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WO2025006569A1 - Combinaisons d'agents de dégradation du récepteur des œstrogènes et d'inhibiteurs de cdk7 pour le traitement du cancer - Google Patents

Combinaisons d'agents de dégradation du récepteur des œstrogènes et d'inhibiteurs de cdk7 pour le traitement du cancer Download PDF

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Publication number
WO2025006569A1
WO2025006569A1 PCT/US2024/035566 US2024035566W WO2025006569A1 WO 2025006569 A1 WO2025006569 A1 WO 2025006569A1 US 2024035566 W US2024035566 W US 2024035566W WO 2025006569 A1 WO2025006569 A1 WO 2025006569A1
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Prior art keywords
cancer
compound
samuraciclib
pharmaceutically acceptable
acceptable salt
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English (en)
Inventor
Richard Walter GEDRICH
Jessica Li Fong TEH
Ashwani K. Bahl
Julia Perkins SMITH
Olga Valota
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Pfizer Corp Belgium
Pfizer Corp SRL
Arvinas Operations Inc
Carrick Therapeutics Ltd
Original Assignee
Pfizer Corp Belgium
Pfizer Corp SRL
Arvinas Operations Inc
Carrick Therapeutics Ltd
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Publication of WO2025006569A1 publication Critical patent/WO2025006569A1/fr
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    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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

Definitions

  • Certain bifunctional compounds target specific cellular proteins for degradation via the ubiquitin-proteasome system.
  • proteolysis targeting chimeric compounds i.e., “PROTAC® protein degraders”
  • ER Estrogen Receptor
  • Such bifunctional molecules exhibit a range of pharmacological activities consistent with the degradation of the ER including, but not limited to, treatment or amelioration of a disease condition such as cancer (e.g., breast cancer, uterine cancer, ovarian cancer, prostate cancer, endometrial cancer), or endometriosis.
  • a bifunctional molecule of particular interest is (5)-3-(5-(4-((l-(4-((lR,25)-6-hydroxy-2- phenyl- 1 ,2,3 ,4-tetrahy dronaphthalen- 1 -y l)phenyl)piperidin-4-y l)methy l)piperazin- 1 -y 1)- 1 - oxoisoindolin-2-yl)piperidine-2, 6-dione or (35)-3-[l,3-dihydro-l-oxo-5-[4-[[l-[4-[(lR,25)- 1 ,2,3 ,4-tetrahy dro-6-hydroxy-2-phenyl- 1 -naphthal enylphenyl]-4-piperidinyl]methyl] - 1 - piperazinyl]-27/-isoindol-2-yl]-2,6-piperidinedi
  • the present disclosure provides, in part, methods for administering Compound A, or a pharmaceutically acceptable salt thereof, to a subject in combination therapies, for treating cancer.
  • This summary is provided to introduce a selection of concepts in a simplified form that are further described below in the detailed description. This summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used in isolation as an aid in determining the scope of the claimed subject matter.
  • kits for treating cancer comprising administering to a subject Compound A having a structure of: or a pharmaceutically acceptable salt thereof, in combination with a selective CDK7 inhibitor.
  • the method comprises administering to a subject Compound A in combination with a selective CDK7 inhibitor.
  • a daily dose of Compound A is administered to the subject.
  • the daily dose of Compound A is 200 mg.
  • the daily dose of Compound A is 100 mg.
  • Compound A and the selective CDK7 inhibitor are administered concurrently or sequentially.
  • Compound A is administered once per day (QD).
  • Compound A is administered once per day (QD).
  • the daily dose of Compound A is administered once per day (QD).
  • Compound A or a pharmaceutically acceptable salt thereof, is administered orally to the subject.
  • Compound A is administered orally to the subject.
  • the daily dose of Compound A, or a pharmaceutically acceptable salt thereof is administered orally to the subject.
  • the subject is in a fed state.
  • the selective CDK7 inhibitor is samuraciclib, or pharmaceutically acceptable salt thereof.
  • a daily dose of samuraciclib, or pharmaceutically acceptable salt thereof is administered to the subject.
  • the daily dose of samuraciclib, or pharmaceutically acceptable salt thereof is 240 mg.
  • the daily dose of samuraciclib, or pharmaceutically acceptable salt thereof is 360 mg.
  • Compound A is administered daily in 28-day cycles and samuraciclib, or a pharmaceutically acceptable salt thereof, is administered once a day for each 28-day cycle.
  • the selective CDK7 inhibitor is samuraciclib.
  • a daily dose of samuraciclib is administered to the subject.
  • the daily dose of samuraciclib is 240 mg.
  • the daily dose of samuraciclib is 360 mg.
  • Compound A is administered daily in 28-day cycles and samuraciclib is administered once a day for each 28-day cycle.
  • the dose of samuraciclib, or pharmaceutically acceptable salt thereof is 240 mg. In embodiments, the dose of samuraciclib, or pharmaceutically acceptable salt thereof, is 360 mg. In embodiments, Compound A is administered daily in 28-day cycles and samuraciclib, or a pharmaceutically acceptable salt thereof, is administered daily in 28-day cycles.
  • the dose of samuraciclib is 240 mg. In embodiments, the dose of samuraciclib is 360 mg. In embodiments, Compound A is administered daily in 28-day cycles and samuraciclib is administered once a day for each 28-day cycle.
  • the cancer is breast cancer, lung cancer, colon cancer, brain cancer, head and neck cancer, prostate cancer, stomach cancer, pancreatic cancer, ovarian cancer, melanoma, endocrine cancer, uterine cancer, testicular cancer, or bladder cancer.
  • the cancer is breast cancer, lung cancer, prostate cancer, pancreatic cancer, or ovarian cancer.
  • the cancer is breast cancer, lung cancer, or prostate cancer.
  • the cancer is breast cancer.
  • the breast cancer is metastatic or locally advanced.
  • the breast cancer is estrogen receptor positive (ER + ) breast cancer.
  • the estrogen receptor positive (ER + ) breast cancer is human epidermal growth factor receptor 2 negative (HER2 ).
  • the subject is human.
  • the present disclosure provides combined preparations of
  • a CDK7 inhibitor for simultaneous, separate, or sequential use in a method of treating cancer.
