day, 30 mg QD means 30 mg administered once a day, etc.
  • QW means once a week e.g., 10 mg QW means 10 mg administered once a week, 20 mg QW means 20 mg administered once a week, 30 mg QW means 30 mg administered once a week, etc.
  • Q2W means once in two weeks e.g., 10 mg Q2W means 10 mg administered once in 2 weeks, 20 mg Q2W means 20 mg administered once in 2 weeks, 30 mg Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Q2W means 30 mg administered once in 2 weeks, etc.
  • Q3W means once in three weeks e.g., 10 mg Q3W means 10 mg administered once in 3 weeks, 20 mg Q3W means 20 mg administered once in 3 weeks, 30 mg Q3W means 30 mg administered once in 3 weeks, etc.
  • Q4W means once in four weeks e.g., 10 mg Q4W means 10 mg administered once in 4 weeks, 20 mg Q4W means 20 mg administered once in 4 weeks, 30 mg Q4W means 30 mg administered once in 4 weeks, etc.
  • XRPD means X-ray powder diffraction, an analytical technique which measures the diffraction of X-rays in the present of a solid component. Materials which are crystalline and have regular repeating arrays of atoms generate a distinctive powder pattern.
  • a “pharmaceutically acceptable carrier or excipient” means a carrier or an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier or an excipient that is acceptable for veterinary use as well as human pharmaceutical use.
  • a “pharmaceutically acceptable carrier/excipient” as used in the specification and claims includes both one and more than one such excipient.
  • disease as used herein is intended to be generally synonymous, and is used interchangeably with, the terms “disorder,” “syndrome,” and “condition” (as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms, and causes the human or animal to have a reduced duration or quality of life.
  • combination therapy means the administration of two or more therapeutic agents to treat a disease described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient.
  • the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.
  • patient is generally synonymous with the term “subject” and includes all mammals including humans. Examples of patients include humans, livestock such as cows, goats, sheep, pigs, and rabbits, and companion animals such as dogs, cats, rabbits, and horses. Preferably, the patient is a human. “Treating” or “treatment” of a disease includes: Attorney Docket No.16036.0005-00304 Ref. No.
  • NKT-24-007PCT (1) preventing the disease, i.e., causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease; (2) inhibiting the disease, i.e., arresting or reducing the development of the disease (i.e., stabilizing) or its clinical symptoms; or (3) relieving the disease, i.e., causing regression of the disease or its clinical symptoms.
  • a “therapeutically effective amount” means the amount of Compound (I) or Compound (I) Form A that, when administered to a patient for treating a disease, is sufficient to affect such treatment for the disease.
  • Embodiments provide a method of treating cancer as described in the first or fourth aspects of the Summary or a compound for use as described in the second or third aspects of the Summary.
  • Embodiment A2 comprises the method or use of embodiment A1, wherein the Compound (I) Form A X-ray powder diffraction pattern comprises peaks at angular positions 15.8, 18.6, and 20.1, wherein the angular positions may vary by + 0.2 o 2 ⁇ .
  • Embodiment A3 comprises the method or use of embodiment A1, wherein the Compound (I) Form A X-ray powder diffraction pattern comprises peaks at angular positions 12.9, 15.8, 18.6, and 20.1, wherein the angular positions may vary by + 0.2 o 2 ⁇ .
  • Embodiment A4 comprises the method or use of embodiment A1, wherein the Compound (I) Form A X-ray powder diffraction pattern comprises peaks at angular positions 11.4, 12.9, 15.8, 18.6, and 20.1, wherein the angular positions may vary by + 0.2 o ⁇ .
  • NKT-24-007PCT Angle (2-Theta °) d value ( ⁇ ) Intensity % 9.2 9.59 6.9
  • NKT-24-007PCT Angle (2-Theta °) d value ( ⁇ ) Intensity % 30.6 2.92 3 A6.
  • the at least two, at least three, at least four, at least five, at least six, or at least seven peaks are selected from 10.1, 11.4, 12.9, 13.7, 19.6, 20.1, 21.4, 21.7, 25.0, and 26.0, wherein the angular positions may vary by + 0.2 o 2 ⁇ . A7.
  • Embodiment A7 comprises the method or use of embodiment A1, wherein the Compound (I) Form A X-ray powder diffraction pattern comprises peaks at angular positions substantially as shown in Fig.4.
  • Embodiment A8 comprises the method or use of any one of embodiments A1 to A7, wherein the angular positions of the X-ray diffraction peaks denoted therein may vary by + 0.1 o 2 ⁇ .
  • Loading Dose Embodiment A9 comprises the method or use of any one of embodiments A1 to A8, wherein the loading dose is from about 20 mg QD, 50 mg QD, about 100 mg QD, about 150 mg QD, about 200 mg QD, about 250 mg QD, or about 300 mg QD. A10.
  • Embodiment A10 comprises the method or use of any one of embodiments A1 to A9, wherein the loading dose is about 50 mg QD.
  • Embodiment A11 comprises the method or use of any one of embodiments A1 to A10, wherein the loading dose is about 50 mg QD and is administered for 3, 4, or 5 consecutive days (for sake of clarity, when 50 mg QD of Compound (I) Form A is administered for 3 consecutive days or for 4 consecutive days, the loading period is 3 days and 4 days, respectively).
  • Embodiment A12 comprises the method or use of any one of embodiments A1 to A10, wherein the loading dose is about 50 mg QD and is administered for 7 ⁇ 1 consecutive days. In an embodiment of A12, the loading dose is about 50 mg QD and is administered for 7 consecutive days.
  • Embodiment A13 comprises the method or use of any one of embodiments A1 to A10, wherein the loading dose is about 50 mg QD and is administered for 14 ⁇ 2 consecutive days. In an embodiment of A13, the loading dose is about 50 mg QD and is administered for 14 ⁇ 1 consecutive days. In another embodiment of A13, the loading dose is about 50 mg QD and is administered for 14 consecutive days. A14.
  • Embodiment A14 comprises the method or use of any one of embodiments A1 to A10, wherein the loading dose is about 50 mg QD and is administered for 28 ⁇ 2 consecutive days. In an embodiment of A14, the loading dose is about 50 mg QD and is administered for 28 ⁇ 1 consecutive days. In another embodiment of A14, the loading dose is about 50 mg QD and is administered for 28 consecutive days.
  • A15 comprises the method or use of any one of embodiments A1 to A9, wherein the loading dose is about 100 mg QD.
  • Embodiment A16 comprises the method or use of any one of embodiments A1 to A9 and A15, wherein the loading dose is about 100 mg QD and is administered for 3, 4, or 5 consecutive days. A17.
  • Embodiment A17 comprises the method or use of any one of embodiments A1 to A9 and A15, wherein the loading dose is about 100 mg QD and is administered for 7 ⁇ 1 consecutive days. In an embodiment of A17, the loading dose is about 100 mg QD and is administered for 7 consecutive days.
  • Embodiment A18 comprises the method or use of any one of embodiments A1 to A9 and A15, wherein the loading dose is about 100 mg QD and is administered for 14 ⁇ 2 consecutive days. In an embodiment of A18, the loading dose is about 100 mg QD and is administered for 14 ⁇ 1 consecutive days. In another embodiment of A18, the loading dose is about 100 mg QD and is administered for 14 consecutive days. A19.
  • Embodiment A19 comprises the method or use of any one of embodiments A1 to A9 and A15, wherein the loading dose is about 100 mg QD and is administered for 28 ⁇ 2 consecutive days. In an embodiment of A19, the loading dose is about 100 mg QD and is administered for 28 ⁇ 1 consecutive days. In another embodiment of A19, the loading dose is about 100 mg QD and is administered for 28 consecutive days. A20.
  • Embodiment A20 comprises the method or use of any one of embodiments A1 to A9, wherein the loading dose is about 150 mg QD. Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT A21.
  • Embodiment A21 comprises the method or use of any one of embodiments A1 to A9 and A20, wherein the loading dose is about 150 mg QD and is administered for 3, 4, or 5 consecutive days.
  • Embodiment A22 comprises the method or use of any one of embodiments A1 to A9 and A20, wherein the loading dose is about 150 mg QD and is administered for 7 ⁇ 1 consecutive days. In an embodiment of A22, the loading dose is about 150 mg QD and is administered for 7 consecutive days.
  • Embodiment A23 comprises the method or use of any one of embodiments A1 to A9 and A20, wherein the loading dose is about 150 mg QD and is administered for 14 ⁇ 2 consecutive days.
  • the loading dose is about 150 mg QD and is administered for 14 ⁇ 1 consecutive days. In another embodiment of A23, the loading dose is about 150 mg QD and is administered for 14 consecutive days.
  • A24 comprises the method or use of any one of embodiments A1 to A9 and A20, wherein the loading dose is about 150 mg QD and is administered for 28 ⁇ 2 consecutive days. In an embodiment of A24, the loading dose is about 150 mg QD and is administered for 28 ⁇ 1 consecutive days. In another embodiment of A24, the loading dose is about 150 mg QD and is administered for 28 consecutive days.
  • A25 Embodiment A25 comprises the method or use of any one of embodiments A1 to A9, wherein the loading dose is about 200 mg QD.
  • Embodiment A26 comprises the method or use of any one of embodiments A1 to A9 and A25, wherein the loading dose is about 200 mg QD and is administered for 3, 4, or 5 consecutive days.
  • A27 comprises the method or use of any one of embodiments A1 to A9 and A25, wherein the loading dose is about 200 mg QD and is administered for 7 ⁇ 1 consecutive days. In an embodiment of A27, the loading dose is about 200 mg QD and is administered for 7 consecutive days.
  • A28 comprises the method or use of any one of embodiments A1 to A9 and A25, wherein the loading dose is about 200 mg QD and is administered for 14 ⁇ 2 consecutive days.
  • the loading dose is about 200 mg QD and is administered for 14 ⁇ 1 consecutive days. In an embodiment of A28, the loading dose is about 200 mg QD and is administered for 14 consecutive days.
  • Embodiment A29 comprises the method or use of any one of embodiments A1 to A9 and A25, wherein the loading dose is about 200 mg QD and is administered for 28 ⁇ 2 consecutive days. In an embodiment of A29, the loading dose is about 200 mg QD and is Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT administered for 28 ⁇ 1 consecutive days. In another embodiment of A29, the loading dose is about 200 mg QD and is administered for 28 consecutive days. A30.
  • Embodiment A30 comprises the method or use of any one of embodiments A1 to A9, wherein the the loading dose is about 250 mg QD.
  • Embodiment A31 comprises the method or use of any one of embodiments A1 to A9 and A30, wherein the loading dose is about 250 mg QD and is administered for 3, 4, or 5 consecutive days.
  • A32 comprises the method or use of any one of embodiments A1 to A9 and A30, wherein the loading dose is about 250 mg QD and is administered for 7 ⁇ 1 consecutive days. In an embodiment of A32, the loading dose is about 250 mg QD and is administered for 7 consecutive days.
  • A33 comprises the method or use of any one of embodiments A1 to A9, wherein the loading dose is about 250 mg QD and is administered for 7 consecutive days.
  • Embodiment A33 comprises the method or use of any one of embodiments A1 to A9 and A30, wherein the loading dose is about 250 mg QD and is administered for 14 ⁇ 2 consecutive days. In an embodiment of A33, the loading dose is about 250 mg QD and is administered for 14 ⁇ 1 consecutive days. In an embodiment of A33, the loading dose is about 250 mg QD and is administered for 14 consecutive days.
  • Embodiment A34 comprises the method or use of any one of embodiments A1 to A9 and A30. wherein the loading dose is about 250 mg QD and is administered for 28 ⁇ 2 consecutive days. In an embodiment of A34, the loading dose is about 250 mg QD and is administered for 28 ⁇ 1 consecutive days.
  • the loading dose is about 250 mg QD and is administered for 28 consecutive days.
  • Embodiment A35 comprises the method or use of any one of embodiments A1 to A9, wherein the loading dose is about 300 mg QD.
  • Embodiment A36 comprises the method or use of any one of embodiments A1 to A9 and, wherein the loading dose is about 300 mg QD and is administered for 3, 4, or 5 consecutive days.
  • A37 comprises the method or use of any one of embodiments A1 to A9 and A35, wherein the loading dose is about 300 mg QD and is administered for 7 ⁇ 1 consecutive days. In an embodiment of A37, the loading dose is about 300 mg QD and is administered for 7 consecutive days.
  • A38 comprises the method or use of any one of embodiments A1 to A9 and A35, wherein the loading dose is about 300 mg QD and is administered for 7 ⁇ 1 consecutive days. In an embodiment of A37, the loading dose is about 300 mg QD and is administered for 7 consecutive days.
  • Embodiment A38 comprises the method or use of any one of embodiments A1 to A9 and A35, wherein the loading dose is about 300 mg QD and is administered for 14 ⁇ 2 consecutive days. In an embodiment of A38, the loading dose is about 300 mg QD and is administered for 14 ⁇ 1 consecutive days. In an embodiment of A38, the loading dose is about 300 mg QD and is administered for 14 consecutive days.
  • Embodiment A39 comprises the method or use of any one of embodiments A1 to A9 and A35, wherein the loading dose is about 300 mg QD and is administered for 28 ⁇ 2 consecutive days.
  • the loading dose is about 300 mg QD and is administered for 28 ⁇ 1 consecutive days. In an embodiment of A39, the loading dose is about 300 mg QD and is administered for 28 consecutive days.
  • Embodiment A40 comprises the method or use of any one of embodiments A1 to A9, wherein the loading dose is about 20 mg QD.
  • Embodiment A41 comprises the method or use of any one of embodiments A1 to A9 and A40, wherein the loading dose is about 20 mg QD and is administered for 3, 4, or 5 consecutive days.
  • A42 Embodiment A42 comprises the method or use of any one of embodiments A1 to A9 and A40, wherein the loading dose is about 20 mg QD and is administered for 7 ⁇ 1 consecutive days.
  • the loading dose is about 20 mg QD and is administered for 7 consecutive days.
  • A43 comprises the method or use of any one of embodiments A1 to A9 and A40, wherein the loading dose is about 20 mg QD and is administered for 14 ⁇ 2 consecutive days. In an embodiment of A43, the loading dose is about 20 mg QD and is administered for 14 ⁇ 1 consecutive days. In an embodiment of A43, the loading dose is about 20 mg QD and is administered for 14 consecutive days.
  • A44 Embodiment A44 comprises the method or use of any one of embodiments A1 to A9 and A40, wherein the loading dose is about 20 mg QD and is administered for 28 ⁇ 2 consecutive days.
  • the loading dose is about 20 mg QD and is administered for 28 ⁇ 1 consecutive days. In another embodiment of A44, the loading dose is about 20 mg QD and is administered for 28 consecutive days.
  • Maintenance Dose Embodiments B B comprises the method or use of any one of embodiments A1 to A44, wherein the maintenance dose comprises the same amount of Compound (I) or Compound (I) Form A as the loading dose, and the maintenance dose is administered to the patient less frequently than the loading dose is administered during the loading period.
  • Embodiment B1 comprises the method or use of any one of embodiments A1 to A14 and B, wherein the maintenance dose is about 50 mg and is administered QW.
  • Embodiment B2 comprises the method or use of any one of embodiments A1 to A8, A15 to A19, and B, wherein the maintenance dose is about 100 mg and is administered QW.
  • Embodiment B3 comprises the method or use of any one of embodiments A1 to A8, A20 to A24, and B, wherein the maintenance dose is about 150 mg and is administered QW.
  • Embodiment B4 comprises the method or use of any one of embodiments A1 to A8, A25 to A29, and B, wherein the maintenance dose is about 200 mg and is administered QW.
  • Embodiment B5 comprises the method or use of any one of embodiments A1 to A8, A30 to A34, and B, wherein the maintenance dose is about 250 mg and is administered QW.
  • Embodiment B6 comprises the method or use of any one of embodiments A1 to A8, A35 to A39, and B, wherein the maintenance dose is about 300 mg and is administered QW.
  • Embodiment B7 comprises the method or use of any one of embodiments A1 to A8, A40 to A44, and B, wherein the maintenance dose is about 20 mg and is administered QW.
  • Embodiment B8 comprises the method or use of any one of embodiments A1 to A14, B, and B1, wherein the maintenance dose is about 50 mg Q2W. B9.
  • Embodiment B9 comprises the method or use of any one of embodiments A1 to A14, B, and B1, wherein the maintenance dose is about 50 mg Q4W.
  • Embodiment B10 comprises the method or use of any one of embodiments A1 to A8, A15 to A19, B, and B2, wherein the maintenance dose is about 100 mg Q2W.
  • Embodiment B11 comprises the method or use of any one of embodiments A1 to A8, A15 to A19, B, and B2, wherein the maintenance dose is about 100 mg Q4W.
  • Embodiment B12 comprises the method or use of any one of embodiments A1 to A8, A20 to A24, B, and B3 wherein the maintenance dose is about 150 mg Q2W. B13.
  • Embodiment B13 comprises the method or use of any one of embodiments A1 to A8, A20 to A24, B, and B3, wherein the maintenance dose is about 150 mg Q4W.
  • Embodiment B14 comprises the method or use of any one of embodiments A1 to A8, A25 to A29, B, and B4, wherein the maintenance dose is about 200 mg Q2W.
  • Embodiment B15 comprises the method or use of any one of embodiments A1 to A8, A25 to A29, B, and B4, wherein the maintenance dose is about 200 mg Q4W. B16.
  • Embodiment B16 comprises the method or use of any one of embodiments A1 to A8, A30 to A34, B, and B5, wherein the maintenance dose is about 250 mg Q2W.
  • Embodiment B17 comprises the method or use of any one of embodiments A1 to A8, A30 to A34, B, and B5, wherein the maintenance dose is about 250 mg Q4W.
  • Embodiment B18 comprises the method or use of any one of embodiments A1 to A8, A35 to A39, B, and B6, wherein the maintenance dose is about 300 mg Q2W. B19.
  • Embodiment C comprises the method or use of any one of embodiments A1 to A8 and A15 to A39, wherein the maintenance dose comprises less Compound (I) or Compound (I) Form A than the loading dose, and the maintenance dose is administered once a day.
  • Embodiment C1 comprises the method or use of any one of embodiments A1 to A8 and A15 to A19, wherein the maintenance dose is 50 mg QD.
  • Embodiment C2 comprises the method or use of any one of embodiments A20 to A24, wherein the maintenance dose is 50 mg QD.
  • Embodiment C3 comprises the method or use of any one of embodiments A20 to A24, wherein the maintenance dose is 100 mg and is administered QD.
  • Embodiment C9 comprises the method or use of any one of embodiments A30 to A34, wherein the maintenance dose is about 150 mg QD.
  • Embodiment C10 comprises the method or use of any one of embodiments A30 to A34, wherein the maintenance dose is about 200 mg QD.
  • Embodiment C11 comprises the method or use of any one of embodiments A35 to A39, wherein the maintenance dose is about 50 mg QD.
  • Embodiment C12 comprises the method or use of any one of embodiments A35 to A39, wherein the maintenance dose is about 100 mg QD.
  • Embodiment C13 comprises the method or use of any one of embodiments A35 to A39, wherein the maintenance dose is about 150 mg QD.
  • Embodiment C14 comprises the method or use of any one of embodiments A35 to A39, wherein the maintenance dose is about 200 mg QD.
  • Embodiment C15 comprises the method or use of any one of embodiments A35 to A39, wherein the maintenance dose is about 250 mg QD.
  • C16 comprises the method or use of any one of embodiments A10 to A39, wherein the maintenance dose is about 50 mg QD.
  • Embodiment D comprises the method or use of any one of embodiments A1 to A8 and A15 to A39, wherein the maintenance dose comprises less Compound (I) or Compound (I) Form A than the loading dose, and the maintenance dose is administered less frequently than the loading dose is administered during the loading period.
  • Embodiment D1 comprises the method or use of any one of embodiments A1 to A8 and A15 to A19, wherein the maintenance dose is 50 mg QW.
  • Embodiment D2 comprises the method or use of any one of embodiments A20 to A24, wherein the maintenance dose is 50 mg QW.
  • Embodiment D3 comprises the method or use of any one of embodiments A20 to A24, wherein the maintenance dose is 100 mg QW. D4.
  • Embodiment D4 comprises the method or use of any one of embodiments A25 to A29, wherein the maintenance dose is about 50 mg QW.
  • Embodiment D5 comprises the method or use of any one of embodiments A25 to A29, wherein the maintenance dose is about 100 mg QW.
  • Embodiment D6 comprises the method or use of any one of embodiments A25 to A29, wherein the maintenance dose is about 150 mg and is administered QW.
  • Embodiment D7 comprises the method or use of any one of embodiments A30 to A34, wherein the maintenance dose is about 50 mg QW.
  • Embodiment D8 comprises the method or use of any one of embodiments A30 to A34, wherein the maintenance dose is about 100 mg QW. D9.
  • Embodiment D9 comprises the method or use of any one of embodiments A30 to A34, wherein the maintenance dose is about 150 mg QW.
  • Embodiment D10 comprises the method or use of any one of embodiments A30 to A34, wherein maintenance dose is about 200 mg QW.
  • Embodiment D11 comprises the method or use of any one of embodiments A35 to A39, wherein the maintenance dose is about 50 mg QW.
  • Embodiment D12 comprises the method or use of any one of embodiments A35 to A39, wherein the maintenance dose is about 100 mg QW. D13.
  • Embodiment D13 comprises the method or use of any one of embodiments A35 to A39, wherein the maintenance dose is about 150 mg QW.
  • Embodiment D14 comprises the method or use of any one of embodiments A35 to A39, wherein the maintenance dose is about 200 mg QW.
  • Embodiment D15 comprises the method or use of any one of embodiments A35 to A39, wherein the maintenance dose is about 250 mg QW.
  • Embodiment D16 comprises the method or use of any one of embodiments A10 to A39, wherein the maintenance dose is about 20 mg QW.
  • Embodiment E1 comprises the method or use of any one of embodiments A1 to A8 is wherein the loading dose is about 100 mg QD or about 200 mg QD.
  • Embodiment E2 comprises the method or use of embodiments A1 to A8 and E1, wherein the loading dose is about 100 mg QD.
  • Embodiment E3 comprises the method or use of any one of embodiments A1 to A8 and E1 to E2, wherein the loading dose is about 100 mg QD and is administered for 7 consecutive days.
  • Embodiment E4 comprises the method or use of any one of embodiments A1 to A8 and E1, wherein the loading dose is about 200 mg QD.
  • Embodiment E5 comprises the method or use of any one of embodiments A1 to A8, E1, and E4, wherein the loading dose is about 200 mg QD and is administered for 7 consecutive days.
  • Embodiment E6 comprises the method or use of embodiment A1 to A8, E1, and E4, wherein the loading dose is about 200 mg QD and is administered for 14 consecutive days.
  • Embodiment E7 comprises the method or use of embodiment A1 to A8, E1, and E4, wherein amount of each of the loading dose is about 200 mg QD and is administered for 28 consecutive days.
  • Embodiment E8 comprises the method or use of any one of embodiments A1 to A8, E2, and E3, wherein the maintainance dose is about 100 mg QW. E9.
  • Embodiment E9 comprises the method or use of any one of embodiments A1 to A8, E4, or E5, wherein the maintainance dose is about 200 mg QW.
  • Embodiment E10 comprises the method or use of any one of embodiments A1 to A8, E4, E5, E6, and E7, wherein the maintainance dose is about 50 mg QD.
  • Embodiment F1 comprises the method or use of any one of embodiments A1 to E10, wherein the loading and maintenance doses are administered orally.
  • Embodiment F2 comprises the method or use of any one of embodiments A1 to E10 and F1, wherein each consecutive loading dose is administered at the same time of day or ⁇ 0.5, 1, 2, 3, or 4 hours before or after the prior loading dose is administered.
  • Embodiment F3 comprises the method or use of any one of embodiments A1 to A39, C to C15, E8, E9, and F1 to F2, wherein each follow-up maintenance dose, when administered QW, is administered at the same time of day ⁇ 0.5, 1, 2, 3, or 4 hours after the first maintenance dose.
  • Embodiment F4 comprises the method or use of any one of embodiments B1 to B6, D1 to D15, E10, and F1 to F2, wherein the first maintenance dose, when administered QW, is administered the following day, after the last loading dose.
  • Embodiment F5 comprises the method or use of any one of embodiments B1 to B6, D1 to D15, E10, and F1 to F2, wherein the first maintenance dose, when administered QW, is administered the second day after the last loading dose.
  • Embodiment F6 comprises the method or use of any one of embodiments B1 to B6, D1 to D15, E10, and F1 to F2, wherein the first maintenance dose, when administered QW, is administered the third day after the last loading dose.
  • F7 comprises the method or use of any one of embodiments B1 to B6, D1 to D15, E10, and F1 to F2, wherein the first maintenance dose, when administered QW, is administered the third day after the last loading dose.
  • Embodiment F7 comprises the method or use of any one of embodiments B1 to B6, D1 to D15, E10, and F1 to F2, wherein the first maintenance dose, when administered QW, is administered the fourth day after the last loading dose.
  • Embodiment F8 comprises the method or use of any one of embodiments B1 to B6, D1 to D15, E10, and F1 to F2 is wherein the first maintenance dose, when administered QW, is administered the fifth day after the last loading dose.
  • Embodiment F9 comprises the method or use of any one of embodiments B1 to B6, D1 to D15, E10, and F1 to F2, wherein the first maintenance dose, when administered QW, is administered the sixth day after the last loading dose.
  • Embodiment F10 comprises the method or use of any one of embodiments B1 to B6, D1 to D15, E10, and F1 to F2, wherein the first maintenance dose, when administered QW, is administered the seventh day after the last loading dose.
  • Embodiment F1 comprises the method or use of any one of embodiments F4 to F10, wherein, following the first maintenance dose, each subsequent maintenance dose is administered seven days after the prior maintenance dose.
  • Embodiment F12 comprises the method or use of any one of embodiments A1 to E10 and F1 to F11, wherein a single bolus of loading dose is administered. F13.
  • Embodiment F13 comprises the method or use of any one of embodiments A1 to E10 and F1 to F11, wherein two or more doses of a loading dose are administered.
  • Embodiment F14 comprises the method or use of any one of embodiments A1 to E10 and F1 to F13, wherein a single bolus of maintenance dose is administered.
  • Embodiment F15 comprises the method or use of any one of embodiments A1 to E10 and F1 to F13, wherein two or more doses of a maintenance dose are administered.
  • F16 comprises the method or use of any one of embodiments A1 to E10 and F1 to F13, wherein two or more doses of a maintenance dose are administered.
  • Embodiment F16 comprises the method or use of any one of embodiments A1 to F15, wherein the dosage regimen is adjusted to provide the optimum desired response (e.g., a steady state of Compound (I) Form A in plasma that is therapeutic), and the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation.
  • Embodiment F17 comprises the method or use of any one of embodiments A1 to F15, wherein the dosage regimen is adjusted by lowering the maintenance dose because the patient experiences a toxicity.
  • Embodiment F18 comprises the method or use of embodiment E10, wherein the dosage regimen is adjusted by lowering the maintenance dose to 30 mg/day QD because the patient experiences a toxicity.
  • F19 is
  • Embodiment F19 comprises the method or use of embodiment E10 or F18, wherein the dosage regimen is adjusted by lowering the maintenance dose to 20 mg/day QD because the patient experiences a toxicity.
  • Embodiment F20 comprises the method or use of embodiment E8, wherein the dosage regimen is adjusted by lowering the maintenance dose to 50 mg QW because the patient experiences a toxicity.
  • Embodiment F21 comprises the method or use of embodiment E8 or F20, wherein the dosage regimen is adjusted by lowering the maintenance dose to 30 mg QW because the patient experiences a toxicity.
  • Embodiment G1 comprises the method or use of any one of embodiments A1 to F21, wherein the patient satisfies at least one of the following conditions: (a) the patient has locally advanced or metastatic ccRCC, and has progressed during treatment, are relapsed, refractory and not amenable to curative therapy or standard therapy and has progressed during treatment with at least 1 prior therapeutic regimen; Attorney Docket No.16036.0005-00304 Ref. No.
  • NKT-24-007PCT (b) the patient has measurable disease per RECIST 1.1 criteria; (c) the patient is ⁇ 18 years of age; (d) the patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2; (e) the patient has a life expectancy of ⁇ 3 months; (f) the patient has adequate organ function defined as follows: (i) a bone marrow ANC ⁇ 1.0 ⁇ 10 9 /L; hemoglobin level ⁇ 10 g/dL without transfusion or erythropoietin support within two weeks prior to a first dose of Compound (I) or Compound (I) Form A; platelet count ⁇ 75,000/ ⁇ L; (ii) hepatic transaminase levels (aspartate aminotransferase /alanine aminotransferase [AST/ALT]) ⁇ 2.5 ⁇ ULN ( ⁇ 5 ⁇ ULN if liver metastases is present); total bilirubin (TBILI
  • Embodiment G2 comprises the method or use of G1, wherein the patient satisfies at least two of the conditions (a) through (j) above.
  • Embodiment G3 comprises the method or use of G1, wherein the patient satisfies at least three of the conditions (a) through (j) above.
  • Embodiment G4 comprises the method or use of G1, wherein the patient satisfies at least four of the conditions (a) through (j) above.
  • G5. Embodiment G5 comprises the method or use of G1, wherein the patient satisfies at least five of the conditions (a) through (j) above.
  • G6 Embodiment G6 comprises the method or use of G1, wherein the patient satisfies at least six of the conditions (a) through (j) above.
  • Embodiment G7 comprises the method or use of G1, wherein the patient satisfies at least seven of the conditions (a) through (j) above.
  • Embodiment G8 comprises the method or use of G1, wherein the patient satisfies at least eight of the conditions (a) through (j) above.
  • Embodiment G12 comprises the method or use of G1, wherein the patient satisfies each of the conditions (a) through (j) above.
  • Embodiment G10 comprises the method or use of any one of embodiments G1 to G9, wherein the patient is excluded from treatment if at least one of the following conditions are satisfied: (aa) the patient has known symptomatic brain metastases requiring > 10 mg/day of prednisone (or its equivalent).
  • NKT-24-007PCT the patient has any current requirement for intermittent or chronic supplemental oxygen prior to first administration of Compound (I) or Compound (I) Form A; (ee) the patient has any chronic lung condition which has required supplemental oxygen in the past prior to first administration of Compound (I) or Compound (I) Form A; (ff) the patient has evidence of impending airway compromise (such as endobronchial tumor, lymphangitic spread, significant extrinsic compression of major airway) prior to first administration of Compound (I) or Compound (I) Form A; (gg) the patient has ascites requiring drainage within 28 days prior to first administration of Compound (I) or Compound (I) Form A; (hh) the patient has a history of of another malignancy prior to first administration of Compound (I) or Compound (I) Form A except for the following: adequately treated local basal cell or squamous carcinoma of the skin, in situ cervical cancer, adequately treated papillary noninvasive bladder cancer, other adequately treated Stage 1 or Stage
  • NKT-24-007PCT No. NKT-24-007PCT
  • the patient has manifestations of malabsorption due to prior gastrointestinal (GI) surgery or GI disease;
  • the patient has any other clinically significant cardiac, respiratory, or other medical or psychiatric condition that might interfere with treatment with Compound (I) or Compound (I) Form A;
  • the patient has had major surgery within four weeks before Compound (I) or Compound (I) Form A administration (in some embodiments, the following procedures are not considered to be major surgeries: thoracentesis, port placement, laparoscopy, thoracoscopy, bronchoscopy, endoscopic or ultrasonographic procedures, mediastinoscopy, skin biopsy, incisional biopsy, image-guided biopsy for diagnostic purposes, and routine dental procedures);
  • qq) the patient has known HIV;
  • the patient has an active infection requiring systemic treatment;
  • ss the patient is actively participating in a therapeutic clinical trial;
  • the patient has received prior treatment with an HIF-2 ⁇ inhibitor, unless
  • Embodiment G15 comprises the method or use of G10, wherein the patient is excluded from treatment if at least six of the conditions (aa) through (tt) above are satisfied.
  • Embodiment G16 comprises the method or use of G10, wherein the patient is excluded from treatment if at least seven of the conditions (aa) through (tt) above are satisfied.
  • G17 comprises the method or use of G10, wherein the patient is excluded from treatment if at least eight of the conditions (aa) through (tt) above are satisfied.
  • G18 Embodiment G18 comprises the method or use of G10, wherein the patient is excluded from treatment if at least nine of the conditions (aa) through (tt) above are satisfied.
  • Embodiment G19 comprises the method or use of G10, wherein the patient is excluded from treatment if at least ten of the conditions (aa) through (tt) above are satisfied.
  • Embodiment G20 comprises the method or use of G10, wherein the patient is excluded from treatment if at least eleven of the conditions (aa) through (tt) above are satisfied.
  • Embodiment G21 comprises the method or use of G10, wherein the patient is excluded from treatment if at least twelve of the conditions (aa) through (tt) above are satisfied.
  • G22 comprises the method or use of G10, wherein the patient is excluded from treatment if at least twelve of the conditions (aa) through (tt) above are satisfied.
  • Embodiment G22 comprises the method or use of G10, wherein the patient is excluded from treatment if each of the conditions (aa) through (tt) above are satisfied.
  • Embodiment G23 comprises the method or use of any one of embodiments G1 to G22, wherein the patient is willing to and able to take a high-fat meal within thirty minutes prior to Compound (I) or Compound (I) Form A dosing on Week 1 Day 1.
  • Embodiment G24 comprises the method or use of any one of embodiments G1 to G22, wherein the patient has adequate hepatic and renal function defined below:
  • Hepatic normal hepatic function (total bilirubin ⁇ upper limit of normal (ULN) and aspartate aminotransferase (AST) ⁇ ULN) or mild hepatic impairment (total bilirubin ⁇ ULN and AST > ULN, or total bilirubin > 1.0 ⁇ to 1.5 ⁇ ULN)
  • Renal measured or calculated creatinine clearance (CrCL) ⁇ 60 mL/min (Cockcroft- Gault formula); G25.
  • Embodiment G25 comprises the method or use of any one of embodiments G1 to G24, wherein the patient is excluded from treatment if the patient has any gastrointestinal (GI) malfunction, surgeries, or conditions that could affect absorption of oral Compound (I) Form A and/or midazolam as assessed by an investigator.
  • GI gastrointestinal
  • Embodiment G26 comprises the method or use of any one of embodiments G1 to G25, wherein the patient is excluded from treatment if the patient uses any drugs, investigational agents, fruits, or herbs that are strong or moderate CYP3A inhibitors or inducers within fourteen days prior to Day -3 (or 5 times the half-life of the drug, whichever is longer).
  • Embodiment G27 comprises the method or use of any one of embodiments G1 to G26, wherein the patient has relapse or progressive disease following prior treatment with belzutifan (in some embodiments, the patient received at least 28 days of treatment with belzutifan).
  • Embodiment G28 comprises the method or use of any one of embodiments G1 to G27, wherein the patient has a willingness to undergo a pretreatment and post-treatment biopsy of the tumor.
  • Embodiment G29 comprises the method or use of any one of embodiments G1 to G28, wherein the patient is excluded from treatment if the patient has a history of toxicity or intolerance to treatment with belzutifan or other HIF-2 ⁇ inhibitor; Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT G30.
  • Embodiment G30 comprises the method or use of any one of embodiments G1 to G29, wherein the patient is excluded from treatment if the patient has a known presence of HIF2- ⁇ mutation G323E or HIF-1B mutation F446L.
  • Embodiment H1 comprises the method or use of any one of embodiments A1 to G30, wherein the cancer to be treated is selected from a cancer in the Utility section below.
  • Embodiment H2 comprises the method or use of any one of embodiments A1 to G30, wherein the cancer to be treated is selected from renal cancer, glioblastoma, neuroblastoma, paraganglioma, pheochromocytoma, somatostatinomas, hemangioblastomas, gastrointestinal stromal tumors, pituitary tumors, bladder cancer, liver cancer, leiomyomas, leiomyosarcomas, polycythaemia, and retinal cancers.
  • Embodiment H3 comprises the method or use of any one of embodiments A1 to F21, wherein the Compound (I) or Compound (I) Form A is administered in combination with at least one other anticancer agent, preferably as provided in the Combinations and Combination Therapy section below.
  • Embodiment H4 comprises the method or use of embodiment H3, wherein the at least one other anticancer agent is selected from palbociclib, ribociclib, abemaciclib, sasanlimab, cemiplimab-rwlc, nivolumab, pembrolizumab, dostarlimab, atezolizumab, durvalumab, avelumab, and rituximab.
  • the at least one other anticancer agent is selected from palbociclib, ribociclib, abemaciclib, sasanlimab, cemiplimab-rwlc, nivolumab, pembrolizuma
  • Embodiment H5 comprises the method or use of embodiment H3, wherein the at least one other anticancer agent is cabozantinib.
  • Embodiment H6 comprises the method or use of any one of embodiments A1 to H5, wherein the patient is a human.
  • Embodiment H7 comprises the method or use of any one of embodiments A1 to H6, wherein the treatment of cancer includes arresting or reducing the development of the cancer or its clinical symptoms.
  • Embodiment H8 comprises the method or use of any one of embodiments A1 to H6, wherein the treatment of cancer includes causing regression of the cancer or its clinical symptoms.
  • Embodiment H9 comprises the method or use of any one of embodiments A1 to H6, wherein the the treatment of cancer includes causing the clinical symptoms of the cancer not to develop where the patient is exposed to or predisposed to the cancer but does not yet experience or display symptoms of the cancer.
  • Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT As will be apparent to those skilled in the art, dosages outside of these disclosed dosages and ranges may be administered in some cases. Further, it is noted that the ordinary skilled clinician or treating physician will know how and when to interrupt, adjust, or terminate therapy in consideration of individual response.
  • Utility Compound (I) and Compound (I) Form A are useful for the treatment of HIF-2 ⁇ -mediated diseases, which include, but are not limited to, various types of cancers, such as acanthoma, acinic cell carcinoma, acoustic neuroma, acral lentiginous melanoma, acrospiroma, acute eosinophilic leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute myeloblastic leukemia with maturation, acute myeloid dendritic cell leukemia, acute myeloid leukemia, acute promyelocytic leukemia, adamantinoma, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenomatoid odontogenic tumor, adrenocortical carcinoma, adult T- cell leukemia, aggressive NK-cell leukemia, AIDS-related cancers, AIDS
  • NKT-24-007PCT gastrointestinal cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, germ cell tumor, germinoma, gestational choriocarcinoma, gestational trophoblastic tumor, giant cell tumor of bone, glioblastoma multiforme, glioma, gliomatosis cerebri, glomus tumor, glucagonoma, gonadoblastoma, granulosa cell tumor, hairy cell leukemia, head and neck cancer, hemangioblastoma, hemangiopericytoma, hemangiosarcoma, hematological malignancy, hepatocellular carcinoma, hepatosplenic T-cell lymphoma, Hodgkin lymphoma, hypopharyngeal cancer, hypothalamic glioma, inflammatory breast cancer, intraocular melanoma, islet cell carcinoma, juvenile myelomonocytic leukemia, Kaposi's sarcom
  • NKT-24-007PCT sarcoma No. NKT-24-007PCT sarcoma, somatostatinoma, soot wart, spinal tumor, splenic marginal zone lymphoma, squamous cell carcinoma, stomach cancer, superficial spreading melanoma, supratentorial primitive neuroectodermal tumor, surface epithelial-stromal tumor, synovial sarcoma, T-cell acute lymphoblastic leukemia, T-cell large granular lymphocyte leukemia, T-cell leukemia, T-cell lymphoma, T-cell prolymphocytic leukemia, teratoma, terminal lymphatic cancer, testicular cancer, thecoma, throat cancer, thymic carcinoma, thymoma, thyroid cancer, transitional cell cancer of renal pelvis and ureter, transitional cell carcinoma, urachal cancer, urethral cancer, urogenital neoplasm, uterine sarcoma, uveal melanoma
  • the methods comprising administering a HIF-2a inhibitor disclosed herein and an immunotherapeutic agent described herein are applied to the treatment of cancers of the adrenal glands, blood, bone marrow, brain, breast, cervix, colon, head and neck, kidney, liver, lung, ovary, pancreas, plasma cells, rectum, retina, skin, spine, throat, or any combination thereof.
  • Pharmaceutical Compositions In general, Compound (I) or Compound (I) Form A will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities.
  • Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like.
  • Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol, and various oils, including those of petroleum, animal, vegetable, or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.
  • Preferred liquid carriers particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.
  • Compound (I) or Compound (I) Form A may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use.
  • sterile liquid carrier for example, saline or sterile pyrogen-free water
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • the suspension may also contain suitable stabilizers or agents, which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • Compound (I) or Compound (I) Form A may also be formulated as a depot preparation. Such long-acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • compositions may take the form of tablets, lozenges, pastilles, or gels formulated in a conventional manner.
  • Such compositions may comprise the active ingredient in a flavored basis, such as sucrose, acacia, or tragacanth.
  • Compound (I) or Compound (I) Form A may also be formulated in rectal compositions, such as suppositories or retention enemas, e.g., containing conventional suppository bases, such as cocoa butter, polyethylene glycol, or other glycerides.
  • rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases, such as cocoa butter, polyethylene glycol, or other glycerides.
  • suitable pharmaceutical excipients and their formulations are described in Remington’s Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 20th ed., 2000).
  • the amount of compound in a formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt. %) basis, from about 0.01-99.99 wt. % of Compound (I) or Compound (I) Form A based on the total formulation, with the balance being one or more suitable pharmaceutical excipients, such as those described above. For example, Compound (I) or Compound (I) Form A may be present at about 1- 80 wt. %. Combinations and Combination Therapies Compound (I) or Compound (I) Form A may be used in combination with one or more other drugs in the treatment of diseases or conditions for which Compound (I) or Compound (I) Form A or the other drugs may have utility.
  • compositions of the present disclosure also include those that contain one or more other drugs, in addition to Compound (I) or Compound (I) Form A.
  • the above combinations include combinations of Compound (I) or Compound (I) Form A with one other drug, two other drugs, three other drugs, or more.
  • Compound (I) or Compound (I) Form A may be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for Attorney Docket No.16036.0005-00304 Ref.
  • the weight ratio of Compound (I) or Compound (I) Form A to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used.
  • the subject in need is suffering from or at risk of suffering from cancer
  • the subject may be treated with Compound (I) or Compound (I) Form A in any combination with one or more anti-cancer agents.
  • one or more of the anti-cancer agents are proapoptotic agents.
  • anti-cancer agents include, but are not limited to, any of the following: gossyphol, genasense, polyphenol E, Chlorofusin, all trans-retinoic acid (ATRA), bryostatin, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), 5-aza-2’-deoxycytidine, all trans retinoic acid, doxorubicin, vincristine, etoposide, gemcitabine, imatinib (Gleevec TM ), geldanamycin, 17-N-Allylamino-17-Demethoxygeldanamycin (17-AAG), flavopiridol, LY294002, bortezomib, trastuzumab, BAY 11-7082, PKC412, or PD184352, Taxol TM , also referred to as “paclitaxel”, which is a well-known anti-cancer drug which acts by enhancing and stabilizing micro
  • BEX235 (dactolisib), CAL101 (idelalisib), GSK2636771, or TG100-115; MTOR inhibitors, such as rapamycin (sirolimus), temsirolimus, everolimus, ridaforolimus, XL388, XL765, AZD2013, PF04691502, PKI-587, BEZ235, or GDC0349; MEK inhibitors, such as AZD6244, trametinib, PD184352, pimasertinib, GDC-0973, or AZD8330; CSF1R inhibitors (PLX3397, LY3022855, etc.) and CSF1R antibodies (IMC-054, RG7155, etc); TGF beta receptor kinase inhibitors, such as LY2157299; or BTK inhibitors, such as ibrutinib.
  • MTOR inhibitors such as rapamycin (sirolimus), temsirol
  • anti-cancer agents include proteasome inhibitors, such as carfilzomib, MLN9708, delanzomib, or bortezomib; BET inhibitors, such as INCB054329, OTX015, CPI-0610; LSD1 inhibitors, such as GSK2979552, INCB059872; HDAC inhibitors, such as panobinostat, vorinostat; DNA methyl transferase inhibitors, such as azacytidine, decitabine, and other epigenetic modulators; SHP-2 inhibitors, such as TNO155; the Bcl2 inhibitor ABT-199, and other Bcl-2 family protein inhibitors; Beta catenin pathway inhibitors, notch pathway inhibitors and hedgehog pathway inhibitors; and antibodies or other therapeutic proteins that target VEGF, including bevacizumab and aflibercept.
  • proteasome inhibitors such as carfilzomib, MLN9708, delanzomib, or bortezo
  • anti-cancer agents that may be employed in combination with a compound of this disclosure include Adriamycin; Dactinomycin; Bleomycin; Vinblastine; Cisplatin; acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmus
  • NKT-24-007PCT hydrochloride No. NKT-24-007PCT hydrochloride; trasrabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine; interleukin II (including recombinant interleukin II, or Ril2), interferon alfa-2a; interferon alfa-2b; interferon alfa-n1; interferon alfa-n3; interferon beta-1a; interferon gamma-1 b; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomus
  • anti-cancer agents that may be employed in combination with Compound (I) or Compound (I) Form A include 20-epi-1; 25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti- dorsalizing morphogenetic protein-1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic
  • anticancer agents that may be employed in combination with a compound of this disclosure include alkylating agents, antimetabolites, natural products, or hormones, e.g., nitrogen Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, etc.), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, etc.), and triazenes (decarbazine, etc.).
  • alkylating agents e.g., antimetabolites, natural products, or hormones, e.g., nitrogen Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, etc.), alky
  • antimetabolites include, but are not limited to, folic acid analogs (e.g., methotrexate), pyrimidine analogs (e.g., cytarabine), and purine analogs (e.g., mercaptopurine, thioguanine, pentostatin).
  • folic acid analogs e.g., methotrexate
  • pyrimidine analogs e.g., cytarabine
  • purine analogs e.g., mercaptopurine, thioguanine, pentostatin
  • Examples of natural products useful in combination with a compound of this disclosure include, but are not limited to, vinca alkaloids (e.g., vincristine), epipodophyllotoxins (e.g., etoposide), antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g., L- asparaginase), and biological response modifiers (e.g., interferon alpha).
  • vinca alkaloids e.g., vincristine
  • epipodophyllotoxins e.g., etoposide
  • antibiotics e.g., daunorubicin, doxorubicin, bleomycin
  • enzymes e.g., L- asparaginase
  • biological response modifiers e.g., interferon alpha
  • alkylating agents examples include, but are not limited to, nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, melphalan, etc.), ethylenimine and methylmelamines (e.g., hexamethlymelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, semustine, streptozocin, etc.), and triazenes (decarbazine, etc.).
  • nitrogen mustards e.g., mechloroethamine, cyclophosphamide, chlorambucil, melphalan, etc.
  • ethylenimine and methylmelamines e.g., hexamethlymelamine, thiotepa
  • alkyl sulfonates e.g
  • antimetabolites include, but are not limited to, folic acid analogs (e.g., methotrexate), pyrimidine analogs (e.g., fluorouracil, floxuridine, cytarabine), and purine analogs (e.g., mercaptopurine, thioguanine, pentostatin).
  • folic acid analogs e.g., methotrexate
  • pyrimidine analogs e.g., fluorouracil, floxuridine, cytarabine
  • purine analogs e.g., mercaptopurine, thioguanine, pentostatin
  • hormones and antagonists useful in combination with a compound of this disclosure include, but are not limited to, adrenocorticosteroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethylstilbestrol, ethinyl estradiol), antiestrogens (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogens (e.g., flutamide), gonadotropin releasing hormone analogs (e.g., leuprolide).
  • adrenocorticosteroids e.g., prednisone
  • progestins e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate
  • platinum coordination complexes e.g., cisplatin, carboblatin
  • anthracenediones e.g., mitoxantrone
  • substituted ureas e.g., hydroxyurea
  • methyl hydrazine derivatives e.g., procarbazine
  • adrenocortical suppressant e.g., mitotane, aminoglutethimide
  • anti-cancer agents that may be employed in combination with Compound (I) or Form A include anti-cancer agents which act by arresting cells in the G2-M phases due by stabilizing microtubules, include Erbulozole (also known as R-55104), Dolastatin 10 (also known as DLS-10 and NSC-376128), Mivobulin isethionate (also known as CI-980), Vincristine, NSC- 639829, Discodermolide (also known as NVP-XX-A-296), ABT-751 (Abbott, also known as E- 7010), Altorhyrtins (such as Altorhyrtin A and Altorhyrtin C), Spongistatins (such as Spongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4, Spongistatin 5, Spongistatin 6, Spongistatin 7, Spongistatin 8, and Spongistatin 9), Cemadotin hydrochloride (also
  • Epothilones such as Epothilone A, Epothilone B, Epothilone C (also known as desoxyepothilone A or dEpoA), Epothilone D (also referred to as KOS-862, dEpoB, and desoxyepothilone B), Epothilone E, Epothilone F, Epothilone B N-oxide, Epothilone A N-oxide, 16-aza-epothilone B, 21-aminoepothilone B (also known as BMS-310705), 21-hydroxyepothilone D (also known as Desoxyepothilone F and dEpoF), 26-fluoroepothilone), Auristatin PE (also known as NSC-654663), Soblidotin (also known as TZT-1027), LS-4559-P (Pharmacia, also
  • One or more additional immune checkpoint inhibitors may be used in combination with Compound (I) or Compound (I) Form A for treatment of HIF-2 ⁇ -associated diseases, disorders, or conditions.
  • immune checkpoint inhibitors include inhibitors (smack molecules or biologics) against immune checkpoint molecules, such as CD27, CD28, CD40, CD122, CD96, CD73, CD39, CD47, OX40, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM, arginase, CD137 (also known as 4-1BB), ICOS, A2AR, A2BR, SHP-2, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, CD96, TIGIT, PD-1, PD-L1 and PD-L2.
  • inhibitors smack molecules or biologics
  • immune checkpoint molecules such as CD27, CD28, CD40, CD122, CD96, CD73, CD39, CD47, OX40, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM, arginase, CD137 (also known as 4-1BB
  • the inhibitor of an immune checkpoint molecule is an inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody.
  • the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446), or MSB0010718C.
  • the anti-PD-L1 monoclonal antibody is MPDL3280A (atezolizumab) or MEDI4736 (durvalumab).
  • the inhibitor of an immune checkpoint molecule is an inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody.
  • the anti-CTLA-4 antibody is ipilimumab or tremelimumab.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of LAG3, e.g., an anti-LAG3 antibody.
  • the anti- LAG3 antibody is BMS-986016 or LAG525.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of GITR, e.g., an anti-GITR antibody.
  • the anti-GITR antibody is TRX518 or, MK-4166, INCAGN01876 or MK-1248.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of OX40, e.g., an anti-OX40 antibody or OX40L fusion protein.
  • the anti-OX40 antibody is MEDI0562 or, INCAGN01949, GSK2831781, GSK-3174998, MOXR-0916, PF-04518600 or LAG525.
  • the OX40L fusion protein is MEDI6383.
  • Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT the inhibitor of an immune checkpoint molecule is an inhibitor of PD-1, e.g. an anti-PD-1 antibody.
  • the anti-PD-1 antibody is sasanlimab, cemiplimab-rwlc, nivolumab, pembrolizumab, dostarlimab, vopratelimab, spartalizumab, camrelizumab, sintilimab, tislelizumab (BGB-A287), toripalimab, INCMGA00012 (MGA012), AMP-224, AMP-514 (MEDI0680), or acrixolimab (YBL-006).
  • the inhibitor of an immune checkpoint molecule is an inhibitor of PD-L1, e.g. an anti- PD-L1 antibody.
  • the anti-PD-L1 antibody is atezolizumab, durvalumab, avelumab, KN035, Cosibelimab, AUNP12, CA-170, or BMS-986189.
  • Compound (I) or Compound (I) Form A may also be used to increase or enhance an immune response, including increasing the immune response to an antigen or to improve immunization; increasing vaccine efficacy; and increasing inflammation.
  • Compound (I) or Compound (I) Form A may be used to enhance the immune response to vaccines including, but not limited to, Listeria vaccines, oncolytic viral vaccines, and cancer vaccines such as GVAX® (granulocyte-macrophage colony-stimulating factor (GM-CF) gene-transfected tumor cell vaccine).
  • GVAX® granulocyte-macrophage colony-stimulating factor (GM-CF) gene-transfected tumor cell vaccine.
  • Anti-cancer vaccines include dendritic cells, synthetic peptides, DNA vaccines and recombinant viruses.
  • Other immune-modulatory agents also include those that block immune cell migration, such as antagonists to chemokine receptors, including CCR2 and CCR4, Sting agonists, and Toll receptor agonists.
  • anti-cancer agents also include those that augment the immune system, such as adjuvants and adoptive T cell transfers.
  • Compounds of this application may be effective in combination with CAR (Chimeric antigen receptor) T cell treatment as a booster for T cell activation. Examples The following examples are merely illustrative of the disclosure and should not be considered limiting the scope of the invention in any way, as these examples and other equivalents thereof will become apparent to those skilled in the art in light of the present disclosure and the accompanying claims.
  • Example 1 Formulation of Compound (I) Form A
  • Compound (I) Form A was formulated as immediate release capsules supplied at 10, 50 and 200 mg dose strengths. Information about the composition of Compound (I) Form A capsules is disclosed in Table 2 below.
  • Compound (I) Form A is being examined in an ongoing open-label, multi-center, non-randomized, multiple- dose study to evaluate the safety, tolerability, PK, PD, and anti-tumor activity of increasing immediate-release, oral doses (in capsules) of Compound (I) Form A as a single agent in sequential dose levels. Summary of Clinical Data As of 16 June 2023, 61 patients have been treated with Compound (I) Form A; 15 of whom were treated with a continuous daily dosing schedule with dosages of 50 mg, 100 mg, 200 Attorney Docket No.16036.0005-00304 Ref. No.
  • NKT-24-007PCT mg or 300 mg once daily (QD) of Compound (I) Form A; and 46 of whom were treated with a loading dose followed by a maintenance dose of Compound (I) Form A at the following dosages: 200 mg QD ⁇ 7 days then 200 mg QW, 200 mg QD ⁇ 14 days then 50 mg QD, 100 mg QD ⁇ 7 days then 100 mg QW, or 200 mg QD ⁇ 28 days then 50 mg QD.
  • Compound (I) has been well tolerated.
  • hypoxia, fatigue, and nausea were the most commonly reported TEAEs leading to treatment interruption occurring in 8/61 patients (13.1%), 6/61 patients (9.8%), and 4/61 patients (6.6%) overall, respectively.
  • a total of 6/61 patients (9.8%) discontinued treatment due to a TEAE.
  • Hypoxia and fatigue were the only TEAEs that resulted in treatment discontinuation in more than 1 patient (hypoxia occurred in 3/61 patients [4.9%] and fatigue occurred in 2/61 patients [3.3%] overall).
  • Serious TEAEs were reported in 19/61 patients (33.1%).
  • Serious TEAEs were treatment related in 5/61 patients (8.2%).
  • Plasma Compound (I) PK data was obtained from 50 patients at 8 dosage levels, including 50 mg, 100 mg, 200 mg, and 300 mg QD of Compound (I) Form A, 100 mg QD ⁇ 7 days then 100 mg QW of Compound (I) Form A, 200 mg QD ⁇ 7 days then 200 mg QW of Compound (I) Form A, 200 mg QD ⁇ 14 days then 50 mg QD of Compound (I) Form A, and 200 mg QD ⁇ 28 days then 50 mg QD of Compound (I) Form A.
  • NKT-24-007PCT EPO data was collected from 61 patients treated with a continuous daily dosing schedule or a loading/maintenance dose schedule of Compound (I) Form A. Rapid and significant EPO suppression was observed at all tested dosages. As of 16 June 2023, 31 out of 61 patients remained on treatment. A 2-compartmental population PK model with first-order oral absorption and first-order elimination adequately described the PK data of Compound (I) after a single dose, multiple doses, as well as PK after dose reductions and dose holds of Compound (I) Form A.
  • the typical PK parameter values (CV%) for absorption rate constant (Ka), apparent total clearance (CL/F), apparent intercompartment clearance (Q/F), apparent volume of distribution of the central compartment (Vc/F), and apparent volume of distribution of the peripheral compartment (Vp/F) of Compound (I) were 0.741 (72%), 0.472 L/h (80%), 27.1 L/h (54%), 133 L (76%), and 543 L (84%), respectively; the model-estimated median terminal t1/2 of Compound (I) was 39 days following administration of Compound (I) Form A.
  • the modeling analysis suggested no time- or concentration-dependent nonlinearity and that the high accumulation of Compound (I) following continuous daily dosing of Compound (I) Form A is due to slow elimination.
  • the EPO model had first-order EPO elimination and zero-order production which was inhibited by Compound (I).
  • the model-estimated half-maximal inhibitory concentration (IC50) and maximum fractional inhibition (Imax) of Compound (I) were 57.3 ng/mL and 0.758, respectively, following administration of Compound (I) Form A.
  • the model adequately described the EPO inhibition at different dosage levels.
