Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—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.
• 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.
• 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 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 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.
• 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.
• 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.
• 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.
• 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

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