  • FIGS. 1A and IB show the relative cell growth of MCF7 cells (FIG. 1A) and T47D cells (FIG. IB) over time for control (DMSO), samuraciclib, Compound A, and a combination of samuraciclib and Compound A. Means -/+ standard errors of the mean (SEM) of 5 independent experiments.
  • FIGS. 3A-3C show the dose-response inhibition of MCF7 cell growth of Compound A (FIG. 3A), samuraciclib (FIG. 3B), and a combination of Compound A and samuraciclib (FIG. 3C). Data is representative of two independent experiments.
  • FIG. 7 shows a scheme of sub-study C (Compound A + samuraciclib) design.
  • PROTAC® protein degrader that targets estrogen receptor (ER) for the potential treatment of breast cancer.
  • Compound A has been shown to be a useful modulator of targeted protein ubiquitination and degradation via the ubiquitin-proteasome pathway.
  • Cyclin-dependent kinases and related serine/threonine protein kinases are important cellular enzymes that perform essential functions in regulating eukaryotic cell division and proliferation.
  • the CDK catalytic units are activated by regulatory subunits known as cyclins. At least sixteen mammalian cyclins have been identified (Johnson DG, Walker CL. Cyclins and Cell Cycle Checkpoints. Annu. Rev. Pharmacol. Toxicol. (1999) 39:295-312).
  • Cyclin B/CDK1, cyclin A/CDK2, cyclin E/CDK2, cyclin D/CDK4, cyclin D/CDK6, and likely other heterodynes are important regulators of cell cycle progression.
  • cyclin/CDK heterodynes include regulation of transcription, DNA repair, differentiation, and apoptosis (Morgan DO, Cyclin-dependent kinases: engines, clocks, and microprocessors. Annu. Rev. Cell. Dev. Biol. (1997) 13:261-91).
  • CDK7-CDK13 have been linked to transcription, only CDK1, 2, 4, and 6 show demonstrable association with the cell cycle.
  • CDK7 has consolidated kinase activities, regulating both the cell cycle and transcription.
  • CDK7 exists as a heterotrimeric complex and is believed to function as a CDKl/2-activating kinase (CAK), whereby phosphorylation of conserved residues in CDK1/2 by CDK7 is required for full catalytic CDK activity and cell cycle progression (Desai et al., “Effects of phosphorylation by CAK on cyclin binding by CDChand CDK2.
  • CDK7 forms the kinase core of the RNA polymerase (RNAP) II general transcription factor complex and is charged with phosphorylating the C-terminal domain (CTD) of RNAP II, a requisite step in gene transcriptional initiation (Serizawa.
  • RNAP RNA polymerase
  • CTD C-terminal domain
  • Samuraciclib displays 45-, 15-, 230- and 30-fold selectivity over CDK1, CDK2 , CDK5 and CDK9, respectively.
  • Samuraciclib inhibits the growth of breast cancer cell lines with GI50 values between 0.2-0.3 pM.
  • Samuraciclib has anti -tumor effects.
  • Samuraciclib is a compound that has the structure:
  • the methods of the present invention may be beneficial for treating cancer (e.g., breast cancer), and, indeed, may have one or more advantages or increased benefits when Compound A is used in combination another therapy, specifically a CDK7 inhibitor.
  • cancer e.g., breast cancer
  • a CDK7 inhibitor e.g., a CDK7 inhibitor
  • preclinical data suggests that the combination of Compound A and samuraciclib show improved safety and efficacy, potential to reduce side effects, including adverse events; potential to overcome resistance mechanisms, such as resistance to endocrine therapy; and potential to achieve similar or improved safety and efficacy through dose modification or dosing regimens, over the monotherapies of Compound A and samuraciclib alone.
  • the term “about” when used to modify a numerically defined parameter means that the parameter may vary by as much as 10% below or above the stated numerical value for that parameter.
  • a dose of about 5 mg means 5 mg ⁇ 10%, i.e., it may vary from 4.5 mg to 5.5 mg.
  • agents including, but not limited to, “agent,” “composition,” “compound,” “drug,” and “therapeutic agent” may be used interchangeably to refer to compounds included in the methods and uses of the present disclosure.
  • the terms, “subject,” “participant,” and “patient,” are used interchangeably, to refer to any animal, including mammals. Mammals according to the disclosure include canine, feline, bovine, caprine, equine, ovine, porcine, rodents, lagomorphs, primates, humans, and the like, and encompass mammals in utero. In embodiments, the subject is a human. Human subjects may be of any gender and at any stage of development.
  • the term “locally advanced or metastatic second line (2L) ER + HER2 breast cancer” refers to breast cancers in subjects who have received prior hormonal/endocrine therapy and chemotherapy in the locally advanced/metastatic setting and whose breast cancers have progressed.
  • Compound A is a Biopharmaceutics Classification System Class IV compound (low solubility/low permeability). Compound A can interconvert to its epimer, Compound B:
  • CDKs Cyclin-dependent kinases
  • serine/threonine kinases are important cellular enzymes that perform essential functions in regulating cell division and proliferation.
  • CDK inhibitors include pan-CDK inhibitors that target a broad spectrum of CDKs or selective CDK inhibitors that target specific CDK(s).
  • Other embodiments also relate to the pharmaceutically acceptable acid addition salts of the compounds described herein. Suitable acid addition salts are formed from acids which form non-toxic salts.
  • Non-limiting examples of suitable acid addition salts include, but are not limited to, the acetate, acid citrate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, bitartrate, borate, camsylate, citrate, cyclamate, edisylate, esylate, ethanesulfonate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methanesulfonate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate,
  • Suitable base addition salts are formed from bases that form non-toxic salts.
  • suitable base salts include the aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, and zinc salts.
  • the compounds described herein that are basic in nature can form a wide variety of salts with various inorganic and organic acids.
  • the acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds described herein are those that form non-toxic acid addition salts, e.g., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and
  • the compounds described herein that are acidic in nature can form a wide variety of salts with various inorganic and organic bases.
  • the bases that may be used to prepare pharmaceutically acceptable base salts of the compounds described herein are those that form non-toxic base salts with such compounds.
  • Such non-toxic base salts include, but are not limited to, those derived from such pharmacologically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine-(meglumine), and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines.
  • Hemisalts of acids and bases may also be formed, for example, hemisulphate, and hemicalcium salts.
  • Compound A having a structure of: pharmaceutically acceptable salt thereof, in combination with a selective CDK7 inhibitor.
