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WO2024049926A1 - Schémas posologiques à base d'agents de dégradation des récepteurs des oestrogènes - Google Patents

Schémas posologiques à base d'agents de dégradation des récepteurs des oestrogènes Download PDF

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Publication number
WO2024049926A1
WO2024049926A1 PCT/US2023/031574 US2023031574W WO2024049926A1 WO 2024049926 A1 WO2024049926 A1 WO 2024049926A1 US 2023031574 W US2023031574 W US 2023031574W WO 2024049926 A1 WO2024049926 A1 WO 2024049926A1
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Prior art keywords
cancer
compound
pharmaceutically acceptable
acceptable salt
ref
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PCT/US2023/031574
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English (en)
Inventor
Ronald Peck
Sheryl Maxine GOUGH
John J. Flanagan
Sibyl ANDERSON
Ian Charles Anthony TAYLOR
Julia Perkins SMITH
Weiwei Tan
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Pfizer Corp Belgium
Pfizer Corp SRL
Arvinas Operations Inc
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Pfizer Corp Belgium
Pfizer Corp SRL
Arvinas Operations Inc
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Priority to CA3266061A priority Critical patent/CA3266061A1/fr
Priority to CN202380075299.4A priority patent/CN120112291A/zh
Priority to EP23776753.8A priority patent/EP4580631A1/fr
Priority to IL319242A priority patent/IL319242A/en
Priority to AU2023336057A priority patent/AU2023336057A1/en
Priority to KR1020257009876A priority patent/KR20250076543A/ko
Priority to JP2025512129A priority patent/JP2025530742A/ja
Publication of WO2024049926A1 publication Critical patent/WO2024049926A1/fr
Priority to MX2025002284A priority patent/MX2025002284A/es
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • 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
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • 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 vepdegestrant (i.e., (S)-3-(5-(4-((1-(4-((1R,2S)- 6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperazin- 1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione or (3S)-3-[1,3-dihydro-1-oxo-5-[4-[[1-[4- [(1R,2S)-1,2,3,4-tetrahydro-6-hydroxy-2-phenyl-1-naphthalenylphenyl]-4-piperidinyl]methyl]-1- piperazinyl]-2H-isoindol-2-yl]-2,6-piperidinedione (referred to herein as “Compound A” or “Cpd A”)), which
  • Compound A is under development as a PROTAC® protein degrader that targets estrogen receptor (ER) for the potential treatment of breast cancer and has been shown to be a useful modulator of targeted protein ubiquitination and degradation via the ubiquitin-proteasome pathway.
  • ER estrogen receptor
  • the present disclosure provides, in part, dosage regimens 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.
  • Provided herein are methods for treating cancer comprising administering to a subject a daily dose of Compound A having a structure of: , or a pharmaceutically acceptable salt thereof, in combination with a CDK4/6 inhibitor, wherein the daily dose of Compound A is about 100 mg or about 200 mg.
  • a daily dose of Compound A having a structure of: in combination with a CDK4/6 inhibitor.
  • the daily dose of Compound A is about 200 mg.
  • the daily dose of Compound A is about 100 mg.
  • the CDK4/6 inhibitor is dalpiciclib, trilaciclib, lerociclib, AT7519M, dinaciclib, ribociclib, abemaciclib, or palbociclib, or a pharmaceutically acceptable salt thereof.
  • the CDK4/6 inhibitor is abemaciclib, ribociclib or palbociclib, or a pharmaceutically acceptable salt thereof. In embodiments, the CDK4/6 inhibitor is abemaciclib, or a pharmaceutically acceptable salt thereof. In embodiments, the CDK4/6 inhibitor is ribociclib, or a pharmaceutically acceptable salt thereof. In embodiments, the CDK4/6 inhibitor is palbociclib, or a pharmaceutically acceptable salt thereof. In embodiments, Compound A, or a pharmaceutically acceptable salt thereof, may be administered daily in 28-day cycles in combination with the CDK4/6 inhibitor. In embodiments, Compound A may be administered daily in 28-day cycles in combination with the CDK4/6 inhibitor.
  • the CDK4/6 inhibitor is palbociclib, or a pharmaceutically acceptable salt thereof.
  • palbociclib may be administered orally once a day at 125 mg/day for 21 days followed by 7 days off treatment for each 28-day cycle.
  • the daily dose of Compound A is administered once per day (QD).
  • the daily dose of Compound A is administered orally to the subject.
  • the subject is in a fed state.
  • 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 may be metastatic or locally advanced.
  • the breast cancer may be estrogen receptor positive (ER+) breast cancer (e.g., human epidermal growth factor receptor 2 negative (HER2-)).
  • ER+ estrogen receptor positive
  • HER2- human epidermal growth factor receptor 2 negative
  • the subject is human.