  • the unique PK with very slow elimination necessitated sequential loading and maintenance dosing schedules to achieve and maintain target exposure levels. See Fig.5.
  • the total maintenance doses of Compound (I) Form A per week are 100 mg and 50 mg for RDE-w and RDE-d, respectively.
  • RDE-w and RDE-d allow a reasonably large range of exposure of Compound (I) with estimated mean Ctrough around 1080 ng/mL and 3600 ng/mL, respectively (a 3.34-fold range).
  • Reference concentrations considered for RDE selection Pharmacologically active concentration thresholds were estimated for Compound (I) Form A using different approaches.
  • Compound (I) Form A inhibited VEGFA secretion in 786-O cells with IC 90 of 201 ng/mL in human plasma (after protein binding adjustment).
  • IC 90 of Compound (I) was estimated to be 2070 ng/mL (after cross- species protein binding normalization).
  • Compound (I) Form A inhibited EPO production with an IC 90 of 516 ng/mL. See Fig.5.
  • Phase 1 Dose Escalation of Compound (I) Form A significant EPO suppression was observed at all tested dosage levels, and the magnitude of suppression was similar to that of belzutifan at the approved dose of 120 mg QD. Significant serum EPO suppression may not reflect adequate HIF2 ⁇ inhibition within the tumor.
  • C avg AUC0-t /t of each patient was used in the analyses, where t is time of the last dose or the time of the event of interest.
  • No statistically significant and clinically meaningful correlation was observed for Grade ⁇ 2 or Grade ⁇ 3 anemia, Grade ⁇ 2 or Grade ⁇ 3 hypoxia.
  • RDE-w 100 mg QD ⁇ 7 days then 100 mg QW
  • RDE-d 200 mg QD ⁇ 14 days then 50 mg QD
  • dosages of Compound (I) Form A were selected based on integrated data analysis.
  • Pharmacologically active concentrations of Compound (I) were achieved at the above RDEs.
  • Both RDE-w and RDE-d were efficacious with manageable safety in the Dose Escalation.
  • PK-PD modeling and Exposure-Response analyses suggested better tumor response at higher exposures of Compound (I).
  • RDE-w allows for Compound (I) exposure comparable to belzutifan (120 mg QD), while RDE-d allows for 3.5 fold higher maintenance dose intensity and potentially better efficacy.
  • NKT-24-007PCT Phase 1 and Phase 2 ⁇ Incidence of adverse events (AEs) characterized overall and by type, seriousness, relationship to study treatment, timing and severity graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0 ⁇ Changes in clinical laboratory parameters, vital signs and electrocardiogram (ECG) parameters and physical examination findings ⁇
  • Compound (I) Form A single-dose and multiple-dose PK parameters such as maximum concentration observed (Cmax), time at which maximal concentration was observed (tmax), area under the concentration-time curve during a dosing interval (AUC 0-t ), area under the concentration time curve from time zero to infinity (AUC0- ⁇ ), if data allow ⁇ ORR (Phase 1 only) ⁇ Duration of response and disease control rate (defined as CR + PR + stable disease for ⁇ 8 weeks) ⁇ Time to response ⁇ Progression free survival ⁇ Overall survival ⁇ 6- and 12-month landmark OS Exploratory Objectives Phase 1 and Phase 2 ⁇ To explore biomarkers
  • Sub-Study Objectives Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT ⁇ Objectives for the drug-drug interaction (DDI) and food effect (FE) sub-study are included in sub-study 1. ⁇ Objectives for the preliminary urinary excretion and metabolite profiling sub-study are included in sub-study 2. ⁇ Objectives for the belzutifan pre-treated patient sub-study are included in sub-study 3. Investigational Plan Overall Study Design This study will be conducted in two parts, Phase 1 and Phase 2. Phase 1 will be conducted as a dose escalation trial in patients with ccRCC tumors to determine the MTD/RDEs of Compound (I) Form A.
  • Phase 2 will be conducted as an expansion trial to further explore the safety, pharmacokinetics, and preliminary efficacy of the MTD or RDE to determine the RP2D in patients with advanced ccRCC.
  • Study procedures are described below and the schedule of assessments is tabulated in Table 3 and Table 4.
  • Patients will undergo clinic visits weekly for the first 4 weeks, then will have a visit two weeks apart at the Week 6 visits, a visit three weeks apart at the Week 9 visit and then every 4 weeks for up to 1 year from the initiation of treatment, or until withdrawal criteria are met as describedbelow. For patients deriving clinical benefit at 1 year and continuing to take study drug after 1 year, visits will occur at 12-week intervals.
  • Routine serum chemistry assessments include glucose, LDH, AST, ALT, ALP, total bilirubin, albumin, electrolytes (Na, K, Cl, CO 2 ), Ca, Mg, PO4, BUN, creatinine, total protein levels, and an iron panel.
  • BNP and NT-proBNP is required at W1D1 and repeated as needed when a grade 3 or higher hypoxia adverse event occurs.
  • Iron panel assessments including iron (Fe), ferritin, transferrin saturation, and total iron binding capacity should be captured at Screening, Week 1, Week 4, Week 9 and every 4 weeks for the first year. 8.
  • Samples for urinalysis will be obtained at the Week 1, 2, 4, 6, 9, 13, and 17 Visits and every 4 weeks for the first year. Thereafter, urinalysis samples will be obtained every 12 weeks. 9.
  • Female patients of child-bearing potential will have a serum pregnancy test within 7 days before the first study drug administration; a serum or urine pregnancy test will be performed at the Week 1, 4, 6, 9, 13, and 17 visits and visits every 4 weeks until treatment discontinuation.
  • home urine pregnancy testing should also be conducted monthly until 6 months after last dose of study drug and contraceptive status should be confirmed up to 6 months after the last dose of study drug.
  • Pregnancy should be reported up to 6 months after the last dose of Compound (I) Form A. 10.
  • An ECG will be obtained before and at 1.5 hours ( ⁇ 15 minutes) after study drug administration at the Week 1 and Week 4 Visits. ECGs will be obtained prior to study drug administration only at Weeks 2, 3, 6, 9, and every 4 weeks, thereafter, through Week 49 (e.g., Week 13, Week, 17, Week 21, etc.).
  • Anti-tumor activity will be assessed via radiographic assessments of the patient’s tumor and will be conducted at Screening/baseline (within 35 days) and every 8 weeks ( ⁇ 1 week) from Week 1 Day 1 for the first year. After the first year, anti-tumor assessments will be conducted every 12 weeks ( ⁇ 1 week). When the last scan in the 8 week interval ends at Week 49, the next week starts the 12 week interval. 12. At the Week 1 visit, 17 mL of whole blood as 2 ⁇ 8.5 mL Pax Gene Tubes should be collected for genetic sequencing. 13.
  • Patients assigned to the QD dosing schedule will take their dose of Compound (I) Form A in the clinic at weeks 2, 3, 6, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, and 49 Visits.
  • a 4 mL blood sample for PK assessments will be obtained before study drug administration on these days. 16.
  • Patients assigned to the QW dosing schedule will take their dose of Compound (I) Form A in the clinic at weeks 2, 3, 5, 6, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, and 49 Visits.
  • a 4 mL blood sample for PK assessments will be obtained before study drug administration on these days. 17.
  • patients will have blood drawn for PD assessments at 1 hour before (+10 minutes/-40 minutes) study drug administration.
  • Patient status information includes ccRCC tumor status; any therapeutic interventions for ccRCC tumors; and survival status. 22. Patients enrolled under PA v10 will have a 6MWT during Screening visit. Table 4: Phase 2 Schedule of Assessments
  • assessments can be performed ⁇ 2 days (48 hours). Pre-dose assessments including local safety labs (hematology, serum chemistry, iron panel, urinalysis, and pregnancy test), Physical Exam, and ECOG can be performed up to 48 hours prior to each corresponding visit. In exceptional circumstances, Medical Monitor approval may be granted to perform these assessments up to 72 hours prior to the corresponding visit. Screening Labs performed within 3 days of W1D1 need not be repeated. PK/PD sample collection windows are included in Table 5. 2. For patients deriving clinical benefit at 1 year and continuing to take study drug after 1 year, visits will be undertaken at 12-week intervals.
  • the 12-week interval will begin after the Week 49 visit. 3. Physical examination to be performed before study drug administration at the Week 1, 4, 6, 9, 13, and 17 Visits and visits every 4 weeks thereafter through Week 49. 4. Vital signs to include systolic and diastolic blood pressure, pulse, respirations, temperature, and oxygen saturation and obtained only prior to study drug administration. Oxygen saturation (measured by pulse oximetry) should be measured at rest before study drug administration and at 6 hours after study drug administration on Week 1 Day 1 and Week 4 Day 1. 5. EORTC-QLQ-C30 should be done on Day 1 of Weeks 1, 4, 9, 13, and then every 4 weeks for the first year of treatment and every 12 weeks during extended treatment. 6. Hematology assessments include complete blood count (CBC), differential, platelet count, and reticulocyte count. 7.
  • Routine serum chemistry assessments include glucose, LDH, AST, ALT, ALP, total bilirubin, albumin, electrolytes (Na, K, Cl, CO 2 ), Ca, Mg, PO4, BUN, creatinine, total protein levels, and an iron panel.
  • BNP and NT-proBNP are required at W1D1 and repeated as needed when a grade 3 or higher hypoxia adverse event occurs.
  • Iron panel assessments including iron (Fe), ferritin, transferrin saturation, and total iron binding capacity should be captured at Screening, Week 1, Week 4, Week 9 and every 4 weeks for the first year. 9.
  • Samples for urinalysis will be obtained at the Week 1, 2, 4, 6, 9, 13, and 17 Visits and every 4 weeks for the first year. Thereafter, urinalysis samples will be obtained every 12 weeks. 10.
  • Female patients of child-bearing potential will have a serum pregnancy test within 7 days before the first study drug administration; a serum or urine pregnancy test will be performed at the Week 1, 4, 6, 9, 13, and 17 visits and visits every 4 weeks until treatment discontinuation.
  • home urine pregnancy testing should also be conducted monthly until 6 months after last dose of study drug and contraceptive status should be confirmed up to 6 months after the last dose of study drug. Pregnancy should be reported up to 6 months after the last dose of Compound (I) Form A.
  • Anti-tumor activity will be assessed via radiographic assessments of the patient’s tumor and will be conducted at Screening/baseline (within 35 days) and every 8 weeks ( ⁇ 1 week) from Week 1 Day 1 for the first year. After the first year, anti-tumor assessments will be conducted every 12 weeks ( ⁇ 1 week). When the last scan in the 8 week interval ends at Week 49, the next week starts the 12 week interval.
  • Screening (within 35 days prior to enrollment), a CT/MRI of the brain should be obtained to rule out newly diagnosed, untreated brain metastases or to document stability of previously treated brain metastases.
  • CT/MRI brain scans should be performed at every on-study tumor assessment for chest/abdomen/pelvis for patients with brain metastases or primary brain tumors. 12.
  • 17 mL of whole blood as 2 ⁇ 8.5 mL Pax Gene Tubes should be collected for genetic sequencing.
  • 20 mL of whole blood as 2 ⁇ 10 mL STRECK tubes should be collected for evaluation of circulating tumor DNA.
  • Archival tumor tissue samples will be requested for all patients at the time of enrollment as 20 unstained slides or formalin–fixed, paraffin-embedded blocks.
  • biopsy tissue samples are required during screening and at Week 9 from the same lesion as the pre-treatment biopsy (preferred) or at least from the same organ.
  • biopsy tissue samples during screening and at Week 9 are optional.
  • Contrast CTs or MRIs utilized during screening and subsequent scans done throughout the duration of the study should be anonymized and uploaded to the central image repository. Instructions can be found in the procedure manual.
  • An echocardiogram or MUGA for left ventricular ejection fraction (LVEF) assessment will be performed at the screening and Week 6 visits (same measurement should be used throughout the study). 17.
  • Compound (I) Form A should be administered after all study assessments have been completed with the exception of post-dose PKs and/or ECGs. 18.
  • long-term follow-up will be assessed approximately every 6 months and may be accomplished via an in-person visit, telephone contact, chart review, etc.
  • Patient status information includes ccRCC tumor status; any therapeutic interventions for ccRCC tumors; and survival status. 19.
  • Patients enrolled under PA v10 will have a 6MWT during Screening visit.
  • ECGs should be time matched with the PK sample to allow concentration-QT analysis.
  • safety ECG (X) should be collected at the indicated timepoints. When ECG timepoints coincide with PK, vital signs, or other PD assessments, ECG collections should always be performed prior to other assessments. 3.
  • RDE-w only 4.
  • RDE-d only Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Phase 1
  • patients with ccRCC will be assigned to sequential dose cohorts. Using a 3 + 3 design, 3 to 6 patients will be enrolled in each dose cohort to receive Compound (I) Form A at a single dose level. The initial dose level will be 200 mg orally once daily.
  • the dose levels will be increased by 100% until the second clinically significant Grade 2 or greater toxicities or dose-limiting toxicity (DLT) that is at least possibly related to the study drug is reported. Thereafter, the dose levels will be increased by 50% or less.
  • DLT dose-limiting toxicity
  • the SRC composed of sponsor representatives and principal investigators from participating sites, will meet to make all dose escalation decisions. Decisions to dose escalate will be made based on observed DLTs as well as additional supportive data such as overall safety profile, PK, pharmacodynamics, and efficacy.
  • Alternative dosing schedules (for example, once weekly, or combination of different dose levels or dosing frequency instead of once daily dosing) may also be considered if the PK/PD profile supports a change in the dosing frequency.
  • the SRC may review the severity of a DLT to determine if additional patients should be evaluated at a particular dose level even if the overall DLT rate would permit continued dose escalation. Escalation will proceed until a dose is deemed intolerable or until the Sponsor and SRC determine that a suitable dose has been achieved based on available data (PK, PD, safety, and clinical activity). All patients at each dose level must complete a minimum of 3 weeks of treatment before enrollment of patients at the next dose level. If 0/3 patients in a dose cohort experience a DLT during the observation period, escalation to the next higher dose level may occur.
  • PK PK
  • PD PD
  • anti-tumor activity data i.e., the dose that will most effectively produce the desired effect while remaining in the range of acceptable toxicity.
  • OBD biologic dose
  • the RDE will be determined based on the MTD, the overall safety profile with continued treatment, and PK data.
  • Patient safety will be monitored with frequent physical examinations, vital sign measurements, electrocardiograms (ECGs), and hematology and chemistry laboratory studies, and by recording all AEs, as in Table 3 and Table 4.
  • serial blood samples will be obtained for analysis of the Compound (I) Form A PK and PD (e.g., assessment of EPO and/or other markers of the HIF2 ⁇ pathway) at the Week 1 (Day 1) and Week 4 Visits, and before study drug administration at additional visits.
  • a formalin-fixed, paraffin-embedded tumor tissue block or 20 unstained slides of tumor sample (archival or recent) for biomarker evaluation will be requested for all patients at study entry.
  • NKT-24-007PCT In the FE/DDI sub-study 1, the urinary excretion and metabolite profiling sub-study 2, and the belzutifan pre-treatment sub-study 3, additional PK assessments will be conducted, as described below.
  • Phase 2 After determination of the RDEs, approximately 50 patients with ccRCC will be enrolled and treated with Compound (I) Form A at the selected RDEs in an effort to further assess anti- tumor activity and safety. Additional PK and PD data will also be collected. Two RDEs were selected based on data from Phase 1 Dose Escalation. See Fig.6. The lower RDE starts with 100 mg QD for 7 days followed by weekly maintenance dose of 100 mg (RDE-w).
  • RDE-d The higher RDE starts with 200 mg QD for 14 days followed by daily maintenance dose of 50 mg (RDE-d).
  • Forty patients with no prior treatment with a HIF2 ⁇ inhibitor will be randomized in a 1:1 fashion to RDE-w and RDE-d, 20 in each arm, to determine the RP2D for Compound (I) Form A.
  • approximately 10 evaluable patients who have had prior treatment with the HIF2 ⁇ inhibitor belzutifan will be enrolled at the RDE-d as described below.
  • Archival tumor tissue samples will be requested for all patients at the time of enrollment as 20 unstained slides or formalin–fixed, paraffin-embedded blocks.
  • biopsy tissue samples are required during screening and at Week 9 from the same lesion as the pre-treatment biopsy (preferred) or at least from the same organ.
  • biopsy tissue samples during screening and at Week 9 are optional.
  • Number of Patients Phase 1 Approximately 61 patients diagnosed with advanced ccRCC may be enrolled in the dose-escalation portion of the study to identify the MTD and/or the RDEs (including 12 patients in the FE/DDI substudy 1 and 5 patients in the urine excretion/metabolite substudy 2).
  • Phase 2 Approximately 50 patients diagnosed with advanced ccRCC may be enrolled in the expansion cohort, including 20 patients at RDE-w and RDE-d, each without prior treatment with HIF2 ⁇ inhibitor belzutifan and 10 patients who have had prior treatment with the HIF2 ⁇ inhibitor belzutifan, as described below for sub-study 3.
  • Treatment Assignment Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Following confirmation of eligibility, patients will be sequentially assigned to the next open dose cohort. The initial dose cohort will begin treatment at a dosage of 200 mg orally, once daily. Additional dosing levels and schedules may be explored based on available patient data.
  • two RDEs were selected based on data from Phase 1 Dose Escalation.
  • RDE-w starts with 100 mg QD for 7 days followed by weekly maintenance dose of 100 mg
  • RDE-d starts with 200 mg QD for 14 days followed by daily maintenance dose of 50 mg. See sub-study 3 below for the sub-study in patients with prior belzutifan treatment for their treatment assignment.
  • Dose Escalation Using a 3 + 3 design 3 patients will be enrolled in each dose cohort. Dose escalation will be in 100% increments until the second Grade 2 or greater toxicity that is at least possibly related to the study drug is reported. Thereafter, sequential dose levels will increase by increments of up to 50% as determined by an SRC taking into consideration the available capsule strengths.
  • Dose-limiting Toxicity Dose-limiting toxicities will be defined as the occurrence of any of the following events in the first 21 days of treatment for which there is no clear alternative explanation (e.g., disease related).
  • Any Grade 4 should be a DLT Hepatic ⁇ Grade 4 elevation of serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ⁇ Grade 3 elevation of serum ALT or AST for > 7 days regardless of serum bilirubin level ⁇ Grade ⁇ 3 elevation of serum ALT or AST in conjunction with a Grade ⁇ 2 elevation in serum bilirubin ⁇ Laboratory criteria meeting Hy’s Law (ALT/AST > 3 ⁇ upper limit of normal (ULN) in conjunction with total bilirubin > 2 ⁇ ULN (without evidence of cholestasis) Pulmonary ⁇ Any Grade ⁇ 3 hypoxia Other ⁇ Grade 3 or 4 non-hematologic AEs except: o Electrolyte abnormalities that last ⁇ 72 hours, are not clinically complicated, and resolve spontaneously or respond to conventional medical interventions.
  • Bone marrow ANC ⁇ 1.0 ⁇ 10 9 /L; Hgb level ⁇ 10 g/dL without transfusion or erythropoietin support within 2 weeks prior to first dose; platelet count ⁇ 75,000/ ⁇ L b.
  • Hepatic transaminase levels (AST/ALT) ⁇ 2.5 ⁇ ULN ( ⁇ 5 ⁇ ULN if liver metastases is present); total bilirubin (TBILI) ⁇ 1.5 ⁇ ULN in the absence of Gilbert’s disease c.
  • Renal serum creatinine level ⁇ 2.0 ⁇ ULN or calculated creatinine clearance (CrCL) ⁇ 40 mL/min (Cockcroft-Gault formula) 8.
  • a female patient is considered to be of childbearing potential unless she has had a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy; has medically documented ovarian failure (with serum estradiol and follicle- stimulating hormone levels within the institutional laboratory postmenopausal range and a negative serum or urine beta human chorionic gonadotropin); or is menopausal (amenorrhea for ⁇ 12 months). 11.
  • a male patient is considered able to father a child unless he has had a bilateral vasectomy with documented aspermia or a bilateral orchiectomy.
  • Able to swallow oral medications 14.
  • Exclusion Criteria Patients will be excluded from this study if they meet any of the following criteria. 1. Known symptomatic brain metastases requiring > 10 mg/day of prednisone (or its equivalent). Patients with previously diagnosed brain metastases are eligible if they have completed their treatment, have recovered from the acute effects of radiation therapy or surgery prior to the start of Compound (I) Form A treatment, fulfill the above steroid requirement for these metastases, and are neurologically stable based on central nervous system imaging ⁇ 4 weeks after central nervous system (CNS)- directed treatment 2. Having one or more of the following conditions: a. A pulse oximetry reading less than 95% at screening; b. Any current requirement for intermittent or chronic supplemental oxygen; Attorney Docket No.16036.0005-00304 Ref. No.
  • NKT-24-007PCT Any chronic lung condition which has required supplemental oxygen in the past d.
  • Evidence of impending airway compromise (such as endobronchial tumor, lymphangitic spread, significant extrinsic compression of major airway) per investigator; e. Ascites requiring drainage within 28 days prior to W1D1 3.
  • History of another malignancy except for the following: adequately treated local basal cell or squamous carcinoma of the skin, in situ cervical cancer, adequately treated papillary noninvasive bladder cancer, other adequately treated Stage 1 or stage 2 cancers currently in complete remission, or any other cancer that has been in complete remission for ⁇ 2 years 4.
  • Has an active infection requiring systemic treatment 14.
  • Is actively participating in another therapeutic clinical trial 15 has received prior treatment with a HIF2 ⁇ inhibitor (unless participating in the substudy 3 that requires previous belzutifan treatment) Withdrawal Criteria Patients have the right to withdraw from the study and study treatment at any time for any reason.
  • NKT-24-007PCT III Patients with cardiac disease resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes fatigue, palpitation, Sub-Study Objectives Primary sub-study objectives: ⁇ To have a preliminary assessment of the effect of Compound (I) Form A treatment on the PK of a single oral dose of midazolam ⁇ To have a preliminary assessment of the effect of a high-fat meal on the PK of oral Compound (I) Form A Secondary sub-study objective: ⁇ To assess incidence of adverse events (AEs) characterized overall and by type, seriousness, relationship to study treatment, timing and severity graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0 Exploratory sub-study objectives: ⁇ To explore biomarkers potentially predictive of response to Compound (I) Form A DDI and FE Sub-Study Design In this pilot drug-drug interaction (DDI) and food effect (FE) sub-study, up to 12 eligible patients with advanced clear
  • Compound (I) Form A After the first dose of Compound (I) Form A, all subsequent Compound (I) Form A doses will be administered on an empty stomach as defined in the main protocol, i.e., Compound (I) Form A should be taken at least 2 hours after the last meal and at least 1 hour before the next meal. See Fig.7.
  • a Schedule of Assessments for the DDI and FE Sub-Study is shown in Table 10.
  • Inclusion Criteria In addition to the inclusion criteria above, the following inclusion criteria are applicable to this sub-study 1. Willing to and able to take a high-fat meal within 30 min prior to the Compound (I) Form A dosing on Week 1 Day 1. 2. Adequate hepatic and renal function a.
  • Hepatic normal hepatic function (total bilirubin ⁇ upper limit of normal (ULN) and aspartate aminotransferase (AST) ⁇ ULN) or mild hepatic impairment (total bilirubin ⁇ ULN and AST > ULN, or total bilirubin > 1.0 ⁇ to 1.5 ⁇ ULN)
  • Renal measured or calculated creatinine clearance (CrCL) ⁇ 60 mL/min (Cockcroft-Gault formula)
  • Exclusion Criteria In addition to the exclusion criteria above, the following exclusion criteria are required in this sub-study: 1.
  • GI gastrointestinal
  • surgeries, or conditions that could affect absorption of oral Compound (I) Form A and/or midazolam as assessed by the investigator Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT 2.
  • Example strong and moderate clinical CYP3A inhibitors can be found at https://www.fda.gov/drugs/drug-interactions-labeling/drug- development-and-drug-interactions-table-substrates-inhibitors-and-inducers#table3-2, and example strong and moderate clinical CYP3A inducers can be found at https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug- interactions-table-substrates-inhibitors-and-inducers#table3-3 and also at https://www.fda.gov/drugs/drug-interactions-labeling/healthcare-professionals-fdas- examples-drugs-interact-cyp-enzymes-and-transporter-systems.
  • the Compound (I) Form A dosage for this sub-study is loading doses of 200 mg QD x 7 days followed by maintenance doses of 200 mg QW.
  • the weekly maintenance doses are expected to maintain relatively steady exposure levels (steady state) following the loading doses.
  • This dosage was evaluated by the Safety Review Committee (SRC) and was deemed safe and well tolerated with no dose limiting toxicity.
  • SRC Safety Review Committee
  • this dose allowed for significant and sustained EPO suppression indicative of HIF2 ⁇ inhibition.
  • This dosage is to be further evaluated in future trials if supported by cumulative data.
  • Drug-Drug Interaction Design In the DDI portion of this sub-study, the second dose of oral midazolam will be on Day 15.
  • This preliminary FE assessment will be based on a partial PK profile on Day 1 up to 24 hours, and estimated C max , T max , and AUC 0-24 . This is considered adequate as the absorption phase is ⁇ 24 hours in duration based on available PK data with cohort median Tmax ⁇ 4.55 hours.
  • Dosage and Administration of Study Drugs Compound (I) Form A
  • Compound (I) Form A will be given to patients at 200 mg QD ⁇ 7 days.
  • Week 2 (Day 8) patients will start 200 mg Compound (I) Form A QW.
  • the dose on Week 1 Day 1 will be given either under fasted conditions (Group 1) or with a high-fat meal (Group 2). Patients will be enrolled to either of the 2 groups in an alternating manner.
  • the fasted conditions and the high-fat meal are defined as below (see Center for Drug Evaluation and Research (2022). "Assessing the Effects of Food on Drugs in INDs and NDAs-- Clinical Pharmacology Considerations.” Food and Drug Administration). Fasted Condition Following an overnight fast of at least 8 hours, patients will receive oral dosing of study drug(s) with 8 oz (240 mL) of room temperature water. No food will be allowed for at least 4 hours post-dose and no water will be allowed for at least 2 hours post-dose.
  • the breakfast meal will be provided by the clinical site.
  • a list of appropriate breakfast meals will be provided to clinical sites and patients by the sponsor.
  • An example test meal would be two eggs fried in butter, two strips of bacon (or ham or cheese of similar caloric content), two slices of toast with butter, 4 oz of hash brown potatoes, and 8 oz (240 mL) of whole-fat milk.
  • a different breakfast meal to suit specific dietary requirements may be substituted by the clinical site, provided that it has a similar amount of calories and protein, and carbohydrate and fat content.
  • Compound (I) Form A will be administered, followed immediately by the second dose of midazolam, to patients in the morning after an overnight fast of at least 8 hours and should be taken with at least 240 mL of room temperature water. The fasting will continue for at least 2 hours before a patient can ingest a standard meal. The water will be restricted for 1 hour before and after the study drug intake. The rest of the doses of Compound (I) Form A will be administered on an empty stomach.
  • Midazolam 5 mg
  • Administration of midazolam Midazolam (5 mg) for oral administration will be procured by each participating site and dispensed using the manufacturer specified dispensing instructions. Qualified personnel will prepare and dispense the midazolam dose in accordance with the current package insert. Two midazolam doses will be administered: the first on Study Day-3 alone, and the other on Day 15 (Week 3) with a co-administration of Compound (I) Form A.
  • Midazolam will be administered to patients in the morning after an overnight fast of at least 8 hours and should be taken with at least 240 mL of room temperature water. The fasting will continue for at least 2 hours before a patient can ingest a standard meal. The water will be restricted for 1 hour before and after the study drug intake.
  • PK parameters will be calculated based on the serial PK data following the first dose on Day 1, including but not limited to C max , T max , C trough , and AUC 0-24 , if data allow.
  • NKT-24-007PCT PK parameters will be calculated based on the serial PK data of midazolam and 1’- hydroxymidazolam following the first dose on Day -3 and Day 15, including but not limited to C max , T max , C last , AUC 0-last , if data allow.
  • PD Marker Assessment Blood samples for the determination of serum concentrations of pharmacodynamic (PD) biomarkers (e.g., EPO) will be collected at multiple time points as shown in Table 11. The date and time of collection of all PD blood samples should be recorded. A validated enzyme-linked immunosorbent assay (ELISA) will be used to determine the serum level of EPO. Details for the collection, processing, storage, and shipment of samples can be found in the study laboratory manual.
  • PD biomarkers e.g., EPO
  • Safety Assessments Ongoing assessment of safety for all patients in this sub-study will be determined by monitoring of symptoms, signs, and abnormal laboratory test results. All clinically significant abnormal laboratory test results will be reported on the Adverse Event CRF and will be followed until a return to normal or baseline levels. Other safety assessments will include vital signs, physical examination, ECG, and ECOG. Sample Size Up to 12 eligible patients will be enrolled to enable 10 evaluable patients. The sample size is empirically selected to allow preliminary assessments of the DDI and the FE. Drug-Drug Interaction and Food Effect Analysis Descriptive summary statistics of PK and PD concentration data will be provided and Mean (SD) PK and PD plots will be generated.
  • SD Mean
  • Serial plasma PK data of Compound (I), midazolam, and 1’-hydroxymidazolam will be analyzed using non-compartmental methods using Phoenix ® WinNonlin ® software, and the results will be further analyzed to determine the FE on Compound (I) Form A and the effect of Compound (I) Form A on oral midazolam PK as the following: Food Effect Analysis Cmax and AUC0-24 of NK2152 will be log-transformed before statistical analysis. The 90% CI for the ratio of the population geometric means between the fed and fasted conditions will be provided. Drug-Drug Interaction Analysis Attorney Docket No.16036.0005-00304 Ref. No.
  • NKT-24-007PCT Cmax and AUCs of midazolam and 1’-hydroxymidazolam as well as the 1’- hydroxymidazolam-to-midazolam AUC ratio will be log-transformed before statistical analysis.
  • the 90 percent CI for the ratio of the population geometric means with and without Compound (I) Form A treatment will be provided.
  • Safety Analysis will be based on all patients who received at least one dose of study drug. Study drug is defined as either Compound (I) Form A or midazolam.
  • data will be summarized using descriptive statistics. Continuous data will be summarized with number of patients (n), arithmetic mean, standard deviation, median, minimum, and maximum. Categorical data will be summarized using frequency counts and percentages.
  • a TEAE is defined as an AE with onset on or after the first dose of study drug (or that worsened from prior to the first dose of study drug). Any AE occurring after the 28-day follow- up period after discontinuation of study drug will be included in listings but will not be included in the summary tables of AEs.
  • Pre-dose assessments including local safety labs (hematology, serum chemistry, iron panel, urinalysis, and pregnancy test), Physical Exam, and ECOG can be performed up to 48 hours prior to each corresponding visit but must be done prior to the high-fat meal on W1D1. In exceptional circumstances, Medical Monitor approval may be granted to perform these assessments up to 72 hours prior to the corresponding visit. Screening Labs performed within 3 days of W1D1 need not be repeated. For FE/DDI sub-study, D-3 midazolam dosing should occur on Monday to ensure collection of required PK samples. PK/PD sample collection windows are included in Table 11. 2. For patients deriving clinical benefit at 1 year and continuing to take study drug after 1 year, visits will be undertaken at 12-week intervals.
  • the 12-week interval will begin after the Week 49 visit. 3.
  • Half of the FE substudy patients will eat a high-fat meal, and the rest will be dosed under fasted conditions.
  • Pre-dose assessments including local safety labs (hematology, serum chemistry, iron panel, urinalysis, and pregnancy test), Physical Exam, VS, ECG, and ECOG must be done prior to high-fat meal on Week 1 Day 1.
  • the high fat meal should be consumed within 30 minutes and prior to administration of the Compound (I) Form A dose.
  • Reminder for site staff to call the patient the day before the visit to remind of overnight fasting. 5.
  • Physical examination to be performed before study drug administration at the Week 1, 4, 6, 9, 13, and 17 Visits and visits every 4 weeks thereafter through week 49. 6.
  • Oxygen saturation (measured by pulse oximetry) should be measured at rest before study drug administration and at 6 hours after study drug administration on Week 1 Day 1 and Week 4 Day 1. 7.
  • Hematology assessments include CBC, differential, platelet count, and reticulocyte count.
  • Routine serum chemistry assessments include glucose, LDH, AST, ALT, ALP, total bilirubin, albumin, electrolytes (Na, K, Cl, CO 2 ), Ca, Mg, PO4, BUN, creatinine, total protein levels, and an iron panel.
  • BNP and NT-proBNP are required at W1D1 and repeated as needed when a grade 3 or higher hypoxia adverse event occurs.
  • Iron panel assessments including Fe, ferritin, transferrin saturation, and total iron binding capacity should be captured at Screening, Week 1, Week 4, Week 9 and every 4 weeks for the first year. 10.
  • Samples for urinalysis will be obtained at the Week 1, 2, 4, 6, 9, 13, and 17 Visits and every 4 weeks for the first year. Thereafter, urinalysis samples will be obtained every 12 weeks. 11.
  • Female patients of child-bearing potential will have a serum pregnancy test within 7 days before the first study drug administration; a serum or urine pregnancy test will be performed at the Week 1, 4, 6, 9, 13, and 17 visits and visits every 4 weeks until treatment discontinuation.
  • home urine pregnancy testing should also be conducted monthly until 6 months after last dose of study drug and contraceptive status should be confirmed up to 6 months after the last dose of study drug.
  • Pregnancy should be reported up to 6 months after the last dose of Compound (I) Form A.
  • An ECG will be obtained before and at 1.5 hours after study drug administration at the Week 1 and Week 4 Visits. ECGs will be obtained prior to study drug administration only at Weeks 2, 3, 6, 9, and every 4 weeks, thereafter, through Week 49 (e.g., Week 13, Week, 17, Week 21, etc.).
  • Anti-tumor activity will be assessed via radiographic assessments of the patient’s tumor and will be conducted at Screening/baseline (within 35 days) and every 8 weeks ( ⁇ 1 week) from Week 1 Day 1 for the first year. After the 1 st year, anti-tumor assessments will be conducted every 12 weeks ( ⁇ 1 week) as outlined in the Schedule of Assessments (Table 3 and Table 4).
  • Sub-study 2 Preliminary Urinary Excretion and Metabolite Profiling
  • Primary sub-study objectives ⁇ To determine plasma PK of Compound (I) after a single dose and repeated doses of Compound (I) Form A ⁇
  • Secondary sub-study objective Attorney Docket No.16036.0005-00304 Ref. No.
  • NKT-24-007PCT To assess incidence of adverse events (AEs) characterized overall and by type, seriousness, relationship to study treatment, timing and severity graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0 Exploratory sub-study objectives: ⁇ To explore biomarkers potentially predictive of response to Compound (I) Form A Urinary Excretion and Metabolite Profiling Sub-Study Design In this sub-study, 5 eligible patients with advanced clear cell renal cell carcinoma will be enrolled. Patients will receive 200 mg Compound (I) Form A QD for Week 1 and Week 2 (Day 1 to Day 14), followed by 50 mg Compound (I) Form A QD starting on Week 3 (Day 15).
  • Serial plasma PK samples will be collected on Day 1 and Day 22, and additional sparse pre-dose plasma samples will be collected during the treatment course.
  • total 24-hour urine will be collected from each patient.
  • Urine will be collected in 3 time periods: 0-2 hours, 2- 6 hours, and 6-24 hours. The first 2 periods (up to 6 hours) will be collected during the clinical visit. The total volumes of urine for each period should be recorded. The third period will not be collected during the clinical visit. Patients will be instructed to collect the total urine, measure and record the volume, and store 2 aliquots of urine samples. Patients will return to the clinic with the urine samples on the second day (Day 23). The plasma and urine samples will be analyzed to determine Compound (I) concentration and urinary excretion.
  • Hepatic normal hepatic function (total bilirubin ⁇ upper limit of normal (ULN) and aspartate aminotransferase (AST) ⁇ ULN) or mild hepatic impairment (total bilirubin ⁇ ULN and AST > ULN, or total bilirubin > 1.0 ⁇ to 1.5 ⁇ ULN)
  • UPN total bilirubin ⁇ upper limit of normal
  • AST aspartate aminotransferase
  • AST aspartate aminotransferase
  • mild hepatic impairment to total bilirubin ⁇ ULN and AST > ULN
  • total bilirubin ⁇ ULN and AST > ULN total bilirubin > 1.0 ⁇ to 1.5 ⁇ ULN
  • Renal measured or calculated creatinine clearance (CrCL) ⁇ 60 mL/min (Cockcroft-Gault formula)
  • Exclusion Criteria In addition to the exclusion criteria abovein the main protocol, the
  • Example strong and moderate clinical CYP3A inhibitors can be found at https://www.fda.gov/drugs/drug-interactions-labeling/drug-development- and-drug-interactions-table-substrates-inhibitors-and-inducers#table3-2, and example strong and moderate clinical CYP3A inducers can be found at https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug- interactions-table-substrates-inhibitors-and-inducers#table3-3.
  • the Compound (I) Form A dosage for this sub-study is loading doses of 200 mg QD ⁇ 14 days followed by maintenance doses of 50 mg QD.
  • the daily maintenance doses are expected to maintain relatively steady exposure levels (approximate steady state) following the loading doses.
  • This dosage was evaluated by the Safety Review Committee (SRC) and was deemed safe and well tolerated with no dose limiting toxicity.
  • SRC Safety Review Committee
  • RP2D Phase 2 dose
  • Urinary excretion design Total 24-hour urine will be collected at approximate steady state on Day 22 in 3 periods. The 24-hour urine collection is to cover the dosing interval.
  • Example strong and moderate clinical CYP3A inhibitors can be found at https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions- table-substrates-inhibitors-and-inducers#table3-2, and example strong and moderate clinical CYP3A inducers can be found at https://www.fda.gov/drugs/drug-interactions-labeling/drug- development-and-drug-interactions-table-substrates-inhibitors-and-inducers#table3-3.
  • Pharmacokinetic Assessment for Compound (I) Form A Blood samples for the determination of plasma Compound (I) concentrations will be collected at multiple time points as shown in Table 13.
  • PK parameters will be calculated based on the serial PK data following the first dose on Day 1 and Day 22, including, but not limited to, Cmax, Tmax, Ctrough, AUC0-24, steady-state CL, and CLr, if data allow.
  • a detailed sample analysis plan for plasma and urine metabolite profiling will be defined in a Metabolite Profiling Plan separately.
  • Safety Analysis will be based on all patients who received at least one dose of Compound (I) Form A. In general, data will be summarized using descriptive statistics. Continuous data will be summarized with the number of patients (n), arithmetic mean, standard deviation, median, minimum, and maximum. Categorical data will be summarized using frequency counts and percentages.
  • a TEAE is defined as an AE with onset on or after the first dose of study drug (or that worsened from prior to the first dose of study drug). Any AE occurring after the 28-day follow- up period after discontinuation of study drug will be included in listings but will not be included in the summary tables of AEs.
  • the number and percentage of patients experiencing 1 or more AEs will be summarized for the following classifications: ⁇ TEAEs by SOC and PT ⁇ TEAEs by SOC, PT and maximum toxicity grade Attorney Docket No.16036.0005-00304 Ref. No.
  • PK/PD samples collection windows are included in Table 13. 2. For patients deriving clinical benefit at 1 year and continuing to take study drug after 1 year, visits will be undertaken at 12-week intervals. The 12-week interval will begin after the Week 49 visit. 3. Site to remind patient that serial urine collection is required at Week 4 visit. 4. Physical examination to be performed before study drug administration at the Week 1, 4, 6, 9, 13, and 17 Visits and visits every 4 weeks thereafter through week 49. 5. Vital signs to include systolic and diastolic blood pressure, pulse, respirations, temperature, and obtained only prior to study drug administration.
  • Oxygen saturation should be measured at rest before study drug administration and at 6 hours after study drug administration on Week 1 Day 1 and Week 4 Day 1.
  • Hematology assessments include CBC, differential, platelet count, and reticulocyte count.
  • Routine serum chemistry assessments include glucose, LDH, AST, ALT, ALP, total bilirubin, albumin, electrolytes (Na, K, Cl, CO2), Ca, Mg, PO4, BUN, creatinine, total protein levels, and an iron panel.
  • BNP and NT-proBNP are required at W1D1 and repeated as needed when a grade 3 or higher hypoxia adverse event occurs.
  • Iron panel assessments including Fe, ferritin, transferrin saturation, and total iron binding capacity should be captured at Screening, Week 1, Week 4, Week 9 and every 4 weeks for the first year.
  • Samples for urinalysis (including microscopic if abnormalities on macroscopic examination) will be obtained at the Week 1, 2, 4, 6, 9, 13, and 17 Visits and every 4 weeks for the first year. Thereafter, urinalysis samples will be obtained every 12 weeks.
  • Female patients of child-bearing potential will have a serum pregnancy test within 7 days before the first study drug administration; a serum or urine pregnancy test will be performed at the Week 1, 4, 6, 9, 13, and 17 visits and visits every 4 weeks until treatment discontinuation.
  • home urine pregnancy testing should also be conducted monthly until 6 months after last dose of study drug and
  • Anti-tumor activity will be assessed via radiographic assessments of the patient’s tumor and will be conducted at Screening/baseline (within 35 days) and every 8 weeks ( ⁇ 1 week) from Week 1 Day 1 for the first year. After the first year, anti-tumor assessments will be conducted every 12 weeks ( ⁇ 1 week) as outlined in the Schedule of Assessments (Table 3 and Table 4). When the last scan in the 8 week interval ends at Week 49, the next week starts the 12 week interval. 13. At week 1 visit, 2ml of whole blood as 2 ⁇ 1 mL Paxgene blood DNA tubes should be collected for the genotyping of drug metabolizing enzymes. 14.
  • Patient status information includes ccRCC tumor status; any therapeutic interventions for ccRCC tumors; and survival status. 20. Patients enrolled under PA v10 will have a 6MWT during Screening visit.
  • HIF2 ⁇ Hypoxia-inducible factor 2 alpha
  • PD Marker Assessment Blood samples for the determination of serum concentrations of PD biomarkers will be collected at multiple time points as shown in the PK and PD sampling schedule (Table 5).
  • Safety Assessments Ongoing assessment of safety for all patients in this sub-study will be determined by monitoring of symptoms, signs, and abnormal laboratory test results. All clinically significant abnormal laboratory test results will be reported on the Adverse Event CRF and will be followed until a return to normal or baseline levels. Other safety assessments will include vital signs, physical examination, ECG, and ECOG. Sample Size Approximately 10 evaluable patients will be enrolled. The sample size is empirically selected to allow assessments of the exploratory objectives of this sub-study. Attorney Docket No.16036.0005-00304 Ref. No.
  • Inclusion/Exclusion Inclusion and exclusion criteria should be reviewed during the time period indicated for Screening in Table 3 and Table 4, Schedule of Assessments. Patients must meet all of the inclusion and none of the exclusion criteria for study entry.
  • Demographics and Medical History Demographic data include gender, age, race, and ethnicity will be collected during the time period indicated for Screening in Table 3 and Table 4. Medical and surgical history will be obtained during Screening and will include documentation of the date/year of advanced solid tumor diagnosis, documentation of prior anti-cancer therapies, prior radiation therapy, prior nephrectomy, and documentation of all currently active and relevant medical and surgical conditions.
  • Vital Signs Vital signs (systolic and diastolic blood pressure, pulse, respirations, temperature, and oxygen saturation) will be assessed as noted in Table 3 and Table 4.
  • ECOG Performance Status Eastern Cooperative Oncology Group (ECOG) performance status will be assessed using the grading system shown in Table 14, at the time points indicated in Table 3 and Table 4.
  • Echocardiogram/MUGA An echocardiogram or multigated acquisition (MUGA) for left ventricular ejection fraction (LVEF) assessment will be performed at the screening and Week 6 visits (same measurement should be used throughout the study). Laboratory Assessments Clinically significant abnormal laboratory findings identified during the screening period should be recorded as medical history in the CRF. Laboratory samples will be obtained according to the schedule in Table 3 and Table 4. Clinically significant abnormal laboratory test results that are considered to be drug related should be followed. Details for the collection, processing, storage, and shipment of samples can be found in the study laboratory manual.
  • Hematology Hematology tests will include RBC count, white blood cell (WBC) count, Hgb, HCT, WBC differential count (neutrophils, lymphocytes, eosinophils, monocytes, and basophils), mean corpuscular Hgb concentration (MCHC), mean corpuscular Hgb (MCH), mean corpuscular volume (MCV), mean platelet volume (MPV), red blood cell distribution width (RDW), platelet count (Plt), and reticulocyte count (retic).
  • WBC white blood cell
  • Hgb HCT
  • WBC differential count neutrils, lymphocytes, eosinophils, monocytes, and basophils
  • MCHC mean corpuscular Hgb concentration
  • MCH mean corpuscular Hgb
  • MCV mean corpuscular volume
  • MPV mean platelet volume
  • RDW red blood cell distribution width
  • Plt platelet count
  • reticulocyte count reticulocyte count
  • Blood Chemistry Routine serum chemistry tests will include sodium (Na), potassium (K), chloride (Cl), bicarbonate (CO2), calcium (Ca), magnesium (Mg), phosphate (PO4), blood urea nitrogen (BUN), creatinine, total protein, glucose, lactate dehydrogenase (LDH), AST, ALT, ALP, TBILI, and albumin.
  • B-type natriuretic peptide (BNP) and N-terminal pro b-type natriuretic peptide (NT-proBNP) are required at W1D1. The same lab test will be repeated as needed when a grade 3 or higher hypoxia adverse event occurs.
  • NKT-24-007PCT Activated Partial Thromboplastin Time Blood samples collected during screening will be used to determine the prothrombin time (PT), the activated partial thromboplastin time (aPTT), and the INR (international normalized ratio) to assess coagulation.
  • Iron Panel Blood samples will be collected for an iron panel to include: iron (Fe), ferritin, transferrin saturation, total iron binding capacity.
  • Urinalysis Urinalysis will include appearance, glucose, ketones, blood, protein, nitrite, bilirubin, specific gravity, pH, urobilinogen, and leukocytes. If the results are positive for blood or protein, a microscopic examination should be included.
  • Pregnancy Test A serum pregnancy test must be performed within 7 days before the first study drug administration. Urine or serum pregnancy tests will be performed according to the Schedule of Assessments in Table 3 and Table 4 for females of child-bearing potential. Response Assessments Anti-tumor activity will be assessed via radiographic assessments of the patient’s tumor and will be conducted at Screening/baseline (within 35 days), within 7 days before the Week 9 Visit, and every 8 weeks ( ⁇ 1 week) thereafter for the first year. After the first year, anti-tumor assessments will be conducted every 12 weeks ( ⁇ 1 week) as outlined in the Schedule of Assessments (Table 3 and Table 4). When the last scan in the 8-week interval ends at Week 49, the next week starts the 12-week interval.
  • RECIST v 1.1 (Table 15 and Table 16).
  • assessments of the patient’s tumor will be made every 12 weeks. Investigators must ensure that original images (or high-quality copies) of all CT/MRI scans of disease areas are filed and available for transmission for a future possible central reading by an independent review depending on preliminary efficacy results and upon request. If possible, bone lesions should not be selected as target lesions. If brain metastases are found at baseline, brain scan or MRIs will be repeated with response assessment scans. For patients discontinuing the study treatment before documented radiographic progression, tumor assessments should continue on schedule approximately every 8 weeks or at Attorney Docket No.16036.0005-00304 Ref. No.
  • NKT-24-007PCT the current scan interval at the time of treatment discontinuation until radiographic evidence of disease progression, the start of a subsequent anticancer therapy, withdrawal of consent, or decision to no longer treat (e.g., supportive care only), whichever is first.
  • Inclusion criterion #13 and exclusion criterion #2 provide guidance for a subject’s eligibility. Test procedures are summarized below: PATIENT PREPARATION 1. Comfortable clothing should be worn. 2. Appropriate shoes for walking should be worn. 3. Patients should use their usual walking aids during the test (cane, walker, etc.). 4. The patient’s usual medical regimen should be continued. 5. A light meal is acceptable before early morning or early afternoon tests. 6. Patients should not have exercised vigorously within 2 hours of beginning the test. MEASUREMENTS 1. A “warm-up” period before the test should not be performed. 2.
  • the patient should sit at rest in a chair, located near the starting position, for at least 10 minutes before the test starts. During this time, check for contraindications, measure pulse and blood pressure, and make sure that clothing and shoes are appropriate, 3. Pulse oximetry is required for this study. If it is performed, measure and record baseline heart rate and oxygen saturation (SpO2) and follow manufacturer’s instructions to maximize the signal and to minimize motion artifact. Make sure the readings are stable before recording. Note pulse regularity and whether the oximeter signal quality is acceptable. Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT 4. Have the patient stand and rate their baseline dyspnea and overall fatigue using the Borg scale. 5.
  • the absolute contraindications include acute myocardial infarction (within 30 days), unstable angina, uncontrolled arrhythmias causing symptoms or haemodynamic compromise, syncope, active endocarditis, acute myocarditis or pericarditis, symptomatic severe aortic stenosis, uncontrolled heart failure, acute pulmonary embolus or pulmonary infarction, thrombosis of lower extremities, suspected dissecting aneurysm, uncontrolled asthma, pulmonary oedema, room air SpO2 at rest ⁇ 85%, acute respiratory failure, acute noncardiopulmonary Attorney Docket No.16036.0005-00304 Ref. No.
  • NKT-24-007PCT disorder that may affect exercise performance or be aggravated by exercise (i.e., infection, renal failure, thyrotoxicosis), and mental impairment leading to inability to cooperate.
  • Patients with any of the findings below should be referred to the physician for individual clinical assessment and a decision about the conduct of the test.
  • Stable exertional angina patients should perform the test after using their anti-angina medication, and rescue nitrate medication should be readily available. All comorbidities and medication use should be recorded prior to the test.
  • Relative Contradictions The following relative contraindications were noted by the ATS Committee 2002 and Holland et al.2014.
  • Chronic systemic corticosteroid use prednisone ⁇ 12.5 mg/day or dexamethasone ⁇ 2 mg/day
  • palliative or supportive purpose is not permitted (unless administered for adrenal insufficiency).
  • Acute emergency administration, topical application, inhaled sprays, eyedrops or local injections are permitted.
  • Anti-convulsant therapies at a stable dose are allowed.
  • Patients may receive limited-fraction palliative radiotherapy after first 3 weeks of Compound (I) Form A dosing to control local tumor-related symptoms if irradiation is unlikely to induce major organ toxicity and only if, in the opinion of the treating investigator, the patient does not have progressive disease.
  • the radiation field cannot encompass a target lesion.
  • G-CSF granulocyte colony stimulating factor
  • Erythropoietin should not be administered during the first 21 days of study drug treatment. Patients should receive all necessary supportive care, including blood products, transfusions, antibiotics, pain medications, bisphosphonates, and replacement hormonal therapies (insulin, thyroid hormones, estrogen/progesterone). Herbal and complementary therapies should not be encouraged because of unknown side effects and potential drug interactions, but any taken by the patient should be documented appropriately on the eCRF.
  • Compound (I) Form A is an inducer of CYP3A4 and CYP2B6.
  • CYP3A4 induction occurs via activation of nuclear PXR, which may result in co-induction of CYP2C8, CYP2C9 and CYP2C19.
  • Compound (I) Form A may, therefore, decrease the exposure of concomitant medications that are substrates of CYP3A4, CYP2B6, CYP2C8, CYP2C9 or CYP2C19; however, the clinical relevance of these effects is not yet clear.
  • Example sensitive clinical substrates of CYP3A4, CYP2B6, CYP2C8, CYP2C9, and CYP2C19 can be found at the following website: https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and- drug-interactions-table-substrates-inhibitors-and-inducers#table3-1.
  • Compound (I) Form A may mildly inhibit liver CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3As at clinically relevant concentrations. Compound (I) Form A may also inhibit CYP3As in the gut. Cautions should be used if Compound (I) Form A is taken with sensitive substrates of CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3As as Compound (I) Form A could potentially increase the exposures of these drugs.
  • Example sensitive clinical substrates of these CYPs can be found at the following website: https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and- drug-interactions-table-substrates-inhibitors-and-inducers#table3-1.
  • Compound (I) Form A could inhibit BCRP in the gut and MATE2-K in the kidney at clinically relevant dose levels. No inhibition of other transporters is expected at clinically relevant clinical dose levels.
  • Example substrates for BCRP and MATE2-K can be found at the following website: https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and- drug-interactions-table-substrates-inhibitors-and-inducers#table4-1. All concomitant medication(s) used during the study and within 28 days before the start of study drug administration will be reported on the appropriate CRF page. Treatment Compliance The investigator or his/her designated and qualified representatives will dispense study drug only to patients enrolled in the study in accordance with the protocol. The study drug must not be used for reasons other than that described in the protocol.
  • Study Drug Packaging and Labeling Compound (I) Form A capsules will be packaged in 5-, 15-, and 30-count high-density polyethylene (HDPE) bottles with induction-seal liners and a child-resistant closure. Each bottle will be labeled per local regulatory requirements. Study drug will be provided to each site pharmacy, and the investigator or designee will provide capsules to each patient, with clear instructions on the number and dose strength of capsules to be taken each day until the next study visit. Study Drug Storage Compound (I) Form A must be stored in a secure location in accordance with the study drug label. Study Drug Administration Following confirmation of eligibility, patients will be sequentially assigned to the next open dose cohort.
  • HDPE high-density polyethylene
  • Study drug should be taken at least 2 hours after the last meal, and patients should refrain from eating for at least 1 hour after taking each dose.
  • the initial dose cohort will begin treatment at a dosage of 200 mg orally, once daily. Dose escalation will be in 100% increments until the second Grade 2 or greater toxicity or DLT that is at least possibly related to study drug is reported. Thereafter, sequential dose levels will increase by increments of up to 50% as determined by an SRC. Intermediate dose levels may be studied as appropriate based on the available safety and PK profiles of Compound (I) Form A. Increments of dose escalation will be adjusted as needed to accommodate available capsule strengths. Every effort should be made to have patients take their study drug at the same time each day.
  • Study Drug Accountability, Handling and Disposal The dispensing pharmacist or designated qualified individual will write the date dispensed, dose strength dispensed, and the patient’s identification number or initials on the Drug Accountability Source Documents. Study medication will be dispensed at appropriate intervals to ensure each patient has adequate supply between study visits. All medication supplied will be accounted for on the Drug Accountability Record. All partially used or unused study drug supplies will be destroyed at the site in accordance with approved written site procedures or returned as described in the pharmacy manual.
  • Pharmacodynamic biomarkers to be assessed may include EPO and other biomarkers of the HIF pathway and ccRCC. Serum EPO level will be determined using a validated ELISA method. Whole blood samples will be collected for sequencing of genes encoding proteins that may be involved in regulating Compound (I) Form A metabolism. Whole blood samples will be collected for the analysis of circulating tumor DNA at the Week 1 and Week 9 visits. Details for the collection, processing, storage, and shipment of samples for these biomarker studies can be found in the study laboratory manual. Refer to Table 5 for PD sample collection schedule for Phase 2 Expansion.
  • Tissue Sample Collection A formalin-fixed paraffin-embedded tumor tissue block or unstained slides of tumor sample (archival or recent) for biomarker evaluation will be requested for all patients at study entry. In the case of unstained slides, 20 slides will be requested to conduct biomarker analyses. Tumor tissue samples may be analyzed for HIF2 ⁇ and HIF1 ⁇ expression, and for other biomarkers that may be predictive of benefit of treatment with Compound (I) Form A. Details for the collection, processing, storage, and shipment of tissue samples for these biomarkers can be found in the study laboratory manual. Analysis Biomarker analyses are dependent on the availability of appropriate biomarker assays and clinical response.
  • Biomarker analysis may be deferred or not performed, if during or at the end of the study, it becomes clear that i) the analysis will not have sufficient scientific justification for the planned biomarker evaluation or ii) there are not enough samples and/or responses to allow for adequate biomarker assessment. In the scenario of study being terminated early or lack of sufficient clinical benefit, completion of biomarker evaluation will be based on scientific justification and the intended utility of the data. Additional Collection If it is determined at any time before the study completion that additional material is needed from a FFPE sample for the successful completion of the protocol specified analyses, the sponsor may request additional material to be retrieved from existing samples. Assessment of Safety Safety Parameters Attorney Docket No.16036.0005-00304 Ref. No.
  • NKT-24-007PCT Safety and tolerability will be determined by symptoms, signs, and abnormal laboratory test results.
  • the investigator will monitor the laboratory test findings. Abnormalities of laboratory test results may or may not, in the opinion of the investigator, be considered clinically significant. All clinically significant abnormal laboratory test results will be reported on the Adverse Event CRF and will be followed until a return to normal or baseline levels. Abnormal laboratory values that require intervention must be reported on the Adverse Event CRF. Any laboratory test result that is abnormal during the course of the study but not considered clinically significant will be followed at the discretion of the investigator.
  • Adverse and Serious Adverse Events Definition of Adverse Events Adverse Event An AE is defined as any untoward medical occurrence in a patient regardless of its causal relationship to study treatment.