  • the method comprises administering to a subject Compound A in combination with a selective CDK7 inhibitor.
  • the daily dose of Compound A having a structure of: , or a pharmaceutically acceptable salt thereof is administered once per day (QD).
  • Compound A, or a pharmaceutically acceptable salt thereof is administered once per day (QD).
  • Compound A is administered once per day (QD).
  • the daily dose of Compound A having a structure of: , or a pharmaceutically acceptable salt thereof, is administered orally to the subject.
  • Compound A is administered orally to the subject.
  • the subject is in a fed state.
  • the dose of Compound A, or a pharmaceutically acceptable salt thereof is about 200 mg. In embodiments, the dose of Compound A is about 200 mg. In embodiments, the dose of Compound A is about 200
  • the daily dose of Compound A having a structure of: thereof is 200 mg.
  • the dose of Compound A, or a pharmaceutically acceptable salt thereof is 200 mg.
  • the dose of Compound A is 200 mg.
  • the daily dose of Compound A having a structure of: , or a pharmaceutically acceptable salt thereof is about 100 mg. In embodiments, the dose of Compound A, or a pharmaceutically acceptable salt thereof, is about 100 mg. In embodiments, the dose of Compound A is about 100 mg.
  • the daily dose of Compound A having a structure of: , or a pharmaceutically acceptable salt thereof is 100 mg. In embodiments, the dose of Compound A, or a pharmaceutically acceptable salt thereof, is 100 mg. In embodiments, the dose of Compound A is 100 mg.
  • Compound A and the selective CDK7 inhibitor are administered concurrently or sequentially.
  • the selective CDK7 inhibitor is samuraciclib, or a pharmaceutically acceptable salt thereof. In embodiments, the selective CDK7 inhibitor is samuraciclib.
  • Compound A, or a pharmaceutically acceptable salt thereof is administered daily in 28-day cycles. In certain embodiments, samuraciclib, or a pharmaceutically acceptable salt thereof, is administered orally once a day for each 28-day cycle. Alternatively, samuraciclib is administered orally once a day for each 28-day cycle.
  • samuraciclib is administered at a dose of about 240 mg daily. In embodiments, samuraciclib, or a pharmaceutically acceptable salt thereof, is administered at a dose of 240 mg daily.
  • samuraciclib is administered at a dose of about 360 mg daily. In embodiments, samuraciclib, or a pharmaceutically acceptable salt thereof, is administered at a dose of 360 mg daily.
  • the cancer is breast cancer, lung cancer, colon cancer, brain cancer, head and neck cancer, prostate cancer, stomach cancer, pancreatic cancer, ovarian cancer, melanoma, endocrine cancer, uterine cancer, testicular cancer, or bladder cancer.
  • the cancer is breast cancer, lung cancer, prostate cancer, pancreatic cancer, or ovarian cancer.
  • the cancer is breast cancer, lung cancer, or prostate cancer.
  • the breast cancer is metastatic or locally advanced.
  • the breast cancer is estrogen receptor positive (ER + ) breast cancer.
  • the subject is human.
  • Compound A having the structure: thereof, for use according to any one of foregoing embodiments.
  • a CDK7K inhibitor for simultaneous, separate, or sequential use in a method of treating cancer.
  • the active agents e.g., Compound A or a pharmaceutically acceptable salt thereof, and a CDK7 inhibitor
  • the active agents may be physically separated, thus allowing for their separate or sequential administration.
  • treatment and “therapy,” as used herein, unless otherwise indicated, refer to the act of treating as “treating” is defined immediately above.
  • beneficial or desired clinical results include, but are not limited to, one or more of the following: reducing the proliferation of (or destroying) neoplastic or cancerous cell; inhibiting metastasis or neoplastic cells; shrinking or decreasing the size of tumor; remission of the cancer; decreasing symptoms resulting from the cancer; increasing the quality of life of those suffering from the cancer; decreasing the dose of other medications required to treat the cancer; delaying the progression the cancer; curing the cancer; overcoming one or more resistance mechanisms of the cancer; and / or prolonging survival of patients the cancer.
  • Positive therapeutic effects in cancer can be measured in a number of ways (see, for example, W. A. Weber, J. Nucl. Med. (2009) 5O:1S-1OS).
  • ‘Fed condition” or “fed state” as used to describe a subject herein means that the subject has eaten less than 4 hours before a time point of interest, such as the time of administering Compound A. In embodiments, a subject in the fed state has not eaten for at most any of 4, 3, 2, 1, or 0.5 hours prior to administration of Compound A.
  • An “amount” for use and for treating a subject refers to an amount that provides, in single or multiple doses, in combination with one or more other agents, a detectable response of any duration of time (transient, medium, or long term), a desired outcome in or an objective or subjective benefit to a subject of any measurable or detectable degree or for any duration of time (e.g., for hours, days, months, years, in remission or cured).
  • Such amounts typically are effective to ameliorate a disease, or one, multiple or all adverse effects / symptoms, consequences, or complications of the disease, to a measurable extent, although reducing or inhibiting a progression or worsening of the disease, or providing stability (i.e., not worsening) state of the disease, is considered a satisfactory outcome.
  • therapeutically effective amount also means an amount of an agent in combination with one or more other agents, effective for producing a desired therapeutic effect upon administration to a subject, for example, to stem the growth, or result in the shrinkage, of a cancerous tumor.
  • a therapeutically effective amount refers to that amount that has the effect of (1) reducing the size of the tumor, (2) inhibiting (that is, slowing to some extent, preferably stopping) tumor metastasis emergence, (3) inhibiting to some extent (that is, slowing to some extent, preferably stopping) tumor growth or tumor invasiveness, and/or (4) relieving to some extent (or, preferably, eliminating) one or more signs or symptoms associated with the cancer.
  • Therapeutic or pharmacological effectiveness of the doses and administration regimens also may be characterized as the ability to induce, enhance, maintain, or prolong disease control and/or overall survival in patients with these specific tumors, which may be measured as prolongation of the time before disease progression.
  • ameliorate refers to any reduction in the extent, severity, frequency, and/or likelihood of a symptom or clinical sign characteristic of a particular disease.
  • Symptom refers to any subjective evidence of disease or of a subject’s condition.