  • FIGs.1A and 1C show relative cell growth kinetics over 120-hours by live cell imaging of MCF7 and T47D cells dosed with Compound A (10 nM) or fulvestrant (1 nM), alone or in combination with abemaciclib (40 nM) at their respective approximate GI 50 concentrations. Each plot is representative of three independent experiments.
  • FIGs.1E and 1G show relative cell growth kinetics over 120-hours by live cell imaging of MCF7 and T47D cells dosed with Compound A (10 nM) and/or ribociclib (40 nM) at their respective approximate GI50 concentrations.
  • FIGs.1B, 1D, 1F and 1H show differences in relative MCF7 and T47D cell growth compared to vehicle control at 120-hours of treatment.
  • Graphs show the mean of three independent 290560299 Arvinas Ref.: ARVN0152WO02 Cooley Ref.: ARVN-049/001WO experiments, except for the T47D fulvestrant arms in FIGs 1B and 1D, which are the result of 2 independent experiments).
  • Error bars standard error of the mean (SEM).
  • FIGs.2A–2L are graphs showing viability and synergistic analysis of MCF7 cells at day-5 dosed with Compound A in combination with abemaciclib or ribociclib in an 8x8 block matrix.
  • FIGs 2A, 2B, 2G, and 2H show single agent curves of Compound A, abemaciclib, Compound A, and ribociclib, respectively.
  • FIG.2C shows Compound A dose-response shift with the addition of abemaciclib.
  • FIG.2I shows Compound A dose-response shift with the addition of ribociclib.
  • FIGs.3A and 3B are graphs showing in-vivo efficacy studies of Compound A in combination with the CDK4/6 inhibitors abemaciclib (FIG.3A) and ribociclib (FIG.3B) using MCF7 orthotopic xenograft models. Mean tumor volumes are reported ⁇ SEM. Single-day dosing holidays are indicated by small black arrows.
  • FIG.4A is a graph showing body weights ( ⁇ SEM) of MCF7 orthotopic xenograft efficacy with Compound A in combination with the CDK4/6 inhibitor abemaciclib. Compounds dosed as single agents or in combination, 10 mice/arm.
  • FIG.4B is a graph showing body weights ( ⁇ SEM) of MCF7 orthotopic xenograft efficacy with Compound A in combination with the CDK4/6 inhibitor ribociclib. Compounds dosed as single agents or in combination, 10 mice/arm.
  • FIG.5 is a graph showing inhibition of tumor growth by Compound A (30 mg/kg, per os [oral dosing; PO]; once daily [QD] x28) or fulvestrant (200 mg/kg, subcutaneously; twice per week for 2 weeks followed by once-weekly for 2 weeks) as single agents or in combination with palbociclib (‘Palbo’; 60 mg/kg, PO; QDx28), a CDK4/6 inhibitor.
  • PO palbociclib
  • a CDK4/6 inhibitor a CDK4/6 inhibitor.
  • Vepdegestrant i.e., (S)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione or (3S)-3-[1,3-dihydro-1-oxo-5-[4-[[1-[4-[(1R,2S)-1,2,3,4-tetrahydro-6- hydroxy-2-phenyl-1-naphthalenylphenyl]-4-piperidinyl]methyl]-1-piperazinyl]-2H-isoindol-2- yl]-2,6-piperidinedione (also referred to herein as “Compound A”)): is under development as a PROTAC® protein
  • Cyclin-dependent kinases and related serine/threonine protein kinases are important cellular enzymes that perform essential functions in regulating eukaryotic cell division and proliferation.
  • 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. Additional functions of 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) 13:261-291). CDK inhibitors have been demonstrated to be useful in treating cancer.
  • CDK4 and CDK6 are important regulators of cell cycle progression at the G1-S checkpoint, which are controlled by D-type cyclins and INK4 endogenous CDK inhibitors, such as p16 INK4a (CDKN2A).
  • Dysregulation of the cyclin D-CDK4/6–INK4–retinoblastoma (Rb) pathway has been reported to be associated with development of endocrine therapy resistance.
  • Clinical trials for the CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib are ongoing for breast and other cancers, as single agents or in combination with other therapeutics.
  • CDK4/6 inhibitors in combination with endocrine therapy has demonstrated significant efficacy in the treatment of hormone receptor (HR)-positive, human epidermal growth factor 2 (HER2)- negative advanced or metastatic breast cancers, and CDK4/6 inhibitors, including palbociclib, ribociclib, and abemaciclib, have been approved in combination with endocrine therapy in a first-or second-line setting.
  • HR hormone receptor
  • HER2 human epidermal growth factor 2
  • abemaciclib abemaciclib
  • Palbociclib or 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H- pyrido[2,3-d]pyrimidin-7-one (also referred to as “PD-0332991”) is a potent and selective inhibitor of CDK4 and CDK6, having the structure: .
  • Palbociclib is described in WHO Drug Information, Vol.27, No.2, page 172 (2013).