  • An AE can be any unfavorable and unintended sign (including any clinically significant abnormal laboratory test result), symptom, or disease temporally associated with the use of the study drug, whether or not it is considered to be study drug related. Included in this definition are any newly occurring events and any previous condition that has increased in severity or frequency since the administration of study drug. Disease progression is a study endpoint and consequently, should not be reported as an AE. However, if a patient dies from disease progression with no other immediate causes, “disease progression” should be reported as a serious adverse event (SAE).
  • SAE serious adverse event
  • NKT-24-007PCT ⁇ Is a congenital anomaly or birth defect in an offspring of a patient taking study drug ⁇ Is an important medical event ⁇
  • life-threatening refers to an event in which the patient is at immediate risk of death at the time of the event. The term does not refer to an event that hypothetically might cause death if it were more severe. Important medical events are those that may not meet any of the criteria defined above; however, they may be considered serious when, based upon appropriate medical judgment, they may jeopardize the patient and may require medical or surgical intervention to prevent one of the other outcomes listed in the SAE definition.
  • Pregnancy is not considered an AE; however, information will be collected for any pregnancies that occur during the study (from the time the first dose of study drug is administered until 6 months after the last dose of study drug). Certain pregnancy outcomes will require submission as an SAE.
  • the investigator is responsible for reporting all SAEs that are observed or reported by the patient during the study (from the time of administration of the first dose of study drug until the final visit indicated in Table 3 and Table 4), regardless of their relationship to study drug or their clinical significance. All SAEs reported or observed during the study must be followed to resolution or until the investigator deems the event to be chronic or the patient to be stable. The investigator may be contacted to obtain additional information on any SAE that has not resolved at the time the patient completes the study.
  • Eliciting Adverse Event Information At every study visit, patients must be asked a standard, non-directed question, such as, “How do you feel?” or “How have you been feeling since your last visit?” to elicit any medically related changes in their well-being. They may also be asked if they have been hospitalized, had any accidents, used any new medications, or changed concomitant medication regimens (including prescription drugs, over-the-counter medications, vitamins, herbal products, and minerals). Responses should be recorded in the source documents. In addition to patient observations, AEs must be documented for any clinically significant diagnosis resulting from abnormal laboratory test values, physical examination findings, or ECG abnormalities, or from other documents that are relevant to patient safety. Assessment of Causality Attorney Docket No.16036.0005-00304 Ref. No.
  • NKT-24-007PCT The investigator must use the following classifications and criteria to characterize the relationship or association of the study drug in causing or contributing to the AE: Unrelated: This relationship suggests that there is no association between the study drug and the reported event. Unlikely: This relationship suggests that the temporal sequence of the event with study drug administration makes a causal relationship improbable and/or other factors also provide plausible explanations. Possible: This relationship suggests that treatment with the study drug caused or contributed to the AE. That is, the event follows a reasonable temporal sequence from the time of study drug administration, and/or, follows a known response pattern to the study drug, but could have been produced by other factors.
  • NKT-24-007PCT abnormal laboratory test values or ECG findings are the result of pathology for which there is an overall diagnosis (e.g., increased creatinine levels in renal failure), only the diagnosis should be reported as an AE.
  • Elective procedures surgeries or therapies
  • These elective procedures should not be recorded as AEs but should be documented in the patient’s source documents as elective (e.g., elective periodontal surgery).
  • a pre-planned procedure is performed early (e.g., as an emergency) because of a worsening of the pre-existing condition, the worsening of the condition should be captured as an AE.
  • the Investigator must update the SAE form electronically in the EDC system for the study and submit any supporting documentation (e.g., patient discharge summary or autopsy reports) to Medpace Clinical Safety via fax or e-mail.
  • Expedited Reporting Regulatory agencies will be notified of any fatal or life-threatening unexpected events associated with the use of the study drug as soon as possible but no later than 7 calendar days after the initial receipt of the information. Initial notification will be followed by a written report within the timeframe established by the appropriate regulatory agency.
  • Pregnancy Female patients of child-bearing potential are defined as patients who are not surgically sterile (no history of bilateral tubal ligation, hysterectomy, or bilateral salpingo-oophorectomy), do not have fallopian inserts with confirmed blockage, have not had reproductive potential terminated by radiation, and have not been postmenopausal for at least 1 year.
  • the investigator must immediately report a pregnancy associated with study drug exposure and record the event.
  • the protocol- required early termination procedures noted in Table 3 and Table 4 must be performed. Other appropriate follow-up procedures should be considered if indicated.
  • Pregnancy is not considered an AE or SAE; however, it must be reported to Medpace Clinical Safety within 24 hours of knowledge of the event. Medpace Clinical Safety will then provide the Investigator/site the Exposure In Utero (EIU) form for completion.
  • EIU Exposure In Utero
  • the Investigator/site must complete the EIU form and fax/email it back to Medpace Clinical Safety.
  • the investigator must follow a pregnant patient, or the pregnant female partner of a male patient (if consenting), and report follow-up information regarding the course of the pregnancy as described above, including perinatal and neonatal outcome.
  • the sample size for Phase 1 of this study is based on the need to establish the MTD and/or the RDEs of Compound (I) Form A as a monotherapy.
  • the sample size for the dose escalation cohorts in Phase 1 are based on a standard 3+3 design for determining the MTD/RDEs. It is anticipated that up to 61 patients may be enrolled in Phase 1.
  • a total of 40 evaluable patients with no prior treatment with a HIF2 ⁇ inhibitor will be randomized in a 1:1 fashion to two dose levels of Compound (I) Form A; 20 in each arm will be enrolled in the Phase 2 portion of the study investigating Compound (I) Form A at the selected RDE-w and RDE-d.
  • approximately 10 patients who have had prior treatment with the HIF2 ⁇ inhibitor belzutifan will be enrolled to evaluate the safety, PK, PD, and preliminary anti-tumor activity in this population at RDE-d as described in sub-study 3.
  • the sample size required of this study is based on the need to establish the MTD and/or the RDEs of Compound (I) Form A during Phase 1 and to assess preliminary anti-tumor activity and ongoing safety assessment during the Phase 2 at the selected RDEs.
  • Analysis Populations The following analysis populations are defined. ⁇ The All Patients analysis set consists of all patients who have been enrolled. This is the population of primary interest for the summaries of disposition. ⁇ The Safety analysis set consists of all patients who receive at least 1 dose of Compound (I) Form A. This is the population of primary interest for the summaries of the safety data. Attorney Docket No.16036.0005-00304 Ref. No.
  • the Efficacy analysis set consists of all patients who receive at least one dose of Compound (I) Form A and have at least one post-baseline tumor assessment or who discontinue from the study treatment prior to their first post-baseline assessment due to death or documented disease progression. This is the population of primary interest for the summaries and analyses of the efficacy and PD data.
  • the PK analysis set consists of all patients who receive at least 1 dose of Compound (I) Form A and have evaluable PK data (at least one PK parameter can be calculated). This is the population used for the PK analyses.
  • Statistical Analyses All statistical analyses and data summaries will be performed using SAS ® (version 9.3 or higher).
  • PK analyses will be performed with Phoenix ® WinNonlin ® software. Inferential statistical methodology will not be employed in any of the data analyses.
  • data will be summarized using descriptive statistics. Continuous data will be summarized with number of patients (n), arithmetic mean, standard deviation, median, minimum, and maximum. Additionally, geometric mean and coefficient of variation will be included where applicable in PK analyses. Categorical data will be summarized using frequency counts and percentages. Time-to-event endpoints will be reported using Kaplan-Meier estimates, along with 95% confidence intervals (CIs) for median time to event. Patients who receive a particular dosage level of Compound (I) Form A will be summarized according to the dose cohort of original assignment, regardless of the dose actually received.
  • CIs 95% confidence intervals
  • Exposure Duration of treatment defined as date of last dose of Compound (I) Form A minus date of first dose plus 1, total dose of Compound (I) Form A (mg), and dose intensity (mg/day), defined as total dose divided by the number of days of dosing, will be summarized.
  • Adverse Events Adverse event incidence will be coded using Medical Dictionary for Regulatory Activities (MedDRA) terminology and classified according to system organ class (SOC) and preferred term (PT). Adverse event severity will be graded according to NCI CTCAE version 5.0 or later. (https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_ Reference_5x7.pdf).
  • a treatment-emergent AE is defined as an AE with onset on or after the first dose of study drug (or that worsened from prior to the first dose of study drug).
  • NKT-24-007PCT The number and percentage of patients experiencing 1 or more AEs will be summarized for the following classifications: ⁇ TEAEs by SOC and PT ⁇ TEAEs by SOC, PT and maximum toxicity grade ⁇ Compound (I) Form A-related TEAEs by SOC and PT ⁇ Compound (I) Form A-related TEAEs by SOC, PT and maximum toxicity grade ⁇ TEAEs leading to treatment discontinuation by SOC and PT ⁇ TEAEs resulting in dose modifications by SOC and PT ⁇ CTCAE Grade ⁇ 3 TEAEs by SOC and PT ⁇ Fatal TEAEs by SOC and PT ⁇ SAEs by SOC and PT ⁇ Compound (I) Form A-related SAEs by SOC and PT Dose-limiting toxicities will be listed.
  • Clinical Laboratory Data Values and change from baseline for hematology, chemistry, and coagulation laboratory parameters will be summarized by visit.
  • Laboratory test values that are graded by CTCAE will be summarized using shift tables comparing the baseline grade to the maximum CTCAE grade after baseline.
  • Other Safety Data Vital sign measurements and change from baseline will be summarized by visit.
  • ECG data and change from baseline will be summarized by visit.
  • Physical examination data will be listed without summary. Echo results will be listed.
  • Absolute scores of the EORTC-QLQ-C30 and the change from baseline will be summarized by visit. Additional concentration-QTc analysis may be conducted.
  • Efficacy Analyses Response Assessment Categories Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Tumor response will be evaluated by the investigator using RECIST 1.1.
  • the post- baseline time point assessment response categories are as follows. ⁇ Complete Response (CR) ⁇ Partial Response (PR) ⁇ Stable Disease (SD) ⁇ Progressive Disease (PD) ⁇ Not Evaluable (NE) Efficacy Endpoints The following efficacy endpoints will be derived from the time point response assessments.
  • ⁇ Best overall response (BOR) is defined as the best confirmed response recorded up until documentation of disease progression or death from any cause, or until the patient withdraws consent.
  • ⁇ ORR is defined at the percentage of patients whose BOR is CR or PR.
  • CBR Clinical benefit rate
  • DOR Duration of response
  • PFS Progression-free survival
  • BOR, ORR, and CBR will be summarized as the number and percentage of patients satisfying the definitions above.
  • a two-sided 95% CI will be calculated for ORR and CBR.
  • DOR, PFS, and OS will be summarized descriptively using the Kaplan-Meier method.
  • Two-sided 95% CIs will be calculated for the median and the 25 th and 75 th percentiles.
  • OS will also be summarized for patients who receive at least 1 dose of Compound (I) Form A.
  • TTR will be summarized descriptively.
  • Pharmacokinetic Analyses The PK parameters will be computed from the individual plasma concentrations using a noncompartmental approach in Phase 1 Dose Escalation.
  • Pharmacokinetic parameters including area under the curve from 0 to last measurable concentration (AUC 0–t ), area under the curve over a dose interval (AUC 0-tau ), maximum concentration (Cmax), tmax, and accumulation ratio (RAC) will be determined for Compound (I) Form A, if data allow.
  • Each PK parameter will be summarized using n, arithmetic mean, standard deviation, minimum, median, maximum, and coefficient of variation for each dose level, pooling the patients from Phase 1 who receive the MTD/RDEs with the patients in Phase 2. Additionally, geometric means will be reported for AUC0-t, AUC0-tau and Cmax parameters. PK parameters will be summarized by cohort or dosage.
  • Plots of mean concentration of plasma Compound (I) versus time will be generated for each dose group in a linear and semi-log fashion. Individual concentration versus time graphs will also be provided. Comparisons across dose levels will be made to descriptively assess dose proportionality using AUC0-t and/or AUC0-tau, and Cmax if data allow.
  • Food effect on Compound (I) Form A PK, effect of Compound (I) Form A on oral midazolam PK, and exploratory metabolite profiling will be conducted in sub-studies 1 and 2. For Phase 2 Expansion, limited PK samples will be collected (Table 5). Additional population PK analysis may be conducted to characterize the PK and covariates that affect the PK. The analysis may be reported separately.
  • Pharmacodynamic Analyses Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Value and percentage change from baseline will be summarized at each collection timepoint.
  • the PD parameters of interest in blood and tissue samples are EPO and other markers of the HIF pathway and ccRCC.
  • the correlation between plasma concentrations of Compound (I) and the changes of PD biomarkers from baseline will be described. Additional exploratory PK/PD modeling may be conducted and reported separately. Analysis Time Points Final Analysis The final analysis of the study is planned to occur when the database is locked.
  • the SRC will meet to review AEs and laboratory toxicities for the dose cohort being studied to determine if escalation to the next higher dose cohort is warranted.
  • the SRC will review the accumulating toxicity information and may pause or terminate the study in the event of an unfavorable risk/benefit profile.
  • Ongoing review of safety data in Phase 1 and Phase 2 will also be reviewed for late- emerging toxicity at intervals of approximately 4 months, and more frequently if necessary.
  • the SRC may recommend protocol amendments to maintain patient safety at any time.
  • any serious adverse events (SAEs) will be forwarded to the SRC upon occurrence.
  • a study monitor will contact and visit the site regularly and will be allowed, on request at a mutually acceptable time, to inspect the various original medical records (paper or electronic) Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT related to the study.
  • the study monitor will be responsible for inspecting the case report forms at regular intervals throughout the study, to verify the adherence to the protocol, and the completeness and correctness of all case report form entries.
  • the investigator agrees to cooperate with the study monitor to ensure that any problems detected in the course of these monitoring visits are resolved.
  • Audits and Inspections Principal investigators and institutions involved in the study will permit study-related monitoring, audits, and IRB review, and regulatory inspection(s), by providing direct access to all study records.
  • the principal investigator agrees to allow the sponsor, representatives of the sponsor, the FDA, or other relevant regulatory authorities access to all study records.
  • the principal investigator or designee should promptly notify the sponsor or designee of any audits scheduled by any regulatory authorities and promptly forward copies of any audit reports received to the sponsor or designee.
  • Quality Control and Quality Assurance Quality Assurance To ensure compliance with GCP and all applicable regulatory requirements, a quality assurance audit may be conducted. Please see below for more details regarding the audit process.
  • Financial Disclosure Principal investigators and sub-investigators are required to provide financial disclosure information before starting the study.
  • the principal investigator and sub-investigators must provide the sponsor or designee with updated information, if any relevant changes occur during the course of the investigation and for 1 year after the completion of the study.
  • NKT-24-007PCT Investigator Documentation Before beginning the study, the principal investigator will be asked to comply with International Council for Harmonisation (ICH) E6(R1) 8.2 and Title 21 of the Code of Federal Regulations (CFR) by providing the essential documents to the sponsor or designee, which include but are not limited to the following.
  • ICH International Council for Harmonisation
  • CFR Code of Federal Regulations
  • curricula vitae and current licensure must be provided.
  • the curricula vitae must have been signed and dated by the principal investigator and sub-investigators within 2 years before study start-up to indicate the documents are accurate and current.
  • Completed financial disclosure forms (see below) to allow the sponsor or designee to submit complete and accurate certification or disclosure statements required under US Title 21 CFR 54.
  • the investigators must provide to the sponsor or designee a commitment to update this information promptly if any relevant changes occur during the course of the investigation and for 1 year after the completion of the study.
  • the protocol and the proposed informed consent form must be reviewed and approved by a properly constituted IRB before study start.
  • Each investigator must provide the sponsor or its designee a signed and dated statement that the protocol and informed consent have been approved by the IRB before consenting patients.
  • the investigator Before study initiation, the investigator is required to sign a protocol signature page confirming agreement to conduct the study in accordance with this protocol and to give access to all relevant data and records to the sponsor, its designee, and regulatory authorities as required.
  • the IRB chairperson or designee must sign all IRB approvals and must identify the IRB by name and address, the clinical protocol, and the date approval and/or favorable opinion was granted.
  • the principal investigator is responsible for obtaining reviews of the clinical research at intervals specified by the IRB, but not exceeding 1 year.
  • the principal investigator must supply the sponsor or designee with written documentation of reviews of the clinical research.
  • Ethical Conduct of the Study This clinical study was designed and shall be implemented and reported in accordance with the ICH Harmonised Tripartite Guidelines for Good Clinical Practice, with applicable local regulations (e.g., US Code of Federal Regulations Title 21), and with the ethical principles in the Declaration of Helsinki.
  • the principal investigator must conduct all aspects of this study in accordance with all national, state, and local laws or regulations.
  • a signed informed consent form in compliance with Title 21 of the United States CFR Part 50, will be obtained from each patient before the patient enters the study.
  • An informed consent template may be provided by the sponsor or designee to the investigators. The consent must be reviewed by the sponsor or designee before IRB submission. Once reviewed, the consent will be submitted by the principal investigator to his or her IRB for review and must be approved Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT before a patient enters the study. If the informed consent form is revised during the course of the study, all participants affected by the revision must sign the revised IRB-approved consent form.
  • each prospective patient Before enrollment, each prospective patient will be given a full explanation of the study and be allowed to read the approved informed consent form. Once the principal investigator or designee is assured that the patient understands the implications of participating in the study, the patient will be asked to give consent to participate in the study by signing the informed consent form. Eligible patients may only be included in the study after providing written (witnessed, where required by law or regulation), IRB-approved informed consent. Informed consent must be obtained before conducting any study-specific procedures (i.e., any procedure described in the protocol). The process of obtaining informed consent must be documented in the patient source documents.
  • Any changes to the proposed consent form suggested by the investigator must be agreed to by the sponsor before submission to the IRB, and a copy of the approved version and the notice of approval must be provided to the sponsor’s designated monitor after IRB approval.
  • the principal investigator or designee will provide a copy of the informed consent form (signed copy to be provided per applicable law) to the patient and/or legal guardian.
  • the original form will be maintained in the patient’s medical records at the site. Confidentiality All laboratory specimens, evaluation forms, reports, and other records will be identified in a manner designed to maintain patient confidentiality. All records will be kept in a secure storage area with limited access.
  • the changes will become effective only after approval of the sponsor, the principal investigator, and the IRB.
  • changes may be implemented, and the amendment must be immediately submitted to the IRB.
  • the principal investigator is responsible for informing the IRB of all problems involving risks to patients according to national legislation.
  • the sponsor will immediately notify FDA in accordance with 21 CFR 312.32. Protocol Deviations
  • the principal investigator or designee must document any protocol deviation.
  • the IRB must be notified of all protocol deviations in a timely manner by the investigator as appropriate. Protocol deviations will be documented by the responsible monitor during monitoring visits, and those observations will be communicated to the investigator. If there is an immediate hazard to a patient, the principal investigator may deviate from the protocol without prior sponsor and IRB approval.
  • evaluable plasma Compound (I) Form A PK data was obtained from 81 patients (79 evaluable) at 8 dosages tested including 50, 100, 200, and 300 mg QD, 100 mg QD ⁇ 7 days then 100 mg QW, 200 mg QD ⁇ 7 days then 200 mg QW, 200 mg QD ⁇ 14 days then 50 mg QD, and 200 mg QD ⁇ 28 days then 50 mg QD.
  • the mean (SE) PK profiles of Compound (I) Form A by dosage are presented in Figs.1A and 1B. In the QD cohorts, plasma Compound (I) Form A concentration continued to accumulate before dose modifications, and no apparent steady-state PK was observed.
  • PK of Compound (I) was characterized following single and multiple oral doses in 83 patients with advanced ccRCC with various dosing regimens in the Dose Escalation phase, including continuous QD dosing and regimens with loading and maintenance doses as summarized in Table 18.
  • the PK parameter estimates are summarized in Table 19.
  • the model parameters were estimated with acceptable precision (RSE ⁇ 34%).
  • the between-subject variability had low shrinkage ( ⁇ 18%).
  • the typical PK parameter values for absorption rate constant (Ka), apparent clearance (CL/F), intercompartment clearance (Q/F), and central (Vc/F) and peripheral volume (Vp/F) of distribution were 0.684 h -1 , 0.512 L/h, 24.4 L/h, 153 L, and 624 L, respectively.
  • the estimated apparent clearance (CL/F) and apparent steady-state volume of distribution (Vss/F) were 0.512 L/h and 777 L, respectively.
  • the model-estimated median terminal t 1/2 was 38 days. Between- patient variability was moderate on CL/F (49%), Vc/F (37%), Vp/F (34%), and Ka (81%).
  • the modeling analysis suggested no time- or concentration-dependent PK nonlinearity. The high accumulation following continuous daily dosing and the model-estimated long t 1/2 were likely due to slow elimination and large distribution volume.
  • V c,i V c,typical x (WT/91) ⁇ THETA
  • V c,i the estimated V c for subject i
  • V c,typical the model estimated among patients in the input Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT
  • Compound (I) Form A had dose-linear and time-dependent PK levels. Slow elimination of Compound (I) was evidenced by its continuous accumulation following QD dosing. Therefore, in subsequent cohorts, various regimens with sequential loading and maintenance dosing schedules were tested. Such regimens were designed to rapidly achieve and maintain certain Compound (I) exposure levels in plasma.
  • the model adequately described the EPO inhibition at different dosages and the model-estimated IC50 and Imax were 63.2 ng/mL and 75.0%, respectively.
  • the PD model parameter values are summarized in Table 20.
  • Table 20 Summary of the Erythropoietin Pharmacodynamic Parameters in the Population PKPD Model Parameter Units Estimate RSE (%) Shrinkage (%) Attorney Docket No.16036.0005-00304 Ref. No.
  • E 0 baseline EPO level
  • K out EPO elimination rate constant
  • IC 50 concentration for 50% inhibition
  • Imax maximal fractional inhibition of EPO production rate
  • OMEGA between-subject variability with assumed log-normal distribution
  • Sigma within-subject additive variability with assumed normal distribution.
  • the PPK model-simulated median (90% confidence interval) plasma Compound (I) concentration-time profiles for the 5 dosages with loading and maintenance dosing regimens are presented in Fig.9.
  • the model-estimated Compound (I) concentrations are summarized in Table 21. All these dosage levels are expected to have clinically significant EPO suppression based on the model estimated IC50 of 63.2 ng/mL.
  • RDE recommended dosage for expansion
  • RDE-high 200 mg QD x 14 then 50 mg QD.
  • Simulated typical PK profiles for tested dosages are presented in Fig.9, and simulated typical PK profiles for additional dosages of clinical interest are presented in Fig.10, Fig.11, and Fig.12.
  • Table 21 Population PK Model-estimated Concentrations for Selected Dosages with Sequential Loading and Maintenance Dosing Regimens
  • C min , C max after the 1st C min , C max in Week 16 These maintenance dosing schedules are proposed based on the thorough characterization of Compound (I) Form A PK following various dosing schedules assessed in the study and Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT integrated PPK analysis.
  • These dosages with long maintenance dosing intervals offer additional dosing convenience, less intestinal drug-drug interaction risks, and clinically meaningful Cmax and C trough ranges.
  • the estimated C max and C trough are summarized in Table 22.
  • the concentration fluctuation remains low, with Cmax/Ctrough ratio of 1.4, 1.9, 2.5, and 3.1 for QW, Q2W, Q3W, and Q4W, respectively.
  • Table 22 Summary of Steady-state C trough and C max (ng/mL) Estimated Using Population PK Model Simulation for different maintenance dosing regimens following 100 mg QD x 7 days Maintenance dose Q4W Q3W Q2W QW (RDE- l w) ; e e y ee s, e e y ee s; - o o e eco e e osage o pa s o
  • the loading dosing schedule can also be varied as shown in Fig.13, including 50 mg QD x 7, 100 mg QD x 7, 200 mg QD x 7, 200 mg QD x 14, and 200 mg QD x 28.
  • Such different loading dosing schedules allow achieving different concentrations quickly but don’t change the steady-state PK during maintenance treatment.
  • the dose can be split over a few days. Splitting a maintenance dose into a few daily doses allows: a) higher total dose per maintenance treatment cycle; and b) lower Cmax /Ctrough ratio compared with a single dose for the same total Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT maintenance dose per cycle.
  • maintenance dose splitting into 2, 4, and 7 daily doses for each 28-day maintenance cycle are simulated as shown in Fig.14, Fig.15, and Fig.16, respectively.
  • Compound (I) Form A showed dose-linear and time-dependent PK. Slow elimination of Compound (I) was evidenced by its continuous accumulation following QD dosing with an estimated elimination t1/2 of 38 days. Therefore, different loading and maintenance dosing regimens were tested to achieve and maintain certain plasma concentration levels.
  • a PPK-PD model was developed and used to simulate for additional dosing regimens, including maintenance regimens with longer dosing intervals and split maintenance dose over a few days in each maintenance treatment cycles.
  • the simulations offer visualization of example dosages that can be safe and efficacious and are of interest for further clinical investigation. These example dosages are based on combination of different dose levels, duration of loading phase, maintenance dosing cycle length, number of doses in each maintenance cycle. Such combinations include reasonable interpolation and extrapolation of dosing designs based on available Compound (I) Form A formulations and Attorney Docket No.16036.0005-00304 Ref. No.
  • NKT-24-007PCT clinical need, especially by considering dosing schedule of combination drugs to further optimize target inhibition, minimize drug-drug interactions, and practical convenience, etc. Selection of Recommended Dosages of Compound (I) Form A for Monotherapy Expansion Due to PK data demonstrating very slow elimination, sequential loading and maintenance dosing schedules were tested to achieve and maintain target exposure levels. Based on review of the overall safety, tolerability, PK, PD, and preliminary efficacy, two RDEs were endorsed by the SRC and selected for further evaluation in the randomized phase 2 expansion of the study: 200 mg QD ⁇ 14 days then 50 mg QD (RDE-d) and 100 mg QD ⁇ 7 days then 100 mg QW (RDE-w).
  • Compound (I) Form A inhibited VEGFA secretion in 786-O cells with IC90 of 201 ng/mL (assumed as 9 ⁇ IC50 after human plasma protein binding adjustment).
  • IC90 201 ng/mL
  • tumor growth inhibition was estimated using a PK-tumor growth inhibition model, and the human equivalent IC90 was 2070 ng/mL (assumed as 9 ⁇ IC50 after cross-species protein binding normalization).
  • NKT-24-007PCT In the preliminary food effect and drug-drug interaction (DDI) sub-study 1, ccRCC patients are being enrolled to receive Compound (I) Form A at 200 mg QD ⁇ 7 then 200 mg QW (8 of 12 patients enrolled as of 5 October 2023). Two oral doses of midazolam were administered on Day -3 and Day 15 with plasma samples collected for PK determination. Food effect was assessed on Day 1 when patients were assigned to take 200 mg Compound (I) Form A under fasting conditions or with a high-fat meal. Preliminary DDI results suggested that Compound (I) Form A is a moderate to strong CYP3A4 inducer at the RDEs. Available data is too limited for food effect assessment.
  • TEAEs Two Grade 5 (fatal) TEAEs were reported (disease progression and haemorrhage intracranial, both unrelated to NKT2152 treatment). Seven patients (8.4%) had a maximum TEAE severity of Grade 4: 2 patients had hypoxia, and the following were reported in 1 patient each: bronchial obstruction, pain in extremity, acute kidney injury, cardiac tamponade, mania, pneumonitis, respiratory failure, and urinary tract infection bacterial. All other TEAEs were ⁇ Grade 3. A summary of TEAEs reported in >10% of all patients are presented in Table 27. The most common TEAEs were anemia (58/83 patients, 69.9%) and fatigue (29/83 patients, 34.9%).
  • Treatment related TEAEs resulting in discontinuation include hypoxia in 4/83 patients (4.8%) and fatigue, pericardial effusion, cystoid macular oedema, and malaise in 1/83 patient each (1.2%).
  • Dose Reductions Due to Adverse Events Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT
  • Dose reductions due to TEAEs occurred in 6/83 patients (7.2%). All TEAEs resulting in dose reduction were deemed treatment related. Fatigue and hypoxia occurred in two patients each (2.4%). The following events occurred in one patient (1.2%) each: anemia, diarrhea, oedema peripheral, pericardial effusion, and vomiting.
  • Treatment Interruptions Due to Adverse Events Treatment interruptions due to TEAEs occurred in 39/83 patients (47.0%). Hypoxia, anemia, fatigue, and nausea were the most commonly reported TEAEs leading to treatment interruption. Hypoxia occurred in 12/83 patients (14.5%); anemia, fatigue, and nausea each occurred in 5/83 patients (6.02%). The majority of TEAEs that resulted in treatment interruption were related to Compound (I) Form A treatment in the opinion of the Investigator, Grade ⁇ 3, and non-serious. Serious Adverse Events and Deaths Serious TEAEs were reported in 28/83 patients (33.7%).
  • Serious TEAEs that were reported as at least possibly treatment related by the investigator occurred in 11/83 patients (13.3%); pericardial effusion and cardiac failure in 1 patient; hypoxia in 5 patients; pericardial effusion, hypoxia, and pleural effusion in 1 patient; cardiac tamponade, pneumonitis, and respiratory failure in 1 patients; optic neuritis in 1 patient; nausea in 1 patients; and fatigue and hypoxia in 1 patient.
  • Another 71-year-old white male patient expired from a serious TEAE of intracranial hemorrhage after over 12 months on treatment.
  • the patient received 4 lines of cancer treatment including nivolumab and ipilimumab.
  • the patient went to see an ophthalmologist due to blurred vision and was diagnosed with cataract with associated and expected cystoid macular edema.
  • increased eye pressure in right eye and new left eye pressure elevation were noted.
  • a fundus exam revealed bilateral cystoid macular edema, bilateral pigment epithelial detachments, and presumed bilateral low grade optic nerve edema.
  • the posterior view of the right-eye is inhibited by the dense cataract but features of retinopathy and optic neuropathy remain clear evident by an optical coherence tomography (OCT) imaging. Study treatment was discontinued.
  • OCT optical coherence tomography
  • the patient was treated with topical prednisone acetate ophthalmic drops and high dose systemic steroids with intravenous methylprednisolone and oral prednisone. Improvement was noted on study day 56, and the event of optic neuritis resolved on study day 66.
  • the investigator reported the events as related to study treatment.
  • the sponsor assessed the events as unrelated to the study treatment considering the previous multiple lines of immunotherapy with immune-mediated toxicities as class drug effects, unclear onset of the blurred vision due to lost follow up to eye care provider since cancer diagnosis, and baseline diabetes and blurred vision.
  • ESA erythropoietin stimulating agents
  • EPO product will be under the treating physician’s discretion in theAmerican Society of Clinical Oncology (ASCO) or institutional guidance.
  • ASCO American Society of Clinical Oncology
  • withholding Compound (I) Form A will be required. If an event resolves to Grade 2 within 12 weeks. Compound (I) Form A may be resumed with dosage reduction by one dose level; if not, Compound (I) Form A must be permanently discontinued. Fatigue Fatigue was reported in 29 (34.9%) patients in the trial. Patients participating in clinical studies of Compound (I) Form A will be monitored for fatigue. Withholding Compound (I) Form A is necessary when a Grade 3 event happens; re-starting at lower dosages may happen when the event resolves to Grade ⁇ 2 as per protocol.
  • hypoxia is an identified risk observed in patients treated with Compound (I) Form A and on the label of the marketed drug in the same class. Withholding Compound (I) Form A is recommended for Grade 2 and required for Grade ⁇ 3 hypoxia. Hypoxia management guidelines are provided in each protocol. In the trial, hypoxia was reported in 27.7% (23 out of 83) of participants, including 17 patients (20.5%) who experienced Grade 3 or worse. Hypoxia generally resolved with treatment including supplemental oxygen and/or dose modification. Patients participating in clinical studies of Compound (I) Form A will have frequent assessments of pulse oximetry as needed to monitor for hypoxia. Management of hypoxia should include treatment of any acute medical event and provision of supplemental oxygen as necessary.
  • Compound (I) Form A is a moderate to strong CYP3A4 inducer at the selected RDEs. Concomitant drugs that are sensitive CYP3A substrates should be avoided. In addition, CYP3A4 induction occurs via activation of nuclear PXR, which may result in co-induction of CYP2C8, CYP2C9 and CYP2C19. Compound (I) Form A may, therefore, also decrease the exposure of concomitant medications that are sensitive substrates of CYP2B6, CYP2C8, CYP2C9 or CYP2C19; however, the clinical relevance of these effects is not yet clear.
  • Compound (I) Form A is taken with sensitive substrates of these enzymes, additional monitoring of the concomitant medication’s effectiveness may be needed.
  • Compound (I) Form A may mildly inhibit liver CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3As at clinically relevant concentrations.
  • Compound (I) Form A may also inhibit CYP3As in the gut. Caution should be used if Compound (I) Form A is taken with sensitive substrates of CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3As.
  • Compound (I) Form A could potentially inhibit BCRP in the gut and MATE2-K in the kidney at clinically relevant dosages. No inhibition of other transporters is expected at clinically relevant clinical dosages. Examples of the above mentioned concomitant medicines can be found at the following website: https://www.fda.gov/drugs/drug-interactions-labeling/healthcare- professionals-fdas-examples-drugs-interact-cyp-enzymes-and-transporter-systems. Pregnancy, Contraception, and Related Requirements There are no data available regarding the potential effects of Compound (I) Form A; however, based on animal studies of related drugs on embryo and fetal development, Compound (I) Form A may cause fetal harm.
  • Compound (I) Form A is excreted in breast milk; therefore, nursing women will not be permitted to enroll in Compound (I) Form A clinical studies.
  • Compound (I) Form A is not considered to pose a genotoxic hazard to humans based on in vitro and in vivo studies. Embryo-fetal toxicity study has not been conducted.
  • Compound (I) Form A showed testicular degeneration and decreased luminal sperm counts at all dose levels in the GLP 28-day rat toxicology study, and prostate gland atrophy and seminiferous tubule degeneration at mid-and high-dose levels in the GLP 28-day dog Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT toxicology study. The effects on male reproductive tract are considered to be relevant human risks (see US FDA Guidance for Industry: Oncology Pharmaceuticals: Reproductive Toxicity Testing and Labeling Recommendations, 2019).
  • NKT-24-007PCT If required per local guidelines or regulations, locally recognized adequate methods of contraception may be described in the local trial documentation. Additional requirement: Regular pregnancy testing is required for female patients of childbearing potential during Compound (I) Form A treatment and up to 6 months after the last dose of Compound (I) Form A. Treatment should be discontinued immediately in any female patients found to have a positive pregnancy test while taking Compound (I) Form A. Male patients must not make semen donations during Compound (I) Form A treatment and for 6 months following the last dose of Compound (I) Form A. Overdose Three patients experienced accidental overdose, deviating from the assigned dose regimen. The patients took extra dose(s) during the weekly dosing period with no associated adverse events reported.
  • HIF-2 ⁇ is a validated target for Von Hippel-Lindau (VHL) disease with germline VHL mutations and clear cell renal cell carcinoma (ccRCC) with somatic VHL deficiency.
  • VHL Von Hippel-Lindau
  • ccRCC clear cell renal cell carcinoma
  • HIF-2 ⁇ is upregulated in solid tumors associated with hypoxia but has restricted normal tissue expression.
  • Compound (I) Form A inhibits transcription of HIF-2 ⁇ -regulated genes important for angiogenesis, glycolysis, and tumorigenesis.
  • the efficacy and safety of Compound (I) Form A in patients with ccRCC were tested in a Part 1 Dose Escalation (Phase 1) portion of the study and are being further tested in an ongoing Part 2 Dose Expansion (Phase 2) of the study.
  • Study Design Data is presented here from the Study described in Example 2 with a clinical cutoff date of 16 June 2024. The study design for the study is shown in Fig.17. Briefly, Compound (I) Form A was tested as a monotherapy against patients with ccRCC.
  • 113 patients were enrolled, including 60 in Dose Escalation. Patient demographics for this study are shown in Fig.18. Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Briefly, a total of 113 heavily pre-treated, high risk ccRCC patients were enrolled.
  • IMDC International Metastatic RCC Database Consortium
  • PK pharmacokinetic
  • PD pharmacodynamic
  • EPO pharmacodynamic
  • PK and EPO graphs are shown in Fig.19 and Fig.20, respectively.
  • Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Briefly, the PK profile of Compound (I) was dose-linear and time independent with an estimated median t 1/2 of 38 days based on a 2-compartmental population PK model. Significant and sustained EPO suppression was observed at all dose levels.
  • Compound (I) exhibited a maximal fractional inhibition of EPO production rate (I max ) of 72%; plasma concentration of Compound (I) for 50% maximal inhibition (IC50) was 16.4 ng/mL.
  • the PK/PD data supported loading and maintenance dosing regimens that quickly achieve and maintain therapeutic exposures.
  • Objective response rate (ORR) In total, 100 patients in the study were deemed efficacy evaluable. Of these 100 patients, 20% exhibited an objective response rate (ORR).
  • the response rate and confidence interval in a Forest plot are shown in Fig.21, and a summary of the response rate and confidence interval for all treated patients and Part I patients is shown in Table 29Error! Reference source not found..
  • ORR objective response rate
  • One patient (1.75%) exhibited a complete response (CR) to treatment
  • 14 patients (24.6%) exhibited a partial response (PR) to treatment
  • 28 patients (49.1%) exhibited stable disease (SD) despite Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT treatment
  • 14 patients (24.6%) exhibited progressive disease (PD) despite treatment.
  • Patients achieved an objective response if the best overall response of CR/PR was observed and confirmed by a follow-up imaging assessment by an investigator in accordance with RECIST 1.1 guidelines.
  • the ORR included patients who had at least one post-baseline tumor response assessment or discontinued treatment due to disease progression (including clinical progression) or death of any cause.
  • the SD category included one patient with an unconfirmed PR, and the PD category included clinical progression patients and deaths of any cause for those without post-baseline tumor assessment.
  • Sum of the longest diameter (SLD) Sum of the longest diameter (SLD) of target lesions were assessed in 95 efficacy- evaluable patients.
  • the percent change of lesion from baseline (Waterfall plot) by IMDC risk category is shown in Fig.22.
  • SLD change over time (Spider plot) by objective response is shown in Fig.23. Briefly, 5 patients were unevaluable.
  • the Disease Control Rate (the proportion of patients with a CR, a PR, or durable SD for 8+ weeks) as assessed by an investigator in accordance with RECIST 1.1 guidelines was 60% (95% confidence interval: 50%, 70%).
  • PFS Progression-free survival
  • Fig.24 A Kaplan-Meier curve of PFS in patients over time is shown in Fig.24, and the median PFS (95% confidence interval) in a Forest plot is shown in Fig.25. Briefly, the median PFS was 7.4 months and PFS rate at twelve months was 42%. Briefly, PFS ended at an earlier date of first PD (including clinical progression) prior to any new anti-cancer treatment or death of any cause and was censored at the date of last response assessment prior to any new anti-cancer treatment.
  • a first group 20 patients were treated with daily maintenance dosing (RDE-d): 200mg QD x 14 days, then 50 mg QD; and a second group of 20 patients were treated with weekly maintenance dosing (RDE-w): 100mg QD x 7 days, then 100mg QD.
  • RDE-d daily maintenance dosing
  • RDE-w weekly maintenance dosing
  • Table 30 The baseline demographics, efficacy, and safety results of this subgroup are summarized in Table 30.
  • patients who received Compound (I) Form A at RDE-w or RDE-d in the dose escalation were grouped.
  • Table 31 The baseline demographics, efficacy, and safety results of this subgroup are summarized in Table 31.
  • Table 30 Subgroup Analysis of Patients Who Received Compound (I) Form A at RDE-w and RDE-d RDE-d: 200 mg Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Prior VEGF TKI Received 28 (90%) 30 (91%) – n (%) ) ) ts who had prior belzutifan treatment at RDE-d. Attorney Docket No.16036.0005-00304 Ref. No.
  • NKT-24-007PCT Table 31 Subgroup Analysis of Patients Who Received Compound (I) Form A at RDE-w and RDE-d in Dose Escalation
  • RDE-w 100 mg QDx7/100
  • RDE-d 200 mg QDx14/50 mg QW mg QD
  • NKT-24-007PCT TTR median (min–max), 6.3 months (3.7 – 7.4) 3.7 months (3.7 – 5.5) months
  • the median follow-up time for patients receiving the RDE-w dose comprising 100 mg QD x 7 followed by 100 mg QW of Compound (I) Form A was 8.2 months, with an overall range of 0.23 – 20.9 months.
  • the median follow-up time for patients receiving the RDE-d dose comprising 200 mg QD x 14 followed by 50 mg QD of Compound (I) Form A was 9.1 months, with an overall range of 1.1-23.4 months.15 patients in the RDE-w patient population (50%) scored a 0 according to established Eastern Cooperative Oncology Group Performance Status (ECOG PS) criteria, 14 patients (47%) scored a 1, and 1 patient (3%) scored a 2.
  • EOG PS Eastern Cooperative Oncology Group Performance Status
  • NKT-24-007PCT patient population 9 patients (29%) received 1 prior line of therapy, 11 patients (35%) received 2 prior lines of therapy, 3 patients (10%) received 3 prior lines of therapy, and 8 patients (26%) received four or more prior lines of therapy.
  • RDE-d patient population 2 patients (6%) received 1 prior line of therapy, 11 patients (33%) received 2 prior lines of therapy, 9 patients (27%) received 3 prior lines of therapy, and 11 patients (34%) received four or more prior lines of therapy.
  • 28 patients (90%) received a prior VEGF tyrosine kinase inhibitor (TKI), and, in the RDE-d patient population, 30 patients (91%) received one.
  • TKI VEGF tyrosine kinase inhibitor
  • the median time to response (TTR) was 5.4 months, with a minimum of 3.7 months and a maximum of 7.4 months.
  • the median TTR was 3.7 months, with a minimum of 1.6 months and a maximum of 5.5 months.
  • the modified progression-free survival (mPFS) was 7.3 months, with an overall range of 3.7 to 10.6 months.
  • the mPFS was 12.6 months, with an overall range of 1.8 to 13.9 months.
  • the PFS at 12 months was 25%, with an overall range of 7% to 49%.
  • the PFS at 12 months was 55%, with an overall range of 34% to 72%.
  • the disease control rate (DCR) was 66.7%, with an overall range of 46.0% to 83.5%.
  • the DCR was 55.2%, with an overall range of 35.7% to 73.6%.
  • SAE serious adverse event
  • the median follow-up time for patients receiving the RDE-d dose in dose escalation comprising 200 mg QD x 14 followed by 50 mg QD of Compound (I) Form A was 20.5 months, with an overall range of 10.3-23.4 months.6 patients in the RDE-w patient population (60%) scored a 0 according to established ECOG PS criteria, 4 patients (40%) scored a 1, and 0 patients (0%) scored a 2.
  • the median TTR was 6.3 months, with a minimum of 3.7 months and a maximum of 7.4 months.
  • the median TTR was 3.7 months, with a minimum of 3.7 months and a maximum of 5.5 months.
  • the mPFS was 7.5 months, with an overall range of 2.0 to 12.7 months.
  • the mPFS was 13.6 months, with an overall range of 1.8 months to an upper limit of months that was not evaluable (“NE”).
  • the PFS at 12 months was 27%, with an overall range of 7% to 54%.
  • the PFS at 12 months was 74%, with an overall range of 39% to 91%.
  • the DCR was 81.8%, with an overall range of 48.2% to 97.7%.
  • the DCR was 75.0%, with an overall range of 42.8% to 94.5%.
  • Regarding safety in the RDE-w patient population, 36.4% experienced any SAE. In the RDE-d patient population, 41.7% experienced any SAE. In the RDE-w patient population, 18.2% experienced a TEAE leading to discontinuation of Compound (I) Form A. In the RDE-d patient population, 16.7% experienced a TEAE leading to discontinuation of Compound (I) Form A.