  • Embodiments of the present invention provide a dose, dosage, and dosing regimen comprising administering to a subject an amount, or an effective amount of Compound A, or a pharmaceutically acceptable salt thereof.
  • the amount, or the therapeutically effective amount can be a daily dose of about 200 mg.
  • a daily dose of Compound A is 200 mg.
  • a daily dose of Compound A is about 100 mg.
  • a daily dose of Compound A is 100 mg.
  • the daily dose of Compound A, or a pharmaceutically acceptable salt thereof is administered once per day (QD).
  • Compound A is administered once per day (QD).
  • the compounds disclosed herein may be administered orally.
  • Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the bloodstream directly from the mouth.
  • the daily dose of Compound A, or a pharmaceutically acceptable salt thereof is administered orally.
  • Compound A is administered orally to the subject.
  • Compound A is administered orally to the subject.
  • Compound A may be present in a pharmaceutical composition, which includes a pharmaceutically acceptable excipient.
  • a “pharmaceutically acceptable excipient” refers to a component that may be included in the compositions described herein, is physiologically suitable for pharmaceutical use, and causes no significant adverse effects nor therapeutic effects to a subject.
  • excipient is used herein to describe any ingredient other than the compound(s) of the invention. The choice of excipient will to a large extent depend on factors such as the mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.
  • the compounds of the methods, uses, or combinations of the present invention may be formulated prior to administration.
  • the formulation preferably will be adapted to the particular mode of administration.
  • These compounds may be formulated with pharmaceutically acceptable excipients as known in the art and administered in a wide variety of dosage forms as known in the art.
  • Dosage unit forms or pharmaceutical compositions suitable for oral administration include, but are not limited to tablets, capsules, such as gelatin capsules, pills, powders, granules, aqueous, and nonaqueous oral solutions and suspensions, packaged in containers adapted for subdivision into individual doses.
  • the daily dosage of samuraciclib, or a pharmaceutically acceptable salt thereof is 120 mg/day, 240 mg/day, or 360 mg/day.
  • a “continuous dosing schedule,” as used herein, is an administration or dosing regimen without dose interruptions, e.g., without days off treatment. Repetition of 28-day treatment cycles without dose interruptions between the treatment cycles is an example of a continuous dosing schedule.
  • the compounds of the combination of the present invention can be administered in a continuous dosing schedule.
  • the compounds of the combination disclosed herein can be administered concurrently in a continuous dosing schedule.
  • Compound A, or a pharmaceutically acceptable salt thereof is administered once daily to comprise a complete cycle of 28-days. Repetition of 28-day treatment cycles is continued during treatment in accordance with the methods and uses of the present disclosure.
  • kits comprising the therapeutic agents of the combination of the present disclosure and written instructions for administration of the therapeutic agents.
  • the written instructions elaborate and qualify the modes of administration of the therapeutic agents, for example, for simultaneous or sequential administration of the therapeutic agents of the present disclosure.
  • the written instructions elaborate and qualify the modes of administration of the therapeutic agents, for example, by specifying the days of administration for each of the therapeutic agents during a 28-day treatment cycle.
  • kits for treating cancer in a subject comprising administering to the subject an effective amount of Compound A, or a pharmaceutically acceptable salt thereof, as described herein in combination with an amount of a selective CDK7 inhibitor.
  • composition refers to the use of Compound A, or a pharmaceutically acceptable salt thereof, with one or more therapeutic agents, wherein Compound A, or a pharmaceutically acceptable salt thereof, and the one or more therapeutic agents are administered intermittently, concurrently, or sequentially, according to the same or different route of administration and according to the same or different dosage schedules.
  • locally advanced breast cancer is defined by the U.S. National Comprehensive Cancer Network as a subset of breast cancer characterized by the most advanced breast tumors in the absence of distant metastasis, wherein the tumors are more than 5 cm in size with regional lymphadenopathy; tumors of any size with direct extension to the chest wall or skin, or both (including ulcer or satellite nodules), regardless of regional lymphadenopathy; presence of regional lymphadenopathy (clinically fixed or matted axillary lymph nodes, or any of infraclavicular, supraclavicular, or internal mammary lymphadenopathy) regardless of tumor stage. (Garg et al. Curr Oncol. 2015 Oct; 22(5): e409-10; National Comprehensive Cancer Network NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. Fort Washington, PA: NCCN; 2015. Ver. 2.2015.)
  • metastatic breast cancer refers to breast cancer that has spread beyond the breast and nearby lymph nodes to other parts of the body, e.g., bones, liver, lungs, or brain, (www. cancer, org/ cancer/br east-cancer. )
  • CRPC castration resistant prostate cancer
  • ER + estrogen receptor positive
  • HER2 human epidermal growth factor receptor 2 negative
  • HR hormone receptor
  • HER2 + human epidermal growth factor receptor 2 positive
  • NSCLC non-small cell lung cancer
  • PR progesterone receptor
  • the cancer is selected from lung cancer, mesothelioma, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, hepatic carcinoma, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin’s disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, hematology malignancy, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell
  • the methods comprise treating cancer in a subject comprising administering to the subject an amount of the compounds described herein that are effective in treating the cancer.
  • the cancer is breast, lung, colon, brain, head and neck, prostate, stomach, pancreatic, ovarian, melanoma, endocrine, uterine, testicular, or bladder.
  • the cancer is breast, lung, prostate, pancreatic, or ovarian.
  • the cancer is breast, lung, or prostate.
  • the cancer is breast cancer.
  • the breast cancer is metastatic breast cancer.
  • the breast cancer is locally advanced breast cancer.
  • the breast cancer is HR + breast cancer.
  • the HR + breast cancer is PR + and/or ER + breast cancer.
  • the breast cancer is PR + breast cancer.
  • the breast cancer is ER + breast cancer.
  • the breast cancer is ER + HER2' breast cancer.
  • the breast cancer is ER + HER2 + breast cancer.
  • the breast cancer is locally advanced or metastatic ER + breast cancer.
  • the breast cancer is locally advanced or metastatic ER + HER2' breast cancer.
  • the breast cancer is locally advanced or metastatic ER + HER2 + breast cancer.
  • the breast cancer is metastatic, ER + , HER2' breast cancer.
  • the breast cancer is metastatic, ER + , HER2' breast cancer that is also locally advanced.
  • the lung cancer is non-small cell lung cancer.