  • Palbociclib and pharmaceutically acceptable salts thereof are disclosed in International Publication No. WO 2003/062236 and U.S. Patent Nos.6,936,612, 7,456,168 and RE47,739; International Publication No. WO 2005/005426 and U.S.
  • the contents of each of the foregoing references are incorporated herein by reference in their entirety.
  • CDK4/6 inhibitor palbociclib in Rb+ advanced breast cancer: phase II activity, safety, and predictive biomarker assessment.
  • Cristofanilli M Turner NC, Bondarenko I, et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial.
  • a substituent includes one or more substituents.
  • 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. For example, a dose of about 5 mg means 5 mg ⁇ 10%, i.e., it may vary from 4.5 mg to 5.5 mg.
  • terms, 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.
  • humans are suitable subjects. Human subjects may be of any gender and at any stage of development.
  • Vepdegestrant i.e., (S)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2- 290560299
  • Compound A is a Biopharmaceutics Classification System Class IV compound (low solubility/low permeability). Compound A can interconvert to its epimer, Compound B: .
  • preclinical data indicates that the exposure of Compound B is limited compared to Compound A ( ⁇ 26%).
  • Evidence indicates that Compound B does not degrade the ER; however, Compound B shows similar antagonism of ER-dependent transcription compared to Compound A.
  • Cyclin-dependent kinases (CDKs) and related 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). 290560299 Arvinas Ref.: ARVN0152WO02 Cooley Ref.: ARVN-049/001WO
  • Examples of CDK4/6 inhibitors include, but are not limited to, abemaciclib, ribociclib, and palbociclib. Additional examples of CDK4/6 inhibitors include lerociclib (also known as G1T38) and trilaciclib (also known as GTI128).
  • a CDK4/6 inhibitor of the present invention includes palbociclib.
  • palbociclib refers to 6- acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3- d]pyrimidin-7-one: , or a pharmaceutically acceptable salt thereof.
  • the CDK4/6 inhibitor is abemaciclib or ribociclib.
  • abemaciclib refers to N-(5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)-5- fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-amine:
  • ribociclib refers to 7-cyclopentyl-N,N-dimethyl-2-[(5-piperazin-1-ylpyridin-2- yl)amino]pyrrolo[2,3-d]pyrimidine-6-carboxamide: 290560299
  • Other embodiments relate to the pharmaceutically acceptable salts of the compounds described herein.
  • Pharmaceutically acceptable salts of the compounds described herein include the acid addition and base addition salts thereof. 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.
  • suitable acid addition salts i.e., salts containing pharmacologically acceptable anions, 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
  • 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 pamoate [i.e., 1,1’-methylene-bis-(2-hydroxy-3-naphthoate
  • the compounds described herein that include a basic moiety, such as an amino group may form 290560299 Arvinas Ref.: ARVN0152WO02 Cooley Ref.: ARVN-049/001WO pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above.
  • the chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of those compounds of the compounds described herein that are acidic in nature 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.
  • Dosage Regimens Provided herein are methods for treating cancer comprising administering to a subject a daily dose of Compound A having a structure of: pharmaceutically acceptable salt thereof, in combination with a CDK4/6 inhibitor. 290560299 Arvinas Ref.: ARVN0152WO02 Cooley Ref.: ARVN-049/001WO Also provided herein are methods for treating cancer comprising administering to a subject a daily dose of Compound A having a structure of: combination with a CDK4/6 inhibitor. In embodiments, the daily dose of Compound A having the structure: pharmaceutically acceptable salt thereof, is administered once per day (QD).
  • the daily dose of Compound A having the structure: pharmaceutically acceptable salt thereof is administered orally to the subject.
  • the subject is in a fed state.
  • the daily dose of Compound A: pharmaceutically acceptable salt thereof is about 200 mg, or an equivalent amount of a pharmaceutically acceptable salt thereof.
  • the daily dose of Compound A: pharmaceutically acceptable salt thereof is 200 mg or an equivalent amount of a pharmaceutically acceptable salt thereof.
  • the daily dose of Compound A In embodiments, the daily dose of Compound A: 290560299 Arvinas Ref.: ARVN0152WO02 Cooley Ref.: ARVN-049/001WO In embodiments, the daily dose of Compound A: pharmaceutically acceptable salt thereof, is about 100 mg or an equivalent amount of a pharmaceutically acceptable salt thereof. In embodiments, the daily dose of Compound A: pharmaceutically acceptable salt thereof, is 100 mg or an equivalent amount of a pharmaceutically acceptable salt thereof.
  • the daily dose of Compound A 290560299 Arvinas Ref.: ARVN0152WO02 Cooley Ref.: ARVN-049/001WO
  • the daily dose of Compound A as a free base.
  • the CDK4/6 inhibitor is dalpiciclib, trilaciclib, lerociclib, AT7519M, dinaciclib, ribociclib, abemaciclib, or palbociclib, or a pharmaceutically acceptable salt thereof.