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Abstract

Disclosed herein are methods of treating cancer with a hypoxia inducible factor-2α (HIF-2α) inhibitor, 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile ((Compound (I)) having the structure:

Description

Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT 3-FLUORO-5-(((1S,2AR)-1,3,3,4,4-PENTAFLUORO-2A-HYDROXY-2,2A,3,4- TETRAHYDRO-1H-CYCLOPENTA[CD]INDEN-7-YL)OXY)- BENZONITRILE DOSING REGIMEN This application claims the benefit of priority of U.S. Provisional Application No. 63/642,703, filed on May 4, 2024, and U.S. Provisional Application No.63/692,084, filed on September 7, 2024, the contents of each are incorporated herein by reference in their entirety. Field of the disclosure Disclosed herein are methods of treating cancer with a hypoxia inducible factor-2α (HIF- 2α) inhibitor, 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H- cyclopenta[cd]inden-7-yl)oxy)benzonitrile (Compound (I)) having the structure: Compound (I) is also referred to as Background Compound (I) is being developed for treating diseases mediated by aberrant activity of HIF-2α including cancer, such as renal cancer, glioblastoma, neuroblastoma, pheochromocytomas and paragangliomas, somatostatinomas, hemangioblastomas, gastrointestinal stromal tumors (GIST), pituitary tumors, leiomyomas, leiomyosarcomas, polycythaemia, and retinal tumors and non-cancer diseases such as pulmonary artery hypertension (PAH), reflux esophagitis, hepatic steatosis, nonalcoholic steatohepatitis (NASH), inflammatory disease such as inflammatory bowel disease, autoimmune disease such as Graft-versus-Host-Disease, and iron overload. Compound (I) and a crystalline form of Compound (I), referred to as Compound (I) Form A, having an X-ray powder diffraction (XRPD) pattern comprising peaks at angular positions 15.8 and 18.6, wherein the angular positions may vary by + 0.2o 2θ as measured by X-ray powder diffraction using (Cu Kα) an X-ray wavelength of 1.5418 Å are disclosed in PCT Application Publication No. WO 2020/214853, filed on April 16, 2020, the entire content of which is incorporated herein by reference. Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Compound (I) Form A is currently in a Phase 1/2 open label dose-escalation and expansion trial (Study) in patients with clear cell renal cell carcinoma (ccRCC) as a monotherapy. Multiple oral doses of Compound (I) Form A, formulated as immediate-release capsules, are being used in the Study to evaluate the safety, tolerability, PK, PD, and anti-tumor activity. The Study consists of two parts or phases: Phase 1, to identify the maximum tolerated dose (MTD) and/or the recommended doses for expansion (RDEs) of Compound (I) Form A in patients with relapsed or refractory ccRCC, and Phase 2, to evaluate the antitumor activity of Compound (I) Form A by objective response rate (ORR) at the RDEs in patients with ccRCC and determine the recommended Phase 2 dose (RP2D). For any therapeutic agent, there is a need to identify a dosing regimen that maximizes its clinical benefits by optimizing its pharmacokinetic (PK) exposure and pharmacodynamic (PD) response while minimizing the adverse events. The methods disclosed herein fullfill this and related needs. Summary During the Study, it was discovered that Compound (I) exhibited slow elimination and high accumulation after 50 mg, 100 mg, 200 mg, or 300 mg once-a-day (QD) dosing of Compound (I) Form A. A PK steady state for Compound (I) was not observed on continuous QD dosing up to 83 days. See Fig.1A. Significant suppression of erythropoietin (EPO), a PD marker of HIF-2α inhibition, with quick onset was observed at all of the above dosage levels. See Fig.2A. Based on the above PK data, it was unexpectedly discovered that Compound (I) Form A could be administered at different sequential loading and maintenance dosing schedules to rapidly achieve and then maintain a potential therapeutic plasma level of Compound (I) in patients. The following loading and maintenance dosing schedules of Compound (I) Form A: (i) 100 mg QD ^ 7 days then 100 mg QW, (ii) 200 mg QD ^ 7 days then 200 mg QW, (iii) 200 mg QD ^ 14 days then 50 mg QD, and (iv) 200 mg QD ^ 28 days then 50 mg QD were evaluated in the above Study. A 2-compartmental population PK model with first-order oral absorption and first-order elimination was developed based on evaluable data available up to October 23, 2023 (n=79) from the above Study. The model described the PK data of Compound (I) after administration of both a single dose and multiple doses of Compound (I) Form A, as well as after dose reductions and dose holds. The PK parameter values for absorption rate constant (Ka), apparent total clearance (CL/F), apparent intercompartment clearance (Q/F), apparent volume of distribution of the central compartment (Vc/F), and apparent volume of distribution of the peripheral compartment (Vp/F) of Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT distribution of Compound (I) were, generally, 0.684 h-1, 0.512 L/h, 24.4 L/h, 153 L, and 624 L, respectively. Higher body weight appeared to correlate with higher Vc/F and Vp/F values but not CL/F. The model-estimated median terminal t1/2 of Compound (I) was 38 days. Between-patient variability was moderate on CL/F (49%), Vc/F (37%), Vp/F (34%), and Ka (81%). The PK modeling analysis suggested no time- or concentration-dependent PK nonlinearity. The high accumulation of Compound (I) following continuous once-daily dosing of Compound (I) Form A and the model-estimated long t1/2 were due to slow elimination and large distribution volume of Compound (I). Next, an indirect population PK-EPO response model was also developed based on the PK and EPO data of Compound (I) (n=79) from the Study. The EPO data was limited to < Week 5 to avoid confounding effects that resulted in EPO rebound. The EPO model had first-order EPO elimination and zero-order EPO production which was inhibited by Compound (I) after administration of Compound (I) Form A. The model described the EPO inhibition at different dosages, and the model-estimated IC50 and Imax of Compound (I) were 63.2 ng/mL and 75.0 %, respectively. See Fig.1B. Suppression of EPO with quick onset was observed at all above dosage levels. See Fig.2B. After administration of Compound (I) Form A, preliminary Compound (I) exposure- response analysis in efficacy and safety populations with evaluable PK data (n = 79) did not reveal clinically meaningful correlations for selected efficacy endpoints (such as ORR, target lesion size change, time to response). Within the observed exposure range, higher average concentrations of Compound (I) correlated with earlier and higher incidences of Grade ≥2 and Grade ≥3 anemia. The exposure-response analysis suggested that lower baseline hemoglobin and O2 saturation were associated with higher risks of anemia and hypoxia, respectively. Based on overall safety, tolerability, PK, PD, and preliminary efficacy data of Compound (I) above, and comparison of the PK exposures with clinically observed and simulated PK of 200 mg QD × 14 days then 50 mg QD and 100 mg QD × 7 days then 100 mg QW (see Fig.3), 200 mg QD × 14 days then 50 mg QD (also referred to herein as recommended dosage for dose expansion phase of the Study with daily maintenance doses or RDE-d) and 100 mg QD × 7 days then 100 mg QW (also referred to herein as recommended dosage for dose expansion phase of the Study with weekly maintenance doses or RDE-w) dosages of Compound (I) Form (A) were selected for evaluation in a randomized phase 2 expansion of the Study in ccRCC patients. In Fig. 3, the model estimated typical PK profiles of Compound (I) at RDE-w and RDE-d are overlaid with the concentration thresholds as labeled. Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Collectively, the available data and analysis continue to support the Dose Expansion study of Compound (I) Form A at RDE-w and RDE-d (a 3.5-fold difference in weekly maintenance dose). Since all the above tested dosage levels of Compound (I) Form A had significant and similar EPO suppression, dosage levels lower than RDE-w may be efficacious and allow better safety and tolerability, and/or reduce drug-drug interaction risks with Compound (I) as Compound (I) is a CYP3A4 inducer, especially in the gut. In parallel, the slow CL/F and long t1/2 of Compound (I) suggest that less frequent maintenance dosing schedules of Compound (I) Form A (e.g., Q2W, Q3W, or Q4W. In one embodiment Q2W or Q4W) may offer similar efficacy as maintenance QW or maintenance QD dosing, better safety and tolerability, and/or a reduction in drug-drug interaction risks with Compound (I) as a CYP3A4 inducer, especially in the gut. Accordingly, amongst the various aspects of the present disclosure, provided herein are dosing regimens for Compound (I) or Compound (I) Form A. In a first aspect, provided is a method of treating cancer comprising administering to a patient in need thereof: (a) a loading dose during a loading period, wherein each loading dose comprises from about 20 mg to about 300 mg of Compound (I) or Compound (I) Form A having an X-ray powder diffraction (XRPD) pattern comprising peaks at angular positions 15.8 and 18.6, wherein the angular positions may vary by + 0.2o 2θ as measured by X-ray powder diffraction using (Cu Kα) an X-ray wavelength of 1.5418 Å; and (b) a maintenance dose during a maintenance period, wherein each maintenance dose comprises less than or the same amount of the Compound (I) or Compound (I) Form A present in the loading dose in (a), provided that, when the amount of Compound (I) or Compound (I) Form A in the maintenance dose is the same as the loading dose in (a), the maintenance dose is administered to the patient less frequently than the loading dose is administered during the loading period. In a second aspect, provided is Compound (I) or Compound (I) Form A having an X-ray powder diffraction pattern comprising peaks at angular positions 15.8 and 18.6, wherein the angular positions may vary by + 0.2o 2θ as measured by X-ray powder diffraction using (Cu Kα) an X-ray wavelength of 1.5418 Å, for use in the manufacture of a medicament for the treatment of cancer in a patient which medicament is administered as: (a) a loading dose during a loading period, wherein each loading dose comprises from about 20 mg to about 300 mg of the Compound (I) or Compound (I) Form A; and Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT (b) a maintenance dose during a maintenance period, wherein each maintenance dose comprises less than or the same amount of the Compound (I) or Compound (I) Form A present in the loading dose in (a), provided that, when the amount of Compound (I) or Compound (I) Form A in the maintenance dose is the same as the loading dose in (a), the maintenance dose is administered to the patient less frequently than the loading dose is administered during the loading period. In a third aspect, provided is Compound (I) or Compound (I) Form A having an X-ray powder diffraction pattern comprising peaks at angular positions 15.8 and 18.6, wherein the angular positions may vary by + 0.2o 2θ as measured by X-ray powder diffraction using (Cu Kα) an X-ray wavelength of 1.5418 Å, for use in the the treatment of cancer comprising administering to a patient in need thereof: (a) a loading dose during a loading period, wherein each loading dose comprises from about 20 mg to about 300 mg of the Compound (I) or Compound (I) Form A; and (b) a maintenance dose during a maintenance period, wherein each maintenance dose comprises less than or the same amount of the Compound (I) or Compound (I) Form A present in the loading dose in (a), provided that, when the amount of Compound (I) or Compound (I) Form A in the maintenance dose is the same as the loading dose in (a), the maintenance dose is administered to the patient less frequently than the loading dose is administered during the loading period. In a fourth aspect, provided is a method of treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of a Compound (I) or Compound (I) Form A having an X-ray powder diffraction (XRPD) pattern comprising peaks at angular positions 15.8 and 18.6, wherein the angular positions may vary by + 0.2o 2θ as measured by X- ray powder diffraction using (Cu Kα) an X-ray wavelength of 1.5418 Å in a dosing regimen comprising: (a) administering a loading dose during a loading period, wherein each loading dose comprises the Compound (I) or Compound (I) Form A; and (b) administering a maintenance dose during a maintenance period, wherein each maintenance dose comprises less than or the same amount of Compound (I) or Compound (I) Form A present in the loading dose in (a), provided that, when the amount of Compound (I) or the Compound (I) Form A in the maintenance dose is the same as the loading dose in (a), the maintenance dose is administered to the patient less frequently than the loading dose is administered during the loading period. In a first subembodiment of the fourth aspect, the therapeutically effective amount of Compound (I) or Compound (I) Form A is the amount of Compound (I) or Compound (I) Form A Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT used in the dosing regimen that yields a median trough plasma concentration of Compound (I) (Ctrough) in the patient ofabout 936 ng/mL (with 90% prediction interval of 265 to 2220 ng/mL) and about 3460 ng/mL (with 90% prediction interval of 1170 to about 8120 ng/mL) at RDE-w and RDE-d, respectively, after the first maintenance dose is administered to the patient (for sake of clarity after the loading dosage and first maintaince dose are administered to the patient). In a second subembodiment of the fourth aspect, the therapeutically effective amount of Compound (I) or Compound (I) Form A is the amount of Compound (I) or Compound (I) Form A used in the dosing regimen that yields a weekly area under the plasma concentration-time curve (AUC0-168h) value of Compound (I) in the patient of about 177000 and about 624000 ng•hr/ml at RDE-w and RDE-d, respectively, for the first week of maintenance treatment (for sake of clarity after the loading dosage and RDE-w or RDE-d are administered to the patient). In a third subembodiment of the fourth aspect, the therapeutically effective amount of Compound (I) or Compound (I) Form A is the amount of Compound (I) or Compound (I) Form A used in the dosing regimen that yields a maximum plasma concentration (Cmax) of Compound (I) in the patient of about 1420 and about 3870 ng/ml at RDE-w and RDE-d, respectively, for the first week of maintenance treatment. In a fourth subembodiment of the fourth aspect, the therapeutically effective amount of Compound (I) or Compound (I) Form A is the amount of Compound (I) or Compound (I) Form A used in the dosing regimen that yields a minimum plasma concentration (Cmin) of Compound (I) in the patient of about 973 and about 3650 ng/ml at RDE-w and RDE-d, respectively, for the first week of maintenance treatment. Brief Description of the Drawings Figs.1A and 1B depict plots of mean (+SE) plasma Compound (I) concentration-time profiles by dosage on linear scale as of the 5 October 2023 analysis in Example 3. Fig.1A depicts cohorts with 50 mg, 100 mg, 200 mg, or 300 mg QD dosing schedules of Compound (I) Form A and Fig.1B depicts cohorts with sequential loading and maintenance treatments of Compound (I) Form A. Figs.2A and 2B depicts plot of mean (+SE) percent serum erythropoietin concentration change from baseline-time profiles by cohort as of the 5 October 2023 analysis in Example 3. Fig. 2A depicts cohorts with 50 mg, 100 mg, 200 mg, or 300 ng QD dosing schedules of Compound (I) Form A and Fig.2B depicts cohorts with sequential loading and maintenance treatments of Compound (I) Form A. Fig.3 depicts model-simulated typical PK profiles of Compound (I) at the proposed RDE- w and RDE-d dosages of Compound (I) Form A. Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Fig.4 depicts a representative XRPD diffractogram of Form A polymorph of 3-fluoro-5- (((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7- yl)oxy)-benzonitrile, Compound (I), crystallized from pentanol and hexane according to the method described in Example 25 in WO 2020/214853. Fig.5 depicts model-simulated typical PK profiles of Compound (I) at the depicted RDE- w and RDE-d dosages of Compound (I) Form A. Fig.6 depicts a Phase 2 Mono-expansion study design involving a first cohort administered a Compound (I) Form A dosage, a second cohort administered a RDE-w dosage of Compound (I) Form A, and a third cohort pre-treated with belzutifan. Fig.7 depicts a study design, wherein patients are administered a regimen comprising 200 mg QD x 7 days of Compound (I) Form A (W1D1 to W1D7) followed by 200 mg QW of Compound (I) Form A starting at W2D1. Fig.8 depicts a study design, wherein patients are administered a regimen comprising 200 mg QD x 14 days of Compound (I) Form A (W1 and W2) followed by 50 mg QD of Compound (I) Form A starting at W3. Fig.9 depicts a population PK model comprising simulated PK profiles of Compound (I) for dosages with sequential loading and maintenance dosing regimens of Compound (I) Form A. Fig.10 depicts simulated Compound (I) PK profiles for Q4W maintenance treatments of 100 mg, 200 mg, and 300 mg of Compound (I) Form A compared to 100 mg QW of Compound (I) Form A following loading doses of 100 mg QD x 7 of Compound (I) Form A. Fig.11 depicts simulated Compound (I) PK profiles for Q3W maintenance treatments of 50 mg, 100 mg, 200 mg, and 300 mg of Compound (I) Form A compared to 100 mg QW of Compound (I) Form A following loading doses of 100 mg QD x 7 of Compound (I) Form A. Fig.12 depicts simulated Compound (I) PK profiles for Q2W maintenance treatments of 50 mg, 100 mg, 200 mg, and 300 mg of Compound (I) Form A compared to 100 mg QW of Compound (I) Form A following loading doses of 100 mg QD x 7 of Compound (I) Form A. Fig.13 depicts simulated PK profiles for tested Compound (I) Form A dosages. Fig.14 depicts simulated Compound (I) PK profiles for 2 days-on/26 days-off maintenance treatments of Compound (I) Form A compared to 100 mg QW following loading doses of 100 mg QD x 7 of Compound (I) Form A. Fig.15 depicts simulated Compound (I) PK profiles for 4 days-on/24 days-off maintenance treatments of Compound (I) Form A compared to 100 mg QW following loading doses of 100 mg QD x 7 of Compound (I) Form A. Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Fig.16 depicts simulated Compound (I) PK profiles for 7 days-on/21 days-off maintenance treatments of Compound (I) Form A compared to 100 mg QW following loading doses of 100 mg QD x 7 of Compound (I) Form A. Fig.17 depicts the study design for the Compound (I) Form A Phase 1/2 open label dose- escalation and expansion trial. Fig.18 depicts the patient demographics for the Compound (I) Form A Phase 1/2 open label dose-escalation and expansion trial, as of the 16 June 2024 analysis in Example 4. Fig.19 depicts PK profiles of Compound (I) following treatment with Compound (I) Form A in the dose escalation portion of the Study, as of the 16 June 2024 analysis in Example 4. Fig.20 depicts EPO levels in patients treated with Compound (I) Form A in the dose escalation portion of the Study, as of the 16 June 2024 analysis in Example 4. Fig.21 depicts the response rate and confidence interval in various categories of patients treated with Compound (I) Form A in the dose escalation portion of the Study, as of the 16 June 2024 analysis in Example 4. Fig.22 depicts the number of target lesions in patients treated with Compound (I) Form A categorized by prognosis in the dose escalation portion of the Study, as of the 16 June 2024 analysis in Example 4. Fig.23 depicts the number of target lesions in patients treated with Compound (I) Form A categorized by objective response in the dose escalation portion of the Study, as of the 16 June 2024 analysis in Example 4. Fig.24 depicts time to disease progression or death of any cause in months in patients treated with Compound (I) Form A in the dose escalation portion of the Study, as of the 16 June 2024 analysis in Example 4. Fig.25 depicts the median progression-free survival (PFS) in months and confidence interval in various categories of patients treated with Compound (I) Form A in the dose escalation portion of the Study. Median and 95% confidence interval were estimated based on Loglog transformation and methods by Breslow, Brookmeyer, and Crowley, as of the 16 June 2024 analysis in Example 4. Fig.26 depicts adverse events reported by > 10% of patients treated with Compound (I) Form A in the dose escalation portion of the Study, as of the 16 June 2024 analysis in Example 4. Detailed Description Definitions: Unless otherwise stated, the following terms used in the specification and claims are defined for the purposes of this application and have the following meaning: Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT As used herein, “a” and “an,” mean one or more, unless the context clearly dictates otherwise. As used herein, “about” means + 10%, in one embodiment + 5% of listed value. For example, a reaction carried out at about 10 °C includes 9 °C and 11 °C, and all temperatures contained in between 9 °C and 11 °C. As used herein, “AUC” means area under the concentration-time curve and is the definite integral of the concentration of an administered compound (e.g, Compound (I)) found in blood plasma, after a dose is given, as a function of time, as measured using liquid chromatography– mass spectrometry. As used herein, “AUClast” means area under the concentration-time curve up to the last measurable concentration after a dose is given. As used herein, “Cmax” means the maximum (peak) concentration of an adminstered compound (e.g, Compound (I)) found in blood plasma, after a dose is given and reflects the rate and extent of absorption, as measured using liquid chromatography–mass spectrometry. As used herein, “Cmin” means the minimum concentration of an adminstered compound (e.g, Compound (I)) found in blood plasma, before a dose is given, as measured using liquid chromatography–mass spectrometry. As used herein, a “loading” dose is an initial dose of a drug (e.g., Compound (I) or Compound (I) Form A) that is given to a patient at the beginning of a course of treatment during the loading period before initiation of a maintenance dose of the drug. The loading dose can be administered QD, twice a day (BID), or three times a day (TID). As used herein, “loading period” means a number of days on which a loading dose is administered to a patient. As used herein a “maintenance” dose is a dose of a drug (e.g., Compound (I) or Compound (I) Form A) administered to maintain therapeutic drug concentrations after administration of a loading dosage. As used herein, “maintenance period” means a number of days on which a maintenance dose is administered to a patient. As used herein, “QD” means once a day e.g., 20 mg QD means 20 mg administered once a day, 30 mg QD means 30 mg administered once a day, etc. As used herein, “QW” means once a week e.g., 10 mg QW means 10 mg administered once a week, 20 mg QW means 20 mg administered once a week, 30 mg QW means 30 mg administered once a week, etc. As used herein, “Q2W” means once in two weeks e.g., 10 mg Q2W means 10 mg administered once in 2 weeks, 20 mg Q2W means 20 mg administered once in 2 weeks, 30 mg Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Q2W means 30 mg administered once in 2 weeks, etc. As used herein, “Q3W” means once in three weeks e.g., 10 mg Q3W means 10 mg administered once in 3 weeks, 20 mg Q3W means 20 mg administered once in 3 weeks, 30 mg Q3W means 30 mg administered once in 3 weeks, etc. As used herein, “Q4W” means once in four weeks e.g., 10 mg Q4W means 10 mg administered once in 4 weeks, 20 mg Q4W means 20 mg administered once in 4 weeks, 30 mg Q4W means 30 mg administered once in 4 weeks, etc. “XRPD” means X-ray powder diffraction, an analytical technique which measures the diffraction of X-rays in the present of a solid component. Materials which are crystalline and have regular repeating arrays of atoms generate a distinctive powder pattern. A “pharmaceutically acceptable carrier or excipient” means a carrier or an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier or an excipient that is acceptable for veterinary use as well as human pharmaceutical use. A “pharmaceutically acceptable carrier/excipient” as used in the specification and claims includes both one and more than one such excipient. The term “disease” as used herein is intended to be generally synonymous, and is used interchangeably with, the terms “disorder,” “syndrome,” and “condition” (as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms, and causes the human or animal to have a reduced duration or quality of life. The term “combination therapy” means the administration of two or more therapeutic agents to treat a disease described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein. The term “patient” is generally synonymous with the term “subject” and includes all mammals including humans. Examples of patients include humans, livestock such as cows, goats, sheep, pigs, and rabbits, and companion animals such as dogs, cats, rabbits, and horses. Preferably, the patient is a human. “Treating” or “treatment” of a disease includes: Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT (1) preventing the disease, i.e., causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease; (2) inhibiting the disease, i.e., arresting or reducing the development of the disease (i.e., stabilizing) or its clinical symptoms; or (3) relieving the disease, i.e., causing regression of the disease or its clinical symptoms. A “therapeutically effective amount” means the amount of Compound (I) or Compound (I) Form A that, when administered to a patient for treating a disease, is sufficient to affect such treatment for the disease. The “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the patient to be treated. For avoidance of doubt, all PK data presented herein relates to the observed Compound (I) concentration following administration of Compound (I) Form A. Embodiments: A1. Embodiment A1 provides a method of treating cancer as described in the first or fourth aspects of the Summary or a compound for use as described in the second or third aspects of the Summary. A2. Embodiment A2 comprises the method or use of embodiment A1, wherein the Compound (I) Form A X-ray powder diffraction pattern comprises peaks at angular positions 15.8, 18.6, and 20.1, wherein the angular positions may vary by + 0.2o 2θ. A3. Embodiment A3 comprises the method or use of embodiment A1, wherein the Compound (I) Form A X-ray powder diffraction pattern comprises peaks at angular positions 12.9, 15.8, 18.6, and 20.1, wherein the angular positions may vary by + 0.2o 2θ. A4. Embodiment A4 comprises the method or use of embodiment A1, wherein the Compound (I) Form A X-ray powder diffraction pattern comprises peaks at angular positions 11.4, 12.9, 15.8, 18.6, and 20.1, wherein the angular positions may vary by + 0.2o θ. A5. Embodiment A5 comprises the method or use of embodiment A1, wherein the Compound (I) Form A exhibits an X-ray powder diffraction pattern comprising at least one peak (in some embodiments at least two peaks, at least three peaks, at least four peaks, at least five peaks, at least six peaks, or at at least seven peaks) at angular positions shown in Table 1 below, in addition to peaks at angular positions 15.8, 18.6, wherein the angular positions may vary by + 0.2o θ. Table 1: Compound (I) Form A X-ray powder diffraction pattern Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Angle (2-Theta °) d value (Å) Intensity % 9.2 9.59 6.9 Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Angle (2-Theta °) d value (Å) Intensity % 30.6 2.92 3 A6. , herein the at least two, at least three, at least four, at least five, at least six, or at least seven peaks are selected from 10.1, 11.4, 12.9, 13.7, 19.6, 20.1, 21.4, 21.7, 25.0, and 26.0, wherein the angular positions may vary by + 0.2o 2θ. A7. Embodiment A7 comprises the method or use of embodiment A1, wherein the Compound (I) Form A X-ray powder diffraction pattern comprises peaks at angular positions substantially as shown in Fig.4. A8. Embodiment A8 comprises the method or use of any one of embodiments A1 to A7, wherein the angular positions of the X-ray diffraction peaks denoted therein may vary by + 0.1o 2θ. Loading Dose Embodiment A9 comprises the method or use of any one of embodiments A1 to A8, wherein the loading dose is from about 20 mg QD, 50 mg QD, about 100 mg QD, about 150 mg QD, about 200 mg QD, about 250 mg QD, or about 300 mg QD. A10. Embodiment A10 comprises the method or use of any one of embodiments A1 to A9, wherein the loading dose is about 50 mg QD. A11. Embodiment A11 comprises the method or use of any one of embodiments A1 to A10, wherein the loading dose is about 50 mg QD and is administered for 3, 4, or 5 consecutive days (for sake of clarity, when 50 mg QD of Compound (I) Form A is administered for 3 consecutive days or for 4 consecutive days, the loading period is 3 days and 4 days, respectively). Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT A12. Embodiment A12 comprises the method or use of any one of embodiments A1 to A10, wherein the loading dose is about 50 mg QD and is administered for 7 ± 1 consecutive days. In an embodiment of A12, the loading dose is about 50 mg QD and is administered for 7 consecutive days. A13. Embodiment A13 comprises the method or use of any one of embodiments A1 to A10, wherein the loading dose is about 50 mg QD and is administered for 14 ± 2 consecutive days. In an embodiment of A13, the loading dose is about 50 mg QD and is administered for 14 ± 1 consecutive days. In another embodiment of A13, the loading dose is about 50 mg QD and is administered for 14 consecutive days. A14. Embodiment A14 comprises the method or use of any one of embodiments A1 to A10, wherein the loading dose is about 50 mg QD and is administered for 28 ± 2 consecutive days. In an embodiment of A14, the loading dose is about 50 mg QD and is administered for 28 ± 1 consecutive days. In another embodiment of A14, the loading dose is about 50 mg QD and is administered for 28 consecutive days. A15. Embodiment A15 comprises the method or use of any one of embodiments A1 to A9, wherein the loading dose is about 100 mg QD. A16. Embodiment A16 comprises the method or use of any one of embodiments A1 to A9 and A15, wherein the loading dose is about 100 mg QD and is administered for 3, 4, or 5 consecutive days. A17. Embodiment A17 comprises the method or use of any one of embodiments A1 to A9 and A15, wherein the loading dose is about 100 mg QD and is administered for 7 ± 1 consecutive days. In an embodiment of A17, the loading dose is about 100 mg QD and is administered for 7 consecutive days. A18. Embodiment A18 comprises the method or use of any one of embodiments A1 to A9 and A15, wherein the loading dose is about 100 mg QD and is administered for 14 ± 2 consecutive days. In an embodiment of A18, the loading dose is about 100 mg QD and is administered for 14 ± 1 consecutive days. In another embodiment of A18, the loading dose is about 100 mg QD and is administered for 14 consecutive days. A19. Embodiment A19 comprises the method or use of any one of embodiments A1 to A9 and A15, wherein the loading dose is about 100 mg QD and is administered for 28 ± 2 consecutive days. In an embodiment of A19, the loading dose is about 100 mg QD and is administered for 28 ± 1 consecutive days. In another embodiment of A19, the loading dose is about 100 mg QD and is administered for 28 consecutive days. A20. Embodiment A20 comprises the method or use of any one of embodiments A1 to A9, wherein the loading dose is about 150 mg QD. Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT A21. Embodiment A21 comprises the method or use of any one of embodiments A1 to A9 and A20, wherein the loading dose is about 150 mg QD and is administered for 3, 4, or 5 consecutive days. A22. Embodiment A22 comprises the method or use of any one of embodiments A1 to A9 and A20, wherein the loading dose is about 150 mg QD and is administered for 7 ± 1 consecutive days. In an embodiment of A22, the loading dose is about 150 mg QD and is administered for 7 consecutive days. A23. Embodiment A23 comprises the method or use of any one of embodiments A1 to A9 and A20, wherein the loading dose is about 150 mg QD and is administered for 14 ± 2 consecutive days. In an embodiment of A23, the loading dose is about 150 mg QD and is administered for 14 ± 1 consecutive days. In another embodiment of A23, the loading dose is about 150 mg QD and is administered for 14 consecutive days. A24. Embodiment A24 comprises the method or use of any one of embodiments A1 to A9 and A20, wherein the loading dose is about 150 mg QD and is administered for 28 ± 2 consecutive days. In an embodiment of A24, the loading dose is about 150 mg QD and is administered for 28 ± 1 consecutive days. In another embodiment of A24, the loading dose is about 150 mg QD and is administered for 28 consecutive days. A25. Embodiment A25 comprises the method or use of any one of embodiments A1 to A9, wherein the loading dose is about 200 mg QD. A26. Embodiment A26 comprises the method or use of any one of embodiments A1 to A9 and A25, wherein the loading dose is about 200 mg QD and is administered for 3, 4, or 5 consecutive days. A27. Embodiment A27 comprises the method or use of any one of embodiments A1 to A9 and A25, wherein the loading dose is about 200 mg QD and is administered for 7 ± 1 consecutive days. In an embodiment of A27, the loading dose is about 200 mg QD and is administered for 7 consecutive days. A28. Embodiment A28 comprises the method or use of any one of embodiments A1 to A9 and A25, wherein the loading dose is about 200 mg QD and is administered for 14 ± 2 consecutive days. In an embodiment of A28, the loading dose is about 200 mg QD and is administered for 14 ± 1 consecutive days. In an embodiment of A28, the loading dose is about 200 mg QD and is administered for 14 consecutive days. A29. Embodiment A29 comprises the method or use of any one of embodiments A1 to A9 and A25, wherein the loading dose is about 200 mg QD and is administered for 28 ± 2 consecutive days. In an embodiment of A29, the loading dose is about 200 mg QD and is Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT administered for 28 ± 1 consecutive days. In another embodiment of A29, the loading dose is about 200 mg QD and is administered for 28 consecutive days. A30. Embodiment A30 comprises the method or use of any one of embodiments A1 to A9, wherein the the loading dose is about 250 mg QD. A31. Embodiment A31 comprises the method or use of any one of embodiments A1 to A9 and A30, wherein the loading dose is about 250 mg QD and is administered for 3, 4, or 5 consecutive days. A32. Embodiment A32 comprises the method or use of any one of embodiments A1 to A9 and A30, wherein the loading dose is about 250 mg QD and is administered for 7 ± 1 consecutive days. In an embodiment of A32, the loading dose is about 250 mg QD and is administered for 7 consecutive days. A33. Embodiment A33 comprises the method or use of any one of embodiments A1 to A9 and A30, wherein the loading dose is about 250 mg QD and is administered for 14 ± 2 consecutive days. In an embodiment of A33, the loading dose is about 250 mg QD and is administered for 14 ± 1 consecutive days. In an embodiment of A33, the loading dose is about 250 mg QD and is administered for 14 consecutive days. A34. Embodiment A34 comprises the method or use of any one of embodiments A1 to A9 and A30. wherein the loading dose is about 250 mg QD and is administered for 28 ± 2 consecutive days. In an embodiment of A34, the loading dose is about 250 mg QD and is administered for 28 ± 1 consecutive days. In an embodiment of A34, the loading dose is about 250 mg QD and is administered for 28 consecutive days. A35. Embodiment A35 comprises the method or use of any one of embodiments A1 to A9, wherein the loading dose is about 300 mg QD. A36. Embodiment A36 comprises the method or use of any one of embodiments A1 to A9 and, wherein the loading dose is about 300 mg QD and is administered for 3, 4, or 5 consecutive days. A37. Embodiment A37 comprises the method or use of any one of embodiments A1 to A9 and A35, wherein the loading dose is about 300 mg QD and is administered for 7 ± 1 consecutive days. In an embodiment of A37, the loading dose is about 300 mg QD and is administered for 7 consecutive days. A38. Embodiment A38 comprises the method or use of any one of embodiments A1 to A9 and A35, wherein the loading dose is about 300 mg QD and is administered for 14 ± 2 consecutive days. In an embodiment of A38, the loading dose is about 300 mg QD and is administered for 14 ± 1 consecutive days. In an embodiment of A38, the loading dose is about 300 mg QD and is administered for 14 consecutive days. Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT A39. Embodiment A39 comprises the method or use of any one of embodiments A1 to A9 and A35, wherein the loading dose is about 300 mg QD and is administered for 28 ± 2 consecutive days. In an embodiment of A39, the loading dose is about 300 mg QD and is administered for 28 ± 1 consecutive days. In an embodiment of A39, the loading dose is about 300 mg QD and is administered for 28 consecutive days. A40. Embodiment A40 comprises the method or use of any one of embodiments A1 to A9, wherein the loading dose is about 20 mg QD. A41. Embodiment A41 comprises the method or use of any one of embodiments A1 to A9 and A40, wherein the loading dose is about 20 mg QD and is administered for 3, 4, or 5 consecutive days. A42. Embodiment A42 comprises the method or use of any one of embodiments A1 to A9 and A40, wherein the loading dose is about 20 mg QD and is administered for 7 ± 1 consecutive days. In an embodiment of A42, the loading dose is about 20 mg QD and is administered for 7 consecutive days. A43. Embodiment A43 comprises the method or use of any one of embodiments A1 to A9 and A40, wherein the loading dose is about 20 mg QD and is administered for 14 ± 2 consecutive days. In an embodiment of A43, the loading dose is about 20 mg QD and is administered for 14 ± 1 consecutive days. In an embodiment of A43, the loading dose is about 20 mg QD and is administered for 14 consecutive days. A44. Embodiment A44 comprises the method or use of any one of embodiments A1 to A9 and A40, wherein the loading dose is about 20 mg QD and is administered for 28 ± 2 consecutive days. In an embodiment of A44, the loading dose is about 20 mg QD and is administered for 28 ± 1 consecutive days. In another embodiment of A44, the loading dose is about 20 mg QD and is administered for 28 consecutive days. Maintenance Dose Embodiments B B. Embodiment B comprises the method or use of any one of embodiments A1 to A44, wherein the maintenance dose comprises the same amount of Compound (I) or Compound (I) Form A as the loading dose, and the maintenance dose is administered to the patient less frequently than the loading dose is administered during the loading period. B1. Embodiment B1 comprises the method or use of any one of embodiments A1 to A14 and B, wherein the maintenance dose is about 50 mg and is administered QW. B2. Embodiment B2 comprises the method or use of any one of embodiments A1 to A8, A15 to A19, and B, wherein the maintenance dose is about 100 mg and is administered QW. Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT B3. Embodiment B3 comprises the method or use of any one of embodiments A1 to A8, A20 to A24, and B, wherein the maintenance dose is about 150 mg and is administered QW. B4. Embodiment B4 comprises the method or use of any one of embodiments A1 to A8, A25 to A29, and B, wherein the maintenance dose is about 200 mg and is administered QW. B5. Embodiment B5 comprises the method or use of any one of embodiments A1 to A8, A30 to A34, and B, wherein the maintenance dose is about 250 mg and is administered QW. B6. Embodiment B6 comprises the method or use of any one of embodiments A1 to A8, A35 to A39, and B, wherein the maintenance dose is about 300 mg and is administered QW. B7. Embodiment B7 comprises the method or use of any one of embodiments A1 to A8, A40 to A44, and B, wherein the maintenance dose is about 20 mg and is administered QW. B8. Embodiment B8 comprises the method or use of any one of embodiments A1 to A14, B, and B1, wherein the maintenance dose is about 50 mg Q2W. B9. Embodiment B9 comprises the method or use of any one of embodiments A1 to A14, B, and B1, wherein the maintenance dose is about 50 mg Q4W. B10. Embodiment B10 comprises the method or use of any one of embodiments A1 to A8, A15 to A19, B, and B2, wherein the maintenance dose is about 100 mg Q2W. B11. Embodiment B11 comprises the method or use of any one of embodiments A1 to A8, A15 to A19, B, and B2, wherein the maintenance dose is about 100 mg Q4W. B12. Embodiment B12 comprises the method or use of any one of embodiments A1 to A8, A20 to A24, B, and B3 wherein the maintenance dose is about 150 mg Q2W. B13. Embodiment B13 comprises the method or use of any one of embodiments A1 to A8, A20 to A24, B, and B3, wherein the maintenance dose is about 150 mg Q4W. B14. Embodiment B14 comprises the method or use of any one of embodiments A1 to A8, A25 to A29, B, and B4, wherein the maintenance dose is about 200 mg Q2W. B15. Embodiment B15 comprises the method or use of any one of embodiments A1 to A8, A25 to A29, B, and B4, wherein the maintenance dose is about 200 mg Q4W. B16. Embodiment B16 comprises the method or use of any one of embodiments A1 to A8, A30 to A34, B, and B5, wherein the maintenance dose is about 250 mg Q2W. B17. Embodiment B17 comprises the method or use of any one of embodiments A1 to A8, A30 to A34, B, and B5, wherein the maintenance dose is about 250 mg Q4W. B18. Embodiment B18 comprises the method or use of any one of embodiments A1 to A8, A35 to A39, B, and B6, wherein the maintenance dose is about 300 mg Q2W. B19. Embodiment B19 comprises the method or use of any one of embodiments A1 to A8, A35 to A39, B, and B6, wherein the maintenance dose is about 300 mg Q4W. Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT B32. Embodiment B32 comprises the method or use of any one of embodiments A1 to A8, A40 to A44, B, and B7, wherein the maintenance dose is about 20 mg Q2W. B33. Embodiment B33 comprises the method or use of any one of embodiments A1 to A8, A40 to A44, B, and B7, wherein the maintenance dose is about 20 mg Q4W. Embodiments C C. Embodiment C comprises the method or use of any one of embodiments A1 to A8 and A15 to A39, wherein the maintenance dose comprises less Compound (I) or Compound (I) Form A than the loading dose, and the maintenance dose is administered once a day. C1. Embodiment C1 comprises the method or use of any one of embodiments A1 to A8 and A15 to A19, wherein the maintenance dose is 50 mg QD. C2. Embodiment C2 comprises the method or use of any one of embodiments A20 to A24, wherein the maintenance dose is 50 mg QD. C3. Embodiment C3 comprises the method or use of any one of embodiments A20 to A24, wherein the maintenance dose is 100 mg and is administered QD. C4. Embodiment C4 comprises the method or use of any one of embodiments A25 to A29, wherein the maintenance dose is about 50 mg and is administered QD. C5. Embodiment C5 comprises the method or use of any one of embodiments A25 to A29, wherein the maintenance dose is about 100 mg QD. C6. Embodiment C6 comprises the method or use of any one of embodiments A25 to A29, wherein the maintenance dose is about 150 mg QD. C7. Embodiment C7 comprises the method or use of any one of embodiments A30 to A34, wherein the maintenance dose is about 50 mg QD. C8. Embodiment C8 comprises the method or use of any one of embodiments A30 to A34, wherein the maintenance dose is about 100 mg QD. C9. Embodiment C9 comprises the method or use of any one of embodiments A30 to A34, wherein the maintenance dose is about 150 mg QD. C10. Embodiment C10 comprises the method or use of any one of embodiments A30 to A34, wherein the maintenance dose is about 200 mg QD. C11. Embodiment C11 comprises the method or use of any one of embodiments A35 to A39, wherein the maintenance dose is about 50 mg QD. C12. Embodiment C12 comprises the method or use of any one of embodiments A35 to A39, wherein the maintenance dose is about 100 mg QD. C13. Embodiment C13 comprises the method or use of any one of embodiments A35 to A39, wherein the maintenance dose is about 150 mg QD. Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT C14. Embodiment C14 comprises the method or use of any one of embodiments A35 to A39, wherein the maintenance dose is about 200 mg QD. C15. Embodiment C15 comprises the method or use of any one of embodiments A35 to A39, wherein the maintenance dose is about 250 mg QD. C16. Embodiment C16 comprises the method or use of any one of embodiments A10 to A39, wherein the maintenance dose is about 50 mg QD. Embodiments D D. Embodiment D comprises the method or use of any one of embodiments A1 to A8 and A15 to A39, wherein the maintenance dose comprises less Compound (I) or Compound (I) Form A than the loading dose, and the maintenance dose is administered less frequently than the loading dose is administered during the loading period. D1. Embodiment D1 comprises the method or use of any one of embodiments A1 to A8 and A15 to A19, wherein the maintenance dose is 50 mg QW. D2. Embodiment D2 comprises the method or use of any one of embodiments A20 to A24, wherein the maintenance dose is 50 mg QW. D3. Embodiment D3 comprises the method or use of any one of embodiments A20 to A24, wherein the maintenance dose is 100 mg QW. D4. Embodiment D4 comprises the method or use of any one of embodiments A25 to A29, wherein the maintenance dose is about 50 mg QW. D5. Embodiment D5 comprises the method or use of any one of embodiments A25 to A29, wherein the maintenance dose is about 100 mg QW. D6. Embodiment D6 comprises the method or use of any one of embodiments A25 to A29, wherein the maintenance dose is about 150 mg and is administered QW. D7. Embodiment D7 comprises the method or use of any one of embodiments A30 to A34, wherein the maintenance dose is about 50 mg QW. D8. Embodiment D8 comprises the method or use of any one of embodiments A30 to A34, wherein the maintenance dose is about 100 mg QW. D9. Embodiment D9 comprises the method or use of any one of embodiments A30 to A34, wherein the maintenance dose is about 150 mg QW. D10. Embodiment D10 comprises the method or use of any one of embodiments A30 to A34, wherein maintenance dose is about 200 mg QW. D11. Embodiment D11 comprises the method or use of any one of embodiments A35 to A39, wherein the maintenance dose is about 50 mg QW. Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT D12. Embodiment D12 comprises the method or use of any one of embodiments A35 to A39, wherein the maintenance dose is about 100 mg QW. D13. Embodiment D13 comprises the method or use of any one of embodiments A35 to A39, wherein the maintenance dose is about 150 mg QW. D14. Embodiment D14 comprises the method or use of any one of embodiments A35 to A39, wherein the maintenance dose is about 200 mg QW. D15. Embodiment D15 comprises the method or use of any one of embodiments A35 to A39, wherein the maintenance dose is about 250 mg QW. D16. Embodiment D16 comprises the method or use of any one of embodiments A10 to A39, wherein the maintenance dose is about 20 mg QW. Embodiments E E1. Embodiment E1 comprises the method or use of any one of embodiments A1 to A8 is wherein the loading dose is about 100 mg QD or about 200 mg QD. E2. Embodiment E2 comprises the method or use of embodiments A1 to A8 and E1, wherein the loading dose is about 100 mg QD. E3. Embodiment E3 comprises the method or use of any one of embodiments A1 to A8 and E1 to E2, wherein the loading dose is about 100 mg QD and is administered for 7 consecutive days. E4. Embodiment E4 comprises the method or use of any one of embodiments A1 to A8 and E1, wherein the loading dose is about 200 mg QD. E5. Embodiment E5 comprises the method or use of any one of embodiments A1 to A8, E1, and E4, wherein the loading dose is about 200 mg QD and is administered for 7 consecutive days. E6. Embodiment E6 comprises the method or use of embodiment A1 to A8, E1, and E4, wherein the loading dose is about 200 mg QD and is administered for 14 consecutive days. E7. Embodiment E7 comprises the method or use of embodiment A1 to A8, E1, and E4, wherein amount of each of the loading dose is about 200 mg QD and is administered for 28 consecutive days. E8. Embodiment E8 comprises the method or use of any one of embodiments A1 to A8, E2, and E3, wherein the maintainance dose is about 100 mg QW. E9. Embodiment E9 comprises the method or use of any one of embodiments A1 to A8, E4, or E5, wherein the maintainance dose is about 200 mg QW. E10. Embodiment E10 comprises the method or use of any one of embodiments A1 to A8, E4, E5, E6, and E7, wherein the maintainance dose is about 50 mg QD. Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Embodiments F F1. Embodiment F1 comprises the method or use of any one of embodiments A1 to E10, wherein the loading and maintenance doses are administered orally. F2. Embodiment F2 comprises the method or use of any one of embodiments A1 to E10 and F1, wherein each consecutive loading dose is administered at the same time of day or ± 0.5, 1, 2, 3, or 4 hours before or after the prior loading dose is administered. F3. Embodiment F3 comprises the method or use of any one of embodiments A1 to A39, C to C15, E8, E9, and F1 to F2, wherein each follow-up maintenance dose, when administered QW, is administered at the same time of day ± 0.5, 1, 2, 3, or 4 hours after the first maintenance dose. F4. Embodiment F4 comprises the method or use of any one of embodiments B1 to B6, D1 to D15, E10, and F1 to F2, wherein the first maintenance dose, when administered QW, is administered the following day, after the last loading dose. F5. Embodiment F5 comprises the method or use of any one of embodiments B1 to B6, D1 to D15, E10, and F1 to F2, wherein the first maintenance dose, when administered QW, is administered the second day after the last loading dose. F6. Embodiment F6 comprises the method or use of any one of embodiments B1 to B6, D1 to D15, E10, and F1 to F2, wherein the first maintenance dose, when administered QW, is administered the third day after the last loading dose. F7. Embodiment F7 comprises the method or use of any one of embodiments B1 to B6, D1 to D15, E10, and F1 to F2, wherein the first maintenance dose, when administered QW, is administered the fourth day after the last loading dose. F8. Embodiment F8 comprises the method or use of any one of embodiments B1 to B6, D1 to D15, E10, and F1 to F2 is wherein the first maintenance dose, when administered QW, is administered the fifth day after the last loading dose. F9. Embodiment F9 comprises the method or use of any one of embodiments B1 to B6, D1 to D15, E10, and F1 to F2, wherein the first maintenance dose, when administered QW, is administered the sixth day after the last loading dose. F10. Embodiment F10 comprises the method or use of any one of embodiments B1 to B6, D1 to D15, E10, and F1 to F2, wherein the first maintenance dose, when administered QW, is administered the seventh day after the last loading dose. F11. Embodiment F1 comprises the method or use of any one of embodiments F4 to F10, wherein, following the first maintenance dose, each subsequent maintenance dose is administered seven days after the prior maintenance dose. Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT F12. Embodiment F12 comprises the method or use of any one of embodiments A1 to E10 and F1 to F11, wherein a single bolus of loading dose is administered. F13. Embodiment F13 comprises the method or use of any one of embodiments A1 to E10 and F1 to F11, wherein two or more doses of a loading dose are administered. F14. Embodiment F14 comprises the method or use of any one of embodiments A1 to E10 and F1 to F13, wherein a single bolus of maintenance dose is administered. F15. Embodiment F15 comprises the method or use of any one of embodiments A1 to E10 and F1 to F13, wherein two or more doses of a maintenance dose are administered. F16. Embodiment F16 comprises the method or use of any one of embodiments A1 to F15, wherein the dosage regimen is adjusted to provide the optimum desired response (e.g., a steady state of Compound (I) Form A in plasma that is therapeutic), and the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. F17. Embodiment F17 comprises the method or use of any one of embodiments A1 to F15, wherein the dosage regimen is adjusted by lowering the maintenance dose because the patient experiences a toxicity. F18. Embodiment F18 comprises the method or use of embodiment E10, wherein the dosage regimen is adjusted by lowering the maintenance dose to 30 mg/day QD because the patient experiences a toxicity. F19. Embodiment F19 comprises the method or use of embodiment E10 or F18, wherein the dosage regimen is adjusted by lowering the maintenance dose to 20 mg/day QD because the patient experiences a toxicity. F20. Embodiment F20 comprises the method or use of embodiment E8, wherein the dosage regimen is adjusted by lowering the maintenance dose to 50 mg QW because the patient experiences a toxicity. F21. Embodiment F21 comprises the method or use of embodiment E8 or F20, wherein the dosage regimen is adjusted by lowering the maintenance dose to 30 mg QW because the patient experiences a toxicity. Patient Criteria Embodiments G G1. Embodiment G1 comprises the method or use of any one of embodiments A1 to F21, wherein the patient satisfies at least one of the following conditions: (a) the patient has locally advanced or metastatic ccRCC, and has progressed during treatment, are relapsed, refractory and not amenable to curative therapy or standard therapy and has progressed during treatment with at least 1 prior therapeutic regimen; Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT (b) the patient has measurable disease per RECIST 1.1 criteria; (c) the patient is ≥ 18 years of age; (d) the patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2; (e) the patient has a life expectancy of ≥ 3 months; (f) the patient has adequate organ function defined as follows: (i) a bone marrow ANC ≥ 1.0 × 109/L; hemoglobin level ≥ 10 g/dL without transfusion or erythropoietin support within two weeks prior to a first dose of Compound (I) or Compound (I) Form A; platelet count ≥ 75,000/μL; (ii) hepatic transaminase levels (aspartate aminotransferase /alanine aminotransferase [AST/ALT]) ≤ 2.5 × ULN (≤ 5 × ULN if liver metastases is present); total bilirubin (TBILI) ≤ 1.5 × ULN in the absence of Gilbert’s disease; and (iii) a renal serum creatinine level ≤ 2.0 X ULN or calculated creatinine clearance (CrCL) ≥ 40 mL/min (as determined by a Cockcroft-Gault formula); (g) if a female patient of childbearing potential, the female patient meets all of the following criteria prior to first administration of Compound (I) or Compound (I) Form A (in some embodiments, a female patient is considered to be of childbearing potential unless she has had a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy; has medically documented ovarian failure (with serum estradiol and follicle-stimulating hormone levels within the institutional laboratory postmenopausal range and a negative serum or urine beta human chorionic gonadotropin); or is menopausal (amenorrhea for ≥ 12 months)): (i) the female patient is not pregnant (negative serum pregnancy test); (ii) the female patient is not breastfeeding; and (iii) the female patient is willing to use a protocol-recommended method or use of contraception or to abstain from heterosexual intercourse from the start of treatment or until at least 6 months after the last dose of treatment; (h) if a male patient who can father a child, the male patient must meet all of the following criteria (in some embodiments of the method or uses disclosed herein, a male patient is considered able to father a child unless he has had a bilateral vasectomy with documented aspermia or a bilateral orchiectomy): (i) the male patient is willing to use a protocol-recommended method or use of contraception or abstain from heterosexual intercourse with females of childbearing potential from the start of treatment until at least 6 months after the Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT last dose of treatment; and (ii) the male patient must be willing to refrain from sperm donation from the start of treatment until at least 6 months after the last dose of treatment; (i) the patient must be able to swallow oral medications; and (j) any ambulatory patient must complete a six-minute walk test (in some embodiments, the walking distance needs to be at least 400 meters, and the change of oxygen saturation needs to be within a 5% range). G2. Embodiment G2 comprises the method or use of G1, wherein the patient satisfies at least two of the conditions (a) through (j) above. G3. Embodiment G3 comprises the method or use of G1, wherein the patient satisfies at least three of the conditions (a) through (j) above. G4. Embodiment G4 comprises the method or use of G1, wherein the patient satisfies at least four of the conditions (a) through (j) above. G5. Embodiment G5 comprises the method or use of G1, wherein the patient satisfies at least five of the conditions (a) through (j) above. G6. Embodiment G6 comprises the method or use of G1, wherein the patient satisfies at least six of the conditions (a) through (j) above. G7. Embodiment G7 comprises the method or use of G1, wherein the patient satisfies at least seven of the conditions (a) through (j) above. G8. Embodiment G8 comprises the method or use of G1, wherein the patient satisfies at least eight of the conditions (a) through (j) above. G9. Embodiment G12 comprises the method or use of G1, wherein the patient satisfies each of the conditions (a) through (j) above. G10. Embodiment G10 comprises the method or use of any one of embodiments G1 to G9, wherein the patient is excluded from treatment if at least one of the following conditions are satisfied: (aa) the patient has known symptomatic brain metastases requiring > 10 mg/day of prednisone (or its equivalent). (bb) the patient with previously diagnosed brain metastases unless they have completed their treatment, have recovered from the acute effects of radiation therapy or surgery prior to the start of Compound (I) or Compound (I) Form A treatment, fulfill any steroid requirement for these metastases, and are neurologically stable based on central nervous system imaging ≥ four weeks after CNS-directed treatment; (cc) the patient has a pulse oximetry reading less than 95% at screening prior to first administration of Compound (I) or Compound (I) Form A; Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT (dd) the patient has any current requirement for intermittent or chronic supplemental oxygen prior to first administration of Compound (I) or Compound (I) Form A; (ee) the patient has any chronic lung condition which has required supplemental oxygen in the past prior to first administration of Compound (I) or Compound (I) Form A; (ff) the patient has evidence of impending airway compromise (such as endobronchial tumor, lymphangitic spread, significant extrinsic compression of major airway) prior to first administration of Compound (I) or Compound (I) Form A; (gg) the patient has ascites requiring drainage within 28 days prior to first administration of Compound (I) or Compound (I) Form A; (hh) the patient has a history of of another malignancy prior to first administration of Compound (I) or Compound (I) Form A except for the following: adequately treated local basal cell or squamous carcinoma of the skin, in situ cervical cancer, adequately treated papillary noninvasive bladder cancer, other adequately treated Stage 1 or Stage 2 cancers currently in complete remission, or any other cancer that has been in complete remission for ≥ 2 years; (ii) the patient has failed to recover from the effects of prior anticancer therapy to baseline level or Grade 1 severity (except for alopecia) per NCI CTCAE prior to first administration of Compound (I) or Compound (I) Form A; (jj) the patient has significant cardiovascular disease, including myocardial infarction, arterial thromboembolism, or cerebrovascular thromboembolism, within six months prior to start of Compound (I) or Compound (I) Form A treatment; symptomatic dysrhythmias or unstable dysrhythmias requiring medical therapy; angina requiring therapy, symptomatic peripheral vascular disease; New York Heart Association Class 3 or 4 congestive heart failure; ≥ Grade 3 hypertension (diastolic blood pressure ≥ 100 mmHg or systolic blood pressure ≥160 mmHg) despite adequate use of anti- hypertensives; or history of congenital prolonged QT syndrome or repeated demonstration of a QTc interval > 480 ms; ejection fraction < 40%; clinically significant pericardial or pleural effusion in the opinion of an investigator; (kk) the patient has received prior investigational therapy or standard therapy within five half-lives of the agent or four weeks before a first administration of Compound (I) or Compound (I) Form A, whichever is shorter; (ll) the patient has a bleeding diathesis or coagulopathy; (mm) the patient has a deep vein thrombosis (DVT)/pulmonary embolism unless the patient is not symptomatic and has received two weeks or more of adequate anticoagulation; Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT (nn) the patient has manifestations of malabsorption due to prior gastrointestinal (GI) surgery or GI disease; (oo) the patient has any other clinically significant cardiac, respiratory, or other medical or psychiatric condition that might interfere with treatment with Compound (I) or Compound (I) Form A; (pp) the patient has had major surgery within four weeks before Compound (I) or Compound (I) Form A administration (in some embodiments, the following procedures are not considered to be major surgeries: thoracentesis, port placement, laparoscopy, thoracoscopy, bronchoscopy, endoscopic or ultrasonographic procedures, mediastinoscopy, skin biopsy, incisional biopsy, image-guided biopsy for diagnostic purposes, and routine dental procedures); (qq) the patient has known HIV; (rr) the patient has an active infection requiring systemic treatment; (ss) the patient is actively participating in a therapeutic clinical trial; (tt) the patient has received prior treatment with an HIF-2α inhibitor, unless prior belzutifan treatment. G11. Embodiment G11 comprises the method or use of G10, wherein the patient is excluded from treatment if at least two of the conditions (aa) through (tt) above are satisfied. G12. Embodiment G12 comprises the method or use of G10, wherein the patient is excluded from treatment if at least three of the conditions (aa) through (tt) above are satisfied. G13. Embodiment G13 comprises the method or use of G10, wherein the patient is excluded from treatment if at least four of the conditions (aa) through (tt) above are satisfied. G14. Embodiment G14 comprises the method or use of G10, wherein the patient is excluded from treatment if at least five of the conditions (aa) through (tt) above are satisfied. G15. Embodiment G15 comprises the method or use of G10, wherein the patient is excluded from treatment if at least six of the conditions (aa) through (tt) above are satisfied. G16. Embodiment G16 comprises the method or use of G10, wherein the patient is excluded from treatment if at least seven of the conditions (aa) through (tt) above are satisfied. G17. Embodiment G17 comprises the method or use of G10, wherein the patient is excluded from treatment if at least eight of the conditions (aa) through (tt) above are satisfied. G18. Embodiment G18 comprises the method or use of G10, wherein the patient is excluded from treatment if at least nine of the conditions (aa) through (tt) above are satisfied. G19. Embodiment G19 comprises the method or use of G10, wherein the patient is excluded from treatment if at least ten of the conditions (aa) through (tt) above are satisfied. Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT G20. Embodiment G20 comprises the method or use of G10, wherein the patient is excluded from treatment if at least eleven of the conditions (aa) through (tt) above are satisfied. G21. Embodiment G21 comprises the method or use of G10, wherein the patient is excluded from treatment if at least twelve of the conditions (aa) through (tt) above are satisfied. G22. Embodiment G22 comprises the method or use of G10, wherein the patient is excluded from treatment if each of the conditions (aa) through (tt) above are satisfied. G23. Embodiment G23 comprises the method or use of any one of embodiments G1 to G22, wherein the patient is willing to and able to take a high-fat meal within thirty minutes prior to Compound (I) or Compound (I) Form A dosing on Week 1 Day 1. G24. Embodiment G24 comprises the method or use of any one of embodiments G1 to G22, wherein the patient has adequate hepatic and renal function defined below: (i) Hepatic: normal hepatic function (total bilirubin ≤ upper limit of normal (ULN) and aspartate aminotransferase (AST) ≤ ULN) or mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin > 1.0 × to 1.5 × ULN) (ii) Renal: measured or calculated creatinine clearance (CrCL) ≥ 60 mL/min (Cockcroft- Gault formula); G25. Embodiment G25 comprises the method or use of any one of embodiments G1 to G24, wherein the patient is excluded from treatment if the patient has any gastrointestinal (GI) malfunction, surgeries, or conditions that could affect absorption of oral Compound (I) Form A and/or midazolam as assessed by an investigator. G26. Embodiment G26 comprises the method or use of any one of embodiments G1 to G25, wherein the patient is excluded from treatment if the patient uses any drugs, investigational agents, fruits, or herbs that are strong or moderate CYP3A inhibitors or inducers within fourteen days prior to Day -3 (or 5 times the half-life of the drug, whichever is longer). G27. Embodiment G27 comprises the method or use of any one of embodiments G1 to G26, wherein the patient has relapse or progressive disease following prior treatment with belzutifan (in some embodiments, the patient received at least 28 days of treatment with belzutifan). G28. Embodiment G28 comprises the method or use of any one of embodiments G1 to G27, wherein the patient has a willingness to undergo a pretreatment and post-treatment biopsy of the tumor. G29. Embodiment G29 comprises the method or use of any one of embodiments G1 to G28, wherein the patient is excluded from treatment if the patient has a history of toxicity or intolerance to treatment with belzutifan or other HIF-2α inhibitor; Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT G30. Embodiment G30 comprises the method or use of any one of embodiments G1 to G29, wherein the patient is excluded from treatment if the patient has a known presence of HIF2-α mutation G323E or HIF-1B mutation F446L. Embodiments H H1. Embodiment H1 comprises the method or use of any one of embodiments A1 to G30, wherein the cancer to be treated is selected from a cancer in the Utility section below. H2. Embodiment H2 comprises the method or use of any one of embodiments A1 to G30, wherein the cancer to be treated is selected from renal cancer, glioblastoma, neuroblastoma, paraganglioma, pheochromocytoma, somatostatinomas, hemangioblastomas, gastrointestinal stromal tumors, pituitary tumors, bladder cancer, liver cancer, leiomyomas, leiomyosarcomas, polycythaemia, and retinal cancers. H3. Embodiment H3 comprises the method or use of any one of embodiments A1 to F21, wherein the Compound (I) or Compound (I) Form A is administered in combination with at least one other anticancer agent, preferably as provided in the Combinations and Combination Therapy section below. H4. Embodiment H4 comprises the method or use of embodiment H3, wherein the at least one other anticancer agent is selected from palbociclib, ribociclib, abemaciclib, sasanlimab, cemiplimab-rwlc, nivolumab, pembrolizumab, dostarlimab, atezolizumab, durvalumab, avelumab, and rituximab. H5. Embodiment H5 comprises the method or use of embodiment H3, wherein the at least one other anticancer agent is cabozantinib. H6. Embodiment H6 comprises the method or use of any one of embodiments A1 to H5, wherein the patient is a human. H7. Embodiment H7 comprises the method or use of any one of embodiments A1 to H6, wherein the treatment of cancer includes arresting or reducing the development of the cancer or its clinical symptoms. H8. Embodiment H8 comprises the method or use of any one of embodiments A1 to H6, wherein the treatment of cancer includes causing regression of the cancer or its clinical symptoms. H9. Embodiment H9 comprises the method or use of any one of embodiments A1 to H6, wherein the the treatment of cancer includes causing the clinical symptoms of the cancer not to develop where the patient is exposed to or predisposed to the cancer but does not yet experience or display symptoms of the cancer. Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT As will be apparent to those skilled in the art, dosages outside of these disclosed dosages and ranges may be administered in some cases. Further, it is noted that the ordinary skilled clinician or treating physician will know how and when to interrupt, adjust, or terminate therapy in consideration of individual response. Utility Compound (I) and Compound (I) Form A are useful for the treatment of HIF-2α-mediated diseases, which include, but are not limited to, various types of cancers, such as acanthoma, acinic cell carcinoma, acoustic neuroma, acral lentiginous melanoma, acrospiroma, acute eosinophilic leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute myeloblastic leukemia with maturation, acute myeloid dendritic cell leukemia, acute myeloid leukemia, acute promyelocytic leukemia, adamantinoma, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenomatoid odontogenic tumor, adrenocortical carcinoma, adult T- cell leukemia, aggressive NK-cell leukemia, AIDS-related cancers, AIDS-related lymphoma, alveolar soft part sarcoma, ameloblastic fibroma, anal cancer, anaplastic large cell lymphoma, anaplastic thyroid cancer, angioimmunoblastic T-cell lymphoma, angiomyolipoma, angiosarcoma, appendix cancer, astrocytoma, atypical teratoid rhabdoid tumor, basal cell carcinoma, basal-like carcinoma, B-cell leukemia, B-cell lymphoma, bellini duct carcinoma, biliary tract cancer, bladder cancer, blastoma, bone cancer, bone tumor, brain stem glioma, brain tumor, breast cancer, brenner tumor, bronchial tumor, bronchioloalveolar carcinoma, brown tumor, Burkitt's lymphoma, carcinoid tumor, carcinoma, carcinosarcoma, Castleman's disease, central nervous system embryonal tumor, cerebellar astrocytoma, cerebral astrocytoma, cervical cancer, cholangiocarcinoma, chondroma, chondrosarcoma, chordoma, choriocarcinoma, choroid plexus papilloma, chronic lymphocytic leukemia, chronic monocytic leukemia, chronic myelogenous leukemia, chronic myeloproliferative disorder, chronic neutrophilic leukemia, clear cell renal cell carcinoma, clear-cell tumor, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, dermatofibrosarcoma protuberans, dermoid cyst, desmoplastic small round cell tumor, diffuse large B cell lymphoma, dysembryoplastic neuroepithelial tumor, embryonal carcinoma, endodermal sinus tumor, endometrial cancer, endometrial uterine cancer, endometrioid tumor, enteropathy -associated T-cell lymphoma, ependymoblastoma, ependymoma, epithelioid sarcoma, erythroleukemia, esophageal cancer, esthesioneuroblastoma, Ewing's sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, extramammary Paget's disease, fallopian tube cancer, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroid cancer, gallbladder cancer, ganglioglioma, ganglioneuroma, gastric cancer, gastric lymphoma, Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT gastrointestinal cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, germ cell tumor, germinoma, gestational choriocarcinoma, gestational trophoblastic tumor, giant cell tumor of bone, glioblastoma multiforme, glioma, gliomatosis cerebri, glomus tumor, glucagonoma, gonadoblastoma, granulosa cell tumor, hairy cell leukemia, head and neck cancer, hemangioblastoma, hemangiopericytoma, hemangiosarcoma, hematological malignancy, hepatocellular carcinoma, hepatosplenic T-cell lymphoma, Hodgkin lymphoma, hypopharyngeal cancer, hypothalamic glioma, inflammatory breast cancer, intraocular melanoma, islet cell carcinoma, juvenile myelomonocytic leukemia, Kaposi's sarcoma, kidney cancer, klatskin tumor, krukenberg tumor, laryngeal cancer, lentigo maligna melanoma, leukemia, lip and oral cavity cancer, liposarcoma, lung cancer, luteoma, lymphangioma, lymphangiosarcoma, lymphoepithelioma, lymphoid leukemia, lymphoma, macroglobulinemia, malignant fibrous histiocytoma, malignant glioma, malignant mesothelioma, malignant peripheral nerve sheath tumor, malignant rhabdoid tumor, malignant triton tumor, malt lymphoma, mantle cell lymphoma, mast cell leukemia, mediastinal germ cell tumor, mediastinal tumor, medullary thyroid cancer, medulloblastoma, medulloepithelioma, melanoma, meningioma, merkel cell carcinoma, mesothelioma, metastatic squamous neck cancer with occult primary, urothelial carcinoma, mixed mullerian tumor, monocytic leukemia, mouth cancer, mucinous tumor, multiple endocrine neoplasia syndrome, multiple myeloma, mycosis fungoides, myelodysplastic disease, myeloid leukemia, myeloid sarcoma, myeloproliferative disease, myxoma, nasal cavity cancer, nasopharyngeal cancer, neoplasm, neurinoma, neuroblastoma, neurofibroma, neuroma, nodular melanoma, non-Hodgkin lymphoma, nonmelanoma skin cancer, non-small cell lung cancer, ocular oncology, oligoastrocytoma, oligodendroglioma, oncocytoma, optic nerve sheath meningioma, oral cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant potential tumor, pancoast tumor, pancreatic cancer, papillary thyroid cancer, papillomatosis, paraganglioma, paranasal sinus cancer, parathyroid cancer, penile cancer, perivascular epithelioid cell tumor, pharyngeal cancer, pheochromocytoma, pineal parenchymal tumor of intermediate differentiation, pineoblastoma, pituicytoma, pituitary adenoma, pituitary tumor, plasma cell neoplasm, pleuropulmonary blastoma, polyembryoma, precursor T-lymphoblastic lymphoma, primitive neuroectodermal tumor, prostate cancer, pseudomyxoma peritonei, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyoma, rhabdomyosarcoma, Richter's transformation, sacrococcygeal teratoma, salivary gland cancer, sarcoma, Schwann omatosis, sebaceous gland carcinoma, secondary neoplasm, seminoma, serous tumor, Sertoli-Leydig cell tumor, sex cord-stromal tumor, sezary syndrome, signet ring cell carcinoma, skin cancer, small blue round cell tumor, small cell carcinoma, small cell lung cancer, small cell lymphoma, small intestine cancer, soft tissue Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT sarcoma, somatostatinoma, soot wart, spinal tumor, splenic marginal zone lymphoma, squamous cell carcinoma, stomach cancer, superficial spreading melanoma, supratentorial primitive neuroectodermal tumor, surface epithelial-stromal tumor, synovial sarcoma, T-cell acute lymphoblastic leukemia, T-cell large granular lymphocyte leukemia, T-cell leukemia, T-cell lymphoma, T-cell prolymphocytic leukemia, teratoma, terminal lymphatic cancer, testicular cancer, thecoma, throat cancer, thymic carcinoma, thymoma, thyroid cancer, transitional cell cancer of renal pelvis and ureter, transitional cell carcinoma, urachal cancer, urethral cancer, urogenital neoplasm, uterine sarcoma, uveal melanoma, vaginal cancer, verner morrison syndrome, verrucous carcinoma, visual pathway glioma, vulvar cancer, Waldenstrom's macroglobulinemia, Warthin's tumor, Wilms' tumor or any combination thereof. In some embodiments, the methods comprising administering a HIF-2a inhibitor disclosed herein and an immunotherapeutic agent described herein are applied to the treatment of cancers of the adrenal glands, blood, bone marrow, brain, breast, cervix, colon, head and neck, kidney, liver, lung, ovary, pancreas, plasma cells, rectum, retina, skin, spine, throat, or any combination thereof. Pharmaceutical Compositions In general, Compound (I) or Compound (I) Form A will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. In general, Compound (I) or Compound (I) Form A will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous, or subcutaneous) administration. The preferred manner of administration is oral using a convenient daily dosage regimen, which can be adjusted according to the degree of affliction. Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions. The choice of formulation depends on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills, or capsules, including enteric coated or delayed release tablets, pills or capsules are preferred) and the bioavailability of the drug substance. The compositions are comprised of, in general, Compound (I) or Compound (I) Form A in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of Compound (I) or Compound (I) Form A. The excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient, that is generally available to one of skill in the art. Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol, and various oils, including those of petroleum, animal, vegetable, or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols. Compound (I) or Compound (I) Form A may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described. Formulations for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compounds, which may contain antioxidants, buffers, bacteriostats and solutes, which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils, such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents, which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. In addition to the formulations described previously, Compound (I) or Compound (I) Form A may also be formulated as a depot preparation. Such long-acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt. Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, pastilles, or gels formulated in a conventional manner. Such compositions may comprise the active ingredient in a flavored basis, such as sucrose, acacia, or tragacanth. Compound (I) or Compound (I) Form A may also be formulated in rectal compositions, such as suppositories or retention enemas, e.g., containing conventional suppository bases, such as cocoa butter, polyethylene glycol, or other glycerides. Other suitable pharmaceutical excipients and their formulations are described in Remington’s Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 20th ed., 2000). The amount of compound in a formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt. %) basis, from about 0.01-99.99 wt. % of Compound (I) or Compound (I) Form A based on the total formulation, with the balance being one or more suitable pharmaceutical excipients, such as those described above. For example, Compound (I) or Compound (I) Form A may be present at about 1- 80 wt. %. Combinations and Combination Therapies Compound (I) or Compound (I) Form A may be used in combination with one or more other drugs in the treatment of diseases or conditions for which Compound (I) or Compound (I) Form A or the other drugs may have utility. Such other drug(s) may be administered, by a route and in an amount commonly used therefore, contemporaneously, or sequentially, with Compound (I) or Compound (I) Form A. When Compound (I) or Compound (I) Form A is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and Compound (I) or Compound (I) Form A is preferred. However, the combination therapy may also include therapies in which Compound (I) or Compound (I) Form A and one or more other drugs are administered on different overlapping schedules. It is also contemplated that, when used in combination with one or more other active ingredients, Compound (I) or Compound (I) Form A and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present disclosure also include those that contain one or more other drugs, in addition to Compound (I) or Compound (I) Form A. The above combinations include combinations of Compound (I) or Compound (I) Form A with one other drug, two other drugs, three other drugs, or more. Likewise, Compound (I) or Compound (I) Form A may be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT which a compound of this disclosure is useful. Such other drugs may be administered, by a route and in an amount commonly used therefore, contemporaneously, or sequentially, with Compound (I) or Compound (I) Form A. When Compound (I) or Compound (I) Form A is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to Compound (I) or Compound (I) Form A can be used. Accordingly, the pharmaceutical compositions of the present disclosure also include those that also contain one or more other active ingredients, in addition to Compound (I) or Compound (I) Form A. The weight ratio of Compound (I) or Compound (I) Form A to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Where the subject in need is suffering from or at risk of suffering from cancer, the subject may be treated with Compound (I) or Compound (I) Form A in any combination with one or more anti-cancer agents. In some embodiments, one or more of the anti-cancer agents are proapoptotic agents. Examples of anti-cancer agents include, but are not limited to, any of the following: gossyphol, genasense, polyphenol E, Chlorofusin, all trans-retinoic acid (ATRA), bryostatin, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), 5-aza-2’-deoxycytidine, all trans retinoic acid, doxorubicin, vincristine, etoposide, gemcitabine, imatinib (GleevecTM), geldanamycin, 17-N-Allylamino-17-Demethoxygeldanamycin (17-AAG), flavopiridol, LY294002, bortezomib, trastuzumab, BAY 11-7082, PKC412, or PD184352, TaxolTM, also referred to as “paclitaxel”, which is a well-known anti-cancer drug which acts by enhancing and stabilizing microtubule formation, and analogs of TaxolTM, such as TaxotereTM. Compounds that have the basic taxane skeleton as a common structure feature, have also been shown to have the ability to arrest cells in the G2-M phases by stabilizing microtubules and may be useful for treating cancer in combination with the compounds described herein. Suitable anti-cancer agents may also include inhibitors of kinase associated cell proliferative disorders. Kinases prone to inhibition include, but are not limited to, Aurora-A, BTK, CDK1, CDK2, CDK3, CDK4, CDK6, CDK5, CDK7, CDK8, CDK9, ephrin receptor kinases, CHK1, CHK2, SRC, Yes, Fyn, Lck, Fer, Fes, Syk, Itk, Bmx, GSK3, JNK, MEK, PAK1, PAK2, PAK3, PAK4, PDK1, PKA, PKC, RAF, Rsk, and SGK. In particular, inhibitors of CDK4/6, including abemaciclib (Verzenio), palbociclib (Ibrance), dalpiciclib, and ribociclib (Kisqali), have the potential to be synergistic with HIF-2α inhibitors and reverse the resistance to HIF-2α inhibition; Other anti-cancer agents may include mitogen-activated protein kinase signaling inhibitors, e.g., U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmannin, or LY294002; Syk inhibitors; antibodies (e.g., rituxan); MET inhibitors, such as foretinib, carbozantinib, or crizotinib; VEGFR inhibitors, such as sunitinib, Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT sorafenib, regorafinib, lenvatinib, vandetanib, cabozantinib, axitinib, pazopanib, or tivozanib; EGFR inhibitors, such as afatinib, brivanib, cabozantinib, erlotinib, gefitinib, neratinib, or lapatinib; PI3K inhibitors, such as XL147, XL765, BKM120 (buparlisib), GDC-0941, BYL719, IPI145, BAY80-6946. BEX235 (dactolisib), CAL101 (idelalisib), GSK2636771, or TG100-115; MTOR inhibitors, such as rapamycin (sirolimus), temsirolimus, everolimus, ridaforolimus, XL388, XL765, AZD2013, PF04691502, PKI-587, BEZ235, or GDC0349; MEK inhibitors, such as AZD6244, trametinib, PD184352, pimasertinib, GDC-0973, or AZD8330; CSF1R inhibitors (PLX3397, LY3022855, etc.) and CSF1R antibodies (IMC-054, RG7155, etc); TGF beta receptor kinase inhibitors, such as LY2157299; or BTK inhibitors, such as ibrutinib. Other anti-cancer agents include proteasome inhibitors, such as carfilzomib, MLN9708, delanzomib, or bortezomib; BET inhibitors, such as INCB054329, OTX015, CPI-0610; LSD1 inhibitors, such as GSK2979552, INCB059872; HDAC inhibitors, such as panobinostat, vorinostat; DNA methyl transferase inhibitors, such as azacytidine, decitabine, and other epigenetic modulators; SHP-2 inhibitors, such as TNO155; the Bcl2 inhibitor ABT-199, and other Bcl-2 family protein inhibitors; Beta catenin pathway inhibitors, notch pathway inhibitors and hedgehog pathway inhibitors; and antibodies or other therapeutic proteins that target VEGF, including bevacizumab and aflibercept. Other anti-cancer agents/drugs that may be used in combination with the compounds of the invention disclosed herein include, but are not limited to, liver X receptor (LXR) modulators, including LXR agonists and LXR beta-selective agonists; and aryl hydrocarbon receptor (AhR) inhibitors. Other anti-cancer agents that may be employed in combination with a compound of this disclosure include Adriamycin; Dactinomycin; Bleomycin; Vinblastine; Cisplatin; acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine; interleukin II (including recombinant interleukin II, or Ril2), interferon alfa-2a; interferon alfa-2b; interferon alfa-n1; interferon alfa-n3; interferon beta-1a; interferon gamma-1 b; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride; semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloride; or combinations thereof. Other anti-cancer agents that may be employed in combination with Compound (I) or Compound (I) Form A include 20-epi-1; 25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti- dorsalizing morphogenetic protein-1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; Bfgf inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorlns; chloroquinoxaline sulfonamide; cicaprost; cis- porphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; 9-dioxamycin; diphenyl spiromustine; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflomithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; fmasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulant peptides; insulin-like growth factor-1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonal antibody, human chorionic gonadotrophin; mopidamol; multiple drug resistance gene inhibitor; multiple tumor suppressor 1-based therapy; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim; Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylerie conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; R.sub.11 retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim; SDI 1 mimetics; semustine; senescence derived 1; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen-binding protein; sizofuran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-cell division inhibitors; stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector system, erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer. Other anticancer agents that may be employed in combination with a compound of this disclosure include alkylating agents, antimetabolites, natural products, or hormones, e.g., nitrogen Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, etc.), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, etc.), and triazenes (decarbazine, etc.). Examples of antimetabolites include, but are not limited to, folic acid analogs (e.g., methotrexate), pyrimidine analogs (e.g., cytarabine), and purine analogs (e.g., mercaptopurine, thioguanine, pentostatin). Examples of natural products useful in combination with a compound of this disclosure include, but are not limited to, vinca alkaloids (e.g., vincristine), epipodophyllotoxins (e.g., etoposide), antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g., L- asparaginase), and biological response modifiers (e.g., interferon alpha). Examples of alkylating agents that may be employed in combination a compound of this disclosure) include, but are not limited to, nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, melphalan, etc.), ethylenimine and methylmelamines (e.g., hexamethlymelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, semustine, streptozocin, etc.), and triazenes (decarbazine, etc.). Examples of antimetabolites include, but are not limited to, folic acid analogs (e.g., methotrexate), pyrimidine analogs (e.g., fluorouracil, floxuridine, cytarabine), and purine analogs (e.g., mercaptopurine, thioguanine, pentostatin). Examples of hormones and antagonists useful in combination with a compound of this disclosure include, but are not limited to, adrenocorticosteroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethylstilbestrol, ethinyl estradiol), antiestrogens (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogens (e.g., flutamide), gonadotropin releasing hormone analogs (e.g., leuprolide). Other agents that may be used in the methods and compositions described herein for the treatment or prevention of cancer include platinum coordination complexes (e.g., cisplatin, carboblatin), anthracenediones (e.g., mitoxantrone), substituted ureas (e.g., hydroxyurea), methyl hydrazine derivatives (e.g., procarbazine), and adrenocortical suppressant (e.g., mitotane, aminoglutethimide). Other anti-cancer agents that may be employed in combination with Compound (I) or Form A include anti-cancer agents which act by arresting cells in the G2-M phases due by stabilizing microtubules, include Erbulozole (also known as R-55104), Dolastatin 10 (also known as DLS-10 and NSC-376128), Mivobulin isethionate (also known as CI-980), Vincristine, NSC- 639829, Discodermolide (also known as NVP-XX-A-296), ABT-751 (Abbott, also known as E- 7010), Altorhyrtins (such as Altorhyrtin A and Altorhyrtin C), Spongistatins (such as Spongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4, Spongistatin 5, Spongistatin 6, Spongistatin 7, Spongistatin 8, and Spongistatin 9), Cemadotin hydrochloride (also known as LU-103793 and Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT NSC-D-669356), Epothilones (such as Epothilone A, Epothilone B, Epothilone C (also known as desoxyepothilone A or dEpoA), Epothilone D (also referred to as KOS-862, dEpoB, and desoxyepothilone B), Epothilone E, Epothilone F, Epothilone B N-oxide, Epothilone A N-oxide, 16-aza-epothilone B, 21-aminoepothilone B (also known as BMS-310705), 21-hydroxyepothilone D (also known as Desoxyepothilone F and dEpoF), 26-fluoroepothilone), Auristatin PE (also known as NSC-654663), Soblidotin (also known as TZT-1027), LS-4559-P (Pharmacia, also known as LS-4577), LS-4578 (Pharmacia, also known as LS-477-P), LS-4477 (Pharmacia), LS- 4559 (Pharmacia), RPR-112378 (Aventis), Vincristine sulfate, DZ-3358 (Daiichi), FR-182877 (Fujisawa, also known as WS-9885B), GS-164 (Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy of Sciences), BSF-223651 (BASF, also known as ILX-651 and LU-223651), SAH- 49960 (Lilly/Novartis), SDZ-268970 (Lilly/Novartis), AM-97 (Armad/Kyowa Hakko), AM-132 (Armad), AM-138 (Armad/Kyowa Hakko), IDN-5005 (Indena), Cryptophycin 52 (also known as LY-355703), AC-7739 (Ajinomoto, also known as AVE-8063A and CS-39.HCl), AC-7700 (Ajinomoto, also known as AVE-8062, AVE-8062A, CS-39-L-Ser.HCl, and RPR-258062A), Vitilevuamide, Tubulysin A, Canadensol, Centaureidin (also known as NSC-106969), T-138067 (Tularik, also known as T-67, TL-138067 and TI-138067), COBRA-1 (Parker Hughes Institute, also known as DDE-261 and WHI-261), H10 (Kansas State University), H16 (Kansas State University), Oncocidin A1 (also known as BTO-956 and DIME), DDE-313 (Parker Hughes Institute), Fijianolide B. Laulimalide, SPA-2 (Parker Hughes Institute), SPA-1 (Parker Hughes Institute, also known as SPIKET-P), 3-IAABU (Cytoskeleton/Mt. Sinai School of Medicine, also known as MF-569), Narcosine (also known as NSC-5366), Nascapine, D-24851 (Asta Medica), A-105972 (Abbott), Hemiasterlin, 3-BAABU (Cytoskeleton/Mt. Sinai School of Medicine, also known as MF-191), TMPN (Arizona State University), Vanadocene acetylacetonate, T-138026 (Tularik), Monsatrol, Inanocine (also known as NSC-698666), 3-1AABE (Cytoskeleton/Mt. Sinai School of Medicine), A-204197 (Abbott), T-607 (Tuiarik, also known as T-900607), RPR-115781 (Aventis), Eleutherobins (such as Desmethyleleutherobin, Desaetyleleutherobin, Isoeleutherobin A, and Z-Eleutherobin), Caribaeoside, Caribaeolin, Halichondrin B, D-64131 (Asta Medica), D- 68144 (Asta Medica), Diazonamide A, A-293620 (Abbott), NPI-2350 (Nereus), Taccalonolide A, TUB-245 (Aventis), A-259754 (Abbott), Diozostatin, (-)-Phenylahistin (also known as NSCL- 96F037), D-68838 (Asta Medica), D-68836 (Asta Medica), Myoseverin B, D-43411 (Zentaris, also known as D-81862), A-289099 (Abbott), A-318315 (Abbott), HTI-286 (also known as SPA- 110, trifluoroacetate salt) (Wyeth), D-82317 (Zentaris), D-82318 (Zentaris), SC-12983 (NCI), Resverastatin phosphate sodium, BPR-OY-007 (National Health Research Institutes), and SSR- 250411 (Sanofi). Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT One or more additional immune checkpoint inhibitors may be used in combination with Compound (I) or Compound (I) Form A for treatment of HIF-2α-associated diseases, disorders, or conditions. Exemplary immune checkpoint inhibitors include inhibitors (smack molecules or biologics) against immune checkpoint molecules, such as CD27, CD28, CD40, CD122, CD96, CD73, CD39, CD47, OX40, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM, arginase, CD137 (also known as 4-1BB), ICOS, A2AR, A2BR, SHP-2, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, CD96, TIGIT, PD-1, PD-L1 and PD-L2. In some embodiments, the immune checkpoint molecule is a stimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS, OX40, GITR, CD137 and STING. In some embodiments, the immune checkpoint molecule is an inhibitory checkpoint molecule selected from B7-H3, B7-H4, BTLA, CTLA-4, IDO, TDO, Arginase, KIR, LAG3, PD-1, TIM3, CD96, TIGIT and VISTA. In some embodiments, the compounds provided herein may be used in combination with one or more agents selected from KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors and TGFR beta inhibitors. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab, pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001, or AMP-224. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab, or pembrolizumab or PDR001. In some embodiments, the anti-PD1 antibody is pembrolizumab. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments, the anti-PD-L1 monoclonal antibody is MPDL3280A (atezolizumab) or MEDI4736 (durvalumab). In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab or tremelimumab. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments, the anti- LAG3 antibody is BMS-986016 or LAG525. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of GITR, e.g., an anti-GITR antibody. In some embodiments, the anti-GITR antibody is TRX518 or, MK-4166, INCAGN01876 or MK-1248. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of OX40, e.g., an anti-OX40 antibody or OX40L fusion protein. In some embodiments, the anti-OX40 antibody is MEDI0562 or, INCAGN01949, GSK2831781, GSK-3174998, MOXR-0916, PF-04518600 or LAG525. In some embodiments, the OX40L fusion protein is MEDI6383. In some embodiments, Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT the inhibitor of an immune checkpoint molecule is an inhibitor of PD-1, e.g. an anti-PD-1 antibody. In some embodiments, the anti-PD-1 antibody is sasanlimab, cemiplimab-rwlc, nivolumab, pembrolizumab, dostarlimab, vopratelimab, spartalizumab, camrelizumab, sintilimab, tislelizumab (BGB-A287), toripalimab, INCMGA00012 (MGA012), AMP-224, AMP-514 (MEDI0680), or acrixolimab (YBL-006). In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-L1, e.g. an anti- PD-L1 antibody. In some embodiments, the anti-PD-L1 antibody is atezolizumab, durvalumab, avelumab, KN035, Cosibelimab, AUNP12, CA-170, or BMS-986189. Compound (I) or Compound (I) Form A may also be used to increase or enhance an immune response, including increasing the immune response to an antigen or to improve immunization; increasing vaccine efficacy; and increasing inflammation. In some embodiments, Compound (I) or Compound (I) Form A may be used to enhance the immune response to vaccines including, but not limited to, Listeria vaccines, oncolytic viral vaccines, and cancer vaccines such as GVAX® (granulocyte-macrophage colony-stimulating factor (GM-CF) gene-transfected tumor cell vaccine). Anti-cancer vaccines include dendritic cells, synthetic peptides, DNA vaccines and recombinant viruses. Other immune-modulatory agents also include those that block immune cell migration, such as antagonists to chemokine receptors, including CCR2 and CCR4, Sting agonists, and Toll receptor agonists. Other anti-cancer agents also include those that augment the immune system, such as adjuvants and adoptive T cell transfers. Compounds of this application may be effective in combination with CAR (Chimeric antigen receptor) T cell treatment as a booster for T cell activation. Examples The following examples are merely illustrative of the disclosure and should not be considered limiting the scope of the invention in any way, as these examples and other equivalents thereof will become apparent to those skilled in the art in light of the present disclosure and the accompanying claims.
Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Example 1 Formulation of Compound (I) Form A Compound (I) Form A was formulated as immediate release capsules supplied at 10, 50 and 200 mg dose strengths. Information about the composition of Compound (I) Form A capsules is disclosed in Table 2 below. Table 2:  Composition of Compound (I) Form A Capsules (10mg, 50 mg, and 200 mg Dose Strengths and Blends) 50 mg and 200 10 mg Strength 10 mg mg Strength 50 mg 200 mg (Bl nd) Str n th (Common Str n th Str n th t Example 2 Compound (1) Form A Phase 1/2 Open Label Dose-Escalation and Expansion Trial in Patients with ccRCC (Protocol Number NKT2152-101, version 10.0) Compound (I) Form A is currently in Phase 1/2 study in patients with ccRCC. Compound (I) Form A is being examined in an ongoing open-label, multi-center, non-randomized, multiple- dose study to evaluate the safety, tolerability, PK, PD, and anti-tumor activity of increasing immediate-release, oral doses (in capsules) of Compound (I) Form A as a single agent in sequential dose levels. Summary of Clinical Data As of 16 June 2023, 61 patients have been treated with Compound (I) Form A; 15 of whom were treated with a continuous daily dosing schedule with dosages of 50 mg, 100 mg, 200 Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT mg, or 300 mg once daily (QD) of Compound (I) Form A; and 46 of whom were treated with a loading dose followed by a maintenance dose of Compound (I) Form A at the following dosages: 200 mg QD × 7 days then 200 mg QW, 200 mg QD × 14 days then 50 mg QD, 100 mg QD × 7 days then 100 mg QW, or 200 mg QD × 28 days then 50 mg QD. Overall, Compound (I) has been well tolerated. A total of 59/61 patients (96.7%) experienced treatment-emergent adverse events (TEAEs). The most common TEAEs were anemia (41/61 patients, 67.2%) and fatigue (25/61 patients, 41.0%). A single Grade 5 TEAE was reported (disease progression unrelated to Compound (I) Form A treatment). Four/61 patients (6.6%) had a maximum TEAE severity of Grade 4: hypoxia, pain in extremity, acute kidney injury, sepsis, and bronchial obstruction in 1 patient each. The MTD was not reached. Four/61 patients (6.6%) experienced a dose reduction of Compound (I) Form A due to TEAEs. No TEAE resulting in a dose reduction occurred in more than 1 patient. Treatment interruptions due to TEAEs occurred in 28/61 patients (45.9%). Hypoxia, fatigue, and nausea were the most commonly reported TEAEs leading to treatment interruption occurring in 8/61 patients (13.1%), 6/61 patients (9.8%), and 4/61 patients (6.6%) overall, respectively. A total of 6/61 patients (9.8%) discontinued treatment due to a TEAE. Hypoxia and fatigue were the only TEAEs that resulted in treatment discontinuation in more than 1 patient (hypoxia occurred in 3/61 patients [4.9%] and fatigue occurred in 2/61 patients [3.3%] overall). Serious TEAEs were reported in 19/61 patients (33.1%). Serious TEAEs were treatment related in 5/61 patients (8.2%). Serious TEAEs that occurred in more than 1 patient overall included hypoxia (4/61 patients, 6.6%), pneumonia (2/61 patients, 3.3%), pericardial effusion (2/61 patients, 3.3%), and pain in extremity (2/61 patients, 3.3%). With a sample cutoff date of 15 February 2023, plasma Compound (I) PK data was obtained from 50 patients at 8 dosage levels, including 50 mg, 100 mg, 200 mg, and 300 mg QD of Compound (I) Form A, 100 mg QD × 7 days then 100 mg QW of Compound (I) Form A, 200 mg QD × 7 days then 200 mg QW of Compound (I) Form A, 200 mg QD × 14 days then 50 mg QD of Compound (I) Form A, and 200 mg QD × 28 days then 50 mg QD of Compound (I) Form A. Based on serial PK data at Week 1 (Day 1), dose-limited absorption rate with higher PK variability was observed at 300 mg of Compound (I) Form A. AUC values were approximately dose proportional following QD dosing on Day 1 and Day 22. For patients receiving continuous QD dosing of Compound (I) Form A, significant accumulation of Compound (I) was observed with cohort mean accumulation of AUC ratio ranging from 8.29 to 10.9 on Day 22, and an apparent steady state of Compound (I)was not achieved based on trough concentration data before dose modifications. Patients receiving loading and maintenance doses of Compound (I) Form A showed relatively flat trough PK profiles of Compound (I) after switching to maintenance doses. Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT EPO data was collected from 61 patients treated with a continuous daily dosing schedule or a loading/maintenance dose schedule of Compound (I) Form A. Rapid and significant EPO suppression was observed at all tested dosages. As of 16 June 2023, 31 out of 61 patients remained on treatment. A 2-compartmental population PK model with first-order oral absorption and first-order elimination adequately described the PK data of Compound (I) after a single dose, multiple doses, as well as PK after dose reductions and dose holds of Compound (I) Form A. The typical PK parameter values (CV%) for absorption rate constant (Ka), apparent total clearance (CL/F), apparent intercompartment clearance (Q/F), apparent volume of distribution of the central compartment (Vc/F), and apparent volume of distribution of the peripheral compartment (Vp/F) of Compound (I) were 0.741 (72%), 0.472 L/h (80%), 27.1 L/h (54%), 133 L (76%), and 543 L (84%), respectively; the model-estimated median terminal t1/2 of Compound (I) was 39 days following administration of Compound (I) Form A. The modeling analysis suggested no time- or concentration-dependent nonlinearity and that the high accumulation of Compound (I) following continuous daily dosing of Compound (I) Form A is due to slow elimination. Subsequently, an indirect population PK-EPO response model was developed based on the PK and EPO data from this study. The EPO model had first-order EPO elimination and zero-order production which was inhibited by Compound (I). The model-estimated half-maximal inhibitory concentration (IC50) and maximum fractional inhibition (Imax) of Compound (I) were 57.3 ng/mL and 0.758, respectively, following administration of Compound (I) Form A. The model adequately described the EPO inhibition at different dosage levels. Rationale for Phase 2 Expansion Dosage Selection RDE Selection Based on Clinical Safety and Efficacy Data Based on review of the overall safety, tolerability, PK, PD, and preliminary efficacy, two RDEs of Compound (I) Form A: 200 mg QD × 14 then 50 mg QD (RDE-d) and 100 mg QD × 7 then 100 mg QW (RDE-w) were endorsed by the Safety Review Committee (SRC) and selected for further evaluation in the phase 2 portion of the study in order to determine a final RP2D. Overall, dosage levels of Compound (I) Form A at or below the RDE-d level were well tolerated with promising preliminary efficacy observed in heavily pre-treated ccRCC patients. As of 18 April 2023, at the 200 mg QD × 14 then 50 mg QD dose level (RDE-d), 9 patients were enrolled and dosed with Compound (I) Form A. Duration of treatment ranged from 57 to 251 days. Overall, safety and tolerability were favorable in this cohort. Two DLTs were observed in 1 patient (Grade 3 fatigue, Grade 3 hypoxia). The most common TEAEs were anemia (100% n=9), nausea (44%, n=4), and fatigue (33%, n=3). Hypoxia occurred in 1 patient (Grade 3). Serious TEAEs occurred in 3 patients, however, only 1 was considered related to Compound (I). Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Drug interruptions due to treatment-related TEAEs (TRAEs) occurred in 22% (n=2), dose reductions due to TRAEs in 11% (n=1), and drug discontinuations due to TRAEs in 11% (n=1) of patients. Promising anti-tumor activity was also observed. Best overall response was PR (confirmed) in 2 patients, SD in 6 patients, and PD in 1 patient. As of 18 April 2023, 5 patients were continuing Compound (I) Form A treatment with a maximum duration of treatment up to 35+ weeks. Four patients discontinued treatment (2 patients due to disease progression and 2 patients due to TEAE). At the 100 mg QD × 7 then 100 mg QW dose level (RDE-w), 9 patients were enrolled and dosed with Compound (I) Form A. Safety and tolerability were favorable in this cohort. No DLTs were observed at this dose level. The most common TEAEs were anemia (89%, n=8) and fatigue (44%, n=4). Two patients reported grade 3 hypoxia. Of note, both patients also had an underlying medical history of chronic obstructive lung disease. Serious TEAEs were reported in 1 patient but were not considered related to Compound (I) Form A. Drug interruptions due to TRAEs occurred in 33% (n=3 patients), dose reductions due to TRAEs in 11% (n=1), and no patients discontinued treatment due to a TRAE. Promising anti-tumor activity was also observed. Best overall response was PR (unconfirmed) in 2 patients, SD in 4 patients, and PD in 2 patients. One patient is not yet evaluable. As of 18 April 2023, 7 patients were continuing Compound (I) Form A treatment with a maximum duration of treatment up to 29+ weeks. Two patients discontinued treatment due to disease progression. Ten patients at an intermediate dosage between RDE-d and RDE-w were enrolled and dosed with Compound (I) Form A. At this intermediate dosage of 200 mg QD × 7 then 200 mg QW dose of Compound (I) Form A, no DLTs were observed. The most common TEAEs were anemia (60%, n=6), hypoxia (30%, n=3), fatigue (50%, n=5), and dizziness (30%, n=3). Of the 3 patients with hypoxia, one had maximum grade 2, and two had maximum grade 3. Serious TEAEs were reported in 3 patients and considered related to Compound (I) in one patient (Grade 3 hypoxia). At this dosage level, best overall response was PR (unconfirmed) in two patients, SD in 4 patients, and PD in 4 patients, and treatment was ongoing in 4 patients as of the data snapshot.6 patients discontinued treatment (4 due to disease progression, 1 due to AE, and 1 due to physician decision). This dosage was well tolerated with promising preliminary efficacy observed. 9 patients at dosage above RDE-d were enrolled and dosed with 200 mg QD × 28 then 50 mg QD of Compound (I) Form A. In this dosage, anemia was observed in 67% (n=6; maximum Grade 1 n=1, maximum Grade 2 n=5) patients. Hypoxia was observed in 44% (n=4; maximum Grade 2 n=1, maximum Grade 3 n=2, maximum Grade 4 n=1) patients. Grade 3 or higher treatment related TEAEs were reported in 44% (n=4) patients (hypoxia n=2, pleural effusion n=2, fatigue n=2, pericardial effusion n=1). Serious TEAEs were reported in 44% (n=4) patients with 2 Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT patients having serious TEAEs considered related to Compound (I): hypoxia (maximum Grade 2 n=1, maximum Grade 4 n=1), fatigue (Grade 3 n=1), pericardial effusion (Grade 3 n=1), pleural effusion (Grade 3 n=1). Best overall response at the 200 mg QD × 28, then 50 mg QD level was PR (unconfirmed) in 2 patients, SD in 1 patient, and PD in 3 patients. As of the 18 April 2023 data snapshot, 3 patients were ongoing. Three patients discontinued treatment due to PD and 3 patients discontinued treatment before the initial post-baseline tumor assessment (2 patients due to TEAEs and 1 patient withdrew consent). Though no DLTs were observed at this cohort, given the overall safety/efficacy profile observed, the SRC did not recommend further evaluation of this dose level. RDE Selection Supported by Clinical Pharmacology Analysis Loading and maintenance dosing regimens PK data from the early cohorts that were treated with QD dosing of Compound (I) Form A showed continuous PK accumulation of Compound (I) and steady state of Compound (I) was not observed. PK simulation profiles at RDE-w and RDE-d suggested that it takes approximately 28 weeks to reach steady-state PK of Compound (I) after QD dosing of Compound (I) Form A according to the population PK model. The unique PK with very slow elimination necessitated sequential loading and maintenance dosing schedules to achieve and maintain target exposure levels. See Fig.5. The total maintenance doses of Compound (I) Form A per week are 100 mg and 50 mg for RDE-w and RDE-d, respectively. After the first maintenance dose of Compound (I) Form A, RDE-w and RDE-d allow a reasonably large range of exposure of Compound (I) with estimated mean Ctrough around 1080 ng/mL and 3600 ng/mL, respectively (a 3.34-fold range). Reference concentrations considered for RDE selection Pharmacologically active concentration thresholds were estimated for Compound (I) Form A using different approaches. Compound (I) Form A inhibited VEGFA secretion in 786-O cells with IC90 of 201 ng/mL in human plasma (after protein binding adjustment). In an A498 xenograft mouse model, tumor growth inhibition was estimated using a PK-tumor growth inhibition model, and the human equivalent IC90 of Compound (I) was estimated to be 2070 ng/mL (after cross- species protein binding normalization). According to the preliminary clinical PK-EPO model, Compound (I) Form A inhibited EPO production with an IC90 of 516 ng/mL. See Fig.5. At RDE- w, the population PK model-estimated mean Ctrough (90% prediction interval) of Compound (I) was 1080 ng/mL (380 – 2300 ng/mL), suggesting that RDE-w is efficacious, consistent with the observed efficacy in patients at this dosage level in the Phase 1 Dose Escalation. Serum EPO level is a sensitive PD marker for HIF2α inhibition. In the pivotal Phase 2 study of belzutifan, patients with VHL disease associated RCC showed a mean EPO decrease by Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT 60.2% following 120 mg belzutifan daily; and, in a Phase 1 dose escalation in patients with advanced RCC, a mean EPO decrease by 63% was observed across tested belzutifan dose levels (see Center for Drug Evaluation and Research (2022). "Assessing the Effects of Food on Drugs in INDs and NDAs--Clinical Pharmacology Considerations." Food and Drug Administration). In the Phase 1 Dose Escalation of Compound (I) Form A, significant EPO suppression was observed at all tested dosage levels, and the magnitude of suppression was similar to that of belzutifan at the approved dose of 120 mg QD. Significant serum EPO suppression may not reflect adequate HIF2α inhibition within the tumor. No correlation between clinical EPO suppression and efficacy has been reported. Higher dosages of belzutifan are being tested in advanced RCC patients at up to 200 mg TID (NCT04846920) which is 5 times the approved belzutifan dose for the initially approved indications (see WELIREGTM (belzutifan) Prescribing Information. Merck & Co., Inc.). In the in vitro VEGFA secretion inhibition study in 786-O cells, the unbound IC50 (IC50,u) values were 22.6 and 2.59 nM for belzutifan and Compound (I) Form A, respectively. After corrections for the potency and unbound fraction in plasma (fu, 0.55 for belzutifan and 0.0487 for Compound (I)), the model-estimated average plasma concentration of Compound (I) at RDE-w and RDE-d in the first week of maintenance treatment were 1.07 and 3.78 times the average steady-state belzutifan concentration at 120 mg QD, respectively, further supporting the RDE selection. Exposure-response analysis Exposure-safety and exposure-efficacy correlations were explored with selected clinical endpoints based on population PK model-estimated individual PK exposures corrected by actual doses. Due to different dosing intervals and dose modifications, average concentration (Cavg), defined as Cavg = AUC0-t /t of each patient was used in the analyses, where t is time of the last dose or the time of the event of interest. In the preliminary exposure-safety analysis, the maximal hemoglobin decrease from baseline correlated with baseline value (p<0.001) but not with Cavg of Compound (I) (p≥0.373). No statistically significant and clinically meaningful correlation was observed for Grade ≥2 or Grade ≥3 anemia, Grade ≥2 or Grade ≥3 hypoxia. A trend of higher probability of Grade ≥3 TEAEs at higher Cavg was observed (p=0.20), but no trend was observed for Grade ≥3 TRAEs (p=0.62). No clinical meaningful correlation was observed between time to the first dose modification due to AEs and average concentration. At the RDE-d, 7 of 9 patients had no dose modification for >14 weeks, suggesting good tolerability and safety. In a preliminary exposure-efficacy analysis, no clinically meaningful correlations with PK exposures of Compound (I) were observed for objective response, time to objective response, or best SLD change. However, patients with higher Cavg tended to have a deeper SLD decrease at the Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT first post-treatment scan (week 9) after excluding 4 patients who showed >50% disease progression (p=0.25). It is possible that the diseases of these 4 patients didn’t dependent on HIF2α signaling. In summary, RDE-w (100 mg QD × 7 days then 100 mg QW) and RDE-d (200 mg QD × 14 days then 50 mg QD) dosages of Compound (I) Form A were selected based on integrated data analysis. Pharmacologically active concentrations of Compound (I) were achieved at the above RDEs. Both RDE-w and RDE-d were efficacious with manageable safety in the Dose Escalation. PK-PD modeling and Exposure-Response analyses suggested better tumor response at higher exposures of Compound (I). RDE-w allows for Compound (I) exposure comparable to belzutifan (120 mg QD), while RDE-d allows for 3.5 fold higher maintenance dose intensity and potentially better efficacy. Trial Objectives and Purpose Primary Objectives Phase 1 ^ To identify the maximum tolerated dose (MTD) and/or the recommended doses for expansion (RDEs) of Compound (I) Form A in patients with relapsed or refractory ccRCC Phase 2 ^ To evaluate the antitumor activity of Compound (I) Form A by ORR at the RDEs in patients with ccRCC ^ To determine the recommended Phase 2 dose (RP2D) Primary Endpoints Phase 1 ^ Incidence of DLT events during the DLT monitoring period (first 21-days of dosing) Phase 2 ^ Achieving investigator assessed ORR defined as either a CR or PR by RECIST 1.1 based on computed tomography (CT) or magnetic resonance imaging (MRI) scans Secondary Objectives ^ To evaluate the overall safety and tolerability of Compound (I) Form A monotherapy ^ To determine the PK profile of Compound (I) Form A monotherapy ^ To assess the PD effects of treatment with Compound (I) Form A ^ To evaluate the ORR of Compound (I) Form A (Phase 1 only) ^ To evaluate PFS, OS, duration of response and disease control rate of Compound (I) Form A Secondary Endpoints Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Phase 1 and Phase 2 ^ Incidence of adverse events (AEs) characterized overall and by type, seriousness, relationship to study treatment, timing and severity graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0 ^ Changes in clinical laboratory parameters, vital signs and electrocardiogram (ECG) parameters and physical examination findings ^ Compound (I) Form A single-dose and multiple-dose PK parameters such as maximum concentration observed (Cmax), time at which maximal concentration was observed (tmax), area under the concentration-time curve during a dosing interval (AUC0-t), area under the concentration time curve from time zero to infinity (AUC0-∞), if data allow ^ ORR (Phase 1 only) ^ Duration of response and disease control rate (defined as CR + PR + stable disease for ≥ 8 weeks) ^ Time to response ^ Progression free survival ^ Overall survival ^ 6- and 12-month landmark OS Exploratory Objectives Phase 1 and Phase 2 ^ To explore biomarkers potentially predictive of response to Compound (I) Form A ^ To determine the effect of Compound (I) Form A on plasma levels of 4β- hydroxycholesterol as a biomarker of CYP3A4 activity ^ To determine the genotypes and infer the phenotypes of metabolic enzymes that are possibly involved in Compound (I) Form A metabolism ^ To evaluate the effect of Compound (I) Form A on the patient reported outcome for quality of life based on European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-C30) (Phase 2 only) Exploratory Endpoints ^ Compound (I) Form A effects on Serum erythropoietin (EPO) and Whole Blood Circulating tumor DNA (ctDNA) ^ Change from baseline in the patient reported outcomes for quality of life based on EORTC-QLQ-C30. Sub-Study Objectives Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT ^ Objectives for the drug-drug interaction (DDI) and food effect (FE) sub-study are included in sub-study 1. ^ Objectives for the preliminary urinary excretion and metabolite profiling sub-study are included in sub-study 2. ^ Objectives for the belzutifan pre-treated patient sub-study are included in sub-study 3. Investigational Plan Overall Study Design This study will be conducted in two parts, Phase 1 and Phase 2. Phase 1 will be conducted as a dose escalation trial in patients with ccRCC tumors to determine the MTD/RDEs of Compound (I) Form A. Phase 2 will be conducted as an expansion trial to further explore the safety, pharmacokinetics, and preliminary efficacy of the MTD or RDE to determine the RP2D in patients with advanced ccRCC. Study procedures are described below and the schedule of assessments is tabulated in Table 3 and Table 4. Patients will undergo clinic visits weekly for the first 4 weeks, then will have a visit two weeks apart at the Week 6 visits, a visit three weeks apart at the Week 9 visit and then every 4 weeks for up to 1 year from the initiation of treatment, or until withdrawal criteria are met as describedbelow. For patients deriving clinical benefit at 1 year and continuing to take study drug after 1 year, visits will occur at 12-week intervals. Patients who are discontinued from treatment or who choose to withdraw will be asked to return to the clinic for a follow-up safety visit 28 days after taking their last dose of study drug. In addition, a sub-study is added to this study to assess the effect of a high-fat meal on the PK of Compound (I) Form A and the effect of Compound (I) Form A treatment on the PK of a single oral dose of midazolam. The design is provided below. The design of another sub-study for preliminary determination of urinary excretion and metabolite profiling is provided below. The sub-study of belzutifan pre-treated patients is provided below.
Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Table 3: Phase 1 Schedule of Assessments Asses Inform Medic Physic Vital Six-m Weigh Heigh ECOG Dispe Drug Hema Serum PT/aP /
Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Iron P Urinal Pregn ECG Tumo DNA Circul PK Sa PD Sa Archi Sampl Image Echoc 0 Study Admi Adver Conco Patien 1. Assessments to be done on Day 1 of each visit week. For the Week 2 – 6 Visits, all patients will return to clinic on Weeks 2, 3, 4, and 6. Procedure windows should be adhered to when completing assessments: Pre-dose and post-dose at 0.5 hours (± 10 minutes), 1 hour (± 10 minutes), 1.5 hours (± 15 minutes), 2 hours (± 15 minutes), 4 hours (± 15 minutes), 6 hours (± 15 minutes), 8 hours (± 30 minutes), 12 hours (±1 hour), and 24 hours ( ± 2 hours). Patients assigned to the
Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT QW dosing schedule will have an additional clinic visit on Week 5 to obtain a single pre-dose PK sample. These assessments can be performed ± 1 day (24 hours). For the Week 9, 13, 17 and visits every 4 weeks thereafter, assessments can be performed ± 2 days (48 hours). Pre-dose assessments including local safety labs (hematology, serum chemistry, iron panel, urinalysis, and pregnancy test), Physical Exam, and ECOG can be performed up to 48 hours prior to each corresponding visit. In exceptional circumstances, Medical Monitor approval may be granted to perform these assessments up to 72 hours prior to the corresponding visit. Screening Labs performed within 3 days of W1D1 need not be repeated. 2. For patients deriving clinical benefit at 1 year and continuing to take study drug after 1 year, visits will be undertaken at 12-week intervals. The 12-week interval will begin after the Week 49 visit. 3. Physical examination to be performed before study drug administration at the Week 1, 4, 6, 9, 13, and 17 Visits and visits every 4 weeks thereafter through Week 49. 4. Vital signs to include systolic and diastolic blood pressure, pulse, respirations, temperature, and oxygen saturation and obtained only prior to study drug administration. Oxygen saturation (measured by pulse oximetry) should be measured at rest before study drug administration and at 6 hours after study drug administration on Week 1 Day 1 and Week 4 Day 1. 5. Hematology assessments include complete blood count (CBC), differential, platelet count, and reticulocyte count. 6. Routine serum chemistry assessments include glucose, LDH, AST, ALT, ALP, total bilirubin, albumin, electrolytes (Na, K, Cl, CO2), Ca, Mg, PO4, BUN, creatinine, total protein levels, and an iron panel. BNP and NT-proBNP is required at W1D1 and repeated as needed when a grade 3 or higher hypoxia adverse event occurs. 7. Iron panel assessments including iron (Fe), ferritin, transferrin saturation, and total iron binding capacity should be captured at Screening, Week 1, Week 4, Week 9 and every 4 weeks for the first year. 8. Samples for urinalysis (including microscopic if abnormalities on macroscopic examination) will be obtained at the Week 1, 2, 4, 6, 9, 13, and 17 Visits and every 4 weeks for the first year. Thereafter, urinalysis samples will be obtained every 12 weeks. 9. Female patients of child-bearing potential will have a serum pregnancy test within 7 days before the first study drug administration; a serum or urine pregnancy test will be performed at the Week 1, 4, 6, 9, 13, and 17 visits and visits every 4 weeks until treatment discontinuation. For female patients of child-bearing potential who discontinue treatment, home urine pregnancy testing should also be conducted monthly until 6 months after last dose of study drug and contraceptive status should be confirmed up to 6 months after the last dose of study drug. Pregnancy should be reported up to 6 months after the last dose of Compound (I) Form A. 10. An ECG will be obtained before and at 1.5 hours (± 15 minutes) after study drug administration at the Week 1 and Week 4 Visits. ECGs will be obtained prior to study drug administration only at Weeks 2, 3, 6, 9, and every 4 weeks, thereafter, through Week 49 (e.g., Week 13, Week, 17, Week 21, etc.).
Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT 11. Anti-tumor activity will be assessed via radiographic assessments of the patient’s tumor and will be conducted at Screening/baseline (within 35 days) and every 8 weeks (± 1 week) from Week 1 Day 1 for the first year. After the first year, anti-tumor assessments will be conducted every 12 weeks (± 1 week). When the last scan in the 8 week interval ends at Week 49, the next week starts the 12 week interval. 12. At the Week 1 visit, 17 mL of whole blood as 2 × 8.5 mL Pax Gene Tubes should be collected for genetic sequencing. 13. At the Week 1 and Week 9 visits, 20 mL of whole blood as 2 × 10 mL STRECK tubes should be collected for evaluation of circulating tumor DNA. 14. At the Week 1 and Week 4 Visits, patients will take their dose of Compound (I) Form A in the clinic and will have 4 mL of blood drawn for PK assessments at 0.5 hour (±10 minutes ) before and at 0.5 hour (±10 minutes), 1 hour (±10 minutes), 1.5 hour (±15 minutes), 2 hours (± 15 minutes), 4 hours (±15 minutes), 8 hours (±30 minutes), and 24 hours (±2 hour) after study drug administration. 15. Patients assigned to the QD dosing schedule will take their dose of Compound (I) Form A in the clinic at weeks 2, 3, 6, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, and 49 Visits. A 4 mL blood sample for PK assessments will be obtained before study drug administration on these days. 16. Patients assigned to the QW dosing schedule will take their dose of Compound (I) Form A in the clinic at weeks 2, 3, 5, 6, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, and 49 Visits. A 4 mL blood sample for PK assessments will be obtained before study drug administration on these days. 17. At the Week 1 and Week 4 visits, patients will have blood drawn for PD assessments at 1 hour before (+10 minutes/-40 minutes) study drug administration. Other samples for PD assessments will be obtained before study drug administration at the Week 2, 3, 6, 9, 13,17, 21, 25, 29, 33, 37, 41, 45, and 49 Visits. Patients will take their dose of Compound (I) Form A in the clinic on these days. 18. Archival tumor tissue samples will be requested for all patients at the time of enrollment as 20 unstained slides or formalin–fixed, paraffin-embedded blocks. 19. Contrast CTs or MRIs utilized during screening and subsequent scans done throughout the duration of the study should be anonymized and uploaded to the central image repository. Instructions can be found in the procedure manual. 20. An echocardiogram or MUGA for left ventricular ejection fraction (LVEF) assessment will be performed at the screening and Week 6 visits (same measurement should be used throughout the study). 21. For consenting patients and after completion of the 28-day post-treatment follow-up visit, long-term follow-up will be assessed approximately every 6 months and may be accomplished via an in-person visit, telephone contact, chart review, etc. Patient status information includes ccRCC tumor status; any therapeutic interventions for ccRCC tumors; and survival status. 22. Patients enrolled under PA v10 will have a 6MWT during Screening visit. Table 4: Phase 2 Schedule of Assessments
Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Asses Inform Medic Physic Vital Six-m Weigh Heigh ECOG EORT Dispe Drug Hema Serum em s ry
Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT PT/aP Iron P Urinal Pregn ECG Tumo DNA Circul PK Sa PD Sa Tissue Image Echoc 6 Study Admi Adver Conco Patien 1. Assessments to be done on Day 1 of each visit week. For the Week 2 – 6 Visits, all patients will return to clinic on Weeks 2, 3, 4, and 6. Procedure windows should be adhered to when completing assessments: Pre-dose and post-dose at 0.5 hours (± 10 minutes), 1 hour (± 10 minutes), 1.5 hours (± 15 minutes), 2 hours (± 15 minutes), 4 hours (± 15 minutes), 6 hours (± 15 minutes), 8 hours (± 30 minutes), 12 hours (± 1 hour), and 24 hours (± 2 hours). For Week 9, 13, 17 and
Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT visits every 4 weeks thereafter, assessments can be performed ± 2 days (48 hours). Pre-dose assessments including local safety labs (hematology, serum chemistry, iron panel, urinalysis, and pregnancy test), Physical Exam, and ECOG can be performed up to 48 hours prior to each corresponding visit. In exceptional circumstances, Medical Monitor approval may be granted to perform these assessments up to 72 hours prior to the corresponding visit. Screening Labs performed within 3 days of W1D1 need not be repeated. PK/PD sample collection windows are included in Table 5. 2. For patients deriving clinical benefit at 1 year and continuing to take study drug after 1 year, visits will be undertaken at 12-week intervals. The 12-week interval will begin after the Week 49 visit. 3. Physical examination to be performed before study drug administration at the Week 1, 4, 6, 9, 13, and 17 Visits and visits every 4 weeks thereafter through Week 49. 4. Vital signs to include systolic and diastolic blood pressure, pulse, respirations, temperature, and oxygen saturation and obtained only prior to study drug administration. Oxygen saturation (measured by pulse oximetry) should be measured at rest before study drug administration and at 6 hours after study drug administration on Week 1 Day 1 and Week 4 Day 1. 5. EORTC-QLQ-C30 should be done on Day 1 of Weeks 1, 4, 9, 13, and then every 4 weeks for the first year of treatment and every 12 weeks during extended treatment. 6. Hematology assessments include complete blood count (CBC), differential, platelet count, and reticulocyte count. 7. Routine serum chemistry assessments include glucose, LDH, AST, ALT, ALP, total bilirubin, albumin, electrolytes (Na, K, Cl, CO2), Ca, Mg, PO4, BUN, creatinine, total protein levels, and an iron panel. BNP and NT-proBNP are required at W1D1 and repeated as needed when a grade 3 or higher hypoxia adverse event occurs. 8. Iron panel assessments including iron (Fe), ferritin, transferrin saturation, and total iron binding capacity should be captured at Screening, Week 1, Week 4, Week 9 and every 4 weeks for the first year. 9. Samples for urinalysis (including microscopic if abnormalities on macroscopic examination) will be obtained at the Week 1, 2, 4, 6, 9, 13, and 17 Visits and every 4 weeks for the first year. Thereafter, urinalysis samples will be obtained every 12 weeks. 10. Female patients of child-bearing potential will have a serum pregnancy test within 7 days before the first study drug administration; a serum or urine pregnancy test will be performed at the Week 1, 4, 6, 9, 13, and 17 visits and visits every 4 weeks until treatment discontinuation. For female patients of child-bearing potential who discontinue treatment, home urine pregnancy testing should also be conducted monthly until 6 months after last dose of study drug and contraceptive status should be confirmed up to 6 months after the last dose of study drug. Pregnancy should be reported up to 6 months after the last dose of Compound (I) Form A.
Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT 11. Anti-tumor activity will be assessed via radiographic assessments of the patient’s tumor and will be conducted at Screening/baseline (within 35 days) and every 8 weeks (± 1 week) from Week 1 Day 1 for the first year. After the first year, anti-tumor assessments will be conducted every 12 weeks (± 1 week). When the last scan in the 8 week interval ends at Week 49, the next week starts the 12 week interval. At Screening (within 35 days prior to enrollment), a CT/MRI of the brain should be obtained to rule out newly diagnosed, untreated brain metastases or to document stability of previously treated brain metastases. CT/MRI brain scans should be performed at every on-study tumor assessment for chest/abdomen/pelvis for patients with brain metastases or primary brain tumors. 12. At the Week 1 visit, 17 mL of whole blood as 2 × 8.5 mL Pax Gene Tubes should be collected for genetic sequencing. 13. At the Week 1 and Week 9 visits, 20 mL of whole blood as 2 × 10 mL STRECK tubes should be collected for evaluation of circulating tumor DNA. 14. Archival tumor tissue samples will be requested for all patients at the time of enrollment as 20 unstained slides or formalin–fixed, paraffin-embedded blocks. In Phase 2 only, for the belzutifan pre-treated cohort, biopsy tissue samples are required during screening and at Week 9 from the same lesion as the pre-treatment biopsy (preferred) or at least from the same organ. For other Phase 2 Expansion cohorts, biopsy tissue samples during screening and at Week 9 are optional. 15. Contrast CTs or MRIs utilized during screening and subsequent scans done throughout the duration of the study should be anonymized and uploaded to the central image repository. Instructions can be found in the procedure manual. 16. An echocardiogram or MUGA for left ventricular ejection fraction (LVEF) assessment will be performed at the screening and Week 6 visits (same measurement should be used throughout the study). 17. On study visit days, Compound (I) Form A should be administered after all study assessments have been completed with the exception of post-dose PKs and/or ECGs. 18. For consenting patients and after completion of the 28-day post-treatment follow-up visit, long-term follow-up will be assessed approximately every 6 months and may be accomplished via an in-person visit, telephone contact, chart review, etc. Patient status information includes ccRCC tumor status; any therapeutic interventions for ccRCC tumors; and survival status. 19. Patients enrolled under PA v10 will have a 6MWT during Screening visit.
Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Table 5: PK and PD Sampling Schedule in Phase 2 Expansion Timepoint Compound (I) PD markers1 ECG2 Day Form A PK1 Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Timepoint Compound (I) PD markers1 ECG2 Day Form A PK1 le. 2. Single ECG collected via central ECG machine is required during Screening. For triplicate readings, ECGs are to be collected 10 seconds in duration, 2 minutes (±1 minute) apart, with patient resting in supine position for 5 minutes prior to recording using central ECG machine. These triplicate ECGs should be time matched with the PK sample to allow concentration-QT analysis. In addition, safety ECG (X) should be collected at the indicated timepoints. When ECG timepoints coincide with PK, vital signs, or other PD assessments, ECG collections should always be performed prior to other assessments. 3. RDE-w only 4. RDE-d only Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Phase 1 In the dose-escalation portion of the study, patients with ccRCC will be assigned to sequential dose cohorts. Using a 3 + 3 design, 3 to 6 patients will be enrolled in each dose cohort to receive Compound (I) Form A at a single dose level. The initial dose level will be 200 mg orally once daily. The dose levels will be increased by 100% until the second clinically significant Grade 2 or greater toxicities or dose-limiting toxicity (DLT) that is at least possibly related to the study drug is reported. Thereafter, the dose levels will be increased by 50% or less. The SRC, composed of sponsor representatives and principal investigators from participating sites, will meet to make all dose escalation decisions. Decisions to dose escalate will be made based on observed DLTs as well as additional supportive data such as overall safety profile, PK, pharmacodynamics, and efficacy. Alternative dosing schedules (for example, once weekly, or combination of different dose levels or dosing frequency instead of once daily dosing) may also be considered if the PK/PD profile supports a change in the dosing frequency. In addition, the SRC may review the severity of a DLT to determine if additional patients should be evaluated at a particular dose level even if the overall DLT rate would permit continued dose escalation. Escalation will proceed until a dose is deemed intolerable or until the Sponsor and SRC determine that a suitable dose has been achieved based on available data (PK, PD, safety, and clinical activity). All patients at each dose level must complete a minimum of 3 weeks of treatment before enrollment of patients at the next dose level. If 0/3 patients in a dose cohort experience a DLT during the observation period, escalation to the next higher dose level may occur. If 1/3 patients in a cohort experiences a DLT, then up to an additional 3 patients will be enrolled to reach a total of up to 6 patients at that dose level. If no more than 1/6 patients develop a DLT, escalation to the next higher dose level may occur. The dose level at which 2 or more of the 3 to 6 patients experience a DLT will be deemed intolerable, and the dose level below will be declared the MTD. At least 6 patients will be treated at the MTD. Intermediate dose levels in dose escalation may be used to further characterize safety and additional dosing levels and schedules may be explored using the same 3 + 3 design. Approximately 61 patients may be enrolled in this part of the study. Patients have been dosed according to the dose-escalation regimens in Table 6 below. Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Table 6: Doses Evaluated 200 mg QD 300 mg QD y g p p or and will be conducted at Screening/baseline and every 8 weeks (± 1 week) from Week 1 Day 1 for the first year. After the first year, anti-tumor assessments will be conducted every 12 weeks (± 1 week) as outlined in the Schedule of Assessments in Table 3 and Table 4. When the last scan in the 8-week interval ends at Week 49, the next week starts the 12-week interval. The same technique will be used for imaging at baseline and each follow-up assessment. In the event that DLTs are not observed and the MTD cannot be identified, efforts will be made, using PK, PD, and anti-tumor activity data, to identify the optimal biologic dose (OBD), i.e., the dose that will most effectively produce the desired effect while remaining in the range of acceptable toxicity. The RDE will be determined based on the MTD, the overall safety profile with continued treatment, and PK data. Patient safety will be monitored with frequent physical examinations, vital sign measurements, electrocardiograms (ECGs), and hematology and chemistry laboratory studies, and by recording all AEs, as in Table 3 and Table 4. In dose escalation cohorts, serial blood samples will be obtained for analysis of the Compound (I) Form A PK and PD (e.g., assessment of EPO and/or other markers of the HIF2α pathway) at the Week 1 (Day 1) and Week 4 Visits, and before study drug administration at additional visits. A formalin-fixed, paraffin-embedded tumor tissue block or 20 unstained slides of tumor sample (archival or recent) for biomarker evaluation will be requested for all patients at study entry. Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT In the FE/DDI sub-study 1, the urinary excretion and metabolite profiling sub-study 2, and the belzutifan pre-treatment sub-study 3, additional PK assessments will be conducted, as described below. Phase 2 After determination of the RDEs, approximately 50 patients with ccRCC will be enrolled and treated with Compound (I) Form A at the selected RDEs in an effort to further assess anti- tumor activity and safety. Additional PK and PD data will also be collected. Two RDEs were selected based on data from Phase 1 Dose Escalation. See Fig.6. The lower RDE starts with 100 mg QD for 7 days followed by weekly maintenance dose of 100 mg (RDE-w). The higher RDE starts with 200 mg QD for 14 days followed by daily maintenance dose of 50 mg (RDE-d). Forty patients with no prior treatment with a HIF2α inhibitor will be randomized in a 1:1 fashion to RDE-w and RDE-d, 20 in each arm, to determine the RP2D for Compound (I) Form A. In addition, approximately 10 evaluable patients who have had prior treatment with the HIF2α inhibitor belzutifan will be enrolled at the RDE-d as described below. Archival tumor tissue samples will be requested for all patients at the time of enrollment as 20 unstained slides or formalin–fixed, paraffin-embedded blocks. In addition, for the belzutifan pre-treated cohort, biopsy tissue samples are required during screening and at Week 9 from the same lesion as the pre-treatment biopsy (preferred) or at least from the same organ. For the other Phase 2 Expansion cohorts, biopsy tissue samples during screening and at Week 9 are optional. Number of Patients Phase 1: Approximately 61 patients diagnosed with advanced ccRCC may be enrolled in the dose-escalation portion of the study to identify the MTD and/or the RDEs (including 12 patients in the FE/DDI substudy 1 and 5 patients in the urine excretion/metabolite substudy 2). Phase 2: Approximately 50 patients diagnosed with advanced ccRCC may be enrolled in the expansion cohort, including 20 patients at RDE-w and RDE-d, each without prior treatment with HIF2α inhibitor belzutifan and 10 patients who have had prior treatment with the HIF2α inhibitor belzutifan, as described below for sub-study 3. Treatment Assignment Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Following confirmation of eligibility, patients will be sequentially assigned to the next open dose cohort. The initial dose cohort will begin treatment at a dosage of 200 mg orally, once daily. Additional dosing levels and schedules may be explored based on available patient data. For expansion phase, two RDEs were selected based on data from Phase 1 Dose Escalation. Upon randomization, RDE-w starts with 100 mg QD for 7 days followed by weekly maintenance dose of 100 mg, and RDE-d starts with 200 mg QD for 14 days followed by daily maintenance dose of 50 mg. See sub-study 3 below for the sub-study in patients with prior belzutifan treatment for their treatment assignment. Dose Escalation Using a 3 + 3 design, 3 patients will be enrolled in each dose cohort. Dose escalation will be in 100% increments until the second Grade 2 or greater toxicity that is at least possibly related to the study drug is reported. Thereafter, sequential dose levels will increase by increments of up to 50% as determined by an SRC taking into consideration the available capsule strengths. Should 0/3 patients in a dose cohort develop a DLT, enrollment of patients in the next higher dose cohort will proceed. If 1/3 patients in a cohort develop a DLT, up to an additional 3 patients will be enrolled to reach a total of up to 6 patients in that dose cohort. If no more than 1/6 patients develop a DLT, escalation to the next higher dose level may occur. Should 2 or more patients in any dose cohort experience DLT, that dose level will be declared intolerable, and the next lower dose level will be declared the MTD. At least 6 patients must be treated at the MTD. Intermediate dose levels may be used to allow for a further exploration of safety. At any dose levels already confirmed to be safe and well tolerated, additional patients can be backfilled at the discretion of the SRC to collect additional PK, pharmacodynamic, and antitumor activity data. The SRC will continue to monitor the cumulative safety data from the cohorts previously declared safe and the current dose cohort under evaluation. Enrollment of patients to the current dose cohort under evaluation will take precedent. The process for dose escalation is described below. Intra-patient dose escalation will be permitted during the dose-escalation portion of this study as described below. Definition of Dose-limiting Toxicity Dose-limiting toxicities will be defined as the occurrence of any of the following events in the first 21 days of treatment for which there is no clear alternative explanation (e.g., disease related). Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Hematologic ^ Any Grade 5 toxicity ^ Febrile neutropenia (absolute neutrophil count [ANC] < 1,000/μL with a single temperature > 38.3°C (101°F) or a sustained temperature of > 38°C (100.4°F) for more than one hour.) ^ Grade 4 neutropenia lasting for > 5 days (in the absence of growth factor support) ^ Grade 3 thrombocytopenia with > Grade 1 bleeding ^ Grade 4 thrombocytopenia ^ Grade 4 anemia unexplained by underlying disease, or bleed Non-hematologic ^ Any Grade 5 toxicity Gastrointestinal ^ Grade 3 nausea, vomiting, or diarrhea that persists for > 72 hours in the absence of optimal medical intervention; or persisting > 48 hours with optimal medical intervention. Any Grade 4 should be a DLT Hepatic ^ Grade 4 elevation of serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ^ Grade 3 elevation of serum ALT or AST for > 7 days regardless of serum bilirubin level ^ Grade ≥ 3 elevation of serum ALT or AST in conjunction with a Grade ≥ 2 elevation in serum bilirubin ^ Laboratory criteria meeting Hy’s Law (ALT/AST > 3 × upper limit of normal (ULN) in conjunction with total bilirubin > 2 × ULN (without evidence of cholestasis) Pulmonary ^ Any Grade ≥ 3 hypoxia Other ^ Grade 3 or 4 non-hematologic AEs except: o Electrolyte abnormalities that last ≤ 72 hours, are not clinically complicated, and resolve spontaneously or respond to conventional medical interventions. Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT ^ Exclusion of other transient non-clinically significant Grade 3 non-hematological toxicities may be determined after discussion with the investigator and the Medical Monitor ^ Any Compound (I) Form A-related toxicity, for which no other cause can be determined, resulting in patients not being able to receive 80% of the intended study drug during the first 21 days of treatment ^ In addition, clinically significant or persistent toxicities that are not included in the above criteria may be considered a DLT following a review by NiKang and investigators Patients who do not receive at least 80% of the intended cumulative Compound (I) Form A doses during the first 21 days of treatment for reasons other than toxicity will not be evaluable for DLTs. Patients enrolled in either the food effect/DDI or urine excretion/metabolic profiling sub- studies will not be evaluated for DLTs. The assigned dose levels/regimens have been cleared by the SRC, and safety assessments will continue. Dose Modification To permit full assessment of the dose being evaluated, no dose modifications will be allowed during the 21-day DLT observation period (except after resolution of a DLT as described below). Patients who experience a DLT may be allowed to continue in the study with a dose modification after consultation with the sponsor’s medical monitor and after resolution of the toxicity to less than Grade 2 or to the baseline level. After the initial 21 days (or in the event of a resolved DLT in the 21-day period), if the patient experiences toxicity that requires dose modification, the guidelines in the Table 7 below will be used to determine the dose modification required. If the investigator believes that the guidelines should not apply, he/she will contact the sponsor’s medical monitor to discuss the circumstances and the appropriate dose modification. Dose reduction of Compound (I) Form A by one and, if needed, 2 dose levels (if available) and/or by changing to a lower dosing frequency will be allowed depending on the type and severity of toxicity encountered. Dose level modifications for patients randomized to receive RDE-d and RDE-w are listed in Table 8. The site should contact the sponsor’s medical monitor to discuss the circumstances and the appropriate dose modification. Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Individual patients who initiated treatment at a dose level below the highest tolerable dose evaluated, and who have not experienced a greater than Grade 2 toxicity during the previous treatment cycle at the Week 17 visit, may have the Compound (I) Form A dose escalated if both the Principal Investigator and the Medical Monitor agree that a dose escalation is medically warranted after considering the potential safety profile of the investigational drug, including cumulative drug toxicity (e.g., for a patient with SD who is tolerating the current dose level of therapy). The maximal intra-patients dose escalation level should be one level below or at the current actively enrolling level. In such patients, successive adjustments to progressively higher dose levels can be made at intervals of ≥ 3 weeks with the condition that the above referenced criteria are satisfied.
Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Table 7: Dose Modifications Toxic Hema Requi Hema Grade ANC Platel Platel Gastr Gr 3 for > antidi Gr 3 > 72 Pulm Gr 4 h ypo a u a es o a -po .
Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Pulm Gr 3 u a es o a -po ;
Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Pulm Gr 2 Hepat Grade accom and a Other Any ≥ medic Any o Any clinic Abbreviations: Gr = grade; ANC = absolute neutrophil count; ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal
Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Table 8: Phase 2 Dose Level Modifications RDE-d: 200 mg QD for 14 days then 50 mg QD If a patient experiences a toxicity as defined in Table 7, the first dose reduction will be to n n n e even a a ox c y a resu s n o ng rea men or a per o o more an 4 days has not resolved to a level which would allow continuation of therapy, there should be a discussion with the Medical Monitor about whether to continue observation until recovery or whether therapy should be discontinued. Replacement of Patients Patients who discontinue study drug administration before the completion of 21 days of treatment or who do not receive at least 80% of the intended doses for the first 21 days for reasons other than toxicity may be replaced in dose escalation. Dose escalation will not take place until the appropriate number of patients has completed treatment for 21 days at the designated dose level. Selection and Withdrawal of Patients Note: Selection criteria for the main study are also applicable to the sub-study. Additional inclusion and exclusion criteria for the sub-studies are detailed below. Inclusion Criteria Patients must meet all of the following criteria to be enrolled in this study. 1. Has the ability to understand and willingness to sign a written informed consent form before the performance of any study procedures Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT 2. Has locally advanced or metastatic ccRCC and has progressed during treatment, are relapsed, refractory and not amenable to curative therapy or standard therapy and has progressed during treatment with at least 1 prior therapeutic regimen 3. Must have measurable disease per the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) 4. Is of age ≥ 18 years 5. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 6. Has a life expectancy of ≥ 3 months 7. Has adequate organ function defined as follows: a. Bone marrow: ANC ≥ 1.0 × 109/L; Hgb level ≥ 10 g/dL without transfusion or erythropoietin support within 2 weeks prior to first dose; platelet count ≥ 75,000/μL b. Hepatic: transaminase levels (AST/ALT) ≤ 2.5 × ULN (≤ 5 × ULN if liver metastases is present); total bilirubin (TBILI) ≤ 1.5 × ULN in the absence of Gilbert’s disease c. Renal: serum creatinine level ≤ 2.0 × ULN or calculated creatinine clearance (CrCL) ≥ 40 mL/min (Cockcroft-Gault formula) 8. If a female patient of child-bearing potential, has a negative serum pregnancy test result within 7 days before first study drug administration 9. If a female patient, must be surgically sterile, must be post-menopausal, or must agree to use physician-approved method of birth control during screening, during the study, and for a minimum of 6 months after the last study drug administration; or if a male patient with a female partner, must agree to use physician-approved method of birth control during screening, during the study, and for a minimum of 6 months after the last study drug administration 10. Female patients of childbearing potential must meet all of the following criteria: a. Not pregnant (negative serum pregnancy test during Screening) b. Not breastfeeding c. Willing to use a protocol-recommended method of contraception or to abstain from heterosexual intercourse from the start of treatment or until at least 6 months after the last dose of treatment. Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Note: A female patient is considered to be of childbearing potential unless she has had a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy; has medically documented ovarian failure (with serum estradiol and follicle- stimulating hormone levels within the institutional laboratory postmenopausal range and a negative serum or urine beta human chorionic gonadotropin); or is menopausal (amenorrhea for ≥ 12 months). 11. Male patients who can father a child must meet all of the following criteria: a. Willing to use a protocol-recommended method of contraception or to abstain from heterosexual intercourse with females of childbearing potential from the start of treatment until at least 6 months after the last dose of treatment, and b. Willing to refrain from sperm donation from the start of treatment until at least 6 months after the last dose of treatment. Note: A male patient is considered able to father a child unless he has had a bilateral vasectomy with documented aspermia or a bilateral orchiectomy. 12. Able to swallow oral medications. 13. Ambulatory subjects need to take a 6-minute walk test (6MWT). Walking distance needs to be at least 400 meters and the change of oxygen saturation needs to be within a 5% range. Exclusion Criteria Patients will be excluded from this study if they meet any of the following criteria. 1. Known symptomatic brain metastases requiring > 10 mg/day of prednisone (or its equivalent). Patients with previously diagnosed brain metastases are eligible if they have completed their treatment, have recovered from the acute effects of radiation therapy or surgery prior to the start of Compound (I) Form A treatment, fulfill the above steroid requirement for these metastases, and are neurologically stable based on central nervous system imaging ≥4 weeks after central nervous system (CNS)- directed treatment 2. Having one or more of the following conditions: a. A pulse oximetry reading less than 95% at screening; b. Any current requirement for intermittent or chronic supplemental oxygen; Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT c. Any chronic lung condition which has required supplemental oxygen in the past d. Evidence of impending airway compromise (such as endobronchial tumor, lymphangitic spread, significant extrinsic compression of major airway) per investigator; e. Ascites requiring drainage within 28 days prior to W1D1 3. History of another malignancy except for the following: adequately treated local basal cell or squamous carcinoma of the skin, in situ cervical cancer, adequately treated papillary noninvasive bladder cancer, other adequately treated Stage 1 or stage 2 cancers currently in complete remission, or any other cancer that has been in complete remission for ≥ 2 years 4. Has failed to recover from the effects of prior anticancer therapy to baseline level or Grade 1 severity (except for alopecia) per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE); patients with treatable adverse effects such as hypothyroidism or hypertension may be enrolled if the adverse effect is controlled with treatment 5. Significant cardiovascular disease, including myocardial infarction, arterial thromboembolism, or cerebrovascular thromboembolism, within 6 months prior to start of Compound (I) Form A treatment; symptomatic dysrhythmias or unstable dysrhythmias requiring medical therapy; angina requiring therapy; symptomatic peripheral vascular disease; New York Heart Association (NYHA) Class 3 or 4 congestive heart failure (Table 9); ≥ Grade 3 hypertension (diastolic blood pressure ≥100 mmHg or systolic blood pressure ≥160 mmHg) despite adequate use of anti- hypertensives; or history of congenital prolonged QT syndrome or repeated demonstration of a QTc interval > 480 ms; ejection fraction < 40%; clinically significant pericardial or pleural effusion in the opinion of the investigator. 6. Has received prior investigational therapy or standard therapy within 5 half-lives of the agent or 4 weeks before the first administration of study drug, whichever is shorter 7. Has a bleeding diathesis or coagulopathy Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT 8. Deep vein thrombosis (DVT)/pulmonary embolism are allowed as long as patient is not symptomatic and received 2 weeks or more of adequate anticoagulation 9. Has manifestations of malabsorption due to prior gastrointestinal (GI) surgery or GI disease 10. Has any other clinically significant cardiac, respiratory, or other medical or psychiatric condition that might interfere with participation in the trial or interfere with the interpretation of trial results 11. Has had major surgery or radiation therapy within 4 weeks before first study drug administration; the following procedures are not considered to be major surgeries: thoracentesis, port placement, laparoscopy, thoracoscopy, bronchoscopy, endoscopic or ultrasonographic procedures, mediastinoscopy, skin biopsy, incisional biopsy, image-guided biopsy for diagnostic purposes, and routine dental procedures 12. Has known human immunodeficiency virus (HIV) 13. Has an active infection requiring systemic treatment 14. Is actively participating in another therapeutic clinical trial 15. Has received prior treatment with a HIF2α inhibitor (unless participating in the substudy 3 that requires previous belzutifan treatment) Withdrawal Criteria Patients have the right to withdraw from the study and study treatment at any time for any reason. The investigator may discontinue a patient from the study and/or study treatment for any of the following reasons. ^ Disease progression ^ Occurrence of an adverse event (AE), development of an intercurrent illness/condition, or change in patient’s condition that leads the investigator to be concerned about the patient’s welfare ^ Dose-limiting or intolerable toxicity ^ Non-compliance with study procedures ^ Failure to comply with study drug administration instructions, to return for follow-up, or to meet other requirements of the study ^ Pregnancy in a female patient during the study ^ Death Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT ^ Withdrawal of consent The primary reason for permanent treatment discontinuation will be recorded in the case report form (CRF). Patients who discontinue from study treatment must complete the safety follow-up visit 28 ± 7 days after the last dose of Compound (I) Form A is taken unless subsequent therapy is initiated earlier, in which case, this visit should occur before the start of subsequent therapy, and long-term follow-up assessments according to the Schedule of Assessments in Table 3 and Table 4. During the safety follow-up visit, the patient should be evaluated for continuation or resolution of any adverse or serious adverse events (AEs/SAEs). The only exception to this is when a patient specifically withdraws consent for any further contact with him or her or persons previously authorized by the patient to provide this information. Patients should notify the Investigator in writing of the decision to withdraw consent from future follow up, whenever possible. The withdrawal of consent should be explained in detail in the medical records by the Investigator, as to whether the withdrawal is only from further receipt of the investigational product or also from study procedures and/or post-treatment study follow-up and entered on the appropriate CRF page. If vital status (whether the patient is alive or dead) is being measured, publicly available information should be used to determine vital status only as appropriately directed in accordance with local law. Consenting patients who discontinue study treatment for any reason will undergo long term follow-up assessments every 6 months for up to 3 years following enrollment of the last patient into the study. Table 9: New York Heart Association Functional Classification Class Functional Capacity: How a patient with cardiac disease feels during physical Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT III Patients with cardiac disease resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes fatigue, palpitation, Sub-Study Objectives Primary sub-study objectives: ^ To have a preliminary assessment of the effect of Compound (I) Form A treatment on the PK of a single oral dose of midazolam ^ To have a preliminary assessment of the effect of a high-fat meal on the PK of oral Compound (I) Form A Secondary sub-study objective: ^ To assess incidence of adverse events (AEs) characterized overall and by type, seriousness, relationship to study treatment, timing and severity graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0 Exploratory sub-study objectives: ^ To explore biomarkers potentially predictive of response to Compound (I) Form A DDI and FE Sub-Study Design In this pilot drug-drug interaction (DDI) and food effect (FE) sub-study, up to 12 eligible patients with advanced clear cell renal cell carcinoma will be enrolled to enable 10 evaluable patients. To assess the effect of Compound (I) Form A treatment on the PK of a single oral dose of midazolam, each patient will receive a single oral dose of 5 mg midazolam on Day -3. Patients will then receive 200 mg Compound (I) Form A QD from Week 1 Day 1 to Day 7, followed by 200 mg Compound (I) Form A QW starting on Day 8 (Week 2). A second oral dose of 5 mg midazolam will be administered on Day 15 (Week 3) with the Compound (I) Form A dose on the Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT same day. Plasma midazolam and 1’-hydroxymidazolam PK will be determined up to 72 hours after both midazolam doses, and the DDI will be assessed within each patient. The effect of a high-fat meal on Compound (I) Form A PK will be evaluated in the same patients as for the DDI assessment. On Week 1 Day 1, patients will receive a single dose of 200 mg Compound (I) Form A under fasted conditions or with a high-fat meal. Patients will be enrolled into Group 1 (fasted) or Group 2 (high-fat meal) in an alternating manner. The FE on Compound (I) Form A PK will be compared between the two groups based on the 24-hour PK profile of Compound (I) Form A. After the first dose of Compound (I) Form A, all subsequent Compound (I) Form A doses will be administered on an empty stomach as defined in the main protocol, i.e., Compound (I) Form A should be taken at least 2 hours after the last meal and at least 1 hour before the next meal. See Fig.7. A Schedule of Assessments for the DDI and FE Sub-Study is shown in Table 10. Inclusion Criteria In addition to the inclusion criteria above, the following inclusion criteria are applicable to this sub-study 1. Willing to and able to take a high-fat meal within 30 min prior to the Compound (I) Form A dosing on Week 1 Day 1. 2. Adequate hepatic and renal function a. Hepatic: normal hepatic function (total bilirubin ≤ upper limit of normal (ULN) and aspartate aminotransferase (AST) ≤ ULN) or mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin > 1.0 × to 1.5 × ULN) b. Renal: measured or calculated creatinine clearance (CrCL) ≥ 60 mL/min (Cockcroft-Gault formula) Exclusion Criteria In addition to the exclusion criteria above, the following exclusion criteria are required in this sub-study: 1. Any gastrointestinal (GI) malfunction, surgeries, or conditions that could affect absorption of oral Compound (I) Form A and/or midazolam as assessed by the investigator Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT 2. Use of any drugs, investigational agents, fruits, or herbs that are strong or moderate CYP3A inhibitors or inducers within 14 days prior to Day -3 (or 5 times the half-life of the drug, whichever is longer). Example strong and moderate clinical CYP3A inhibitors can be found at https://www.fda.gov/drugs/drug-interactions-labeling/drug- development-and-drug-interactions-table-substrates-inhibitors-and-inducers#table3-2, and example strong and moderate clinical CYP3A inducers can be found at https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug- interactions-table-substrates-inhibitors-and-inducers#table3-3 and also at https://www.fda.gov/drugs/drug-interactions-labeling/healthcare-professionals-fdas- examples-drugs-interact-cyp-enzymes-and-transporter-systems. Study Design Rationale Compound (I) Form A dosage selection The Compound (I) Form A dosage for this sub-study is loading doses of 200 mg QD x 7 days followed by maintenance doses of 200 mg QW. The weekly maintenance doses are expected to maintain relatively steady exposure levels (steady state) following the loading doses. This dosage was evaluated by the Safety Review Committee (SRC) and was deemed safe and well tolerated with no dose limiting toxicity. In addition, this dose allowed for significant and sustained EPO suppression indicative of HIF2α inhibition. This dosage is to be further evaluated in future trials if supported by cumulative data. Drug-Drug Interaction Design In the DDI portion of this sub-study, the second dose of oral midazolam will be on Day 15. This will be after 7-day Compound (I) Form A loading doses and 1 maintenance dose on Day 8 and will be co-administered with a second Compound (I) Form A maintenance dose on Day 15. Given the CYP3A4 degradation t1/2 of approximately 1 day in the gut and approximately 3 days in the liver, and an estimated overall t1/2 of 36 hours, the design of the midazolam dosing is considered adequate to reveal clinically meaningful CYP3A4 induction and effect on the oral midazolam PK (see Yang, et al. Curr Drug Metab 9: 384-394, 2008; Rowland Yeo, et al. Eur J Pharm Sci 43: 160-173, 2011). Food reduces absorption of midazolam due to the delayed absorption and increased first- pass effect (see Bornemann, et al.26: 55–59, 1986). As a result, midazolam dosing should be after overnight fasting and at least 1 hour before a meal. Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Food Effect Design Given the slow elimination of Compound (I) and ethical considerations, within-patient FE assessment with a crossover design is not feasible. Thus, the FE will be assessed with two parallel groups (up to 6 patients per group). In addition, it is infeasible to collect complete PK profiles as that would require a long washout period with dosing interruption. This preliminary FE assessment will be based on a partial PK profile on Day 1 up to 24 hours, and estimated Cmax, Tmax, and AUC0-24. This is considered adequate as the absorption phase is < 24 hours in duration based on available PK data with cohort median Tmax ≤ 4.55 hours. Dosage and Administration of Study Drugs Compound (I) Form A On Week 1 Day 1, Compound (I) Form A will be given to patients at 200 mg QD × 7 days. On Week 2 (Day 8), patients will start 200 mg Compound (I) Form A QW. The dose on Week 1 Day 1 will be given either under fasted conditions (Group 1) or with a high-fat meal (Group 2). Patients will be enrolled to either of the 2 groups in an alternating manner. The fasted conditions and the high-fat meal are defined as below (see Center for Drug Evaluation and Research (2022). "Assessing the Effects of Food on Drugs in INDs and NDAs-- Clinical Pharmacology Considerations." Food and Drug Administration). Fasted Condition Following an overnight fast of at least 8 hours, patients will receive oral dosing of study drug(s) with 8 oz (240 mL) of room temperature water. No food will be allowed for at least 4 hours post-dose and no water will be allowed for at least 2 hours post-dose. Fed Condition with a high-fat meal Following an overnight fast of at least 8 hours, patients will consume a high-fat (approximately 50% of total caloric content), high-calorie (approximately 800–1000 calories total) breakfast meal containing approximately 500 to 600 calories from fat, approximately 250 calories from carbohydrates, and approximately 150 calories from protein, in the clinic. Patients must begin eating the meal 30 (±5) min prior to the planned administration of Compound (I) Form A on Week 1 Day 1. Patients should eat this meal in 30 min or less; however, oral Compound (I) Form A should be administered 30 min after the start of the meal, regardless of whether the meal was completed or not. Patients will ingest oral Compound (I) Form A with 8 oz (240 mL) of room temperature water. No food will be allowed for at least 4 hours post-dose. No water will be allowed for at least 2 hours post-dose. Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT The breakfast meal will be provided by the clinical site. A list of appropriate breakfast meals will be provided to clinical sites and patients by the sponsor. An example test meal would be two eggs fried in butter, two strips of bacon (or ham or cheese of similar caloric content), two slices of toast with butter, 4 oz of hash brown potatoes, and 8 oz (240 mL) of whole-fat milk. A different breakfast meal to suit specific dietary requirements may be substituted by the clinical site, provided that it has a similar amount of calories and protein, and carbohydrate and fat content. The nutrient content of the proposed meal must be calculated and submitted to the sponsor (or designee) for review and approval at least 3 days in advance of the patient’s scheduled fed day. On Day 15 (Week 3), Compound (I) Form A will be administered, followed immediately by the second dose of midazolam, to patients in the morning after an overnight fast of at least 8 hours and should be taken with at least 240 mL of room temperature water. The fasting will continue for at least 2 hours before a patient can ingest a standard meal. The water will be restricted for 1 hour before and after the study drug intake. The rest of the doses of Compound (I) Form A will be administered on an empty stomach. Administration of midazolam Midazolam (5 mg) for oral administration will be procured by each participating site and dispensed using the manufacturer specified dispensing instructions. Qualified personnel will prepare and dispense the midazolam dose in accordance with the current package insert. Two midazolam doses will be administered: the first on Study Day-3 alone, and the other on Day 15 (Week 3) with a co-administration of Compound (I) Form A. Midazolam will be administered to patients in the morning after an overnight fast of at least 8 hours and should be taken with at least 240 mL of room temperature water. The fasting will continue for at least 2 hours before a patient can ingest a standard meal. The water will be restricted for 1 hour before and after the study drug intake. The USPI for midazolam will be used as the reference safety information for safety reporting (see Midazolam hydrochloride syrup Prescribing Information. Padagis US, LLC). Concomitant Medication In addition to the restrictions described above, the following restrictions are required in this sub-study: Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Use of the following medications are not allowed from Day -3 to Day 18 a. Strong or moderate CYP2C19 or CYP3A4 inhibitors b. Strong or moderate CYP2C19 or CYP3A4 inducers c. grapefruit, grapefruit juice, pomelo, or Seville oranges (CYP3A4 inhibitors) or St. John’s wort (CYP3A4 inducer) Other herbal and complementary therapies should not be encouraged because of unknown side effects and potential drug interactions, but any taken by the patient should be documented appropriately on the eCRF. Example strong and moderate clinical CYP3A inhibitors can be found at https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions- table-substrates-inhibitors-and-inducers#table3-2, and example strong and moderate clinical CYP3A inducers can be found at https://www.fda.gov/drugs/drug-interactions-labeling/drug- development-and-drug-interactions-table-substrates-inhibitors-and-inducers#table3-3. Pharmacokinetic Assessment for Compound (I) Form A Blood samples for the determination of plasma Compound (I) concentrations will be collected at multiple time points as shown in Table 11. The date and time of collection of all PK blood samples should be recorded. A validated LC-MS/MS method will be used to assay the samples for plasma concentrations of Compound (I). Details for the collection, processing, storage, and shipment of samples can be found in the study laboratory manual. PK parameters will be calculated based on the serial PK data following the first dose on Day 1, including but not limited to Cmax, Tmax, Ctrough, and AUC0-24, if data allow. Pharmacokinetic Assessment for Midazolam and 1’-hydroxymidazolam Blood samples for the determination of plasma concentrations of midazolam and its metabolite 1’-hydroxymidazolam will be collected at multiple time points as shown Table 11. The date and time of collection of all PK blood samples should be recorded. A validated LC-MS/MS method will be used to assay the samples for plasma concentrations of midazolam and 1’-hydroxymidazolam. Details for the collection, processing, storage, and shipment of samples can be found in the study laboratory manual. Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT PK parameters will be calculated based on the serial PK data of midazolam and 1’- hydroxymidazolam following the first dose on Day -3 and Day 15, including but not limited to Cmax, Tmax, Clast, AUC0-last, if data allow. PD Marker Assessment Blood samples for the determination of serum concentrations of pharmacodynamic (PD) biomarkers (e.g., EPO) will be collected at multiple time points as shown in Table 11. The date and time of collection of all PD blood samples should be recorded. A validated enzyme-linked immunosorbent assay (ELISA) will be used to determine the serum level of EPO. Details for the collection, processing, storage, and shipment of samples can be found in the study laboratory manual. Safety Assessments Ongoing assessment of safety for all patients in this sub-study will be determined by monitoring of symptoms, signs, and abnormal laboratory test results. All clinically significant abnormal laboratory test results will be reported on the Adverse Event CRF and will be followed until a return to normal or baseline levels. Other safety assessments will include vital signs, physical examination, ECG, and ECOG. Sample Size Up to 12 eligible patients will be enrolled to enable 10 evaluable patients. The sample size is empirically selected to allow preliminary assessments of the DDI and the FE. Drug-Drug Interaction and Food Effect Analysis Descriptive summary statistics of PK and PD concentration data will be provided and Mean (SD) PK and PD plots will be generated. Serial plasma PK data of Compound (I), midazolam, and 1’-hydroxymidazolam will be analyzed using non-compartmental methods using Phoenix® WinNonlin® software, and the results will be further analyzed to determine the FE on Compound (I) Form A and the effect of Compound (I) Form A on oral midazolam PK as the following: Food Effect Analysis Cmax and AUC0-24 of NK2152 will be log-transformed before statistical analysis. The 90% CI for the ratio of the population geometric means between the fed and fasted conditions will be provided. Drug-Drug Interaction Analysis Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Cmax and AUCs of midazolam and 1’-hydroxymidazolam as well as the 1’- hydroxymidazolam-to-midazolam AUC ratio will be log-transformed before statistical analysis. The 90 percent CI for the ratio of the population geometric means with and without Compound (I) Form A treatment will be provided. Safety Analysis Safety analyses will be based on all patients who received at least one dose of study drug. Study drug is defined as either Compound (I) Form A or midazolam. In general, data will be summarized using descriptive statistics. Continuous data will be summarized with number of patients (n), arithmetic mean, standard deviation, median, minimum, and maximum. Categorical data will be summarized using frequency counts and percentages. A TEAE is defined as an AE with onset on or after the first dose of study drug (or that worsened from prior to the first dose of study drug). Any AE occurring after the 28-day follow- up period after discontinuation of study drug will be included in listings but will not be included in the summary tables of AEs. The number and percentage of patients experiencing 1 or more AEs will be summarized for the following classifications: ^ TEAEs by SOC and PT ^ TEAEs by SOC, PT and maximum toxicity grade ^ Compound (I) Form A-related or midazolam-related TEAEs by SOC and P ^ Compound (I) Form A-related or midazolam-related TEAEs by SOC, PT and maximum toxicity grade ^ TEAEs leading to treatment discontinuation by SOC and PT ^ TEAEs resulting in dose modifications by SOC and PT ^ CTCAE Grade ≥ 3 TEAEs by SOC and PT ^ Fatal TEAEs by SOC and PT ^ SAEs by SOC and PT ^ Compound (I) Form A-related or midazolam-related SAEs by SOC and PT Additional safety analysis will be described in the statistical analysis plan. Efficacy Analysis Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Tumor response will be evaluated by the investigator using RECIST 1.1. Efficacy analyses as described belowwill be summarized for the patients in the sub-study. Further details will be included in the statistical analysis plan.
Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Table 10: Schedule of Assesments for DDI PK and FE Sub-study Asses Mida Pre-d Asses Infor study Infor sub-st Medi Physi Vital g s
Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Six-m Weig Heigh ECO Dispe Drug Hema Serum PT/aP Iron P Urina Pregn ECG1 Tumo DNA Circu PK an Archi Samp Imag Echo 9
Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Study Admi Adve Conc Patien 1. Assessments to be done at Screening and on Day 1 of each visit week. For the Week 2 – 6 Visits, all patients will return to clinic on Weeks 2, 3, 4, and 6. Patients assigned to the QW dosing schedule will have an additional clinic visit on Week 5 to obtain a single pre-dose PK sample. These assessments can be performed ± 1 day. For the Week 9, 13, 17 and visits every 4 weeks thereafter through Week 49, assessments can be performed ± 2 days (48 hours). Pre-dose assessments including local safety labs (hematology, serum chemistry, iron panel, urinalysis, and pregnancy test), Physical Exam, and ECOG can be performed up to 48 hours prior to each corresponding visit but must be done prior to the high-fat meal on W1D1. In exceptional circumstances, Medical Monitor approval may be granted to perform these assessments up to 72 hours prior to the corresponding visit. Screening Labs performed within 3 days of W1D1 need not be repeated. For FE/DDI sub-study, D-3 midazolam dosing should occur on Monday to ensure collection of required PK samples. PK/PD sample collection windows are included in Table 11. 2. For patients deriving clinical benefit at 1 year and continuing to take study drug after 1 year, visits will be undertaken at 12-week intervals. The 12-week interval will begin after the Week 49 visit. 3. Half of the FE substudy patients will eat a high-fat meal, and the rest will be dosed under fasted conditions. Pre-dose assessments including local safety labs (hematology, serum chemistry, iron panel, urinalysis, and pregnancy test), Physical Exam, VS, ECG, and ECOG must be done prior to high-fat meal on Week 1 Day 1. The high fat meal should be consumed within 30 minutes and prior to administration of the Compound (I) Form A dose. 4. Reminder for site staff to call the patient the day before the visit to remind of overnight fasting. 5. Physical examination to be performed before study drug administration at the Week 1, 4, 6, 9, 13, and 17 Visits and visits every 4 weeks thereafter through week 49. 6. Vital signs to include systolic and diastolic blood pressure, pulse, respirations, temperature and obtained at Day –3 and prior to study drug administration. Oxygen saturation (measured by pulse oximetry) should be measured at rest before study drug administration and at 6 hours after study drug administration on Week 1 Day 1 and Week 4 Day 1. 7. Hematology assessments include CBC, differential, platelet count, and reticulocyte count.
Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT 8. Routine serum chemistry assessments include glucose, LDH, AST, ALT, ALP, total bilirubin, albumin, electrolytes (Na, K, Cl, CO2), Ca, Mg, PO4, BUN, creatinine, total protein levels, and an iron panel. BNP and NT-proBNP are required at W1D1 and repeated as needed when a grade 3 or higher hypoxia adverse event occurs. 9. Iron panel assessments including Fe, ferritin, transferrin saturation, and total iron binding capacity should be captured at Screening, Week 1, Week 4, Week 9 and every 4 weeks for the first year. 10. Samples for urinalysis (including microscopic if abnormalities on macroscopic examination) will be obtained at the Week 1, 2, 4, 6, 9, 13, and 17 Visits and every 4 weeks for the first year. Thereafter, urinalysis samples will be obtained every 12 weeks. 11. Female patients of child-bearing potential will have a serum pregnancy test within 7 days before the first study drug administration; a serum or urine pregnancy test will be performed at the Week 1, 4, 6, 9, 13, and 17 visits and visits every 4 weeks until treatment discontinuation. For female patients of child-bearing potential who discontinue treatment, home urine pregnancy testing should also be conducted monthly until 6 months after last dose of study drug and contraceptive status should be confirmed up to 6 months after the last dose of study drug. Pregnancy should be reported up to 6 months after the last dose of Compound (I) Form A. 12. An ECG will be obtained before and at 1.5 hours after study drug administration at the Week 1 and Week 4 Visits. ECGs will be obtained prior to study drug administration only at Weeks 2, 3, 6, 9, and every 4 weeks, thereafter, through Week 49 (e.g., Week 13, Week, 17, Week 21, etc.). 13. Anti-tumor activity will be assessed via radiographic assessments of the patient’s tumor and will be conducted at Screening/baseline (within 35 days) and every 8 weeks (± 1 week) from Week 1 Day 1 for the first year. After the 1st year, anti-tumor assessments will be conducted every 12 weeks (± 1 week) as outlined in the Schedule of Assessments (Table 3 and Table 4). When the last scan in the 8 week interval ends at Week 49, the next week starts the 12 week interval. 14. At the Week 1 visit, 2 mL of whole blood as 2 × 1 mL Paxgene blood DNA tubes should be collected for genetic sequencing of drug-metabolizing enzymes. 15. At the Week 1 and Week 9 visits, 20 mL of whole blood as 2 × 10 mL STRECK tubes should be collected for evaluation of circulating tumor DNA. 16. See Table 11 for details. 17. Archival tumor tissue samples will be requested for all patients at the time of enrollment as 20 unstained slides or formalin–fixed, paraffin-embedded blocks. 18. Contrast CTs or MRIs utilized during screening and subsequent scans done throughout the duration of the study should be anonymized and uploaded to the central image repository. Instructions can be found in the procedure manual. 19. An echocardiogram or MUGA for left ventricular ejection fraction (LVEF) assessment will be performed at the screening and Week 6 visits (same measurement should be used throughout the study).
Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT 20. For consenting patients and after completion of the 28-Day post-treatment follow-up visit, long-term follow-up will be assessed approximately every 6 months and may be accomplished via an in-person visit, telephone contact, chart review, etc. Patient status information includes ccRCC tumor status; any therapeutic interventions for ccRCC tumors; and survival status. 21. Patients enrolled under PA v10 will have a 6MWT during Screening visit.
Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Table 11: Pharmacokinetic and Pharmacodynamic Sampling Schedule for the Sub- Study Day Midazolam PK Compound (I) Form A PK PD markers Day -3 Pre-dose Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Day Midazolam PK Compound (I) Form A PK PD markers Week 3 24 hours post dose ± 2 hrs Sub-study 2: Preliminary Urinary Excretion and Metabolite Profiling Sub-study Sub-Study Objectives Primary sub-study objectives: ^ To determine plasma PK of Compound (I) after a single dose and repeated doses of Compound (I) Form A ^ To determine urinary clearance (CLr) of Compound (I) after repeated doses ^ To conduct preliminary metabolite profiling in plasma and urine samples after repeated doses Secondary sub-study objective: Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT ^ To assess incidence of adverse events (AEs) characterized overall and by type, seriousness, relationship to study treatment, timing and severity graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0 Exploratory sub-study objectives: ^ To explore biomarkers potentially predictive of response to Compound (I) Form A Urinary Excretion and Metabolite Profiling Sub-Study Design In this sub-study, 5 eligible patients with advanced clear cell renal cell carcinoma will be enrolled. Patients will receive 200 mg Compound (I) Form A QD for Week 1 and Week 2 (Day 1 to Day 14), followed by 50 mg Compound (I) Form A QD starting on Week 3 (Day 15). Serial plasma PK samples will be collected on Day 1 and Day 22, and additional sparse pre-dose plasma samples will be collected during the treatment course. On Day 22, total 24-hour urine will be collected from each patient. Urine will be collected in 3 time periods: 0-2 hours, 2- 6 hours, and 6-24 hours. The first 2 periods (up to 6 hours) will be collected during the clinical visit. The total volumes of urine for each period should be recorded. The third period will not be collected during the clinical visit. Patients will be instructed to collect the total urine, measure and record the volume, and store 2 aliquots of urine samples. Patients will return to the clinic with the urine samples on the second day (Day 23). The plasma and urine samples will be analyzed to determine Compound (I) concentration and urinary excretion. In addition, the Day 22 plasma samples and urine samples will be analyzed for metabolite profiling. See Fig.8. A Schedule of Assessments for the Urinary Excretion and Metabolite Profiling Sub-Study is shown in Table 12. Inclusion Criteria In addition to the inclusion criteria above in the main protocol, the following inclusion criteria are applicable to this sub-study: 1. Adequate hepatic and renal function a. Hepatic: normal hepatic function (total bilirubin ≤ upper limit of normal (ULN) and aspartate aminotransferase (AST) ≤ ULN) or mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin > 1.0 × to 1.5 × ULN) Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT b. Renal: measured or calculated creatinine clearance (CrCL) ≥ 60 mL/min (Cockcroft-Gault formula) Exclusion Criteria In addition to the exclusion criteria abovein the main protocol, the following exclusion criteria are required in this sub-study: 1. Use of any drugs, investigational agents, fruits, or herbs that are strong or moderate CYP3A inhibitors or inducers within 14 days prior to Day -3 (or 5 times the half-life of the drug, whichever is longer). Example strong and moderate clinical CYP3A inhibitors can be found at https://www.fda.gov/drugs/drug-interactions-labeling/drug-development- and-drug-interactions-table-substrates-inhibitors-and-inducers#table3-2, and example strong and moderate clinical CYP3A inducers can be found at https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug- interactions-table-substrates-inhibitors-and-inducers#table3-3. Study Design Rationale Compound (I) Form A dosage selection The Compound (I) Form A dosage for this sub-study is loading doses of 200 mg QD × 14 days followed by maintenance doses of 50 mg QD. The daily maintenance doses are expected to maintain relatively steady exposure levels (approximate steady state) following the loading doses. This dosage was evaluated by the Safety Review Committee (SRC) and was deemed safe and well tolerated with no dose limiting toxicity. Currently, a recommended Phase 2 dose (RP2D) hasn’t been determined. Urinary excretion design Total 24-hour urine will be collected at approximate steady state on Day 22 in 3 periods. The 24-hour urine collection is to cover the dosing interval. The design is based on practical feasibility, i.e., urine will be collected up to 6 hours (0-2 and 2-6 hours) during clinical visit and 6-24 hours at home (or off-site stay). Dosage and Administration of Study Drugs Compound (I) Form A On Week 1 Day 1, loading doses of Compound (I) Form A will be given to patients at 200 mg QD × 14 days. On Week 3 (Day 15), patients will start maintenance doses of 50 mg Compound (I) Form A QD. Compound (I) Form A doses will be administered on an empty Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT stomach at least 2 hours after the last meal and at least 1 hour before the next meal as defined in the main protocol. Concomitant Medication In addition to the restrictions above, the following restrictions are required in this sub- study: Use of the following medications are not allowed from Day 1 to Day 24 a. Strong or moderate CYP2C19 or CYP3A4 inhibitors b. Strong or moderate CYP2C19 or CYP3A4 inducers c. grapefruit, grapefruit juice, pomelo, or Seville oranges (CYP3A4 inhibitors) or St. John’s wort (CYP3A4 inducer) Other herbal and complementary therapies should not be encouraged because of unknown side effects and potential drug interactions, but any taken by the patient should be documented appropriately on the eCRF. Example strong and moderate clinical CYP3A inhibitors can be found at https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions- table-substrates-inhibitors-and-inducers#table3-2, and example strong and moderate clinical CYP3A inducers can be found at https://www.fda.gov/drugs/drug-interactions-labeling/drug- development-and-drug-interactions-table-substrates-inhibitors-and-inducers#table3-3. Pharmacokinetic Assessment for Compound (I) Form A Blood samples for the determination of plasma Compound (I) concentrations will be collected at multiple time points as shown in Table 13. The date and time of collection of all PK blood samples should be recorded. Similarly, the total urine samples (3 periods) should have date and time recorded for the start and end of each period with urine volumes recorded. Validated LC-MS/MS methods will be used to determine plasma and urine concentrations of Compound (I). Details for the collection, processing, storage, and shipment of samples can be found in the study laboratory manual. PK parameters will be calculated based on the serial PK data following the first dose on Day 1 and Day 22, including, but not limited to, Cmax, Tmax, Ctrough, AUC0-24, steady-state CL, and CLr, if data allow. A detailed sample analysis plan for plasma and urine metabolite profiling will be defined in a Metabolite Profiling Plan separately. Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT PD Marker Assessment Blood samples for the determination of serum concentrations of pharmacodynamic (PD) biomarkers (e.g., EPO) will be collected at multiple time points as shown in Table 13. The date and time of collection of all PD blood samples should be recorded. A validated enzyme-linked immunosorbent assay (ELISA) will be used to determine the serum level of EPO. Details for the collection, processing, storage, and shipment of samples can be found in the study laboratory manual. Safety Assessments Ongoing assessment of safety for all patients in this sub-study will be determined by monitoring of symptoms, signs, and abnormal laboratory test results. All clinically significant abnormal laboratory test results will be reported on the Adverse Event CRF and will be followed until a return to normal or baseline levels. Other safety assessments will include vital signs, physical examination, ECG, and ECOG. Sample Size Five evaluable patients will be enrolled. Unevaluable patient(s) will be replaced. The sample size is empirically selected to allow preliminary assessments of urinary excretion and metabolite profiling. Safety Analysis Safety analyses will be based on all patients who received at least one dose of Compound (I) Form A. In general, data will be summarized using descriptive statistics. Continuous data will be summarized with the number of patients (n), arithmetic mean, standard deviation, median, minimum, and maximum. Categorical data will be summarized using frequency counts and percentages. A TEAE is defined as an AE with onset on or after the first dose of study drug (or that worsened from prior to the first dose of study drug). Any AE occurring after the 28-day follow- up period after discontinuation of study drug will be included in listings but will not be included in the summary tables of AEs. The number and percentage of patients experiencing 1 or more AEs will be summarized for the following classifications: ^ TEAEs by SOC and PT ^ TEAEs by SOC, PT and maximum toxicity grade Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT ^ Compound (I) Form A-related TEAEs by SOC and PT ^ Compound (I) Form A-related TEAEs by SOC, PT and maximum toxicity grade ^ TEAEs leading to treatment discontinuation by SOC and PT ^ TEAEs resulting in dose modifications by SOC and PT ^ CTCAE Grade ≥ 3 TEAEs by SOC and PT ^ Fatal TEAEs by SOC and PT ^ SAEs by SOC and PT ^ Compound (I) Form A-related SAEs by SOC and PT Additional safety analysis will be described in the statistical analysis plan. Efficacy Analysis Tumor response will be evaluated by the investigator using RECIST 1.1. Efficacy analyses as described below will be summarized for the patients in the sub-study. Further details will be included in the statistical analysis plan.
Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Table 12: Schedule of Assessments for Urinary Excretion and Metabolite Profiling Asses Asses Infor study Infor sub-st Medi Physi Vital Six-m Weig Heigh ECOG
Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Dispe Drug Hema Serum PT/aP Iron P Urina Pregn ECG1 Tumo DNA Circu PK an Archi Samp Imag Echo 8 Study Admi Adve Conco a e ca os
Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Patien 1. Assessments to be done at Screening and on Day 1 of each visit week. For the Week 2 – 6 Visits, patients will return to clinic on Weeks 2, 3, 4, and 6. These assessments can be performed ± 1 day. For the Week 9, 13, 17 and visits every 4 weeks thereafter, assessments can be performed ± 2 days (48 hours). Pre-dose assessments including local safety labs (hematology, serum chemistry, iron panel, urinalysis, and pregnancy test), Physical Exam, and ECOG can be performed up to 48 hours prior to each corresponding visit. In exceptional circumstances, Medical Monitor approval may be granted to perform these assessments up to 72 hours prior to the corresponding visit. Screening Labs performed within 3 days of W1D1 need not be repeated. PK/PD samples collection windows are included in Table 13. 2. For patients deriving clinical benefit at 1 year and continuing to take study drug after 1 year, visits will be undertaken at 12-week intervals. The 12-week interval will begin after the Week 49 visit. 3. Site to remind patient that serial urine collection is required at Week 4 visit. 4. Physical examination to be performed before study drug administration at the Week 1, 4, 6, 9, 13, and 17 Visits and visits every 4 weeks thereafter through week 49. 5. Vital signs to include systolic and diastolic blood pressure, pulse, respirations, temperature, and obtained only prior to study drug administration. Oxygen saturation (measured by pulse oximetry) should be measured at rest before study drug administration and at 6 hours after study drug administration on Week 1 Day 1 and Week 4 Day 1. 6. Hematology assessments include CBC, differential, platelet count, and reticulocyte count. 7. Routine serum chemistry assessments include glucose, LDH, AST, ALT, ALP, total bilirubin, albumin, electrolytes (Na, K, Cl, CO2), Ca, Mg, PO4, BUN, creatinine, total protein levels, and an iron panel. BNP and NT-proBNP are required at W1D1 and repeated as needed when a grade 3 or higher hypoxia adverse event occurs. 8. Iron panel assessments including Fe, ferritin, transferrin saturation, and total iron binding capacity should be captured at Screening, Week 1, Week 4, Week 9 and every 4 weeks for the first year. 9. Samples for urinalysis (including microscopic if abnormalities on macroscopic examination) will be obtained at the Week 1, 2, 4, 6, 9, 13, and 17 Visits and every 4 weeks for the first year. Thereafter, urinalysis samples will be obtained every 12 weeks. 10. Female patients of child-bearing potential will have a serum pregnancy test within 7 days before the first study drug administration; a serum or urine pregnancy test will be performed at the Week 1, 4, 6, 9, 13, and 17 visits and visits every 4 weeks until treatment discontinuation. For female patients of child- bearing potential who discontinue treatment, home urine pregnancy testing should also be conducted monthly until 6 months after last dose of study drug and
Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT contraceptive status should be confirmed up to 6 months after the last dose of study drug. Pregnancy should be reported up to 6 months after the last dose of Compound (I) Form A. 11. An ECG will be obtained before and at 1.5 hours after study drug administration at the Week 1 and Week 4 Visits. ECGs will be obtained prior to study drug administration only at Weeks 2, 3, 6, 9, and every 4 weeks, thereafter, through Week 49 (e.g., Week 13, Week, 17, Week 21, etc.). 12. Anti-tumor activity will be assessed via radiographic assessments of the patient’s tumor and will be conducted at Screening/baseline (within 35 days) and every 8 weeks (± 1 week) from Week 1 Day 1 for the first year. After the first year, anti-tumor assessments will be conducted every 12 weeks (± 1 week) as outlined in the Schedule of Assessments (Table 3 and Table 4). When the last scan in the 8 week interval ends at Week 49, the next week starts the 12 week interval. 13. At week 1 visit, 2ml of whole blood as 2 × 1 mL Paxgene blood DNA tubes should be collected for the genotyping of drug metabolizing enzymes. 14. At the Week 1 and Week 9 visits, 20ml of whole blood as 2 × 10 mL STRECK tubes should be collected for evaluation of circulating tumor DNA. 15. See Table 13 for details. 16. Archival tumor tissue samples will be requested for all patients at the time of enrollment as 20 unstained slides or formalin–fixed, paraffin-embedded blocks. 17. Contrast CTs or MRIs utilized during screening and subsequent scans done throughout the duration of the study should be anonymized and uploaded to the central image repository. Instructions can be found in the procedure manual. 18. An echocardiogram or MUGA for left ventricular ejection fraction (LVEF) assessment will be performed at the screening and Week 6 visits (same measurement should be used throughout the study). 19. For consenting patients and after completion of the 28-day post-treatment follow-up visit, long-term follow-up will be assessed approximately every 6 months and may be accomplished via an in-person visit, telephone contact, chart review, etc. Patient status information includes ccRCC tumor status; any therapeutic interventions for ccRCC tumors; and survival status. 20. Patients enrolled under PA v10 will have a 6MWT during Screening visit.
Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Table 13: Pharmacokinetic and Pharmacodynamic Sampling Schedule for the Sub-Study Day Week Week Week Week Week Week p y
Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Day Week Week Week Week Week Week Week Week Week Week Week Week Week 1. Predose samples will be collected within 2 hours prior to the dose. Refer to the Laboratory Manual for details. 2. The 0-2 hr total urine and the 2-6 hr total urine will be collected during Day 22 clinical visit. The 6-24 hr total urine will be collected at home or off-site and returned to the clinic at Week 4 Day 23. Refer to the Laboratory Manual for details.
Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Sub-study 3: Phase 2 Expansion: Belzutifan Pre-treated Cohort Exploratory Sub-study Sub-Study Objectives The same study objectives noted for the main study apply to this exploratory sub-study of belzutifan pre-treated patients; however, due to the limited sample size (N=10), all objectives in this cohort are considered exploratory. Sub-Study Design Approximately 10 evaluable patients who have had prior treatment with the HIF2α inhibitor belzutifan will be enrolled. Patients in the belzutifan pre-treated cohort will receive Compound (I) Form A at the highest of the selected RDEs. The overall study design described for Phase 1 and Phase 2 and the schedule of events in Table 3 and Table 4 apply to this exploratory sub-study. Inclusion Criteria In addition to the 13 inclusion criteria in the main protocol, the following inclusion criteria are applicable to this sub-study: 1. Relapse or progressive disease following prior treatment with belzutifan a. Patient must have received at least 28 days of treatment with belzutifan 2. Willingness to undergo a pretreatment and post-treatment biopsy of the tumor. Note: Study patients who are found after initiation of protocol therapy to have inadequate biopsy tissue will not be considered to have deviated from the protocol enrollment criteria if the presence or adequacy of biopsy tissue is the only enrollment criterion that is not fulfilled. However, patients who, after informed consent, are considered to have tumors amenable to pretreatment biopsy will be considered screen failures. Exclusion Criteria Exclusion criteria #1-14 in the main studyapply to this exploratory sub-study. Exclusion criterion #15 is not applicable to this exploratory sub-study which includes patients who have received prior treatment with belzutifan (a HIF2α inhibitor). In addition to the 14 exclusion criteria in the main protocol, the following exclusion criteria are applicable to this sub-study: 1. History of toxicity or intolerance to treatment with belzutifan or other HIF2α inhibitor. Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT 2. Known presence of HIF2α mutation G323E or HIF-1B mutation F446L. Study Design Rationale Hypoxia-inducible factor 2 alpha (HIF2α) has emerged as a critical oncogenic driver in ccRCC, which often constitutively expresses high levels of HIF2α due to the high frequency of VHL functional deficiency. Belzutifan (trade name) targets HIF2α and is currently marketed and indicated for VHL disease who require therapy for associated RCC. Disease response rates to belzutifan treatment have been limited and resistance mechanisms to treatment are largely unknown. In this substudy, the antitumor activity of Compound (I) Form A, a potent and more selective HIF2α inhibitor, will be investigated in a subset of patients who have had a previous relapse after treatment with belzutifan. The rationales for selecting the RDEs are provided above. Dosage and Administration of Study Drugs See below. Concomitant Medication See below. Pharmacokinetic Assessment for Compound (I) Form A Blood samples for the determination of plasma concentrations of Compound (I) will be collected at multiple time points as shown in the PK and PD sampling schedule (Table 5). PD Marker Assessment Blood samples for the determination of serum concentrations of PD biomarkers (e.g., EPO) will be collected at multiple time points as shown in the PK and PD sampling schedule (Table 5). Safety Assessments Ongoing assessment of safety for all patients in this sub-study will be determined by monitoring of symptoms, signs, and abnormal laboratory test results. All clinically significant abnormal laboratory test results will be reported on the Adverse Event CRF and will be followed until a return to normal or baseline levels. Other safety assessments will include vital signs, physical examination, ECG, and ECOG. Sample Size Approximately 10 evaluable patients will be enrolled. The sample size is empirically selected to allow assessments of the exploratory objectives of this sub-study. Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Safety Analysis See below. Efficacy Analysis See below. Treatment of Patients Study Procedures Informed Consent Written informed consent must be obtained from the patient before any study-related procedures are performed and whenever the study procedures change, or new safety information becomes available that may affect the patient’s willingness to participate. Procedures conducted as part of the patient’s routine clinical management (e.g., blood count, imaging study) and obtained before signing of informed consent may be used for screening or baseline purposes provided the procedure meets the Protocol-defined criteria and has been performed in the timeframe of the study (i.e., within 21 days of Week 1 Day 1). All information associated with eligibility requirements must be entered into the appropriate electronic case report form (eCRF) pages. Inclusion/Exclusion Inclusion and exclusion criteria should be reviewed during the time period indicated for Screening in Table 3 and Table 4, Schedule of Assessments. Patients must meet all of the inclusion and none of the exclusion criteria for study entry. Demographics and Medical History Demographic data include gender, age, race, and ethnicity will be collected during the time period indicated for Screening in Table 3 and Table 4. Medical and surgical history will be obtained during Screening and will include documentation of the date/year of advanced solid tumor diagnosis, documentation of prior anti-cancer therapies, prior radiation therapy, prior nephrectomy, and documentation of all currently active and relevant medical and surgical conditions. Vital Signs Vital signs (systolic and diastolic blood pressure, pulse, respirations, temperature, and oxygen saturation) will be assessed as noted in Table 3 and Table 4. All blood pressure measurements should be taken after the patient has rested in a seated or semi-recumbent position. Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Oxygen saturation should be measured by pulse oximetry at pre-dose and 6-hour timepoints on Week 1 Day 1 and Week 4 (Day 22) visits and at any time a patient presents with any new or worsening respiratory symptoms. If a patient shows changes on pulse oximetry or other pulmonary-related signs (e.g., hypoxia, fever) or symptoms (e.g., dyspnea, cough, fever) consistent with possible pulmonary AEs, the patient should be immediately evaluated to rule out pulmonary toxicity. Physical Examination The physical examination will include evaluation of the head, eyes, ears, nose and throat, and cardiovascular, dermatological, musculoskeletal, respiratory, GI, and neurological systems. Height will be assessed during Screening only. Physical examinations should be performed according to the Schedule of Assessments (Table 3 and Table 4). Before administration of the first dose of study drug, any new or worsened abnormalities (other than those due to protocol- required procedures) should be recorded as medical history. After the initiation of study drug administration, any clinically significant new or worsened abnormalities noted on the physical examination will be recorded as AEs. No rectal or pelvic examination is required. Eastern Cooperative Oncology Group Performance Status Eastern Cooperative Oncology Group (ECOG) performance status will be assessed using the grading system shown in Table 14, at the time points indicated in Table 3 and Table 4. Table 14: ECOG Performance Status Grade ECOG f Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Electrocardiogram During Phase 1, a 12-lead ECG will be obtained after 5-15 minutes of rest in the supine or semi-recumbent positions using equipment at the site and according to the schedule in Table 3 and Table 4. The investigator or designee will evaluate the ECG for abnormalities. In addition, ECGs will be collected in triplicate at selected timepoints in Phase 2 Expansion (Table 5). Echocardiogram/MUGA An echocardiogram or multigated acquisition (MUGA) for left ventricular ejection fraction (LVEF) assessment will be performed at the screening and Week 6 visits (same measurement should be used throughout the study). Laboratory Assessments Clinically significant abnormal laboratory findings identified during the screening period should be recorded as medical history in the CRF. Laboratory samples will be obtained according to the schedule in Table 3 and Table 4. Clinically significant abnormal laboratory test results that are considered to be drug related should be followed. Details for the collection, processing, storage, and shipment of samples can be found in the study laboratory manual. Hematology Hematology tests will include RBC count, white blood cell (WBC) count, Hgb, HCT, WBC differential count (neutrophils, lymphocytes, eosinophils, monocytes, and basophils), mean corpuscular Hgb concentration (MCHC), mean corpuscular Hgb (MCH), mean corpuscular volume (MCV), mean platelet volume (MPV), red blood cell distribution width (RDW), platelet count (Plt), and reticulocyte count (retic). Blood Chemistry Routine serum chemistry tests will include sodium (Na), potassium (K), chloride (Cl), bicarbonate (CO2), calcium (Ca), magnesium (Mg), phosphate (PO4), blood urea nitrogen (BUN), creatinine, total protein, glucose, lactate dehydrogenase (LDH), AST, ALT, ALP, TBILI, and albumin. B-type natriuretic peptide (BNP) and N-terminal pro b-type natriuretic peptide (NT-proBNP) are required at W1D1. The same lab test will be repeated as needed when a grade 3 or higher hypoxia adverse event occurs. Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Activated Partial Thromboplastin Time Blood samples collected during screening will be used to determine the prothrombin time (PT), the activated partial thromboplastin time (aPTT), and the INR (international normalized ratio) to assess coagulation. Iron Panel Blood samples will be collected for an iron panel to include: iron (Fe), ferritin, transferrin saturation, total iron binding capacity. Urinalysis Urinalysis will include appearance, glucose, ketones, blood, protein, nitrite, bilirubin, specific gravity, pH, urobilinogen, and leukocytes. If the results are positive for blood or protein, a microscopic examination should be included. Pregnancy Test A serum pregnancy test must be performed within 7 days before the first study drug administration. Urine or serum pregnancy tests will be performed according to the Schedule of Assessments in Table 3 and Table 4 for females of child-bearing potential. Response Assessments Anti-tumor activity will be assessed via radiographic assessments of the patient’s tumor and will be conducted at Screening/baseline (within 35 days), within 7 days before the Week 9 Visit, and every 8 weeks (± 1 week) thereafter for the first year. After the first year, anti-tumor assessments will be conducted every 12 weeks (± 1 week) as outlined in the Schedule of Assessments (Table 3 and Table 4). When the last scan in the 8-week interval ends at Week 49, the next week starts the 12-week interval. Response will be assessed using RECIST v 1.1 (Table 15 and Table 16). After one year, assessments of the patient’s tumor will be made every 12 weeks. Investigators must ensure that original images (or high-quality copies) of all CT/MRI scans of disease areas are filed and available for transmission for a future possible central reading by an independent review depending on preliminary efficacy results and upon request. If possible, bone lesions should not be selected as target lesions. If brain metastases are found at baseline, brain scan or MRIs will be repeated with response assessment scans. For patients discontinuing the study treatment before documented radiographic progression, tumor assessments should continue on schedule approximately every 8 weeks or at Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT the current scan interval at the time of treatment discontinuation until radiographic evidence of disease progression, the start of a subsequent anticancer therapy, withdrawal of consent, or decision to no longer treat (e.g., supportive care only), whichever is first. Table 15: RECIST 1.1 Summary Time Point Response: Patients with Target (± Non- target) Disease Target lesions Non-target lesions New lesions Overall response not , . , . Table 16: Time Point Response: Patients with Non-target Disease Only Non-target lesions New lesions Overall response A ‘Non-CR/non-PD is preferred over ‘stable disease’ for non-target disease since SD is increasingly used as endpoint for assessment of efficacy in some studies so to assign this category when no lesions can be measured is not advised. Quality of Life Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT For Phase 2, quality of life will be self-assessed using EORTC-QLQ-C30 in the clinic at the specified time points prior to dosing. Patients will be instructed to complete the assessment without any help from friends or family members. It is recommended that assessments are completed in the morning. All scheduled assessments of the EORTC-QLQ-C30 cannot be taken home and must be completed in the clinic prior to any other study or medical procedure. Six-Minute Walk Test (6MWT) A six-minute walk test (6MWT) (see ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories, Am J Respir Crit Care Med 166:111-7, 2002; Holland, et al. Eur Respir J.44:1428-46, 2014) and pulse oximetry measurement are required during screening. Inclusion criterion #13 and exclusion criterion #2 provide guidance for a subject’s eligibility. Test procedures are summarized below: PATIENT PREPARATION 1. Comfortable clothing should be worn. 2. Appropriate shoes for walking should be worn. 3. Patients should use their usual walking aids during the test (cane, walker, etc.). 4. The patient’s usual medical regimen should be continued. 5. A light meal is acceptable before early morning or early afternoon tests. 6. Patients should not have exercised vigorously within 2 hours of beginning the test. MEASUREMENTS 1. A “warm-up” period before the test should not be performed. 2. The patient should sit at rest in a chair, located near the starting position, for at least 10 minutes before the test starts. During this time, check for contraindications, measure pulse and blood pressure, and make sure that clothing and shoes are appropriate, 3. Pulse oximetry is required for this study. If it is performed, measure and record baseline heart rate and oxygen saturation (SpO2) and follow manufacturer’s instructions to maximize the signal and to minimize motion artifact. Make sure the readings are stable before recording. Note pulse regularity and whether the oximeter signal quality is acceptable. Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT 4. Have the patient stand and rate their baseline dyspnea and overall fatigue using the Borg scale. 5. Set the lap counter to zero and the timer to 6 minutes. Assemble all necessary equipment (lap counter, timer, clipboard, Borg Scale, worksheet) and move to the starting point. 6. Instruct the patient as follows: “The object of this test is to walk as far as possible for 6 minutes. You will walk back and forth in this hallway. Six minutes is a long time to walk, so you will be exerting yourself. You will probably get out of breath or become exhausted. You are permitted to slow down, to stop, and to rest as necessary. You may lean against the wall while resting, but resume walking as soon as you are able. You will be walking back and forth around the cones. You should pivot briskly around the cones and continue back the other way without hesitation. Now I’m going to show you. Please watch the way I turn without hesitation.” Demonstrate by walking one lap yourself. Walk and pivot around a cone briskly. “Are you ready to do that? I am going to use this counter to keep track of the number of laps you complete. I will click it each time you turn around at this starting line. Remember that the object is to walk AS FAR AS POSSIBLE for 6 minutes, but don’t run or jog. Start now, or whenever you are ready.” 7. Position the patient at the starting line. You should also stand near the starting line during the test. Do not walk with the patient. As soon as the patient starts to walk, start the timer. 8. Do not talk to anyone during the walk. Use an even tone of voice when using the standard phrases of encouragement. Watch the patient. Do not get distracted and lose count of the laps. Each time the participant returns to the starting line, click the lap counter once (or mark the lap on the worksheet). Let the participant see you do it. Exaggerate the click using body language, like using a stopwatch at a race. After the first minute, tell the patient the following (in even tones): “You are doing well. You have 5 minutes to go.” When the timer shows 4 minutes remaining, tell the patient the following: “Keep up the good work. You have 4 minutes to go.” When the timer shows 3 minutes remaining, tell the patient the following: “You are doing well. You are halfway done.” When the timer shows 2 minutes remaining, tell the patient the following: “Keep up the good work. You have only 2 minutes left.” When the timer Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT shows only 1 minute remaining, tell the patient: “You are doing well. You have only 1 minute to go.” Do not use other words of encouragement (or body language to speed up). If the patient stops walking during the test and needs a rest, say this: “You can lean against the wall if you would like; then continue walking whenever you feel able.” Do not stop the timer. If the patient stops before the 6 minutes are up and refuses to continue (or you decide that they should not continue), wheel the chair over for the patient to sit on, discontinue the walk, and note on the worksheet the distance, the time stopped, and the reason for stopping prematurely. When the timer is 15 seconds from completion, say this: “In a moment I’m going to tell you to stop. When I do, just stop right where you are and I will come to you.”When the timer rings (or buzzes), say this: “Stop!” Walk over to the patient. Consider taking the chair if they look exhausted. Mark the spot where they stopped by placing a bean bag or a piece of tape on the floor. 9. Post-test: Record the postwalk Borg dyspnea and fatigue levels and ask this: “What, if anything, kept you from walking farther?” 10. This study uses a pulse oximeter. Please measure SpO2 and pulse rate from the oximeter and then remove the sensor. 11. Record the number of laps from the counter (or tick marks on the worksheet). 12. Record the additional distance covered (the number of meters in the final partial lap) using the markers on the wall as distance guides. Calculate the total distance walked, rounding to the nearest meter, and record it on the worksheet. 13. Congratulate the patient on good effort and offer a drink of water. Absolute contraindications The following absolute contraindications for the 6MWT are noted by the ATS Committee 2002 and Holland et al.2014. The absolute contraindications include acute myocardial infarction (within 30 days), unstable angina, uncontrolled arrhythmias causing symptoms or haemodynamic compromise, syncope, active endocarditis, acute myocarditis or pericarditis, symptomatic severe aortic stenosis, uncontrolled heart failure, acute pulmonary embolus or pulmonary infarction, thrombosis of lower extremities, suspected dissecting aneurysm, uncontrolled asthma, pulmonary oedema, room air SpO2 at rest ≤85%, acute respiratory failure, acute noncardiopulmonary Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT disorder that may affect exercise performance or be aggravated by exercise (i.e., infection, renal failure, thyrotoxicosis), and mental impairment leading to inability to cooperate. Patients with any of the findings below should be referred to the physician for individual clinical assessment and a decision about the conduct of the test. Stable exertional angina patients should perform the test after using their anti-angina medication, and rescue nitrate medication should be readily available. All comorbidities and medication use should be recorded prior to the test. Relative Contradictions The following relative contraindications were noted by the ATS Committee 2002 and Holland et al.2014. Left main coronary stenosis or its equivalent, stable exertional angina, moderate stenotic valvular heart disease, severe untreated arterial hypertension at rest (180 mmHg systolic, 100 mmHg diastolic), tachyarrhythmias or bradyarrhythmias, high-degree atrioventricular block, hypertrophic cardiomyopathy, significant pulmonary hypertension, advanced or complicated pregnancy, electrolyte abnormalities, and orthopaedic impairment that prevents walking. Concomitant Medications Patients may not receive systemic anti-neoplastic therapy including chemotherapy, hormonal therapy, or any investigational anti-neoplastic agent during the course of this study. Chronic systemic corticosteroid use (prednisone ≥ 12.5 mg/day or dexamethasone ≥2 mg/day) for palliative or supportive purpose is not permitted (unless administered for adrenal insufficiency). Acute emergency administration, topical application, inhaled sprays, eyedrops or local injections are permitted. Anti-convulsant therapies at a stable dose are allowed. Patients may receive limited-fraction palliative radiotherapy after first 3 weeks of Compound (I) Form A dosing to control local tumor-related symptoms if irradiation is unlikely to induce major organ toxicity and only if, in the opinion of the treating investigator, the patient does not have progressive disease. The radiation field cannot encompass a target lesion. Radiation to a target lesion is considered to be a treatment decision for progressive disease, and patients who receive radiation for a target lesion should be removed from study treatment unless, in the opinion of the investigator, the patient would continue to benefit from study treatment in discussion with the Sponsor medical monitor. Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Administration of prophylactic anti-emetics are not allowed prior to the first dose of study drug but may be given if needed during study treatment. During the first 21 days of treatment, granulocyte colony stimulating factor (G-CSF) should be administered only for severe or prolonged neutropenia or for neutropenic sepsis. There will be no constraint on the use of growth factors during subsequent treatment; however, prophylactic use is discouraged and adherence to the American Society of Clinical Oncology (ASCO) guidelines is recommended. Erythropoietin should not be administered during the first 21 days of study drug treatment. Patients should receive all necessary supportive care, including blood products, transfusions, antibiotics, pain medications, bisphosphonates, and replacement hormonal therapies (insulin, thyroid hormones, estrogen/progesterone). Herbal and complementary therapies should not be encouraged because of unknown side effects and potential drug interactions, but any taken by the patient should be documented appropriately on the eCRF. The preclinical data indicated that Compound (I) Form A is metabolically stable with CYPs; however, the amount of Compound (I) Form A oxidative metabolite formed with CYP2C19 was much higher than with other CYPs. As a precaution, it is recommended that strong inhibitors of CYP2C19 be avoided in patients receiving Compound (I) Form A. Given the abundant expression levels of CYP3As, clinically significant contributions of CYP3As to Compound (I) Form A metabolism cannot be excluded. Examples of strong clinical CYP2C19 and CYP3A4 perpetrators can be found at the following websites: https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions- table-substrates-inhibitors-and-inducers#table3-2 and https://www.fda.gov/drugs/drug- interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and- inducers#table3-3. Hormone-based contraceptives regardless of dosing route are not considered effective as Compound (I) Form A could induce CYP3A4 and reduce efficacy of such drugs. See below for requirements on effective birth control. In vitro results indicate that Compound (I) Form A is an inducer of CYP3A4 and CYP2B6. In addition, CYP3A4 induction occurs via activation of nuclear PXR, which may result in co-induction of CYP2C8, CYP2C9 and CYP2C19. Compound (I) Form A may, therefore, decrease the exposure of concomitant medications that are substrates of CYP3A4, CYP2B6, CYP2C8, CYP2C9 or CYP2C19; however, the clinical relevance of these effects is not yet clear. If Compound (I) Form A is taken with sensitive substrates of these enzymes, additional Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT monitoring of the concomitant medication’s effectiveness may be needed. Example sensitive clinical substrates of CYP3A4, CYP2B6, CYP2C8, CYP2C9, and CYP2C19 can be found at the following website: https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and- drug-interactions-table-substrates-inhibitors-and-inducers#table3-1. In vitro results indicate that Compound (I) Form A may mildly inhibit liver CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3As at clinically relevant concentrations. Compound (I) Form A may also inhibit CYP3As in the gut. Cautions should be used if Compound (I) Form A is taken with sensitive substrates of CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3As as Compound (I) Form A could potentially increase the exposures of these drugs. Example sensitive clinical substrates of these CYPs can be found at the following website: https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and- drug-interactions-table-substrates-inhibitors-and-inducers#table3-1. In addition, Compound (I) Form A could inhibit BCRP in the gut and MATE2-K in the kidney at clinically relevant dose levels. No inhibition of other transporters is expected at clinically relevant clinical dose levels. Example substrates for BCRP and MATE2-K can be found at the following website: https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and- drug-interactions-table-substrates-inhibitors-and-inducers#table4-1. All concomitant medication(s) used during the study and within 28 days before the start of study drug administration will be reported on the appropriate CRF page. Treatment Compliance The investigator or his/her designated and qualified representatives will dispense study drug only to patients enrolled in the study in accordance with the protocol. The study drug must not be used for reasons other than that described in the protocol. The number of capsules returned at a visit will be used to assess compliance; any discrepancy from the expected number of returned capsules will be discussed with the patient. Patients who fail to comply with the requirements of the study will be withdrawn from the study. Patients who have not received at least 80% of the planned doses of study drug or missed more than one Compound (I) Form A maintenance weekly dose in the 21-day DLT observation period for reasons other than treatment related toxicity will not be considered DLT evaluable and may be replaced in dose escalation. Randomization and Blinding Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT In the phase 1 dose-escalation part of the trial, no randomization or blinding will be performed. In the phase 2 dose expansion part, following confirmation of eligibility at Day 1, 40 patients with no prior treatment with a HIF2α inhibitor will be randomized (1:1) via an Interactive Response Technology (IRT) system to either RDE-w (100 mg QD × 7 then 100 mg QW) or RDE-d (200 mg QD × 14 then 50 mg QD). No blinding will be performed. Study Drug Materials and Management Study Drug Compound (I) Form A Capsules are supplied as immediate-release capsules in 3 dose strengths, 10 mg (oblong), 50 mg (oblong), and 200 mg (oblong), for oral administration. Study Drug Packaging and Labeling Compound (I) Form A capsules will be packaged in 5-, 15-, and 30-count high-density polyethylene (HDPE) bottles with induction-seal liners and a child-resistant closure. Each bottle will be labeled per local regulatory requirements. Study drug will be provided to each site pharmacy, and the investigator or designee will provide capsules to each patient, with clear instructions on the number and dose strength of capsules to be taken each day until the next study visit. Study Drug Storage Compound (I) Form A must be stored in a secure location in accordance with the study drug label. Study Drug Administration Following confirmation of eligibility, patients will be sequentially assigned to the next open dose cohort. Study drug should be taken at least 2 hours after the last meal, and patients should refrain from eating for at least 1 hour after taking each dose. For Phase 1 Dose Escalation, the initial dose cohort will begin treatment at a dosage of 200 mg orally, once daily. Dose escalation will be in 100% increments until the second Grade 2 or greater toxicity or DLT that is at least possibly related to study drug is reported. Thereafter, sequential dose levels will increase by increments of up to 50% as determined by an SRC. Intermediate dose levels may be studied as appropriate based on the available safety and PK profiles of Compound (I) Form A. Increments of dose escalation will be adjusted as needed to accommodate available capsule strengths. Every effort should be made to have patients take their study drug at the same time each day. Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT For Phase 2 Dose Expansion, patients will be randomized to receive Compound (I) Form A at RDE-w or RDE-d. For patients assigned to the RDE-w, study drug will be administered once daily during the first study week on study days 1-7. Then the weekly maintenance dose will start on Week 2, Study Day 8. For patients assigned to the RDE-d, study drug will be administered once daily during the first 14 days. Then the daily maintenance dose will start on Week 3, Study Day 15. For patients receiving daily dosing, missed doses may be made up if taken within 4 hours after the scheduled administration time. Study drug may not be taken within 8 hours before the scheduled time for administration of the next dose. Patients who vomit after study drug administration should not retake that study drug dose but should resume taking study drug at the next scheduled administration time. For patients receiving weekly dosing, missed doses may be made up as long as the next scheduled dose is more than 3 days (72 hours) away. Patients should not take a missed dose of Compound (I) Form A if it is within 3 days (72 hours) of the next scheduled dose. For patients that consume more than their prescribed dose, consideration should be given as to whether dose administration should be temporarily interrupted. Observation for any symptomatic side effects should be instituted, and safety laboratory parameters should be followed closely (consistent with the protocol or more frequently, as needed). Appropriate supportive management to mitigate adverse effects should be initiated. The occurrence of a dose deviation does not preclude further protocol therapy as long as the patient appears to be safely benefiting from treatment and the circumstances that led to the initial deviation are unlikely to recur. Study Drug Accountability, Handling and Disposal The dispensing pharmacist or designated qualified individual will write the date dispensed, dose strength dispensed, and the patient’s identification number or initials on the Drug Accountability Source Documents. Study medication will be dispensed at appropriate intervals to ensure each patient has adequate supply between study visits. All medication supplied will be accounted for on the Drug Accountability Record. All partially used or unused study drug supplies will be destroyed at the site in accordance with approved written site procedures or returned as described in the pharmacy manual. The investigator will maintain a record of the amount and dates when unused supplies were either destroyed or returned for destruction. All records will be retained as noted below. Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Pharmacokinetic Assessments Blood Sample Collection and Analysis Blood samples for the determination of plasma Compound (I) concentrations will be collected at multiple time points throughout the study as noted in Table 3 and Table 4. The date and time of collection of all PK blood samples should be recorded. Validated liquid chromatography/mass spectrometry (LC-MS/MS) methods will be used to assay the samples for plasma concentrations of Compound (I). Additional blood and urine samples will be collected for determination of plasma concentrations of Compound (I) and midazolam and for Compound (I) metabolite profiling in the sub-studies 1 and 2, as described above. Refer to Table 5 for PK sample collection schedule in Phase 2 Expansion. Details for the collection, processing, storage, and shipment of samples can be found in the study laboratory manual. Pharmacokinetic Analysis The following PK parameters of Compound (I) Form A will be calculated for all patients by non-compartmental analysis in Phase 1 Dose Escalation: ^ Time to maximum observed plasma concentration (tmax) ^ Maximum observed plasma concentration (Cmax) ^ Area under the plasma concentration–time curve from 0 to last measurable concentration (AUC0–t), computed using the linear up/log down trapezoidal rule ^ Area under the plasma concentration–time over the dose interval (0-24 hours) (AUC0–24) computed, using the linear up/log down trapezoidal rule assuming plasma concentrations can be quantified over this time interval ^ Accumulation ratio (RAUC), calculated by AUC0-tau after multiple doses/AUC0-tau after the first dose ^ Accumulation ratio (RCmax), calculated by Cmax after multiple doses/Cmax after the first dose Pharmacodynamic and Biomarker Assessments Blood Sample Collection Samples for analysis of PD effects (biomarkers) for Phase 1 Dose Escalation will be collected at multiple time points throughout the study as noted in Table 3 and Table 4. Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Pharmacodynamic biomarkers to be assessed may include EPO and other biomarkers of the HIF pathway and ccRCC. Serum EPO level will be determined using a validated ELISA method. Whole blood samples will be collected for sequencing of genes encoding proteins that may be involved in regulating Compound (I) Form A metabolism. Whole blood samples will be collected for the analysis of circulating tumor DNA at the Week 1 and Week 9 visits. Details for the collection, processing, storage, and shipment of samples for these biomarker studies can be found in the study laboratory manual. Refer to Table 5 for PD sample collection schedule for Phase 2 Expansion. Tissue Sample Collection A formalin-fixed paraffin-embedded tumor tissue block or unstained slides of tumor sample (archival or recent) for biomarker evaluation will be requested for all patients at study entry. In the case of unstained slides, 20 slides will be requested to conduct biomarker analyses. Tumor tissue samples may be analyzed for HIF2α and HIF1α expression, and for other biomarkers that may be predictive of benefit of treatment with Compound (I) Form A. Details for the collection, processing, storage, and shipment of tissue samples for these biomarkers can be found in the study laboratory manual. Analysis Biomarker analyses are dependent on the availability of appropriate biomarker assays and clinical response. Biomarker analysis may be deferred or not performed, if during or at the end of the study, it becomes clear that i) the analysis will not have sufficient scientific justification for the planned biomarker evaluation or ii) there are not enough samples and/or responses to allow for adequate biomarker assessment. In the scenario of study being terminated early or lack of sufficient clinical benefit, completion of biomarker evaluation will be based on scientific justification and the intended utility of the data. Additional Collection If it is determined at any time before the study completion that additional material is needed from a FFPE sample for the successful completion of the protocol specified analyses, the sponsor may request additional material to be retrieved from existing samples. Assessment of Safety Safety Parameters Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Safety and tolerability will be determined by symptoms, signs, and abnormal laboratory test results. The investigator will monitor the laboratory test findings. Abnormalities of laboratory test results may or may not, in the opinion of the investigator, be considered clinically significant. All clinically significant abnormal laboratory test results will be reported on the Adverse Event CRF and will be followed until a return to normal or baseline levels. Abnormal laboratory values that require intervention must be reported on the Adverse Event CRF. Any laboratory test result that is abnormal during the course of the study but not considered clinically significant will be followed at the discretion of the investigator. Adverse and Serious Adverse Events Definition of Adverse Events Adverse Event An AE is defined as any untoward medical occurrence in a patient regardless of its causal relationship to study treatment. An AE can be any unfavorable and unintended sign (including any clinically significant abnormal laboratory test result), symptom, or disease temporally associated with the use of the study drug, whether or not it is considered to be study drug related. Included in this definition are any newly occurring events and any previous condition that has increased in severity or frequency since the administration of study drug. Disease progression is a study endpoint and consequently, should not be reported as an AE. However, if a patient dies from disease progression with no other immediate causes, “disease progression” should be reported as a serious adverse event (SAE). All AEs that are observed or reported by the patient during the study (from the time of administration of the first dose of study drug until the final visit indicated in Table 3 and Table 4) must be reported, regardless of their relationship to study drug or their clinical significance. Serious Adverse Event An SAE is any AE occurring at any dose and regardless of causality that meets any of the following criteria. ^ Results in death ^ Is life-threatening ^ Requires in-patient hospitalization or prolongation of existing hospitalization ^ Results in persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT ^ Is a congenital anomaly or birth defect in an offspring of a patient taking study drug ^ Is an important medical event ^ The term “life-threatening” refers to an event in which the patient is at immediate risk of death at the time of the event. The term does not refer to an event that hypothetically might cause death if it were more severe. Important medical events are those that may not meet any of the criteria defined above; however, they may be considered serious when, based upon appropriate medical judgment, they may jeopardize the patient and may require medical or surgical intervention to prevent one of the other outcomes listed in the SAE definition. Pregnancy is not considered an AE; however, information will be collected for any pregnancies that occur during the study (from the time the first dose of study drug is administered until 6 months after the last dose of study drug). Certain pregnancy outcomes will require submission as an SAE. The investigator is responsible for reporting all SAEs that are observed or reported by the patient during the study (from the time of administration of the first dose of study drug until the final visit indicated in Table 3 and Table 4), regardless of their relationship to study drug or their clinical significance. All SAEs reported or observed during the study must be followed to resolution or until the investigator deems the event to be chronic or the patient to be stable. The investigator may be contacted to obtain additional information on any SAE that has not resolved at the time the patient completes the study. Eliciting Adverse Event Information At every study visit, patients must be asked a standard, non-directed question, such as, “How do you feel?” or “How have you been feeling since your last visit?” to elicit any medically related changes in their well-being. They may also be asked if they have been hospitalized, had any accidents, used any new medications, or changed concomitant medication regimens (including prescription drugs, over-the-counter medications, vitamins, herbal products, and minerals). Responses should be recorded in the source documents. In addition to patient observations, AEs must be documented for any clinically significant diagnosis resulting from abnormal laboratory test values, physical examination findings, or ECG abnormalities, or from other documents that are relevant to patient safety. Assessment of Causality Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT The investigator must use the following classifications and criteria to characterize the relationship or association of the study drug in causing or contributing to the AE: Unrelated: This relationship suggests that there is no association between the study drug and the reported event. Unlikely: This relationship suggests that the temporal sequence of the event with study drug administration makes a causal relationship improbable and/or other factors also provide plausible explanations. Possible: This relationship suggests that treatment with the study drug caused or contributed to the AE. That is, the event follows a reasonable temporal sequence from the time of study drug administration, and/or, follows a known response pattern to the study drug, but could have been produced by other factors. Probable: This relationship suggests that a reasonable temporal sequence of the event with study drug administration exists and, based upon the known pharmacological action of the study drug, known or previously reported adverse reactions to the study drug or class of drugs, or judgment based on the investigator’s clinical experience, the association of the event with study drug administration seems likely. Assessment of Severity The investigator will grade the severity of the AEs as Grades 1, 2, 3, 4, or 5 based on NCI CTCAE, version 5.0 or subsequent versions released during the study. If the CTCAE do not apply, severity should be defined as shown in Table 17. Table 17: Adverse Event Severity Grades Grade Description r y Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Grade Description 5 Death related to AE. _ _ _ _ Reference_5x7.pdf), will be provided to the investigator. Recording Adverse Events All conditions present before administration of the first dose of study drug should be documented as medical history. All drug-related AEs and abnormal laboratory test results reported or observed during the study must be followed to resolution (either return to baseline or within normal limits). All other AEs will be followed through the final visit indicated in Table 3 and Table 4. Information to be collected includes type of event, date of onset, date of resolution, investigator-specified assessment of severity and relationship to study drug, seriousness, action taken, and outcome. While an AE is ongoing, changes in the severity (e.g., worsening and improving) for a reporting period (e.g., between visits), each change in severity will be reported as a separate AE until the event resolves. Adverse events characterized as intermittent require documentation of onset and duration. Adverse events resulting from concurrent illnesses, reactions to concurrent illnesses, reactions to concurrent medications, or progression of disease states must also be reported. Pre- existing conditions (present before the start of the AE collection period) are considered concurrent medical conditions and should NOT be recorded as AEs. However, if the patient experiences a worsening or complication of such a concurrent condition, the worsening or complication (except disease progression) should be recorded as an AE. Investigators should ensure that the AE term recorded captures the change in the condition (e.g., “worsening of…”). Each AE should be recorded to represent a single diagnosis. Accompanying signs (including abnormal laboratory test values or ECG findings) or symptoms should NOT be recorded as additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded as an AE(s). Changes in laboratory test values or ECG parameters are only considered to be AEs if they are judged to be clinically significant (i.e., if some action or intervention is required or if the investigator judges the change to be beyond the range of normal physiologic fluctuation). If Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT abnormal laboratory test values or ECG findings are the result of pathology for which there is an overall diagnosis (e.g., increased creatinine levels in renal failure), only the diagnosis should be reported as an AE. Elective procedures (surgeries or therapies) that were scheduled before the start of AE collection are not considered AEs. These elective procedures should not be recorded as AEs but should be documented in the patient’s source documents as elective (e.g., elective periodontal surgery). However, if a pre-planned procedure is performed early (e.g., as an emergency) because of a worsening of the pre-existing condition, the worsening of the condition should be captured as an AE. Reporting Serious Adverse Events Any AE that meets the previously described criteria for “serious” must be reported to the sponsor’s designee within 24 hours from the time when site personnel first learn about the event. All SAEs occurring from the time of administration of the first dose of study drug until the final visit indicated in Table 3 and Table 4 must be reported to Medpace Clinical Safety within 24 hours of the knowledge of the occurrence. After the final visit, any SAE that the Investigator considers related to study drug must be reported to the Medpace Clinical Safety or the Sponsor/designee. The investigator must continue to follow the patient until the SAE has subsided or until the condition becomes chronic in nature, stabilizes (in the case of persistent impairment), or the patient dies. Within 24 hours of receipt of follow-up information, the Investigator must update the SAE form electronically in the EDC system for the study and submit any supporting documentation (e.g., patient discharge summary or autopsy reports) to Medpace Clinical Safety via fax or e-mail. Expedited Reporting Regulatory agencies will be notified of any fatal or life-threatening unexpected events associated with the use of the study drug as soon as possible but no later than 7 calendar days after the initial receipt of the information. Initial notification will be followed by a written report within the timeframe established by the appropriate regulatory agency. For other SAEs that do not meet the fatal or life-threatening unexpected criteria but are deemed by the investigator to be associated with the use of the study drug (that is, “possible” or “probable” in causality Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT assessment), the appropriate regulatory agencies will be notified in writing within the timeframe established by those regulatory agencies.copies of any reports will be provided to regulatory agencies regarding serious and unexpected SAEs to the investigators for their information and submission to their institutional review board (IRB), as appropriate. Principal investigators are responsible for informing their IRB of any SAEs at their site, as appropriate. SAE correspondence with regulatory authorities or IRBs must be submitted to for recording in the study file. Pregnancy Female patients of child-bearing potential are defined as patients who are not surgically sterile (no history of bilateral tubal ligation, hysterectomy, or bilateral salpingo-oophorectomy), do not have fallopian inserts with confirmed blockage, have not had reproductive potential terminated by radiation, and have not been postmenopausal for at least 1 year. Methods of Birth Control During screening, while taking study drug, and until 6 months (approximately 5 × t1/2) after taking the final dose of study drug, female patients of child-bearing potential and male patients who have female partners of child-bearing potential must practice one of the following methods of birth control: ^ Total abstinence (defined as refraining from heterosexual intercourse during the entire period outlined above), ^ Male or female sterilization ^ Placement of an intrauterine device ^ Use of a condom In vitro and preliminary clinical data suggested that Compound (I) Form A is a CYP3A4 inducer and can render some hormonal contraceptives ineffective during Compound (I) Form A treatment and up to 6 months after Compound (I) Form A treatment. Established use of oral, inserted, injected or implanted hormonal methods of contraception are allowed provided one of the above four effective methods is used in combination with the hormonal method. Suspected Pregnancy During the study, all females of child-bearing potential must be instructed to contact the investigator immediately if they suspect they might be pregnant (e.g., late or missed menstrual Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT period). Male patients must be instructed to contact the investigator if a sexual partner suspects she may be pregnant. If a patient or investigator suspects that the patient may be pregnant, study drug administration must be held until the results of a serum pregnancy test are available. If pregnancy is confirmed, the patient must discontinue taking study drug. The investigator must immediately report a pregnancy associated with study drug exposure and record the event. The protocol- required early termination procedures noted in Table 3 and Table 4 must be performed. Other appropriate follow-up procedures should be considered if indicated. Pregnancy is not considered an AE or SAE; however, it must be reported to Medpace Clinical Safety within 24 hours of knowledge of the event. Medpace Clinical Safety will then provide the Investigator/site the Exposure In Utero (EIU) form for completion. The Investigator/site must complete the EIU form and fax/email it back to Medpace Clinical Safety. The investigator must follow a pregnant patient, or the pregnant female partner of a male patient (if consenting), and report follow-up information regarding the course of the pregnancy as described above, including perinatal and neonatal outcome. Infants resulting from such pregnancies should be followed for a minimum of 8 weeks. The investigator may be contacted to request additional information throughout the course of the pregnancy. If the outcome of the pregnancy meets the criteria for immediate classification as an SAE (i.e., postpartum complication, spontaneous abortion, stillbirth, neonatal death, or congenital anomaly), the Investigator should follow the procedures for reporting an SAE. Special Situation Reports Special situation reports include reports of investigational medicinal product overdose. ^ Overdose: Refers to the administration of a quantity of a medicinal product given per administration or cumulatively (accidentally or intentionally), which is above the maximum recommended dose according to the protocol. Clinical judgement should always be applied. In cases of a discrepancy in the drug accountability, overdose will be established only when it is clear that the patient has taken additional dose(s) or the Investigator has reason to suspect that the patient has taken additional dose(s). All special situation events as described above must be reported within 24 hours of knowledge of the event. All AEs associated with these report should be reported as AEs or SAEs Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT as well as recorded on the AE eCRF and/or the SAE report form. Details of the symptoms and signs, clinical management, and outcome should be provided, when available. Statistical Considerations This section describes the statistical methodology to be used in the analysis of protocol endpoints. These methods will be documented in a formal statistical analysis plan (SAP) detailing the analyses to be performed, which will be developed before the final database lock. The SAP will serve as the final arbiter of all statistical analyses. The SAP will describe the analysis of all safety, efficacy, PK, and PD response variables. Any changes to the methodology described in the final approved SAP will be described in the clinical study report. Determination of Sample Size The sample size for Phase 1 of this study is based on the need to establish the MTD and/or the RDEs of Compound (I) Form A as a monotherapy. The sample size for the dose escalation cohorts in Phase 1 are based on a standard 3+3 design for determining the MTD/RDEs. It is anticipated that up to 61 patients may be enrolled in Phase 1. A total of 40 evaluable patients with no prior treatment with a HIF2α inhibitor will be randomized in a 1:1 fashion to two dose levels of Compound (I) Form A; 20 in each arm will be enrolled in the Phase 2 portion of the study investigating Compound (I) Form A at the selected RDE-w and RDE-d. In addition, approximately 10 patients who have had prior treatment with the HIF2α inhibitor belzutifan will be enrolled to evaluate the safety, PK, PD, and preliminary anti-tumor activity in this population at RDE-d as described in sub-study 3. The sample size required of this study is based on the need to establish the MTD and/or the RDEs of Compound (I) Form A during Phase 1 and to assess preliminary anti-tumor activity and ongoing safety assessment during the Phase 2 at the selected RDEs. Analysis Populations The following analysis populations are defined. ^ The All Patients analysis set consists of all patients who have been enrolled. This is the population of primary interest for the summaries of disposition. ^ The Safety analysis set consists of all patients who receive at least 1 dose of Compound (I) Form A. This is the population of primary interest for the summaries of the safety data. Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT ^ The Efficacy analysis set consists of all patients who receive at least one dose of Compound (I) Form A and have at least one post-baseline tumor assessment or who discontinue from the study treatment prior to their first post-baseline assessment due to death or documented disease progression. This is the population of primary interest for the summaries and analyses of the efficacy and PD data. ^ The PK analysis set consists of all patients who receive at least 1 dose of Compound (I) Form A and have evaluable PK data (at least one PK parameter can be calculated). This is the population used for the PK analyses. Statistical Analyses All statistical analyses and data summaries will be performed using SAS® (version 9.3 or higher). All PK analyses will be performed with Phoenix® WinNonlin® software. Inferential statistical methodology will not be employed in any of the data analyses. In general, data will be summarized using descriptive statistics. Continuous data will be summarized with number of patients (n), arithmetic mean, standard deviation, median, minimum, and maximum. Additionally, geometric mean and coefficient of variation will be included where applicable in PK analyses. Categorical data will be summarized using frequency counts and percentages. Time-to-event endpoints will be reported using Kaplan-Meier estimates, along with 95% confidence intervals (CIs) for median time to event. Patients who receive a particular dosage level of Compound (I) Form A will be summarized according to the dose cohort of original assignment, regardless of the dose actually received. Unless stated otherwise, all analyses and summaries will be presented by dose cohort for Phase 1 (including the sub-studies 1 and 2 within the cohorts in dose escalation with the same dose level), for all patients in Phase 2 by the RDE arms randomized to, and collectively for all patients. The summaries and analyses for Phase 2 will include the patients in the two RDE arms they are randomized to and additionally summarize all patients in the dosage levels they are assigned/randomized from Phase 1 (including the sub-studies 1 and 2) and Phase 2. Patients who have had prior treatment with the HIF2α inhibitor belzutifan as described in sub-study 3 will be summarized separately, unless indicated otherwise. All collected and derived data will be listed by dose cohort. Handling of Missing, Unused, or Spurious Data Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT No imputation of values will be performed for missing data from the treatment period of the study. For PK analysis, Compound (I) plasma concentrations that are below the limit of quantitation of the assay will be set to zero if they occur before the first measurable concentration of the PK profile and treated as “missing” if they occur after the first measurable concentration of the PK profile. Standard clinical trial monitoring and data management practices will be used to ensure the integrity of study data. Patient Characteristics and Patient Disposition The number of patients who are enrolled, the number of patients who receive at least one dose, the reason for treatment discontinuation, and reason for study discontinuation will be summarized for the All Patients analysis set. Demographics (including gender, age, race, and ethnicity), disease characteristics, medical history, and concomitant medications will be summarized for the Safety analysis set. Safety Analyses The summaries of the safety data will be provided for the Safety analysis set. Data will be summarized for each dose cohort in Phase 1 and Phase 2, all patients treated at the same dosages in both phases, including the MTD/RDEs without the patients with prior HIF-2α inhibitor treatment, and collectively for all patients. Patients who have had prior treatment with the HIF2α inhibitor belzutifan will be summarized separately. Exposure Duration of treatment, defined as date of last dose of Compound (I) Form A minus date of first dose plus 1, total dose of Compound (I) Form A (mg), and dose intensity (mg/day), defined as total dose divided by the number of days of dosing, will be summarized. Adverse Events Adverse event incidence will be coded using Medical Dictionary for Regulatory Activities (MedDRA) terminology and classified according to system organ class (SOC) and preferred term (PT). Adverse event severity will be graded according to NCI CTCAE version 5.0 or later. (https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_ Reference_5x7.pdf). A treatment-emergent AE (TEAE) is defined as an AE with onset on or after the first dose of study drug (or that worsened from prior to the first dose of study drug). Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT The number and percentage of patients experiencing 1 or more AEs will be summarized for the following classifications: ^ TEAEs by SOC and PT ^ TEAEs by SOC, PT and maximum toxicity grade ^ Compound (I) Form A-related TEAEs by SOC and PT ^ Compound (I) Form A-related TEAEs by SOC, PT and maximum toxicity grade ^ TEAEs leading to treatment discontinuation by SOC and PT ^ TEAEs resulting in dose modifications by SOC and PT ^ CTCAE Grade ≥ 3 TEAEs by SOC and PT ^ Fatal TEAEs by SOC and PT ^ SAEs by SOC and PT ^ Compound (I) Form A-related SAEs by SOC and PT Dose-limiting toxicities will be listed. The number of deaths and cause of death will be summarized overall and according to whether the death occurred within 28 days after the last dose of Compound (I) Form A or >28 days after the last dose. Clinical Laboratory Data Values and change from baseline for hematology, chemistry, and coagulation laboratory parameters will be summarized by visit. Laboratory test values that are graded by CTCAE will be summarized using shift tables comparing the baseline grade to the maximum CTCAE grade after baseline. Other Safety Data Vital sign measurements and change from baseline will be summarized by visit. ECG data and change from baseline will be summarized by visit. Physical examination data will be listed without summary. Echo results will be listed. Absolute scores of the EORTC-QLQ-C30 and the change from baseline will be summarized by visit. Additional concentration-QTc analysis may be conducted. Efficacy Analyses Response Assessment Categories Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Tumor response will be evaluated by the investigator using RECIST 1.1. The post- baseline time point assessment response categories are as follows. ^ Complete Response (CR) ^ Partial Response (PR) ^ Stable Disease (SD) ^ Progressive Disease (PD) ^ Not Evaluable (NE) Efficacy Endpoints The following efficacy endpoints will be derived from the time point response assessments. ^ Best overall response (BOR) is defined as the best confirmed response recorded up until documentation of disease progression or death from any cause, or until the patient withdraws consent. ^ ORR is defined at the percentage of patients whose BOR is CR or PR. ^ Clinical benefit rate (CBR) is defined as the percentage of patients whose best overall response is CR or PR (confirmed or unconfirmed), or SD, where the duration of SD is 8 weeks or more. ^ Duration of response (DOR) is defined for patients whose BOR is PR or CR as the time from date of first documentation of PR or better until date of disease progression or death from any cause, whichever is earlier, plus 1 day. Patients who do not progress and do not die will be censored on the date of last response assessment. ^ Progression-free survival (PFS) is defined as the time from date of the first dose of Compound (I) Form A until date of disease progression or death from any cause, whichever is earlier, plus 1 day. Patients who do not progress and do not die will be censored on the date of last response assessment. If no post-baseline response assessments are obtained for a patient, PFS will censored at Day 1 (i.e., duration of 1 day). ^ Overall Survival (OS) is defined as time from first dose to death due to any cause. Patients who are alive at the end of the study will be censored at the last known alive date. The OS rates at 6 months and 12 months will be estimated. Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT ^ Time to Response (TTR) is defined for patients with a confirmed CR or PR as the time from first dose to the first CR or PR which is subsequently confirmed. BOR, ORR, and CBR will be summarized as the number and percentage of patients satisfying the definitions above. In addition, a two-sided 95% CI will be calculated for ORR and CBR. DOR, PFS, and OS will be summarized descriptively using the Kaplan-Meier method. Two-sided 95% CIs will be calculated for the median and the 25th and 75th percentiles. OS will also be summarized for patients who receive at least 1 dose of Compound (I) Form A. TTR will be summarized descriptively. Pharmacokinetic Analyses The PK parameters will be computed from the individual plasma concentrations using a noncompartmental approach in Phase 1 Dose Escalation. Pharmacokinetic parameters, including area under the curve from 0 to last measurable concentration (AUC0–t), area under the curve over a dose interval (AUC0-tau), maximum concentration (Cmax), tmax, and accumulation ratio (RAC) will be determined for Compound (I) Form A, if data allow. Each PK parameter will be summarized using n, arithmetic mean, standard deviation, minimum, median, maximum, and coefficient of variation for each dose level, pooling the patients from Phase 1 who receive the MTD/RDEs with the patients in Phase 2. Additionally, geometric means will be reported for AUC0-t, AUC0-tau and Cmax parameters. PK parameters will be summarized by cohort or dosage. Plots of mean concentration of plasma Compound (I) versus time will be generated for each dose group in a linear and semi-log fashion. Individual concentration versus time graphs will also be provided. Comparisons across dose levels will be made to descriptively assess dose proportionality using AUC0-t and/or AUC0-tau, and Cmax if data allow. Food effect on Compound (I) Form A PK, effect of Compound (I) Form A on oral midazolam PK, and exploratory metabolite profiling will be conducted in sub-studies 1 and 2. For Phase 2 Expansion, limited PK samples will be collected (Table 5). Additional population PK analysis may be conducted to characterize the PK and covariates that affect the PK. The analysis may be reported separately. Pharmacodynamic Analyses Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Value and percentage change from baseline will be summarized at each collection timepoint. The PD parameters of interest in blood and tissue samples are EPO and other markers of the HIF pathway and ccRCC. The correlation between plasma concentrations of Compound (I) and the changes of PD biomarkers from baseline will be described. Additional exploratory PK/PD modeling may be conducted and reported separately. Analysis Time Points Final Analysis The final analysis of the study is planned to occur when the database is locked. Interim Analysis During the dose-escalation phase of the study, the SRC will meet to review AEs and laboratory toxicities for the dose cohort being studied to determine if escalation to the next higher dose cohort is warranted. In addition, the SRC will review the accumulating toxicity information and may pause or terminate the study in the event of an unfavorable risk/benefit profile. Ongoing review of safety data in Phase 1 and Phase 2 will also be reviewed for late- emerging toxicity at intervals of approximately 4 months, and more frequently if necessary. The SRC may recommend protocol amendments to maintain patient safety at any time. In addition, any serious adverse events (SAEs) will be forwarded to the SRC upon occurrence. Direct Access to Source Data/Documents Study Monitoring The sponsor or designee will monitor this study in accordance with current Good Clinical Practices (GCP) guidelines. By signing this protocol, the investigator grants permission to the sponsor or designee and appropriate regulatory authorities to conduct onsite monitoring of all appropriate study documentation. To ensure the accuracy of data collected on the case report forms, it is mandatory that sponsor representatives (e.g., study monitor) have direct access to original source documents (e.g., paper or electronic patient records, patient charts, and laboratory reports) needed to verity the entries on case report forms. During the review of these documents, the anonymity of the patient will be respected with strict adherence to professional standards of confidentiality. A study monitor will contact and visit the site regularly and will be allowed, on request at a mutually acceptable time, to inspect the various original medical records (paper or electronic) Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT related to the study. The study monitor will be responsible for inspecting the case report forms at regular intervals throughout the study, to verify the adherence to the protocol, and the completeness and correctness of all case report form entries. The investigator agrees to cooperate with the study monitor to ensure that any problems detected in the course of these monitoring visits are resolved. Audits and Inspections Principal investigators and institutions involved in the study will permit study-related monitoring, audits, and IRB review, and regulatory inspection(s), by providing direct access to all study records. In the event of an audit, the principal investigator agrees to allow the sponsor, representatives of the sponsor, the FDA, or other relevant regulatory authorities access to all study records. The principal investigator or designee should promptly notify the sponsor or designee of any audits scheduled by any regulatory authorities and promptly forward copies of any audit reports received to the sponsor or designee. Quality Control and Quality Assurance Quality Assurance To ensure compliance with GCP and all applicable regulatory requirements, a quality assurance audit may be conducted. Please see below for more details regarding the audit process. Financial Disclosure Principal investigators and sub-investigators are required to provide financial disclosure information before starting the study. In addition, the principal investigator and sub-investigators must provide the sponsor or designee with updated information, if any relevant changes occur during the course of the investigation and for 1 year after the completion of the study. Any potential investigator who has a vested financial interest in the success of this study may not participate in this study. Sponsor Obligations The sponsor or designee is not financially responsible for further testing/treatment of any medical condition that may be detected during the screening process. In addition, in the absence of specific arrangements, the sponsor or designee is not financially responsible for treatment of non-study-related fatalities, physical injuries, or damage to health that may occur during the clinical study, as well as the patient’s underlying disease. Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Investigator Documentation Before beginning the study, the principal investigator will be asked to comply with International Council for Harmonisation (ICH) E6(R1) 8.2 and Title 21 of the Code of Federal Regulations (CFR) by providing the essential documents to the sponsor or designee, which include but are not limited to the following. ^ An original investigator-signed investigator agreement page of the protocol ^ The IRB approval of the protocol ^ The IRB-approved informed consent, samples of site advertisements for recruitment for this study, and any other written information regarding this study that is to be provided to the patient or legal guardians ^ A Form FDA 1572, fully executed, and all updates on a new fully executed Form FDA 1572 ^ Curricula vitae for the principal investigator and each sub-investigator listed on Form FDA 1572. A curricula vitae and current licensure, as applicable, must be provided. The curricula vitae must have been signed and dated by the principal investigator and sub-investigators within 2 years before study start-up to indicate the documents are accurate and current. ^ Completed financial disclosure forms (see below) to allow the sponsor or designee to submit complete and accurate certification or disclosure statements required under US Title 21 CFR 54. In addition, the investigators must provide to the sponsor or designee a commitment to update this information promptly if any relevant changes occur during the course of the investigation and for 1 year after the completion of the study. ^ Laboratory certifications and normal ranges for any laboratories used by the site for the conduct of this study Use of Information All information regarding Compound (I) Form A supplied by sponsor to the investigator is privileged and confidential. The investigator agrees to use this information to accomplish the study and will not use it for other purposes without consent from the sponsor. Furthermore, the investigator is obligated to provide the sponsor with complete data obtained during the study. The information obtained from the clinical study will be used towards the development of Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Compound (I) Form A and may be disclosed to regulatory authority(ies), other investigators, corporate partners, or consultants as required. Ethics Institutional Review Board (IRB) Review The protocol and the proposed informed consent form must be reviewed and approved by a properly constituted IRB before study start. Each investigator must provide the sponsor or its designee a signed and dated statement that the protocol and informed consent have been approved by the IRB before consenting patients. Before study initiation, the investigator is required to sign a protocol signature page confirming agreement to conduct the study in accordance with this protocol and to give access to all relevant data and records to the sponsor, its designee, and regulatory authorities as required. The IRB chairperson or designee must sign all IRB approvals and must identify the IRB by name and address, the clinical protocol, and the date approval and/or favorable opinion was granted. The principal investigator is responsible for obtaining reviews of the clinical research at intervals specified by the IRB, but not exceeding 1 year. The principal investigator must supply the sponsor or designee with written documentation of reviews of the clinical research. Ethical Conduct of the Study This clinical study was designed and shall be implemented and reported in accordance with the ICH Harmonised Tripartite Guidelines for Good Clinical Practice, with applicable local regulations (e.g., US Code of Federal Regulations Title 21), and with the ethical principles in the Declaration of Helsinki. The principal investigator must conduct all aspects of this study in accordance with all national, state, and local laws or regulations. Written Informed Consent Because the study will be conducted under a United States Investigational New Drug Application, a signed informed consent form, in compliance with Title 21 of the United States CFR Part 50, will be obtained from each patient before the patient enters the study. An informed consent template may be provided by the sponsor or designee to the investigators. The consent must be reviewed by the sponsor or designee before IRB submission. Once reviewed, the consent will be submitted by the principal investigator to his or her IRB for review and must be approved Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT before a patient enters the study. If the informed consent form is revised during the course of the study, all participants affected by the revision must sign the revised IRB-approved consent form. Before enrollment, each prospective patient will be given a full explanation of the study and be allowed to read the approved informed consent form. Once the principal investigator or designee is assured that the patient understands the implications of participating in the study, the patient will be asked to give consent to participate in the study by signing the informed consent form. Eligible patients may only be included in the study after providing written (witnessed, where required by law or regulation), IRB-approved informed consent. Informed consent must be obtained before conducting any study-specific procedures (i.e., any procedure described in the protocol). The process of obtaining informed consent must be documented in the patient source documents. Any changes to the proposed consent form suggested by the investigator must be agreed to by the sponsor before submission to the IRB, and a copy of the approved version and the notice of approval must be provided to the sponsor’s designated monitor after IRB approval. The principal investigator or designee will provide a copy of the informed consent form (signed copy to be provided per applicable law) to the patient and/or legal guardian. The original form will be maintained in the patient’s medical records at the site. Confidentiality All laboratory specimens, evaluation forms, reports, and other records will be identified in a manner designed to maintain patient confidentiality. All records will be kept in a secure storage area with limited access. Clinical information will not be released without the written permission of the patient (or the patient’s guardian), except as necessary for monitoring and auditing by the sponsor, its designee, the FDA or applicable regulatory authorities, or the IRB. The principal investigator and all employees and coworkers involved with this study may not disclose or use for any purpose other than performance of the study, any data, record, or other unpublished confidential information disclosed to them for the purpose of the study. Prior written agreement from the sponsor or designee must be obtained for the disclosure of any said confidential information to other parties. Modification of the Protocol Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Any changes that arise after the approval of the protocol must be documented as protocol amendments. The FDA must be notified of protocol amendments. The changes will become effective only after approval of the sponsor, the principal investigator, and the IRB. In cases when the protocol is modified to enhance patient safety, changes may be implemented, and the amendment must be immediately submitted to the IRB. The principal investigator is responsible for informing the IRB of all problems involving risks to patients according to national legislation. In case of urgent safety measures, the sponsor will immediately notify FDA in accordance with 21 CFR 312.32. Protocol Deviations The principal investigator or designee must document any protocol deviation. The IRB must be notified of all protocol deviations in a timely manner by the investigator as appropriate. Protocol deviations will be documented by the responsible monitor during monitoring visits, and those observations will be communicated to the investigator. If there is an immediate hazard to a patient, the principal investigator may deviate from the protocol without prior sponsor and IRB approval. The sponsor and IRB must be notified of the deviation immediately. Data Handling and Recordkeeping Retention of Records The investigator will maintain all study records according to ICH-GCP and applicable regulatory requirement(s). Records will be retained for at least 2 years after the last marketing application is approved or 2 years after formal discontinuation of the clinical development of the investigational product. If the investigator withdraws from the responsibility of keeping the study records, custody must be transferred to a person willing to accept the responsibility. The sponsor must be notified in writing if a custodial change occurs. Case Report Forms All CRF data will be entered in paper or electronic forms at the investigational site. If an EDC system is used to capture data electronically for all enrolled patients, the system will be 21 CFR Part 11 compliant. Example 3 Preliminary Data and Analysis from the Phase 1/2 Study Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Overview of Clinical Studies Data is presented here from the Study described in Example 2 with a cutoff date for safety data of 08 November 2023 and a sample cutoff date for the PK and PD analyses of 5 October 2023. The study is actively enrolling. As of 08 November 2023, a total of 83 ccRCC patients were treated with Compound (I) Form A monotherapy. Fifteen patients were treated with a continuous daily dosing schedule with dosages of 50 mg (n=3), 100 mg (n=3), 200 mg (n=6), or 300 mg (n=3) once daily (QD). Sixty-eight patients were treated with loading doses followed by maintenance doses at the following dosages: 200 mg QD × 7 days then 200 mg once weekly (QW) (n=21), 200 mg QD × 14 days then 50 mg QD (n=21), 100 mg QD × 7 days then 100 mg QW (n=17), or 200 mg QD × 28 days then 50 mg QD (n=9). As of 08 November 2023, 40 out of the 83 patients remained on treatment. Investigators conducted tumor assessment according to Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST 1.1). Clinical Pharmacokinetics and Pharmacodynamics With a sample cutoff date of 5 October 2023, evaluable plasma Compound (I) Form A PK data was obtained from 81 patients (79 evaluable) at 8 dosages tested including 50, 100, 200, and 300 mg QD, 100 mg QD × 7 days then 100 mg QW, 200 mg QD × 7 days then 200 mg QW, 200 mg QD × 14 days then 50 mg QD, and 200 mg QD × 28 days then 50 mg QD. The mean (SE) PK profiles of Compound (I) Form A by dosage are presented in Figs.1A and 1B. In the QD cohorts, plasma Compound (I) Form A concentration continued to accumulate before dose modifications, and no apparent steady-state PK was observed. In the cohorts with sequential loading and maintenance treatments, apparent steady-state PK was reached and maintained except for 200 mg QD × 28 days then 50 mg QD which was designed for more complete initial target inhibition during the loading phase followed by less intensive maintenance treatment. The PK data was further analyzed using a population PK model. Continuous QD dosing resulted in continuous increases in Compound (I) concentration up to 16 weeks without a dose modification, suggesting long effective half-life. Based on preliminary population PK analysis, alternative treatment schedules with sequential loading and maintenance dosing were tested to allow quickly achieve and maintain different exposure levels. EPO data was collected from 83 patients. Mean (SE) percent changes from baseline up to Week 9 by dosage are presented in Figs.2A and 2B. Rapid and significant EPO suppression was Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT observed at all tested dosages. A few weeks after treatment, EPO levels partially recovered from the nadir in some patients. Such EPO recovery in a temporal correlation with decreasing hemoglobin levels is considered as a system compensation mechanism for anemia. Similar EPO recovery trajectory was reported for belzutifan with EPO levels recovered by Week 9 (US FDA, NDA Multi-disciplinary Review and Evaluation – NDA 215383 WELIREG [belzutifan]). The EPO data was further analyzed in PK-EPO modeling. Population Pharmacokinetic/Pharmacodynamic Modeling and Exposure-Response Analysis The PK of Compound (I) was characterized following single and multiple oral doses in 83 patients with advanced ccRCC with various dosing regimens in the Dose Escalation phase, including continuous QD dosing and regimens with loading and maintenance doses as summarized in Table 18. Table 18: Phase 1/2 study dose escalation cohorts 50 mg QD (n=3) A 2-compartmental population PK model with first-order oral absorption and first-order elimination adequately described the PK data after a single dose, multiple doses, as well as PK after dose reductions and dose holds (n=79) was developed based on evaluable data available up to October 23, 2023 (n=79). The PK parameter estimates are summarized in Table 19. The model parameters were estimated with acceptable precision (RSE <34%). The between-subject variability had low shrinkage (<18%). The typical PK parameter values for absorption rate constant (Ka), apparent clearance (CL/F), intercompartment clearance (Q/F), and central (Vc/F) and peripheral volume (Vp/F) of distribution were 0.684 h-1, 0.512 L/h, 24.4 L/h, 153 L, and 624 L, respectively. Higher body Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT weight appeared to correlate with higher Vc/F and Vp/F values but not CL/F. The estimated apparent clearance (CL/F) and apparent steady-state volume of distribution (Vss/F) were 0.512 L/h and 777 L, respectively. The model-estimated median terminal t1/2 was 38 days. Between- patient variability was moderate on CL/F (49%), Vc/F (37%), Vp/F (34%), and Ka (81%). The modeling analysis suggested no time- or concentration-dependent PK nonlinearity. The high accumulation following continuous daily dosing and the model-estimated long t1/2 were likely due to slow elimination and large distribution volume. Table 19: Summary of the Population PK Model Parameter Estimates Parameter Units Estimate RSE (%) Shrinkage (% 1)0 CL/F L/h 0512 101 y ppa e ea a ce; c ppa e e a s u o o u e; F=Apparent Distribution Clearance; Vp/F=Apparent Peripheral Distribution Volume; Ka=Absorption Rate Constant; WT=body weight; Omega=between-subject variability with assumed log-normal distribution; Sigma=within-subject proportional variability with assumed normal distribution. The effect of WT on Vc is reported as exponent THETA in equation Vc,i=Vc,typical x (WT/91)^THETA, where Vc,i is the estimated Vc for subject i, Vc,typical is the model estimated among patients in the input Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT In summary, Compound (I) Form A had dose-linear and time-dependent PK levels. Slow elimination of Compound (I) was evidenced by its continuous accumulation following QD dosing. Therefore, in subsequent cohorts, various regimens with sequential loading and maintenance dosing schedules were tested. Such regimens were designed to rapidly achieve and maintain certain Compound (I) exposure levels in plasma. In population PK analysis, a linear model adequately described the PK data at all dose levels. The modeling analysis suggested no time- or concentration-dependent nonlinearity and that the high accumulation of Compound (I) following continuous daily dosing of Compound (I) Form A is due to slow elimination. Subsequently, an indirect population PK-EPO response model was developed based on the PK and EPO data from this study (n=79). EPO data was limited to < Week 5 to avoid confounding effects that resulted in EPO rebound. The EPO model had first-order EPO elimination and zero-order EPO production which was inhibited by Compound (I) Form A. The model adequately described the EPO inhibition at different dosages and the model-estimated IC50 and Imax were 63.2 ng/mL and 75.0%, respectively. The PD model parameter values are summarized in Table 20. Table 20: Summary of the Erythropoietin Pharmacodynamic Parameters in the Population PKPD Model Parameter Units Estimate RSE (%) Shrinkage (%) Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Acronyms: E0=baseline EPO level; Kout=EPO elimination rate constant; IC50=concentration for 50% inhibition; Imax=maximal fractional inhibition of EPO production rate; OMEGA=between-subject variability with assumed log-normal distribution; Sigma=within-subject additive variability with assumed normal distribution. EPO production rate (Kin) was assumed follow zero-order kinetics and derived as a secondary parameter based on steady-state condition, ie, Kin=E0^Kout. The PPK model-simulated median (90% confidence interval) plasma Compound (I) concentration-time profiles for the 5 dosages with loading and maintenance dosing regimens are presented in Fig.9. The model-estimated Compound (I) concentrations are summarized in Table 21. All these dosage levels are expected to have clinically significant EPO suppression based on the model estimated IC50 of 63.2 ng/mL. Among the 5 dosages, two have been selected as recommended dosage for expansion (RDE) and are being further evaluated in the Phase 2 Expansion (RDE-low: 100 mg QD x 7 then 100 mg QW; RDE-high: 200 mg QD x 14 then 50 mg QD). Simulated typical PK profiles for tested dosages are presented in Fig.9, and simulated typical PK profiles for additional dosages of clinical interest are presented in Fig.10, Fig.11, and Fig.12. Table 21: Population PK Model-estimated Concentrations for Selected Dosages with Sequential Loading and Maintenance Dosing Regimens Dosage Cmin, Cmax after the 1st Cmin, Cmax in Week 16 These maintenance dosing schedules are proposed based on the thorough characterization of Compound (I) Form A PK following various dosing schedules assessed in the study and Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT integrated PPK analysis. These dosages with long maintenance dosing intervals offer additional dosing convenience, less intestinal drug-drug interaction risks, and clinically meaningful Cmax and Ctrough ranges. The estimated Cmax and Ctrough, as well as their ratios, are summarized in Table 22. Despite the long dosing intervals, the concentration fluctuation remains low, with Cmax/Ctrough ratio of 1.4, 1.9, 2.5, and 3.1 for QW, Q2W, Q3W, and Q4W, respectively. Table 22: Summary of Steady-state Ctrough and Cmax (ng/mL) Estimated Using Population PK Model Simulation for different maintenance dosing regimens following 100 mg QD x 7 days Maintenance dose Q4W Q3W Q2W QW (RDE- l w) ; e e y ee s, e e y ee s; - o o e eco e e osage o pa s o In addition to various maintenance dosing regimens, the loading dosing schedule can also be varied as shown in Fig.13, including 50 mg QD x 7, 100 mg QD x 7, 200 mg QD x 7, 200 mg QD x 14, and 200 mg QD x 28. Such different loading dosing schedules allow achieving different concentrations quickly but don’t change the steady-state PK during maintenance treatment. Moreover, for each maintenance treatment cycle, the dose can be split over a few days. Splitting a maintenance dose into a few daily doses allows: a) higher total dose per maintenance treatment cycle; and b) lower Cmax /Ctrough ratio compared with a single dose for the same total Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT maintenance dose per cycle. For illustration, maintenance dose splitting into 2, 4, and 7 daily doses for each 28-day maintenance cycle are simulated as shown in Fig.14, Fig.15, and Fig.16, respectively. The steady-state Cmax, Ctrough, and Cmax /Ctrough ratio are summarized in Table 23. Lower concentration fluctuation is expected, with Cmax /Ctrough ratio of 3.1, 2.5, and 1.9 for 2 days-on/26 days-off, 4 days-on/24 days-off, and 7 days-on/21 days-off, respectively. Table 23: Summary of Steady-state Ctrough and Cmax (ng/mL) Estimated Using Population PK Model Simulation for Maintenance Dosing Regimens with Split Doses Following Loading Doses of 100 mg QD x 7 Maintenance 2 days on 26 4 days on 24 7 days on 21 QW (RDE- dose da s off da s off da s off low) E- low=lower recommended dosage for Expansion In summary, Compound (I) Form A showed dose-linear and time-dependent PK. Slow elimination of Compound (I) was evidenced by its continuous accumulation following QD dosing with an estimated elimination t1/2 of 38 days. Therefore, different loading and maintenance dosing regimens were tested to achieve and maintain certain plasma concentration levels. A PPK-PD model was developed and used to simulate for additional dosing regimens, including maintenance regimens with longer dosing intervals and split maintenance dose over a few days in each maintenance treatment cycles. The simulations offer visualization of example dosages that can be safe and efficacious and are of interest for further clinical investigation. These example dosages are based on combination of different dose levels, duration of loading phase, maintenance dosing cycle length, number of doses in each maintenance cycle. Such combinations include reasonable interpolation and extrapolation of dosing designs based on available Compound (I) Form A formulations and Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT clinical need, especially by considering dosing schedule of combination drugs to further optimize target inhibition, minimize drug-drug interactions, and practical convenience, etc. Selection of Recommended Dosages of Compound (I) Form A for Monotherapy Expansion Due to PK data demonstrating very slow elimination, sequential loading and maintenance dosing schedules were tested to achieve and maintain target exposure levels. Based on review of the overall safety, tolerability, PK, PD, and preliminary efficacy, two RDEs were endorsed by the SRC and selected for further evaluation in the randomized phase 2 expansion of the study: 200 mg QD × 14 days then 50 mg QD (RDE-d) and 100 mg QD × 7 days then 100 mg QW (RDE-w). A final RP2D of Compound (I) Form A for monotherapy in ccRCC will be determined at the end of the expansion phase. RDE selection was also supported by preclinical in vitro and in vivo efficacy study results. Compound (I) Form A inhibited VEGFA secretion in 786-O cells with IC90 of 201 ng/mL (assumed as 9 × IC50 after human plasma protein binding adjustment). In an A498 xenograft mouse model, tumor growth inhibition was estimated using a PK-tumor growth inhibition model, and the human equivalent IC90 was 2070 ng/mL (assumed as 9 × IC50 after cross-species protein binding normalization). According to the preliminary clinical PK-EPO model, Compound (I) Form A inhibited EPO production with an IC90 of 568 ng/mL (assumed as 9 × IC50). At selected RDE-w and RDE-d, the population PK model-estimated median Ctrough (90% prediction interval) at Week 17 was 936 ng/mL (265 – 2220 ng/mL) and 3460 ng/mL (1170 – 8120 ng/mL), respectively. Preliminary exposure-response analysis did not reveal clinically meaningful correlations for selected efficacy endpoints (ORR, target lesion size change, time to response, etc.). Higher time-average Compound (I) Form A concentrations correlated with earlier and higher incidences of Grade ≥2 and Grade ≥3 anemia. The analysis suggested that lower baseline hemoglobin and O2 saturation were associated with higher risks of anemia and hypoxia, respectively. Collectively, the updated data and analysis continue to support the Dose Expansion study at RDE-w and RDE-d (a 3.5 fold range in weekly maintenance dose). Additional Clinical Pharmacology Sub-Studies 1 and 2 To further investigate safety, PK, PD, and efficacy of Compound (I), additional studies are enrolling including two PK sub-studies 1 and 2, as is described in Example 2. Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT In the preliminary food effect and drug-drug interaction (DDI) sub-study 1, ccRCC patients are being enrolled to receive Compound (I) Form A at 200 mg QD × 7 then 200 mg QW (8 of 12 patients enrolled as of 5 October 2023). Two oral doses of midazolam were administered on Day -3 and Day 15 with plasma samples collected for PK determination. Food effect was assessed on Day 1 when patients were assigned to take 200 mg Compound (I) Form A under fasting conditions or with a high-fat meal. Preliminary DDI results suggested that Compound (I) Form A is a moderate to strong CYP3A4 inducer at the RDEs. Available data is too limited for food effect assessment. Preliminary DDI results showed that Compound (I) Form A reduced oral midazolam AUC and Cmax by approximately 80% and 59%, respectively. Available data is too limited for food effect assessment. Given the observed CYP3A4 induction and the linear Compound (I) PK with regards to dose and time, significant involvement of CYP3As in Compound (I) elimination is unlikely. Enrollment is ongoing. In the urinary excretion and metabolite profiling sub-study 2, patients are being enrolled to receive Compound (I) Form A at 200 mg QD × 14 then 50 mg QD (recommended dosage for expansion-daily [RDE-d]) (3 of 5 patients enrolled as of 5 October 2023). On Day 22, ≤ 2.2% daily dose of 50 mg was recovered as the intact Compound (I) in 24-hour total urine, suggesting that urinary excretion is a minor elimination pathway. The main metabolism included oxidation, hydrolysis, and glucuronidation. Compound (I) was the predominant drug-related moiety in plasma but a minor one in urine. Enrollment is ongoing. Safety A summary of patient demographics is provided in Table 24. Compound (I) Form A exposure is summarized in Table 25. As of 08 November 2023, 83 patients have been treated in the dose escalation (n = 71) and expansion (n = 12) phases at the dosages noted in Table 24. The majority of dosed patients were male (71.1%, n=59) with a median age of 62 (range: 38-87) years. The baseline Eastern Cooperative Oncology Group Performance Status (ECOG PS) was 0 in 42.2% (n=35), 1 in 55.4% (n=46), and 2 in 2.4% (n=2) of patients. Patients were heavily pre- treated with 66.3% (n=55) having received 3 or more lines of prior anti-cancer systemic therapy (note: one patient’s treatment history has not been entered in database), 94% (n=78) having received a prior VEGF TKI, and 97.6% (n=81) having received prior immunotherapy. Across all dose schedules median duration of treatment was 14.7 weeks (range: 0.9 to 96.3 weeks). Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Table 24: Patient Demographics Continuous Dosing Loading/Maintenance Dosing Schedule Schedule (QD) r a 9 1 2 2 ) 1 Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT n 3 3 6 3 21 21 17 9 83 65.3 53.3 61.7 58.7 61.5 8
Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Table 25: Compound (I) Form A Exposure Varia Durati n Media Min-m Data cutoff date: 08 November 2023 Max = maximum; min = minimum; QD = once daily; QW = once weekly; RDE-w/d = recommended dosage for expansion-weekly regimen/daily regimen
Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Adverse Events As of 08 November 2023, 82 (98.8%) of the 83 patients experienced TEAEs. An overall summary of TEAEs is provided in Table 26. The majority of patients who experienced TEAEs had at least one treatment related event (78 patients, 94%). Nine patients (10.8%) discontinued treatment due to TEAEs; 6 patients (7.23%) due to treatment related events. The most commonly reported TEAEs that resulted in treatment discontinuation were hypoxia (4 patients, 4.8%, all reported as treatment related), fatigue (2 patients, 2.4%, treatment related in 1 patient), and pleural effusion (2 patients, 2.4%, all reported as not treatment related). Two Grade 5 (fatal) TEAEs were reported (disease progression and haemorrhage intracranial, both unrelated to NKT2152 treatment). Seven patients (8.4%) had a maximum TEAE severity of Grade 4: 2 patients had hypoxia, and the following were reported in 1 patient each: bronchial obstruction, pain in extremity, acute kidney injury, cardiac tamponade, mania, pneumonitis, respiratory failure, and urinary tract infection bacterial. All other TEAEs were ≤ Grade 3. A summary of TEAEs reported in >10% of all patients are presented in Table 27. The most common TEAEs were anemia (58/83 patients, 69.9%) and fatigue (29/83 patients, 34.9%). Events of anemia were treatment related in 54/83 patients (65.1%). Events of fatigue were treatment related in 24/83 patients (28.9%). Dose Limiting Toxicities Two patients experienced 2 DLTs: One patient who received treatment with Compound (I) Form A 200 mg QD × 14 days then 50 mg QD experienced Grade 3 fatigue and Grade 3 hypoxia on Day 13. The event of hypoxia resulted in treatment interruption. Both events were related to Compound (I) Form A in the opinion of the investigator and resolved on Day 16. One patient, who was a part of the 200 mg QD × 28 days then 50 mg QD cohort, experienced Grade 3 fatigue and Grade 3 hypoxia on Day 8. Both events were related to Compound (I) Form A in the opinion of the investigator; the hypoxia resolved on Day 13 and the fatigue was ongoing as of 08 November 2023. The MTD has not been reached. Treatment Discontinuations Due to Adverse Events A total of 9/83 patients (10.8%) discontinued treatment due to a TEAE. Hypoxia, fatigue and pleural effusion were the only TEAEs that resulted in treatment discontinuation in more than 1 patient (hypoxia occurred in 4/83 patients [4.8%], fatigue occurred in 2/83 patients [2.4%], and pleural effusion in 2/83 [2.4%]). Treatment related TEAEs resulting in discontinuation include hypoxia in 4/83 patients (4.8%) and fatigue, pericardial effusion, cystoid macular oedema, and malaise in 1/83 patient each (1.2%). Dose Reductions Due to Adverse Events Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Dose reductions due to TEAEs occurred in 6/83 patients (7.2%). All TEAEs resulting in dose reduction were deemed treatment related. Fatigue and hypoxia occurred in two patients each (2.4%). The following events occurred in one patient (1.2%) each: anemia, diarrhea, oedema peripheral, pericardial effusion, and vomiting. Treatment Interruptions Due to Adverse Events Treatment interruptions due to TEAEs occurred in 39/83 patients (47.0%). Hypoxia, anemia, fatigue, and nausea were the most commonly reported TEAEs leading to treatment interruption. Hypoxia occurred in 12/83 patients (14.5%); anemia, fatigue, and nausea each occurred in 5/83 patients (6.02%). The majority of TEAEs that resulted in treatment interruption were related to Compound (I) Form A treatment in the opinion of the Investigator, Grade ≤ 3, and non-serious. Serious Adverse Events and Deaths Serious TEAEs were reported in 28/83 patients (33.7%). Hypoxia occurred in 8/83 patients (9.64%); the following occurred in 2/83 patients (2.4%) each: bronchial obstruction, pain in extremity, pathological fracture, pericardial effusion, pleural effusion, and urinary tract infection. Serious TEAEs that led to treatment discontinuation occurred in 6/83 patients (7.2%): 1 patient due to a serious event of pleural effusion, 1 patient due to a serious event of acute kidney injury, 1 patient due to a serious event of hypoxia, 1 patient due to serious events of depressed level of consciousness and cognitive disorder, 1 patient due to serious events of fatigue and hypoxia, and 1 patient due to serious events of hypoxia, pericardial effusion, and pleural effusion. Serious TEAEs that were reported as at least possibly treatment related by the investigator occurred in 11/83 patients (13.3%); pericardial effusion and cardiac failure in 1 patient; hypoxia in 5 patients; pericardial effusion, hypoxia, and pleural effusion in 1 patient; cardiac tamponade, pneumonitis, and respiratory failure in 1 patients; optic neuritis in 1 patient; nausea in 1 patients; and fatigue and hypoxia in 1 patient. One patient expired as a result of a serious TEAE of disease progression that was not related to Compound (I) Form A treatment and occurred on Day 29. Another 71-year-old white male patient expired from a serious TEAE of intracranial hemorrhage after over 12 months on treatment. His tumor within the lung and liver continuously shrunk according to RECIST1.1, which included partial response for 5.5 months. The intracranial hemorrhage event was reported as unrelated to Compound (I) Form A and the investigator attributed the event to patient’s underlying hypertension. Additionally, a single report of cystoid macular edema and optic neuritis reported in a 66- year-old African male patient. At baseline, the patient had blurred vision, remote right eye injury with irreversible damage to iris and pupil, type 2 diabetes, and hypertension. The patient lost Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT follow up with an eye care provider for 4 years since the diagnosis of cancer. Prior to this study, the patient received 4 lines of cancer treatment including nivolumab and ipilimumab. On study day 10, the patient went to see an ophthalmologist due to blurred vision and was diagnosed with cataract with associated and expected cystoid macular edema. On study day 23, increased eye pressure in right eye and new left eye pressure elevation were noted. On study day 37, a fundus exam revealed bilateral cystoid macular edema, bilateral pigment epithelial detachments, and presumed bilateral low grade optic nerve edema. The posterior view of the right-eye is inhibited by the dense cataract but features of retinopathy and optic neuropathy remain clear evident by an optical coherence tomography (OCT) imaging. Study treatment was discontinued. The patient was treated with topical prednisone acetate ophthalmic drops and high dose systemic steroids with intravenous methylprednisolone and oral prednisone. Improvement was noted on study day 56, and the event of optic neuritis resolved on study day 66. The investigator reported the events as related to study treatment. The sponsor assessed the events as unrelated to the study treatment considering the previous multiple lines of immunotherapy with immune-mediated toxicities as class drug effects, unclear onset of the blurred vision due to lost follow up to eye care provider since cancer diagnosis, and baseline diabetes and blurred vision.
Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Table 26: Overall Incidence of Treatment-Emergent Adverse Events to TEA due to due to s
Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Data cutoff date: 08 November 2023 DLT = dose limiting toxicity; QD = once daily; QW = once weekly; RDE-w/d = recommended dosage for expansion-weekly regimen/daily regimen; TEAE = treatment- emergent adverse event Relatedness to treatment is based on the investigator’s assessment of possibly or probably related to study drug.
Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Table 27: Treatment-Emergent Adverse Events Occurring in ≥ 10% of Patients Overall . . . . Data cutoff date: 08 November 2023 MedDRA = Medical Dictionary for Regulatory Activities; QD = once daily; QW = once weekly; SOC = system organ class; TEAE = treatment-emergent adverse event TEAEs are coded using MedDRA v25.0.
Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Efficacy As of the data cutoff date (08 November 2023), 83 patients have been treated with Compound (I) Form A and evaluation of efficacy is ongoing. Across all dosages evaluated, promising anti-tumor activity was observed. Among 68 efficacy evaluable patients, 15 (22.1%) achieved overall objective response (confirmed CR/PR). Among 66 patients with post-baseline scans, 46 (69.7%) demonstrated tumor shrinkage, with a median duration of treatment 21.4 weeks (Range: 4-96 weeks); 39 patients (59.1%) demonstrated tumor shrinkage at the first post-baseline scan ranging from -53.0% to -2.1% change from baseline of the sum of longest diameter (SLD). Median follow-up time for all 83 enrolled patients was relatively short (0.3-24 months); of these 83 patients, only 12 (14.5%) have been enrolled to two randomized RDE arms under phase 2. Summary of Data Clinical As of 08 November 2023, 83 patients have been treated with Compound (I) Form A. The majority of patients were male (71.1%, n=59) with a median age of 62 (38-87) years. The baseline ECOG PS was 0 in 42.5% (n=35), 1 in 55.4% (n=46), and 2 in 2.4% (n=2) of patients. Patients were heavily pre-treated with 66.3% (n=55) having received 3 or more lines of prior anti-cancer systemic therapy and 94.0% (n=78) of patients having received a prior TKI and 97.6% (n=81) having received prior immunotherapy. Across all dose cohorts, mean duration of treatment was 14.7 weeks (range: 0.9 to 96.3 weeks). Overall, across all dosages, Compound (I) Form A was well tolerated. Two patients experienced 2 DLTs (both had Grade 3 fatigue and Grade 3 hypoxia). Two patients experienced a Grade 5 TEAE (disease progression resulting in death, and haemorrhage intracranial resulting in death, both not related to Compound (I) Form A treatment in the opinion of the investigator). Anemia and hypoxia have been reported as adverse events (AEs) associated with the approved HIF2α inhibitor belzutifan (see WELIREGTM (belzutifan) Prescribing Information. Merck & Co., Inc.). With Compound (I) Form A, anemia was the most commonly reported TEAE occurring in 58 patients (69.9%) (Grade 1 or 2 in 47/83 patients [56.6%], and Grade 3, 4, or 5 in 11/83 patients [13.3%]). Hypoxia was reported in 23/83 patients (27.7%) (Grade 1 or 2 in 6/83 patients [7.2%] and Grade 3, 4, or 5 in 17/83 patients [20.5%]). Serious TEAEs were reported in 28/83 patients (33.7%). Serious TEAEs that occurred in more than 1 patient overall included hypoxia (8/83 patients, 9.64%); and bronchial obstruction, pain in extremity, Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT pathological fracture, pericardial effusion, pleural effusion, and urinary tract infection each occurring in 2/83 patients (2.41%). Serious TEAEs that were reported as at least possibly treatment related by the investigator occurred in 11/83 patients (13.3%). Serious TEAEs that were reported as at least possibly related in more than 1 patient included hypoxia in 7 patients and pericardial effusion in 2 patients. As of 08 November 2023, 40 out of 83 patients remained on treatment. Potential Risks This section provides information on potential adverse events based on nonclinical data, initial clinical data, and published data for the HIF2α class of inhibitors. Potential Reproductive Effects Reproductive toxicity studies in animals have not been performed with Compound (I) Form A. Findings in the reproductive tract of Compound (I) Form A-treated male rats and dogs included testicular degeneration with attendant cell debris in the epididymides and decreased luminal sperm (rats) and atrophy of the prostate gland and seminiferous tubule degeneration (dogs). While findings in dogs were reversible at the end of the 28-day treatment-free recovery period, findings in rats progressed upon cessation of dosing. No toxicity was observed in the reproductive organs of female animals. Embryotoxicity, while still unknown for Compound (I) Form A, is included as a black box warning on belzutifan’s label. As a precaution, patients must avoid pregnancy in order to participate in Compound (I) Form A trials. Patients will be informed of the potential risk of embryotoxicity. Potential Liver Toxicity Liver findings (i.e., hepatocellular hypertrophy with attendant increased liver weight parameters) were observed in Compound (I)-treated rats and dogs. These findings are likely related to hepatic DME induction, an adaptive response associated with increases in liver weight, induction of gene expression, and morphological changes in hepatocytes. In Compound (I)-treated animals, anatomic findings in the liver were accompanied by increases in serum alanine aminotransferase (ALT; rat and dog), alkaline phosphatase (ALP; dog only) and gamma glutamyltransferase (GGT; rat and dog) activity. As described in Ennulat 2010, the effects of DME induction on the clinical pathology markers of hepatobiliary injury and function in animals as well as humans are not well established (see Ennulat, et al. Toxicol Pathol 38: 810-828, 2010). However, in rats, when histologic findings are limited to hepatocellular hypertrophy, DME induction is not expected to be associated with consistent Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT or substantive changes in hepatobiliary marker enzymes, such as ALT, ALP and/or GGT. In dogs treated with phenobarbital or corticosteroids, increased liver ALP or GGT activity suggests that direct or indirect induction of select hepatobiliary injury markers can occur both in the absence of liver injury and independently of induction of DME activity. Although correlations between tissue and serum levels of hepatobiliary markers are limited and inconsistent, increases in serum/plasma activities that are substantial or involve changes in other markers generally reflect hepatobiliary insult rather than DME induction. In Compound (I)-treated rats, these findings in the liver are likely associated with findings in the thyroid gland. All liver-related clinical and anatomic pathology findings in Compound (I)-treated rats and dogs were fully reversible in both rats and dogs upon cessation of dosing. According to the ongoing study in ccRCC patients (N=83), elevation of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) occurred in 9.6% and 6.0% of patients, respectively. There was one patient who experienced Grade 3 AST elevation which was reported as unrelated to study treatment. All other instances of AST elevation and of ALT elevation were Grade ≤ 2. Identified Risks Anemia Reversible decreases in red cell mass in both rats and dogs, as evidenced by decreased red blood cell counts and hemoglobin and hematocrit values, were observed at all Compound (I) Form A dosages in both rats and dogs. This effect on the erythron is considered an on- target effect because HIF2α is important in the regulation of EPO. Anemia has been the most common TEAE reported in the trial in 58 out of 83 patients (69.9%) who received at least one dose of Compound (I) Form A. In this study, anemia was well managed with EPO replacement and/or blood transfusion along with dose modifications per protocol, with no patients discontinuing the study due to anemia. Patients participating in clinical studies of Compound (I) Form A will have frequent hematology assessments per protocol to monitor the onset or worsening of anemia. To treat severe anemia, blood transfusion is recommended if meeting local blood transfusion guidelines. Exogenous erythropoietin stimulating agents (ESA) may be an effective management strategy in addition to blood transfusion, given that decreased EPO is the potential etiology of Compound (I) Form A treatment-induced anemia. While ESA therapy has been associated with cardiovascular adverse effects, most significantly venous thromboembolism when used to treat cancer-related anemia (see Rao, et al. “Efficacy and Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT cardiovascular Adverse effects of erythropoiesis Stimulating Agents in the treatment of Cancer-Related Anemia: A Systematic Review of randomized controlled trials.” Cureus, 2021), there is no evidence that ESA administration adversely impacts the overall efficacy of belzutifan in VHL disease-associated RCC patients (see Maughan et al., Journal of Clinical Oncology, 42:3, 2024). Please refer to the prescribing information for ESAs for more information. Use of EPO product will be under the treating physician’s discretion in theAmerican Society of Clinical Oncology (ASCO) or institutional guidance. For instructions for management of Grade 3 or worse anemia, please refer to the study protocol. In general, withholding Compound (I) Form A will be required. If an event resolves to Grade 2 within 12 weeks. Compound (I) Form A may be resumed with dosage reduction by one dose level; if not, Compound (I) Form A must be permanently discontinued. Fatigue Fatigue was reported in 29 (34.9%) patients in the trial. Patients participating in clinical studies of Compound (I) Form A will be monitored for fatigue. Withholding Compound (I) Form A is necessary when a Grade 3 event happens; re-starting at lower dosages may happen when the event resolves to Grade ≤ 2 as per protocol. Important Identified Risks Hypoxia Hypoxia, as detected by pulse oximetry, is an identified risk observed in patients treated with Compound (I) Form A and on the label of the marketed drug in the same class. Withholding Compound (I) Form A is recommended for Grade 2 and required for Grade ≥ 3 hypoxia. Hypoxia management guidelines are provided in each protocol. In the trial, hypoxia was reported in 27.7% (23 out of 83) of participants, including 17 patients (20.5%) who experienced Grade 3 or worse. Hypoxia generally resolved with treatment including supplemental oxygen and/or dose modification. Patients participating in clinical studies of Compound (I) Form A will have frequent assessments of pulse oximetry as needed to monitor for hypoxia. Management of hypoxia should include treatment of any acute medical event and provision of supplemental oxygen as necessary. Drug-Drug Interactions In vitro results indicate that Compound (I) is metabolically stable with CYPs; however, the amount of Compound (I) oxidative metabolite formed with CYP2C19 was much higher than with other CYPs. As a precaution, it is recommended that strong inhibitors or inducers of CYP2C19 should be avoided in patients receiving Compound (I) Form A. Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT In vitro, Compound (I) Form A induced CYP3A4 and CYP2B6 in human hepatocytes. Preliminary clinical data suggested that Compound (I) Form A is a moderate to strong CYP3A4 inducer at the selected RDEs. Concomitant drugs that are sensitive CYP3A substrates should be avoided. In addition, CYP3A4 induction occurs via activation of nuclear PXR, which may result in co-induction of CYP2C8, CYP2C9 and CYP2C19. Compound (I) Form A may, therefore, also decrease the exposure of concomitant medications that are sensitive substrates of CYP2B6, CYP2C8, CYP2C9 or CYP2C19; however, the clinical relevance of these effects is not yet clear. If Compound (I) Form A is taken with sensitive substrates of these enzymes, additional monitoring of the concomitant medication’s effectiveness may be needed. In vitro results indicate that Compound (I) Form A may mildly inhibit liver CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3As at clinically relevant concentrations. Compound (I) Form A may also inhibit CYP3As in the gut. Caution should be used if Compound (I) Form A is taken with sensitive substrates of CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3As. In addition, Compound (I) Form A could potentially inhibit BCRP in the gut and MATE2-K in the kidney at clinically relevant dosages. No inhibition of other transporters is expected at clinically relevant clinical dosages. Examples of the above mentioned concomitant medicines can be found at the following website: https://www.fda.gov/drugs/drug-interactions-labeling/healthcare- professionals-fdas-examples-drugs-interact-cyp-enzymes-and-transporter-systems. Pregnancy, Contraception, and Related Requirements There are no data available regarding the potential effects of Compound (I) Form A; however, based on animal studies of related drugs on embryo and fetal development, Compound (I) Form A may cause fetal harm. Pregnant women or women intending to become pregnant will not be permitted to enroll in Compound (I) Form A clinical studies. It is unknown if Compound (I) Form A is excreted in breast milk; therefore, nursing women will not be permitted to enroll in Compound (I) Form A clinical studies. Compound (I) Form A is not considered to pose a genotoxic hazard to humans based on in vitro and in vivo studies. Embryo-fetal toxicity study has not been conducted. Compound (I) Form A showed testicular degeneration and decreased luminal sperm counts at all dose levels in the GLP 28-day rat toxicology study, and prostate gland atrophy and seminiferous tubule degeneration at mid-and high-dose levels in the GLP 28-day dog Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT toxicology study. The effects on male reproductive tract are considered to be relevant human risks (see US FDA Guidance for Industry: Oncology Pharmaceuticals: Reproductive Toxicity Testing and Labeling Recommendations, 2019). In vitro and preliminary clinical data suggest that Compound (I) Form A is a CYP3A4 inducer and can render some hormonal contraceptives ineffective (see US FDA, Guidance for Industry: Clinical Drug Interaction Studies with Combined Oral Contraceptives, 2023). Contraception Requirements Female patients of childbearing potential and their male partners must practice effective methods of contraception, as described below, during Compound (I) Form A treatment and for 6 months (ie, approximately 5 × t1/2) after the last dose of Compound (I) Form A. A woman is considered of childbearing potential (WOCBP) after menarche and until becoming post-menopausal (12 continuous months of amenorrhea with no identified cause other than menopause) unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. Male patients of reproductive potential must wear condoms during intercourse, and their female partners who are pregnant or have childbearing potential are advised to practice highly effective methods of contraception during Compound (I) Form A treatment and for 6 months after the last dose of Compound (I) Form A. A male patient is considered to be of reproductive potential unless he has had a bilateral orchiectomy. During screening, while taking study drug, and until 6 months after taking the final dose of Compound (I) Form A, female patients of childbearing potential and male patients who have female partners of childbearing potential must practice one of the following methods of contraception: ^ Total abstinence (defined as refraining from heterosexual intercourse during the entire period outlined above) ^ Bilateral tubal ligation or bilateral vasectomy. ^ Placement of an intrauterine device, including devices with hormone releasing systems ^ Hormonal contraceptive methods that inhibit ovulation. These methods must be supplemented by a barrier method such as a male condom. Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT If required per local guidelines or regulations, locally recognized adequate methods of contraception may be described in the local trial documentation. Additional requirement: Regular pregnancy testing is required for female patients of childbearing potential during Compound (I) Form A treatment and up to 6 months after the last dose of Compound (I) Form A. Treatment should be discontinued immediately in any female patients found to have a positive pregnancy test while taking Compound (I) Form A. Male patients must not make semen donations during Compound (I) Form A treatment and for 6 months following the last dose of Compound (I) Form A. Overdose Three patients experienced accidental overdose, deviating from the assigned dose regimen. The patients took extra dose(s) during the weekly dosing period with no associated adverse events reported. There is no antidote for Compound (I) Form A. In case of overdose, patients should be monitored closely and managed for clinical signs and symptoms. Patients should be re- educated/reminded on the assigned dose regimens and applicable instructions for dose compliance. Reference Safety Information for Assessment of Expectedness of Serious Adverse Reactions The Reference Safety Information (RSI) is intended to be used for the assessment of expectedness of serious adverse drug reactions that are reported in clinical trials for the purpose of identifying and reporting suspected unexpected serious adverse reactions (SUSARs), in shown in Table 28. Table 28: Serious Adverse Reactions for Compound (I) Form A considered expected for safety reporting purposes SOC SARs Number of patients exposed (N) =83 Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT *n = number of patients who have experienced the SAR; SAR = Serious Adverse Reaction; SOC = System Organ Class **: Hypoxia with fatal outcome is not considered as expected. Example 4 Efficacy and Safety of Compound (I) Form A in Patients with Previously Treated Advanced Clear Cell Renal Carcinoma (accRCC): Preliminary Results of a Phase 1/2 Study HIF-2α is a validated target for Von Hippel-Lindau (VHL) disease with germline VHL mutations and clear cell renal cell carcinoma (ccRCC) with somatic VHL deficiency. HIF-2α is upregulated in solid tumors associated with hypoxia but has restricted normal tissue expression. Compound (I) Form A inhibits transcription of HIF-2α-regulated genes important for angiogenesis, glycolysis, and tumorigenesis. The efficacy and safety of Compound (I) Form A in patients with ccRCC were tested in a Part 1 Dose Escalation (Phase 1) portion of the study and are being further tested in an ongoing Part 2 Dose Expansion (Phase 2) of the study. Study Design Data is presented here from the Study described in Example 2 with a clinical cutoff date of 16 June 2024. The study design for the study is shown in Fig.17. Briefly, Compound (I) Form A was tested as a monotherapy against patients with ccRCC. In Part 1 Dose Escalation, a starting dose of 200mg, daily (QD) of Compound (I) Form A was administered to 6 patients. Additional groups of patients were then administered 50mg QD (n=3), 100 mg QD (n=3), and 300 mg (n=3) of Compound (I) Form A. Subsequently, patients were enrolled in 4 cohorts to receive sequential loading and maintenance treatments of Compound (I) Form A, including 200mg QD for 28 days followed by 50 mg QD (n=9), 200 mg QD for 14 days followed by 50 mg QD (n=12), 200 mg QD for 7 days followed by 200 mg weekly (QW) (n=13), and 100 mg QD for 7 days followed by 100 mg QW (n=11). In addition, Part 1 included a preliminary food effect/drug-drug interaction substudy (n=8, 12 planned, 200 mg QD x 7 days then 200 mg QW), and a preliminary urinary excretion and metabolite profiling substudy (n=3, 5 planned, RDE-d). Part 2 also included a substudy with patients who received prior belzutifan treatment (n=2, 10 planned, RDE-d). In total, 113 patients were enrolled, including 60 in Dose Escalation. Patient demographics for this study are shown in Fig.18. Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Briefly, a total of 113 heavily pre-treated, high risk ccRCC patients were enrolled. Ability/Disability at baseline for 113 patients was assessed by the Eastern Cooperative Oncology Group Performance Status (ECOG PS) assessment.48 patients (42.9%) scored a 0, indicating that they were fully active and able to carry on all predisease performance without restriction; 62 patients (55.4%) scored a 1, indicating that they were restricted in physically strenuous activity, but ambulatory and able to carry out work of a light and sedentary nature (e.g., light house work, office work); and 2 patient (1.8%) scored a 2, indicating that they were ambulatory and capable of all self-care but unable to carry out any work activities and, additionally, were up and about more than 50% of waking hours. One patient had missing ECOG values at baseline. International Metastatic RCC Database Consortium (IMDC) risk was assessed in these 113 patients.6 patients (5.3%) had a favorable prognosis; 66 patients (58.4%) had an intermediate prognosis; and 41 patients (36.3%) had a poor prognosis. The number of prior lines of therapy were also quantified in the 113 patients.15 patients (13.3%) had one prior line of therapy; 31 patients (27.4%) had two prior lines of therapy; 29 patients (25.7%) had three prior lines of therapy; and 38 patients (33.6%) had four prior lines of therapy). In total, patients had been subjected to a median of 3 prior lines of therapy, ranging from 1-9 total.106 patients (93.8%) had been subjected to a prior VEGF tyrosine kinase inhibitor; 110 patients (97.3%) had been subjected to a prior immune-oncology therapy; and 32 patients (28.3%) had been subjected to a prior mTOR inhibitor. In part 1 portion of the study, sixty patients were enrolled. Baseline ECOG PS was 0 for 28 patients (47.5%), 1 for 30 patients (50.8%), and 2 for 1 patient (1.7%). One patient had missing ECOG values at baseline. IMDC risk was favorable for 3 patients (5.0%), intermediate for 36 patients (60.0%), and poor for 21 patients (35.0%). Six patients (10.0%) had one prior line of therapy; 12 patients (20.0%) had two prior lines of therapy; 19 patients (31.7%) had three prior lines of therapy; and 23 patients (38.3%) had four prior lines of therapy). In total, patients had been subjected to a median of 3 prior lines of therapy, ranging from 1-8 total.59 patients (98.3%) had been subjected to a prior VEGF tyrosine kinase inhibitor; 59 patients (98.3%) had been subjected to a prior immune-oncology therapy; and 25 patients (41.7%) had been subjected to a prior mTOR inhibitor. Mean pharmacokinetic (PK)/pharmacodynamic (PD) and EPO Profiles Mean pharmacokinetic (PK)/pharmacodynamic (PD) and EPO profiles were assessed following loading and maintenance dosing of Compound (I) Form A. PK and EPO graphs are shown in Fig.19 and Fig.20, respectively. Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Briefly, the PK profile of Compound (I) was dose-linear and time independent with an estimated median t1/2 of 38 days based on a 2-compartmental population PK model. Significant and sustained EPO suppression was observed at all dose levels. Compound (I) exhibited a maximal fractional inhibition of EPO production rate (Imax) of 72%; plasma concentration of Compound (I) for 50% maximal inhibition (IC50) was 16.4 ng/mL. The PK/PD data supported loading and maintenance dosing regimens that quickly achieve and maintain therapeutic exposures. Objective response rate (ORR) In total, 100 patients in the study were deemed efficacy evaluable. Of these 100 patients, 20% exhibited an objective response rate (ORR). The response rate and confidence interval in a Forest plot are shown in Fig.21, and a summary of the response rate and confidence interval for all treated patients and Part I patients is shown in Table 29Error! Reference source not found.. Table 29: Summary of Objective Response Best Overall Response All Patients Part 1 Dose n (%) (N=100) Esclation Patients Briefly, in all evaluable patients, 1 patient (1.00%) exhibited a complete response (CR) to treatment, 19 patients (19.0%) exhibited a partial response (PR) to treatment, 52 patients (52.0%) exhibited stable disease (SD) despite treatment, and 28 patients (28.0%) exhibited progressive disease (PD) despite treatment. The median time in therapeutic range (TTR) was 3.7 months, with a range from 1.6 – 9.1 months. The median duration of response was not evaluable. In Part 1 Dose Esclation patient group, 57 patients were deemed efficacy evaluable. Of these 57 patients, 26.3% exhibited an objective response rate (ORR). One patient (1.75%) exhibited a complete response (CR) to treatment, 14 patients (24.6%) exhibited a partial response (PR) to treatment, 28 patients (49.1%) exhibited stable disease (SD) despite Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT treatment, and 14 patients (24.6%) exhibited progressive disease (PD) despite treatment. Patients achieved an objective response if the best overall response of CR/PR was observed and confirmed by a follow-up imaging assessment by an investigator in accordance with RECIST 1.1 guidelines. The ORR included patients who had at least one post-baseline tumor response assessment or discontinued treatment due to disease progression (including clinical progression) or death of any cause. The SD category included one patient with an unconfirmed PR, and the PD category included clinical progression patients and deaths of any cause for those without post-baseline tumor assessment. Sum of the longest diameter (SLD) Sum of the longest diameter (SLD) of target lesions were assessed in 95 efficacy- evaluable patients. The percent change of lesion from baseline (Waterfall plot) by IMDC risk category is shown in Fig.22. SLD change over time (Spider plot) by objective response is shown in Fig.23. Briefly, 5 patients were unevaluable. The Disease Control Rate (the proportion of patients with a CR, a PR, or durable SD for 8+ weeks) as assessed by an investigator in accordance with RECIST 1.1 guidelines was 60% (95% confidence interval: 50%, 70%). Progression-free survival (PFS) Progression-free survival (PFS) was assessed in the 100 efficacy-evaluable patients. A Kaplan-Meier curve of PFS in patients over time is shown in Fig.24, and the median PFS (95% confidence interval) in a Forest plot is shown in Fig.25. Briefly, the median PFS was 7.4 months and PFS rate at twelve months was 42%. Briefly, PFS ended at an earlier date of first PD (including clinical progression) prior to any new anti-cancer treatment or death of any cause and was censored at the date of last response assessment prior to any new anti-cancer treatment. Related Adverse Events Related Adverse Events (AEs) that were reported for >10% subjects of 113 safety evaluable patients are reported in Fig.26. Briefly, in general the pattern of related AEs was similar across all dose levels. Regarding dose-limiting toxicity, 1/12 subjects experienced DLTs (fatigue and hypoxia) at 200 mg QD x 14 then 50 mg QD, and 1/9 subjects experienced DLTs (fatigue and hypoxia) at 200 mg QD x 28 then 50 mg QD. Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Part 2 Dose Expansion portion of the study is ongoing in which patients were randomized to receive one of two recommended dosages for expansion (RDEs). A first group 20 patients were treated with daily maintenance dosing (RDE-d): 200mg QD x 14 days, then 50 mg QD; and a second group of 20 patients were treated with weekly maintenance dosing (RDE-w): 100mg QD x 7 days, then 100mg QD. In a subgroup analysis, patients who received Compound (I) Form A at RDE-w or RDE-d in the study were grouped. The baseline demographics, efficacy, and safety results of this subgroup are summarized in Table 30. In a subgroup analysis, patients who received Compound (I) Form A at RDE-w or RDE-d in the dose escalation were grouped. The baseline demographics, efficacy, and safety results of this subgroup are summarized in Table 31. Table 30: Subgroup Analysis of Patients Who Received Compound (I) Form A at RDE-w and RDE-d RDE-d: 200 mg Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Prior VEGF TKI Received 28 (90%) 30 (91%) – n (%) ) ) ts who had prior belzutifan treatment at RDE-d. Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT Table 31: Subgroup Analysis of Patients Who Received Compound (I) Form A at RDE-w and RDE-d in Dose Escalation RDE-w: 100 mg QDx7/100 RDE-d: 200 mg QDx14/50 mg QW mg QD Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT TTR, median (min–max), 6.3 months (3.7 – 7.4) 3.7 months (3.7 – 5.5) months As shown in Table 30, the median follow-up time for patients receiving the RDE-w dose comprising 100 mg QD x 7 followed by 100 mg QW of Compound (I) Form A was 8.2 months, with an overall range of 0.23 – 20.9 months. The median follow-up time for patients receiving the RDE-d dose comprising 200 mg QD x 14 followed by 50 mg QD of Compound (I) Form A was 9.1 months, with an overall range of 1.1-23.4 months.15 patients in the RDE-w patient population (50%) scored a 0 according to established Eastern Cooperative Oncology Group Performance Status (ECOG PS) criteria, 14 patients (47%) scored a 1, and 1 patient (3%) scored a 2. In the RDE-d patient population, 15 patients (46%) scored a 0, 18 patients (55%) scored a 1, and 0 patients (0%) scored a 2.1 patient (3%) in the RDE-w patient population received a favorable diagnosis according to established International Metastatic RCC Database Consortium (IMDC) risk categories, 23 patients (74%) received an intermediate diagnosis, and 7 patients (23%) received a poor diagnosis.2 patients (6%) in the RDE-d patient population received a favorable diagnosis, 16 patients (49%) received an intermediate diagnosis, and 15 patients (45%) received a poor diagnosis. In the RDE-w Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT patient population, 9 patients (29%) received 1 prior line of therapy, 11 patients (35%) received 2 prior lines of therapy, 3 patients (10%) received 3 prior lines of therapy, and 8 patients (26%) received four or more prior lines of therapy. In the RDE-d patient population, 2 patients (6%) received 1 prior line of therapy, 11 patients (33%) received 2 prior lines of therapy, 9 patients (27%) received 3 prior lines of therapy, and 11 patients (34%) received four or more prior lines of therapy. In the RDE-w patient population, 28 patients (90%) received a prior VEGF tyrosine kinase inhibitor (TKI), and, in the RDE-d patient population, 30 patients (91%) received one. In the RDE-w patient population, 30 patients (97%) received a prior immuno-oncology (IO) therapy, and, in the RDE-d patient population, 32 patients (97%) received one. In the RDE-w patient population, 4 patients (13%) received a prior mTOR inhibitor therapy, and, in the RDE-d patient population, 9 patients (27%) received one. Regarding efficacy, in the RDE-w patient population, an 18.5% overall response rate (ORR) was observed, with an overall range of 6.3% to 38.1%.0 patients (0%) exhibited a complete response (CR), 5 patients (18.5%) exhibited a partial response (PR), 17 patients (63%) exhibited stable disease (SD), and 5 patients (18.5%) exhibited progressive disease (PD). In the RDE-d patient population, a 13.8% ORR was observed, with an overall range of 3.9% to 31.7%.0 patients (0%) exhibited a CR, 4 patients (13.8%) exhibited a PR, 14 patients (48.3%) exhibited SD, and 11 patients (37.9%) exhibited PD. For the RDE-w patient population, the median time to response (TTR) was 5.4 months, with a minimum of 3.7 months and a maximum of 7.4 months. For the RDE-d patient population, the median TTR was 3.7 months, with a minimum of 1.6 months and a maximum of 5.5 months. For the RDE- w patient population, the modified progression-free survival (mPFS) was 7.3 months, with an overall range of 3.7 to 10.6 months. For the RDE-d patient population, the mPFS was 12.6 months, with an overall range of 1.8 to 13.9 months. For the RDE-w patient population, the PFS at 12 months was 25%, with an overall range of 7% to 49%. For the RDE-d patient population, the PFS at 12 months was 55%, with an overall range of 34% to 72%. For the RDE-w patient population, the disease control rate (DCR) was 66.7%, with an overall range of 46.0% to 83.5%. For the RDE-d patient population, the DCR was 55.2%, with an overall range of 35.7% to 73.6%. Regarding safety, in the RDE-w patient population, 35.5% experienced any serious adverse event (SAE). In the RDE-d patient population, 33.3% experienced any SAE. In the RDE-w patient population, 12.9% experienced a treatment-emergent adverse event (TEAE) Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT leading to discontinuation of Compound (I) Form A. In the RDE-d patient population, 15.2% experienced a TEAE leading to discontinuation of Compound (I) Form A. In the RDE-w patient population, 35.3% experienced any grade 3 or higher treatment-related adverse event (TRAE).16.1% of the RDE-w patient population experienced anemia, 12.9% experienced hypoxia, and 0% experienced fatigue. In the RDE-d patient population, 33.3% experienced any grade 3 or higher TRAE.15.2% of the RDE-d patient population experienced anemia, 18.2% experienced hypoxia, and 6.1% experienced fatigue. As shown in Table 31, the median follow-up time for patients receiving the RDE-w dose in dose escalation comprising 100 mg QD x 7 followed by 100 mg QW of Compound (I) Form A was 20.2 months, with an overall range of 13.2 – 20.9 months. The median follow-up time for patients receiving the RDE-d dose in dose escalation comprising 200 mg QD x 14 followed by 50 mg QD of Compound (I) Form A was 20.5 months, with an overall range of 10.3-23.4 months.6 patients in the RDE-w patient population (60%) scored a 0 according to established ECOG PS criteria, 4 patients (40%) scored a 1, and 0 patients (0%) scored a 2. In the RDE-d patient population, 6 patients (50%) scored a 0, 6 patients (50%) scored a 1, and 0 patients (0%) scored a 2.0 patients (0%) in the RDE-w patient population received a favorable diagnosis according to established IMDC risk categories, 7 patients (64%) received an intermediate diagnosis, and 4 patients (36%) received a poor diagnosis.1 patient (8%) in the RDE-d patient population received a favorable diagnosis, 9 patients (75%) received an intermediate diagnosis, and 2 patients (17%) received a poor diagnosis. In the RDE-w patient population, 2 patients (18%) received 1 prior line of therapy, 3 patients (27%) received 2 prior lines of therapy, 2 patients (18%) received 3 prior lines of therapy, and 4 patients (37%) received four or more prior lines of therapy. In the RDE-d patient population, 1 patient (8%) received 1 prior line of therapy, 3 patients (25%) received 2 prior lines of therapy, 4 patients (33%) received 3 prior lines of therapy, and 4 patients (34%) received four or more prior lines of therapy. In the RDE-w patient population, 11 patients (100%) received a prior VEGF TKI, and, in the RDE-d patient population, 11 patients (92%) received one. In the RDE-w patient population, 11 patients (100%) received a prior IO therapy, and, in the RDE-d patient population, 12 patients (100%) received one. In the RDE-w patient population, 3 patients (27%) received a prior mTOR inhibitor therapy, and, in the RDE-d patient population, 4 patients (33%) received one. Regarding efficacy, in the RDE-w patient population, an 36.4% ORR was observed, with an overall range of 10.9% to 69.2%.0 patients (0%) exhibited a CR, 4 patients (36.4.%) Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT exhibited a PR, 5 patients (45.5%) exhibited SD, and 2 patients (18.2%) exhibited PD. In the RDE-d patient population, a 25.0% ORR was observed, with an overall range of 5.5% to 57.2%.0 patients (0%) exhibited a CR, 3 patients (25.0%) exhibited a PR, 7 patients (58.3%) exhibited SD, and 2 patients (16.7%) exhibited PD. For the RDE-w patient population, the median TTR was 6.3 months, with a minimum of 3.7 months and a maximum of 7.4 months. For the RDE-d patient population, the median TTR was 3.7 months, with a minimum of 3.7 months and a maximum of 5.5 months. For the RDE-w patient population, the mPFS was 7.5 months, with an overall range of 2.0 to 12.7 months. For the RDE-d patient population, the mPFS was 13.6 months, with an overall range of 1.8 months to an upper limit of months that was not evaluable (“NE”). For the RDE-w patient population, the PFS at 12 months was 27%, with an overall range of 7% to 54%. For the RDE-d patient population, the PFS at 12 months was 74%, with an overall range of 39% to 91%. For the RDE-w patient population, the DCR was 81.8%, with an overall range of 48.2% to 97.7%. For the RDE-d patient population, the DCR was 75.0%, with an overall range of 42.8% to 94.5%. Regarding safety, in the RDE-w patient population, 36.4% experienced any SAE. In the RDE-d patient population, 41.7% experienced any SAE. In the RDE-w patient population, 18.2% experienced a TEAE leading to discontinuation of Compound (I) Form A. In the RDE-d patient population, 16.7% experienced a TEAE leading to discontinuation of Compound (I) Form A. In the RDE-w patient population, 36.4% experienced any grade 3 or higher TRAE.9% of the RDE-w patient population experienced anemia, 27% experienced hypoxia, and 0% experienced fatigue. In the RDE-d patient population, 25.0% experienced any grade 3 or higher TRAE.8% of the RDE-d patient population experienced anemia, 17% experienced hypoxia, and 8% experienced fatigue. In summary, Compound (I) Form A demonstrated robust anti-tumor activity in heavily pretreated advanced ccRCC patients. Compound (I) showed linear PK and significant and prolonged EPO suppression at all tested dosage levels of Compound (I) Form A. The safety profile for Compound (I) Form A was consistent with this class of agent. The available data continues to support further evaluation of the two RDEs in the Dose Expansion.

Claims

Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT What is Claimed: 1. A method of treating cancer comprising administering to a patient in need thereof: (a) a loading dose during a loading period, wherein the loading dose comprises from about 20 mg to about 300 mg of Compound (I) or Compound (I) Form A polymorph of Compound (I) having an X-ray powder diffraction pattern comprising peaks at angular positions 15.8 and 18.6, wherein the angular positions may vary by + 0.2o 2θ as measured using an X-ray wavelength of 1.5418 Å; and (b) a maintenance dose during a maintenance period, wherein each maintenance dose comprises less than or the same amount of Compound (I) or the Compound (I) Form A present in the loading dose in (a); provided that, when the amount of Compound (I) or the Compound (I) Form A in the maintenance dose is the same as in the loading dose, the maintenance dose is administered to the patient less frequently than the loading dose is administered during the loading period. 2. The method of claim 1, wherein the Compound (I) Form A X-ray powder diffraction pattern comprises peaks at angular positions 15.8, 18.6, and 20.1, wherein the angular positions may vary by + 0.2o 2θ. 3. The method of claim 1, wherein the Compound (I) Form A X-ray powder diffraction pattern comprises peaks at angular positions 12.9, 15.8, 18.6, and 20.1, wherein the angular positions may vary by + 0.2o 2θ. 4. The method of claim 1, wherein the Compound (I) Form A X-ray powder diffraction pattern comprises peaks at angular positions 11.4, 12.9, 15.8, 18.6, and 20.1, wherein the angular positions may vary by + 0.2o θ. 5. The method of claim 1, wherein the Compound (I) Form A X-ray powder diffraction pattern comprises peaks at angular positions substantially as shown in Fig.4. 6. The method of any one of claims 1 to 5, wherein the amount of loading dose is about 100 mg QD. 7. The method of any one of claims 1 to 6, wherein the amount of loading dose is about 100 mg QD and is administered for 7 consecutive days. 8. The method of any one of claims 1 to 5, wherein the amount of loading dose is about 200 mg QD. 9. The method of any one of claims 1 to 5 and 8, wherein the amount of loading dose is about 200 mg QD and is administered for 7 consecutive days. Attorney Docket No.16036.0005-00304 Ref. No. NKT-24-007PCT 10. The method of any one of claims 1 to 5 and 8, wherein the amount of loading dose is about 200 mg QD and is administered for 14 consecutive days. 11. The method of any one of claims 1 to 5 and 8, wherein the amount of loading dose is about 200 mg QD and is administered for 28 consecutive days. 12. The method of any one of claims 1 to 7, wherein the amount of maintainance dose is about 100 mg QW. 13. The method of any one of claims 1 to 5, 8, and 9, wherein the amount of maintainance dose is about 200 mg QW. 14. The method of any one of claims 1 to 5, 8, 10, and 11, wherein the amount of maintainance dose is about 50 mg QD. 15. The method of any one of claims 1 to 14, wherein the Compound (I) or the Compound (I) Form A is administered in combination with at least one other anticancer agent. 16. The method of any one of claims 1 to 15, wherein the cancer is selected from a renal cancer, a glioblastoma, a neuroblastoma, a paraganglioma, a pheochromocytoma, a somatostatinoma, a hemangioblastoma, a gastrointestinal stromal tumor, a pituitary tumors, a bladder cancer, a liver cancer, a leiomyoma, a leiomyosarcoma, a polycythaemia, and a retinal cancer. 17. The method of any one of claims 1 to 16, wherein the at least one other anticancer agent is selected from abemaciclib, cemiplimab-rwlc, nivolumab, pembrolizumab, dostarlimab, atezolizumab, durvalumab, and avelumab.
PCT/US2024/056721 2024-05-04 2024-11-20 3-fluoro-5-(((ls,2ar)-1,3,3,4, 4-pentafluoro-2a-hydroxy-2,2a, 3,4-tetrahydro-lh-cyclopenta[cd]inden-7- yl)oxy)- benzonitrile dosing regimen for use in the treatment of cancer Pending WO2025235034A1 (en)

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