  • the lung cancer is locally advanced or metastatic non-small cell lung cancer.
  • the prostate cancer is CRPC.
  • the prostate cancer is locally advanced or metastatic CRPC.
  • methods of treating solid tumors in a subject comprising administering to the subject an amount of the compounds described herein that are effective in treating the solid tumor.
  • the solid tumor is breast, lung, colon, brain, head and neck, prostate, stomach, pancreatic, ovarian, melanoma, endocrine, uterine, testicular, or bladder.
  • the solid tumor is breast, lung, prostate, pancreatic, or ovarian.
  • the solid tumor is breast, lung, or prostate.
  • the solid tumor is breast cancer.
  • the breast cancer is HR + breast cancer.
  • the HR + breast cancer is PR + and/or ER + breast cancer ER + breast cancer.
  • the solid tumor is breast cancer.
  • the breast cancer is ER + HER2 + breast cancer.
  • the solid tumor is breast cancer.
  • the breast cancer is locally advanced or metastatic ER + HER2' breast cancer.
  • the solid tumor is breast cancer.
  • the breast cancer is locally advanced or metastatic ER + HER2 + breast cancer.
  • the solid tumor is lung cancer.
  • the lung cancer is non-small cell lung cancer.
  • the solid tumor is lung cancer.
  • the lung cancer is locally advanced or metastatic non-small cell lung cancer.
  • the method comprises treating hematologic tumors in a subject comprising administering to the subject an amount of the compounds described herein that is effective in treating the hematologic tumor.
  • the hematologic tumor is leukemia, lymphoma, or multiple myeloma.
  • the hematologic tumor is leukemia or lymphoma.
  • the method comprises administering Compound A, or a pharmaceutically acceptable salt thereof, in combination with a selective CDK7 inhibitor to the subject.
  • the method comprises administering Compound A, or a pharmaceutically acceptable salt thereof, in combination with a selective CDK7 inhibitor to the subject.
  • Embodiment 1 A method for treating cancer comprising administering to a subject
  • Compound A having a structure of: or a pharmaceutically acceptable salt thereof, in combination with a selective CDK7 inhibitor.
  • Embodiment 2 The method of embodiment 1, wherein a daily dose of Compound A, or a pharmaceutically acceptable salt thereof, is administered to the subject.
  • Embodiment 3 The method of embodiment 2, wherein the daily dose is 200 mg.
  • Embodiment 3 A The method of embodiment 2, wherein the daily dose is 100 mg.
  • Embodiment 4 The method of any one of embodiments 1 to 3, wherein Compound A and the selective CDK7 inhibitor are administered concurrently or sequentially.
  • Embodiment 5 The method of any one of embodiments 1 to 4, wherein the daily dose of Compound A, or a pharmaceutically acceptable salt thereof, is administered once per day (QD).
  • Embodiment 6 The method of any one of embodiments 1 to 5, wherein the daily dose of Compound A or a pharmaceutically acceptable salt thereof, is administered orally to the subject.
  • Embodiment 6A The method of any one of embodiments 1 to 5, wherein the dose of Compound A or a pharmaceutically acceptable salt thereof, is administered orally to the subject.
  • Embodiment 7 The method of any one of embodiments 1 to 6, wherein the subject is in a fed state.
  • Embodiment 8 The method of any one of embodiments 1 to 7, wherein the selective CDK7 inhibitor is samuraciclib, or pharmaceutically acceptable salt thereof.
  • Embodiment 9 The method of embodiment 8, wherein a daily dose of samuraciclib, or pharmaceutically acceptable salt thereof, is administered to the subject.
  • Embodiment 9A The method of embodiment 8, wherein a dose of samuraciclib, or pharmaceutically acceptable salt thereof, is administered to the subject.
  • Embodiment 10 The method of embodiment 9, wherein the daily dose of samuraciclib, or pharmaceutically acceptable salt thereof, is 240 mg.
  • Embodiment 10A The method of embodiment 9A, wherein the dose of samuraciclib, or pharmaceutically acceptable salt thereof, is 240 mg.
  • Embodiment 11 The method of embodiment 9, wherein the daily dose of samuraciclib, or pharmaceutically acceptable salt thereof, is 360 mg.
  • Embodiment 11 A The method of embodiment 9A, wherein the dose of samuraciclib, or pharmaceutically acceptable salt thereof, is 360 mg.
  • Embodiment 12 The method of any one of embodiments 8 to 11, wherein Compound A, or pharmaceutically acceptable salt thereof, is administered daily in 28-day cycles and samuraciclib, or a pharmaceutically acceptable salt thereof, is administered once a day for each 28-day cycle.
  • Embodiment 13 The method of any one of embodiments 1 to 7, wherein the selective CDK7 inhibitor is samuraciclib.
  • Embodiment 14 The method of embodiment 8, wherein a daily dose of samuraciclib is administered to the subject.
  • Embodiment 15 The method of embodiment 9, wherein the daily dose of samuraciclib is 240 mg.
  • Embodiment 16 The method of embodiment 9, wherein the daily dose of samuraciclib is 360 mg.
  • Embodiment 17 The method of any one of embodiments 13 to 16, wherein Compound A, or pharmaceutically acceptable salt thereof, is administered daily in 28-day cycles and samuraciclib is administered once a day for each 28-day cycle.
  • Embodiment 18 The method of any one of embodiments 1 to 17, wherein the cancer is breast cancer, lung cancer, colon cancer, brain cancer, head and neck cancer, prostate cancer, stomach cancer, pancreatic cancer, ovarian cancer, melanoma, endocrine cancer, uterine cancer, testicular cancer, or bladder cancer.
  • Embodiment 19 The method of embodiment 18, wherein the cancer is breast cancer, lung cancer, prostate cancer, pancreatic cancer, or ovarian cancer.
  • Embodiment 20 The method of embodiment 18, wherein the cancer is breast cancer, lung cancer, or prostate cancer.
  • Embodiment 21 The method of embodiment 20, wherein the cancer is breast cancer.
  • Embodiment 22 The method of embodiment 21, wherein the breast cancer is metastatic or locally advanced.
  • Embodiment 23 The method of embodiment 21 or 22, wherein the breast cancer is estrogen receptor positive (ER+) breast cancer.