  • the CDK4/6 inhibitor is dalpiciclib, trilaciclib, lerociclib, AT7519M, dinaciclib, ribociclib, abemaciclib, or palbociclib.
  • the CDK4/6 inhibitor is abemaciclib, ribociclib, or palbociclib, or a pharmaceutically acceptable salt thereof. In embodiments, wherein the CDK4/6 inhibitor is abemaciclib, ribociclib, or palbociclib. In embodiments, the CDK4/6 inhibitor is abemaciclib, or a pharmaceutically acceptable salt thereof. In embodiments, the CDK4/6 inhibitor is abemaciclib. In embodiments, the CDK4/6 inhibitor is ribociclib, or a pharmaceutically acceptable salt thereof. In embodiments, the CDK4/6 inhibitor is ribociclib.
  • the CDK4/6 inhibitor is palbociclib, or a pharmaceutically acceptable salt thereof. In embodiments, the CDK4/6 inhibitor is palbociclib. In embodiments, Compound A is administered daily in 28-day cycles. In certain embodiments, palbociclib, or a pharmaceutically acceptable salt thereof, is administered orally once a day at 125 mg/day for 21 days followed by 7 days off treatment 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-). 290560299 Arvinas Ref.: ARVN0152WO02 Cooley Ref.: ARVN-049/001WO
  • the subject is human. Also disclosed herein Compound A: pharmaceutically acceptable salt thereof, for use according to any one of foregoing embodiments.
  • Compound A is: pharmaceutically acceptable salt thereof, for use according to any one of foregoing embodiments. Also disclosed herein are uses of Compound A: pharmaceutically acceptable salt thereof, in the manufacture of a medicament according to any one of foregoing embodiments. Also disclosed herein are uses of Compound A: 290560299 Arvinas Ref.: ARVN0152WO02 Cooley Ref.: ARVN-049/001WO pharmaceutically acceptable salt thereof, in the manufacture of a medicament according to any one of foregoing embodiments.
  • Each of the embodiments described herein may be combined with any other embodiment(s) described herein not inconsistent with the embodiment(s) with which it is combined.
  • treat and “treating” a cancer or a cancer-associated disease mean to administer a combination therapy according to the present disclosure to a subject, participant or patient having a cancer, or diagnosed with a cancer, to achieve at least one positive therapeutic effect, such as, for example, reduced number of cancer cells, reduced tumor size, reduced rate of cancer cell infiltration into peripheral organs, or reduced rate of tumor metastasis or tumor growth, reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
  • 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) 50:1S– 10S).
  • Feed 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 eaten within 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.
  • a 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 290560299 Arvinas Ref.: ARVN0152WO02 Cooley Ref.: ARVN-049/001WO pharmaceutically acceptable salt thereof.
  • the amount, or the therapeutically effective amount can be a daily dose of about 200 mg. In another embodiment, a daily dose is 200 mg. In embodiments, the daily dose of Compound A, or a pharmaceutically acceptable salt thereof, 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, or a pharmaceutically acceptable salt thereof 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.
  • 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.
  • palbociclib, or a pharmaceutically acceptable salt thereof is administered at a daily dosage of about 125 mg once daily, about 100 mg once daily, about 75 mg once daily, about 50 mg daily, or about 25 mg daily.
  • palbociclib, or a pharmaceutically acceptable salt thereof is administered at a daily dosage of about 125 mg once a day.
  • palbociclib, or a pharmaceutically acceptable salt thereof is administered at a dose of about 100 mg once daily, about 75 mg once daily, or about 50 mg once daily.
  • palbociclib, or a pharmaceutically acceptable salt thereof is administered at a dose of about 100 mg once daily. In embodiments, palbociclib, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 75 mg once daily. In embodiments, palbociclib, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 50 mg once daily.
  • Dosage amounts refer to the dose of the free base form of palbociclib, or are calculated as the free base equivalent of an administered palbociclib salt form. For example, a dosage or amount of palbociclib, such as 100 mg, 75 mg, or 50 mg, refers to the free base equivalent.
  • abemaciclib, or a pharmaceutically acceptable salt thereof is administered at a daily dosage of about 400 mg (e.g., about 200 mg twice daily), about 300 mg (e.g., about 150 mg twice daily), about 200 mg (e.g., about 100 mg twice daily), or about 100 mg (e.g., about 50 mg twice daily).
  • abemaciclib, or a pharmaceutically acceptable salt thereof is administered at a daily dosage of about 300 mg (e.g., about 150 mg twice daily), about 200 mg (e.g., about 100 mg twice daily), or about 100 mg (e.g., about 50 mg twice daily).