  • ER+ estrogen receptor positive
  • Embodiment 24 The method of embodiment 23, wherein the estrogen receptor positive (ER+) breast cancer is human epidermal growth factor receptor 2 negative (HER2-).
  • ER+ estrogen receptor positive
  • HER2- human epidermal growth factor receptor 2 negative
  • Embodiment 25 The method of any one of embodiments 1 to 24, wherein the subject is human.
  • Embodiment 26 A method for treating cancer comprising administering to a subject
  • Compound A having a structure of: in combination with a selective CDK7 inhibitor.
  • Embodiment 27 The method of embodiment 26, wherein a daily dose of Compound A is administered to the subject.
  • Embodiment 28 The method of embodiment 27, wherein the daily dose is 200 mg.
  • Embodiment 29 The method of any one of embodiments 26 to 28, wherein Compound A and the selective CDK7 inhibitor are administered concurrently or sequentially.
  • Embodiment 30 The method of any one of embodiments 26 to 29, wherein the daily dose of Compound A is administered once per day (QD).
  • Embodiment 31 The method of any one of embodiments 26 to 30, wherein the daily dose of Compound A is administered orally to the subject.
  • Embodiment 32 The method of any one of embodiments 26 to 31, wherein the subject is in a fed state.
  • Embodiment 33 The method of any one of embodiments 26 to 32, wherein the selective CDK7 inhibitor is samuraciclib, or pharmaceutically acceptable salt thereof.
  • Embodiment 34 The method of embodiment 33, wherein a daily dose of samuraciclib, or pharmaceutically acceptable salt thereof, is administered to the subject.
  • Embodiment 35 The method of embodiment 34, wherein the daily dose of samuraciclib, or pharmaceutically acceptable salt thereof, is 240 mg.
  • Embodiment 36 The method of embodiment 34, wherein the daily dose of samuraciclib, or pharmaceutically acceptable salt thereof, is 360 mg.
  • Embodiment 37 The method of any one of embodiments 33 to 36, wherein Compound A is administered daily in 28-day cycles and samuraciclib, or a pharmaceutically acceptable salt thereof, is administered once a day for each 28-day cycle.
  • Embodiment 38 The method of any one of embodiments 26 to 32, wherein the selective CDK7 inhibitor is samuraciclib.
  • Embodiment 39 The method of embodiment 38, wherein a daily dose of samuraciclib is administered to the subject.
  • Embodiment 40 The method of embodiment 39, wherein the daily dose of samuraciclib is 240 mg.
  • Embodiment 41 The method of embodiment 39, wherein the daily dose of samuraciclib is 360 mg.
  • Embodiment 42 The method of any one of embodiments 38 to 41, wherein Compound A is administered daily in 28-day cycles and samuraciclib is administered once a day for each 28- day cycle.
  • Embodiment 43 The method of any one of embodiments 26 to 42, wherein the cancer is breast cancer, lung cancer, colon cancer, brain cancer, head and neck cancer, prostate cancer, stomach cancer, pancreatic cancer, ovarian cancer, melanoma, endocrine cancer, uterine cancer, testicular cancer, or bladder cancer.
  • Embodiment 44 The method of embodiment 43, wherein the cancer is breast cancer, lung cancer, prostate cancer, pancreatic cancer, or ovarian cancer.
  • Embodiment 45 The method of embodiment 43, wherein the cancer is breast cancer, lung cancer, or prostate cancer.
  • Embodiment 46 The method of embodiment 43, wherein the cancer is breast cancer.
  • Embodiment 47 The method of embodiment 46, wherein the breast cancer is metastatic or locally advanced.
  • Embodiment 48 The method of embodiment 46 or 47, wherein the breast cancer is estrogen receptor positive (ER+) breast cancer.
  • ER+ estrogen receptor positive
  • Embodiment 49 The method of embodiment 48, wherein the estrogen receptor positive (ER+) breast cancer is human epidermal growth factor receptor 2 negative (HER2-).
  • Embodiment 50 The method of any one of embodiments 26 to 49, wherein the subject is human.
  • Embodiment 51 Compound A: comprising administering Compound A or the pharmaceutically acceptable salt thereof to a subject in combination with a selective CDK7 inhibitor. for use in a method of treating cancer, the method comprising administering Compound A to a subject in combination with a selective CDK7 inhibitor.
  • Embodiment 53 A combined preparation of:
  • Embodiment 54 The combined preparation for use of embodiment 53, wherein the combined preparation is of (i) Compound A, and (ii) the selective CDK7 inhibitor.
  • Embodiment 55 Compound A or the pharmaceutically acceptable salt thereof for use of embodiment 51, Compound A for use of embodiment 52, or the combined preparation for use of embodiment 53 or 54, wherein a daily dose of Compound A, or the pharmaceutically acceptable salt thereof, is administered to the subject.
  • Embodiment 56 Compound A, the pharmaceutically acceptable salt thereof, or the combined preparation for use of embodiment 55, wherein the daily dose is 100 mg or 200 mg.
  • Embodiment 57 Compound A, the pharmaceutically acceptable salt thereof, or the combined preparation for use of any one of embodiments 51 to 56, wherein the selective CDK7 inhibitor is administered concurrently with or sequentially to Compound A or the pharmaceutically acceptable salt thereof.
  • Embodiment 58 Compound A, the pharmaceutically acceptable salt thereof, or the combined preparation for use of any one of embodiments 51 to 57, wherein the daily dose of Compound A, or the pharmaceutically acceptable salt thereof, is administered once per day (QD).
  • Embodiment 59 Compound A, the pharmaceutically acceptable salt thereof, or the combined preparation for use of any one of embodiments 51 to 58, wherein the daily dose of Compound A or the pharmaceutically acceptable salt thereof, is administered orally to the subject.
  • Embodiment 60 Compound A, the pharmaceutically acceptable salt thereof, or the combined preparation for use of any one of embodiments 51 to 59, wherein the subject is in a fed state.
  • Embodiment 61 Compound A, the pharmaceutically acceptable salt thereof, or the combined preparation for use of any one of embodiments 51 to 60, wherein the selective CDK7 inhibitor is samuraciclib, or a pharmaceutically acceptable salt thereof.
  • Embodiment 62 Compound A, the pharmaceutically acceptable salt thereof, or the combined preparation for use of embodiment 61, wherein a daily dose of samuraciclib, or pharmaceutically acceptable salt thereof, is administered to the subject.