  • abemaciclib, or a pharmaceutically acceptable salt thereof is administered at a daily dosage of 300 mg (e.g., about 150 mg twice daily). In an embodiment, abemaciclib, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 200 mg (e.g., about 100 mg twice daily). In embodiments, abemaciclib, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 50 mg twice daily about 100 mg (e.g., about 50 mg twice daily). Dosage amounts, provided herein, refer to the dose of the free base form of abemaciclib, or are calculated as the free base equivalent of an administered abemaciclib salt form.
  • a dosage or amount of abemaciclib refers to the free base equivalent.
  • ribociclib, or a pharmaceutically acceptable salt thereof is administered at a daily dosage of about 600 mg once daily, about 400 mg once daily, about 200 mg once daily, or 290560299 Arvinas Ref.: ARVN0152WO02 Cooley Ref.: ARVN-049/001WO about 50 mg once daily.
  • ribociclib, or a pharmaceutically acceptable salt thereof is administered at a daily dosage of about 600 mg once daily.
  • ribociclib, or a pharmaceutically acceptable salt thereof is administered at a dose of about 400 mg once daily.
  • ribociclib is administered at a dose of about 200 mg once daily.
  • Dosage amounts refer to the dose of the free base form of ribociclib, or are calculated as the free base equivalent of an administered ribociclib salt form.
  • a dosage or amount of ribociclib such as 600 mg, 400 mg, 200 mg, refers to the free base equivalent.
  • Repetition of the administration or dosing regimens may be conducted as necessary to achieve the desired reduction or diminution of cancer cells.
  • 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 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.
  • the standard recommended dosing regimen which includes the standard dosing schedule, for palbociclib, or a pharmaceutically acceptable salt thereof, is administration once daily for 21 consecutive days followed by 7 days off treatment to comprise a complete cycle of 28-days.
  • the standard clinical dosing regimen, for palbociclib, or a pharmaceutically acceptable salt thereof is administration of 125 mg once daily for 21 consecutive days followed by 7 days off treatment to comprise a complete cycle of 28-days. Repetition of the 28-day cycles is continued during treatment with the combination of the present invention.
  • the standard clinical dosing regimen, for ribociclib, or a pharmaceutically acceptable salt thereof is administration of 600 mg once daily for 21 consecutive days followed by 7 days off treatment to comprise a complete cycle of 28-days.
  • 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.
  • the term “locally advanced,” as used herein, as it relates to cancer, may or may not be treated with curative intent.
  • locally advanced breast cancer (LABC) is defined by the U.S.
  • 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, brain. (www.cancer.org/cancer/breast-cancer.) Those skilled in the art will be able to recognize and diagnose locally advanced and metastatic cancer in a patient or subject.
  • 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 carcinoma, carcinoma of
  • 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 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 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. In embodiments, the prostate cancer is locally advanced or metastatic CRPC.
  • the solid tumor 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 solid tumor is breast cancer, lung cancer, prostate cancer, pancreatic cancer, or ovarian cancer.
  • the solid tumor is breast cancer, lung cancer, or prostate cancer.
  • 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 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 solid tumor is prostate cancer.
  • the prostate cancer is CRPC.
  • the solid tumor is prostate cancer.
  • the prostate cancer is locally advanced or metastatic castration resistant prostate cancer. Also disclosed herein are methods of treating hematologic tumors in a subject.
  • 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.
  • Also disclosed herein are methods of treating cancer in a subject with locally advanced or metastatic ER+ HER2- breast cancer, CRPC, or NSCLC whose disease progressed on or is intolerant to standard therapy.
  • the method comprises administering Compound A in combination with a CDK4/6 inhibitor to the subject.
  • therapeutic combinations comprising: (i) Compound A: (Compound A), or a pharmaceutically acceptable salt thereof; and (ii) a CDK4/6 inhibitor; 290560299 Arvinas Ref.: ARVN0152WO02 Cooley Ref.: ARVN-049/001WO for simultaneous, separate, or sequential use in a method of treating cancer; wherein the method comprises administering a daily dose of Compound A, or a pharmaceutically acceptable salt thereof.
  • Also disclosed herein are therapeutic combinations comprising: (i) Compound A: (Compound A); and (ii) a CDK4/6 inhibitor; for simultaneous, separate or sequential use in a method of treating cancer; wherein the method comprises administering a daily dose of Compound A.
  • Compound A 290560299 Arvinas Ref.: ARVN0152WO02 Cooley Ref.: ARVN-049/001WO (Compound A), for use in a method of treating cancer wherein the method comprises administering Compound A, and wherein the method further comprises administering a CDK4/6 inhibitor. Also disclosed herein is a CDK4/6 inhibitor for use in a method of treating cancer, wherein the method further comprises administering Compound A, or a pharmaceutically acceptable salt thereof. Also disclosed herein is a CDK4/6 inhibitor for use in a method of treating cancer, wherein the method further comprises administering Compound A.
  • the method comprises administering a daily dose of about 200 mg of Compound A, or an equivalent amount of a pharmaceutically acceptable salt thereof. In embodiments, the method comprises administering a daily dose of about 200 mg of Compound A. In embodiments, the method comprises administering a daily dose of about 100 mg of Compound A.
  • FIH Study An overview of the FIH Study is provided in Table 1 below.
  • the FIH Study will assess the safety and tolerability, and determine the MTD and/or RP2D, of Compound A, in combination with palbociclib, in patients with locally advanced or mBC.
  • the study will also assess clinical activity of Compound A at the RP2Ds in combination with palbociclib. Additional evaluation will include single- and multiple-dose pharmacokinetics and biochemical activity.
  • Study Design Part C of the FIH Study is a Phase 1b evaluating the combination of Compound A and palbociclib. Method of Administration Compound A was orally administered in combination with palbociclib (Part C), in 28- day cycles, in doses shown in Table 1.
  • the Clinical Pharmacology Study consists of 3 independent cohorts: 1) an open-label, randomized, 2-period, crossover Fed/Fasted cohort to determine food effects; 2) an open-label, 2-period, fixed sequence PPI cohort to evaluate interactions with esomeprazole; and 3) an open-label, randomized, 2 period, crossover rBA cohort to evaluate 2 tablet formulations.
  • an open-label, randomized, 2-period, fixed sequence PPI cohort to evaluate interactions with esomeprazole and 3) an open-label, randomized, 2 period, crossover rBA cohort to evaluate 2 tablet formulations.
  • As of the data cut-off date of 16 Jun 2022 47 participants have been treated in the 3 cohorts of Clinical Pharmacology Study. (14 participants in Fed/Fasted, 17 participants in PPI, and 16 participants in rBA cohorts).
  • Example 1 Pharmacokinetics (PK) in Patients with Breast Cancer (the FIH Study)
  • PK Pharmacokinetics
  • Preliminary PK data from Part C of the FIH Study were available from dose levels ranging from 180 to 500 mg QD.
  • Preliminary results indicated dose-dependent increases in Cmax and AUCtau for Compound A, Compound B, and the sum of Compound A + Compound B up to 500 mg QD on both Cycle 1 Day 1 and Day 15.
  • the clinical DDI potential between Compound A and palbociclib was evaluated by comparing the plasma PK exposure parameters of palbociclib and Compound A (Cmax and AUCtau) obtained in Part C on Cycle 1 Day 15 and the relevant PK data observed in the previously completed studies where palbociclib or Compound A was administered as a single agent.
  • PK data from Part C suggested a lack of the effect of palbociclib on Compound A 290560299 Arvinas Ref.: ARVN0152WO02 Cooley Ref.: ARVN-049/001WO exposure, as evidenced by similar Cmax and AUCtau of Compound A in patients receiving Compound A with palbociclib compared with those patients receiving Compound A monotherapy.
  • the median Tmax ranged from 6.0 to 8.0 hours across the cohorts.
  • the geometric mean T1/2 following a single 200 mg dose was approximately 40 hours under fed condition.
  • Statistical analysis showed that food intake significantly increased Compound A Cmax and AUCinf 3- to 2-fold, respectively, as compared with fasted conditions. Therefore, patients should be instructed to take Compound A with food.
  • Compound A AUC values were similar when administered with PPI or without PPI, although PPI decreased Compound A median C max about 18% which is not considered clinical meaningful. This indicates that there are no effects of PPI on exposure of Compound A when administered with a moderate-fat meal.
  • AEs Arvinas Ref.: ARVN0152WO02 Cooley Ref.: ARVN-049/001WO
  • Example 3 Safety in Healthy Volunteers (the Clinical Pharmacology Study)
  • Adverse events (AEs) were coded to system organ class and preferred term according to the medical dictionary for regulatory activities (MedDRA), version 24.1. The severity of adverse events was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.
  • NCI CTCAE National Cancer Institute Common Terminology Criteria for Adverse Events
  • a treatment-emergent adverse event (TEAE) is an AE occurring after the first dose of Compound A and within 30 days of the last Compound A dose regardless of study drug attribution or grade.
  • a treatment-related adverse event is an AE assessed as “Possibly Related,” “Probably Related,” or “Related” to Compound A by the investigator.
  • Treatment-Emergent Adverse Events TEAEs
  • TEAEs Treatment-Emergent Adverse Events
  • a TEAE is an AE occurring after the first dose of Compound A and within 30 days of the last Compound A dose regardless of study drug attribution or grade.
  • a TRAE is an AE assessed as “Possibly Related,” “Probably Related,” or “Related” to Compound A by the investigator. Preliminary safety data for the FIH Study is presented below. Part C continues to enroll. Adverse Event Summary Based on a 06 Jun 2022 data cut-off, regardless of study drug attribution and grade, TEAEs were observed in 157 of the total 176 patients treated with Compound A in the ongoing FIH Study (all parts).