  • Embodiment 63 Compound A, the pharmaceutically acceptable salt thereof, or the combined preparation for use of embodiment 62, wherein the daily dose of samuraciclib, or pharmaceutically acceptable salt thereof, is 240 mg.
  • Embodiment 64 Compound A, the pharmaceutically acceptable salt thereof, or the combined preparation for use of embodiment 62, wherein the daily dose of samuraciclib, or pharmaceutically acceptable salt thereof, is 360 mg.
  • Embodiment 65 Compound A, the pharmaceutically acceptable salt thereof, or the combined preparation for use of any one of embodiments 61 to 64, wherein Compound A, or the pharmaceutically acceptable salt thereof, is administered daily in 28-day cycles and the samuraciclib, or pharmaceutically acceptable salt thereof, is administered once a day for each 28- day cycle.
  • Embodiment 66 Compound A, the pharmaceutically acceptable salt thereof, or the combined preparation for use of any one of embodiments 51 to 60, wherein the selective CDK7 inhibitor is samuraciclib.
  • Embodiment 67 Compound A, the pharmaceutically acceptable salt thereof, or the combined preparation for use of embodiment 61, wherein a daily dose of samuraciclib is administered to the subject.
  • Embodiment 68 Compound A, the pharmaceutically acceptable salt thereof, or the combined preparation for use of embodiment 62, wherein the daily dose of samuraciclib is 240 mg.
  • Embodiment 69 Compound A, the pharmaceutically acceptable salt thereof, or the combined preparation for use of embodiment 62, wherein the daily dose of samuraciclib is 360 mg.
  • Embodiment 70 Compound A, the pharmaceutically acceptable salt thereof, or the combined preparation for use of any one of embodiments 66 to 69, wherein Compound A, or pharmaceutically acceptable salt thereof, is administered daily in 28-day cycles and samuraciclib is administered once a day for each 28-day cycle.
  • Embodiment 71 Compound A, the pharmaceutically acceptable salt thereof, or the combined preparation for use of any one of embodiments 51 to 70, wherein the cancer is breast cancer, lung cancer, colon cancer, brain cancer, head and neck cancer, prostate cancer, stomach cancer, pancreatic cancer, ovarian cancer, melanoma, endocrine cancer, uterine cancer, testicular cancer, or bladder cancer.
  • Embodiment 72 Compound A, the pharmaceutically acceptable salt thereof, or the combined preparation for use of embodiment 71, wherein the cancer is breast cancer, lung cancer, prostate cancer, pancreatic cancer, or ovarian cancer.
  • Embodiment 73 Compound A, the pharmaceutically acceptable salt thereof, or the combined preparation for use of embodiment 71, wherein the cancer is breast cancer, lung cancer, or prostate cancer.
  • Embodiment 74 Compound A, the pharmaceutically acceptable salt thereof, or the combined preparation for use of embodiment 73, wherein the cancer is breast cancer.
  • Embodiment 75 Compound A, the pharmaceutically acceptable salt thereof, or the combined preparation for use of embodiment 74, wherein the breast cancer is metastatic or locally advanced.
  • Embodiment 76 Compound A, the pharmaceutically acceptable salt thereof, or the combined preparation for use of embodiment 74 or 75, wherein the breast cancer is estrogen receptor positive (ER + ) breast cancer.
  • ER + estrogen receptor positive
  • Embodiment 77 Compound A, the pharmaceutically acceptable salt thereof, or the combined preparation for use of embodiment 76, wherein the estrogen receptor positive (ER + ) breast cancer is human epidermal growth factor receptor 2 negative (HER2 ).
  • ER + estrogen receptor positive
  • HER2 human epidermal growth factor receptor 2 negative
  • Embodiment 78 Compound A, the pharmaceutically acceptable salt thereof, or the combined preparation for use of any one of embodiments 51 to 77, wherein the subject is human.
  • CERAN complete estrogen receptor antagonist
  • HER2 human epidermal growth factor receptor 2
  • SERCA selective estrogen receptor covalent antagonist
  • MCF7 or T47D cells were seeded in 6 well plates and treated with the indicated concentrations of compounds. The plates were then placed in the Incucyte® S3 Live-Cell Analysis System and images were acquired every 4 hours for a total of 5 days. Control cells were treated with DMSO. Data were analyzed using the Incucyte® Software v2020C, which quantified cell surface area coverage as confluence values. Relative growth was calculated for all timepoints for all growth conditions relative to the confluence value observed for the control at 120 hours (FIGs. 1A, IB, 2A, and 2B and Table 1). Graphing and statistical analyses were performed using Graphpad Prism (GraphPad Software).
  • MCF7 or T47D cells were seeded at 2x10 3 cells in 200pL of media per well in 96 well plates and incubated overnight at 37°C.
  • the effect of Compound A and samuraciclib on cell proliferation was measured for each drug individually at concentrations ranging from 100 nM to 0.046 nM (3-fold dilutions) (FIG. 3A and FIG. 5A) and 1000 nM to 0.46 nM (FIG. 3B and FIG. 5B), respectively, and for the combination the drug was used at concentrations ranging from 10 nM to 0.046 nM (3-fold dilutions) (FIG. 3C and FIG. 5C).
  • FIGs. 1, 2, 3, 4, 5, and 6 show Compound A in combination with samuraciclib demonstrates enhanced efficacy in ER + breast cancer cells than as single agents.
  • GI50 mean half-maximal growth inhibitory concentration
  • TACTIVE-U is an umbrella study comprising multiple sub-studies that independently evaluate Compound A in participants with ER + A/MBC.
  • Compound A will act as the backbone therapy given in combination with other anticancer agents thought to have clinical relevance in ER + breast cancer.
  • the purpose of the umbrella study is to evaluate the safety, antitumor activity and pharmacokinetics (PK) of Compound A in combination with other approved and/or novel anticancer therapies thought to have clinical relevance in ER + breast cancer.
  • Each sub-study under this umbrella design will be conducted in the tumor type ER + A/MBC. Each sub-study will be managed independently with its own specific eligibility criteria and data analysis plan.
  • Sub-study C aims to evaluate the safety, antitumor activity and PK of Compound A in combination with samuraciclib in the treatment of participants with ER + /HER2‘ A/MBC.