  • Example 5 TACTIVE-U: phase 1b/2 umbrella study of Compound A, a PROteolysis Targeting Chimera (PROTAC) estrogen receptor (ER) degrader, combined with other anticancer treatments in ER+ advanced or metastatic breast cancer Patients eligible for sub-studies A and B are aged ⁇ 18 years, have histologically or cytologically confirmed ER+/HER2- advanced or metastatic breast cancer not amenable to surgical resection with ⁇ 1 measurable lesion, and have received ⁇ 2 lines of prior therapy for advanced or metastatic disease, including 1 line of any CDK4/6 inhibitor–based regimen.
  • PROTAC PROteolysis Targeting Chimera
  • ER estrogen receptor
  • sub-study A patients will receive Compound A orally once daily (QD) in a dose escalation/de-escalation approach and abemaciclib orally twice daily (BID) continuously.
  • sub-study B patients will receive Compound A orally QD in a dose escalation/de-escalation approach and ribociclib orally QD; Compound A will be given continuously and ribociclib will be given for 21 days followed by 7 days off treatment.
  • the primary endpoint of the phase 1b portion is dose-limiting toxicities to determine the recommended phase 2 dose of Compound A in combination with abemaciclib or ribociclib.
  • Secondary endpoints of phase 1b are progression- free survival (PFS), antitumor activity (overall response rate [ORR], clinical benefit rate [CBR], and duration of response [DOR]), safety (type, frequency, and severity of adverse events and laboratory abnormalities), and plasma concentrations of study drugs; AUC tau and C max of Compound A +/- ribociclib will be determined for sub-study B.
  • Phase 2 further evaluates the antitumor activity of the combinations; the primary endpoint is ORR and secondary endpoints include overall survival, PFS, antitumor activity (CBR and DOR), safety, plasma concentration of study drugs, and changes in circulating tumor DNA.
  • the plate was then placed in the Incucyte® S3 Live-Cell Analysis System and images were acquired every 4 hours for a total of 5 days. 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 (FIG.1A and 1C). Graphing and statistical analyses were performed using Graphpad Prism (GraphPad Software).
  • TGI observed with the combination of fulvestrant and abemaciclib did not achieve the level observed with the combination of Compound A and abemaciclib.
  • Treatment of MCF7 tumor-bearing mice with Compound A and ribociclib as single agents resulted in 87% TGI and 58% TGI, respectively, whereas the combination resulted in greater TGI (124%) than either single agent alone (FIG.3B).
  • MCF7 xenograft model Briefly, MCF7 cells were orthotopically implanted into the mammary fat pads of NOD/SCID female mice.17 ⁇ -estradiol 0.72 mg 90-day pellet (Innovative Research of America) were implanted 2-3 days prior to MCF7 cell implant. For combination arms, Compound A was administered first followed by combination partners 1 hour later. Compound A- and/or combination partner- treated mice were dosed orally once daily.
  • Fulvestrant-treated mice were dosed subcutaneously twice per week for 2 weeks followed by once weekly for 2 weeks. More specifically, synergism between Compound A and abemaciclib and ribociclib was followed up in-vivo using the MCF7 orthotopic xenograft model. Eight- to ten-week-old female NOD/SCID mice were surgically implanted with a 0.36 mg 90-day release 17 ⁇ -estradiol pellet subcutaneously. One to two days later each mouse was injected with 5x10 6 /200 ⁇ L MCF7 cells into one mammary fat pad.
  • Cells were prepared in a 50/50 RPMI-1640 phenol red-free media/Corning Matrigel Membrane Matrix mix at 25x10 6 cells/ml. Dosing initiated once tumors reached an average of 200 mm 3 . Where oral combinations were dosed, Compound A (30 mg/kg) was dosed first and abemaciclib (30 mg/kg) and ribociclib (75 mg/kg) 30-60 minutes later. Fulvestrant (200 mg/kg, subcutaneously; twice per week for 2 weeks followed by once-weekly for 2 weeks) was also evaluated as a single agent and in combination with abemaciclib and ribociclib. Drugs indicated were dosed as single agents or in combination to 10 mice/arm.
  • a single-day dosing holiday was implemented on all arms if any body weight loss approached 10% (days 11, 12, 19, and 20 of the ribociclib study). Body weights were well maintained with a single day dosing holiday (FIGs. 4A and 4B). Tumor volumes were measured twice per week in efficacy studies and calculated using (width 2 x length)/2, where all measurements are in millimeters (mm) and the tumor volume is in mm 3 . Body weights were recorded twice per week. At study termination mice were euthanized 18-hours post-last dose ad harvested tissue was snap-frozen on dry ice.
  • TGI (%) [ 1- ] x 100 (Tumor volume, vehicle, Day X) – (Tumor volume, vehicle, Day 0)
  • TGI (%) [ 1- ] x 100 (Tumor volume, vehicle, Day X) – (Tumor volume, vehicle, Day 0)
  • TGI (%) [ 1- ] x 100 (Tumor volume, vehicle, Day X) – (Tumor volume, vehicle, Day 0)
  • the growth inhibition for Compound A in combination with abemaciclib was 111%. Fulvestrant inhibited tumor growth by 42% as a single agent and when combined with abemaciclib by 77%.
  • FIGs 1 and 2 show Compound A in combination with CDK4/6 inhibitors (i.e., abemaciclib and ribociclib) demonstrates enhanced efficacy and evidence of synergy in vitro.
  • Compound A in combination with the CDK4/6 inhibitors abemaciclib and ribociclib led to enhanced tumor regressions in MCF7 xenografts as compared to single agents alone.
  • these data highlight the potential utility of Compound A as a combination partner for clinically relevant targeted agents for treatment of early and late-stage ER+ disease.
  • Example 6 A study to learn about Compound 1 in people with ER+/HER2- Advanced Breast Cancer in China Brief summary The purpose of this clinical trial is to learn about the pharmacokinetics. safety and tolerability of compound 1 for the potential treatment of advanced estrogen receptor positive and human epidermal growth factor receptor 2 negative breast cancer.
  • This study is seeking participants have - ER+/HER2- advanced breast cancer - received at least 1 line of endocrine therapy with or without CDK4/6 inhibitor - received up to 2 prior regimens of chemotherapy for advanced setting. All participants in this study will receive Compound A. Compound A will be given by mouth at home once a day. The experiences of people receiving the study medicine will be examined. This will help determine if the study medicine is safe and effective.
  • the most common palbociclib treatment-related TEAEs observed in ⁇ 10% of patients treated with all doses Compound A and 125mg Palbociclib include neutropenia in all patients (100%), fatigue (60.9%), platelet count decreased (45.7%), anemia (34.8%) and white blood cell count decreased (26.1%), Constipation (17.4%), Diarrhea (17.4%) and Nausea (17.4%). Death was reported in a total of 5 (10.9%) out of 46 participants. Of them, 3 (6.5%) were found related to disease under study or complications thereof, and the remaining 2 (4.3%) deaths were reported as related to “other”.
  • x One patient dosed with 200 mg Compound A + 125 mg palbociclib QD experienced Grade 1 weight loss considered to be related to both Compound Aand palbociclib by the investigator.
  • x One patient dosed with 200 mg Compound A + 125 mg Palbociclib QD experienced Grade 1 cough deemed unrelated to Compound A or palbociclib. The patient was taken off study and the discontinuation reason was subject withdrawal.
  • x One patient dosed with 200 mg Compound A + 125 mg palbociclib QD experienced Grade 1 dizziness deemed unrelated to Compound Aor palbociclib.

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Abstract

L'invention concerne des méthodes de traitement du cancer comprenant l'administration à un sujet d'une dose quotidienne de composé A, ou d'un sel pharmaceutiquement acceptable de celui-ci, en association avec un inhibiteur de CDK4/6.
PCT/US2023/031574 2022-08-31 2023-08-30 Schémas posologiques à base d'agents de dégradation des récepteurs des oestrogènes Ceased WO2024049926A1 (fr)

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CA3266061A CA3266061A1 (fr) 2022-08-31 2023-08-30 Schémas posologiques à base d'agents de dégradation des récepteurs des oestrogènes
CN202380075299.4A CN120112291A (zh) 2022-08-31 2023-08-30 雌激素受体降解剂的给药方案
EP23776753.8A EP4580631A1 (fr) 2022-08-31 2023-08-30 Schémas posologiques à base d'agents de dégradation des récepteurs des oestrogènes
IL319242A IL319242A (en) 2022-08-31 2023-08-30 Estrogen Receptor Blocker Dosage Regimen
AU2023336057A AU2023336057A1 (en) 2022-08-31 2023-08-30 Dosage regimens of estrogen receptor degraders
KR1020257009876A KR20250076543A (ko) 2022-08-31 2023-08-30 에스트로겐 수용체 분해제의 투여량 요법
JP2025512129A JP2025530742A (ja) 2022-08-31 2023-08-30 エストロゲン受容体分解物質の投与計画
MX2025002284A MX2025002284A (es) 2022-08-31 2025-02-25 Regímenes de dosificación de degradadores de receptores de estrógeno

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US202363454485P 2023-03-24 2023-03-24
US202363454422P 2023-03-24 2023-03-24
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Cited By (2)

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Publication number Priority date Publication date Assignee Title
US12208095B2 (en) 2019-08-26 2025-01-28 Arvinas Operations, Inc. Methods of treating breast cancer with tetrahydronaphthalene derivatives as estrogen receptor degraders
WO2025007920A1 (fr) * 2023-07-06 2025-01-09 海创药业股份有限公司 Médicament combiné pour dégrader le récepteur des œstrogènes et son utilisation

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