  • TACTIVE-U is an umbrella study comprising multiple sub-studies that independently evaluate Compound A in participants with ER + A/MBC.
  • Compound A will act as the backbone therapy given in combination with other anticancer agents thought to have clinical relevance in ER + breast cancer.
  • Sub-study C is a prospective, open-label, multi center, Phase lb/2 sub-study to evaluate the safety, antitumor activity, and PK of Compound A in combination with samuraciclib in the treatment of participants with ER + /HER2‘ A/MBC.
  • Phase lb dose escalation/de-escalation phase to evaluate the safety and tolerability of Compound A in combination with samuraciclib and select up to two recommended doses for dose expansion for the combination (combination RDEs) via the mTPI-2 dose-finding design.
  • Phase 2 if at least 2 dose levels from Phase lb (e.g., two combination RDEs) are considered tolerable, a randomized dose optimization Phase 2 will be conducted to further evaluate the safety, tolerability, PK and antitumor activity of Compound A in combination with samuraciclib to determine the RP2D of the combination. If only one dose level from Phase lb is considered tolerable, a single arm Phase 2 dose expansion will be conducted. [0254] In addition, the potential DDI between Compound A and samuraciclib will be evaluated, at the doses selected as RDE(s), in a DDI assessment cohort(s) with approximately 3-6 participants/ cohort.
  • Phase 2 if at least 2 dose levels from Phase lb (e.g., two combination RDEs) are considered tolerable, a randomized dose optimization Phase 2 will be conducted to further evaluate the safety, tolerability, PK and antitumor activity of Compound A in combination with samuraciclib to determine the RP2D of
  • Phase lb In Phase lb the starting dose level of Compound A will be 100 mg QD and the starting dose level of samuraciclib will be 240 mg QD. Up to 2 starting dose levels may be investigated for Compound A (100 mg QD and 200 mg QD), and for samuraciclib (240 mg QD and 360 mg QD). The decision to escalate the starting dose level of Compound A and samuraciclib will be using mTPI-2 decision criteria based on the number of DLT-evaluable participants and the number of DLTs in those participants during the DLT observation period.
  • a minimum of 3 DLT-evaluable participants will be required in each cohort at a given dose level before a decision is made of de-escalating, escalating, or staying at the same dose level. Additional participants will be enrolled in a specific cohort to replace participants who are not considered DLT-evaluable, where required.
  • Phase 2 In the Phase 2 portion of the study up to two RDEs will be further explored.
  • Participants will be characterized at study entry according to TP53 mutation status and presence of liver metastases. To enable a balanced study population the sponsor may use their discretion to limit enrolment to approximately 30% for both TP53 mutation and presence of liver metastases.
  • DDI Assessment Cohort(s) Participants in the DDI assessment cohort(s) will be treated with the combination agents as follows:
  • Samuraciclib will be administered alone on Day -13 at the dose selected as RDE.
  • Compound A will be administered QD alone from Day -10 to Day -4, inclusive at the dose selected as RDE.
  • Samuraciclib will be administered in combination with Compound A on Day -3, followed by washout period of samuraciclib on Day -2 and Day -1 ; Compound A will continue to be administered QD alone during the washout period on Day -2 and Day -1.
  • Compound A will then be administered QD in combination with samuraciclib QD starting on Cycle 1 Day 1 (C1D1).
  • DDI assessment cohorts may be required to fully assess potential DDI at different dose levels.
  • the participants from the DDI assessment cohort(s) will not be included in the DLT-evaluable population.
  • Participants who discontinue or require a dose reduction of study drugs, and participant who misses 3 or more consecutive doses of study drugs prior to completion of the last PK sampling on Cycle 2 Day 1 (C2D1) may be considered unevaluable for PK analyses and may be replaced.
  • Participants who miss any dose of study drugs or miss any of the PK samples on any of the PK days up to and including Cycle 2 Day 1 (C2D1), or who vomit within 6 hours after dosing on any of the PK days up to and including Cycle 2 Day 1 (C2D1) may be considered unevaluable for PK analyses and may be replaced.
  • Approximately 67 participants will be treated in sub-study C, including approximately 15 participants in Phase lb and 40 participants in Phase 2 assuming 2 dose levels are carried forward, and 6-12 evaluable participants for the DDI cohort(s).
  • the number of participants to be enrolled in Phase lb will depend on the observed safety profile, which will determine the number of participants at each dose level and the number of dose levels explored.
  • At least 6 DLT- evaluable participants will be treated at the RDE(s) in Phase lb before proceeding to Phase 2. Based on the doses selected as RDE(s) for Phase 2, there will be one or more DDI assessment cohort(s) at the end of Phase lb, with approximately 3-6 parti cipants/cohort.
  • Phase 2 approximately 20 participants for each arm will be enrolled and treated. If only one RDE is selected to move forward into Phase 2 dose expansion approximately 20 participants will be enrolled and treated.
  • Tumor block collected at the time of diagnosis with local recurrent or metastatic disease or archival tumor tissue is required for inclusion.
  • Adjuvant treatment if the disease-free interval between initiation of endocrine therapy and first line treatment of locally advanced or metastatic disease was >24 months.
  • Participants must have at least 1 measurable lesion as defined by RECIST vl.l. Participants with bone lesions only can be included if at least one bone lesion has a measurable component as for RECIST vl.l.
  • definitively treated eg, radiotherapy, stereotactic surgery
  • clinically stable including participants with residual CNS symptoms/deficits
  • discontinued anti-seizure medications and corticosteroids for at least 28 days prior to first dose of IMP.
  • the screening period will occur within 28 days prior to first dose. Study intervention will be administered in 28-day cycles.
  • the starting dose level of Compound A will be 100 mg QD, administered continuously on 28-day cycles and with food.
  • the starting dose of samuraciclib will be 240 mg QD administered continuously on 28-day cycles with or without food.

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Abstract

L'invention concerne des méthodes de traitement du cancer comprenant l'administration à un sujet d'un composé A, ou d'un sel pharmaceutiquement acceptable de celui-ci, en combinaison avec un inhibiteur sélectif de CDK7.
PCT/US2024/035566 2023-06-27 2024-06-26 Combinaisons d'agents de dégradation du récepteur des œstrogènes et d'inhibiteurs de cdk7 pour le traitement du cancer Pending WO2025006569A1 (fr)

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