Administration of CYP3a inhibitors in the treatment of cancer

Abstract

The invention relates to methods for treating cancer comprising administering to a subject Compound A having a structure of:, or a pharmaceutically acceptable salt thereof, wherein the subject has been administered a CYP3A inhibitor, and particularly, a CYP3A4 inhibitor.

Description

[0001] Attorney Docket No.: 100C-401880-WO

[0002] Arvinas Docket No.: ARVN0182WO

[0003] ADMINISTRATION OF CYP3A INHIBITORS IN THE TREATMENT OF CANCER

[0004] CROSS REFERENCE TO REEATED APPLICATIONS

[0005] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 686,107, filed August 22, 2024, the content of which is incorporated herein by reference in its entirety.

[0006] BACKGROUND OF THE INVENTION

[0007] Certain bifunctional compounds can target specific cellular proteins for degradation via the ubiquitin-proteasome system. Examples of such proteolysis targeting chimeric compounds (i.e., “PROTAC® protein degraders”) that target the estrogen receptor (ER) for ubiquitination and subsequent degradation are disclosed in U.S. Pat. No. 10,647,698, which is incorporated herein by reference in its entirety. 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, or endometrial cancer), or endometriosis.

[0008] A bifunctional molecule of particular interest is (S)-3-(5-(4-((l-(4-((lR,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)-

[0009] 1 ,2,3,4-tetrahydro-6-hydroxy-2-phenyl- 1 -naphthalenylphenyl] -4-piperidinyl] methyl] -1- pipcrazinyl |-2 / 7-isoindol-2-yl |-2,6-pipcridincdionc (referred to herein as “Compound A”), which has the molecular formula of C45H49N5O4 and the following structure:

[0010] 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.

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[0013] CYP3A is an enzyme subfamily in the cytochrome P450 (CYP) superfamily and includes isoforms CYP3A4, CYP3A5, CYP3A7, and CYP3A43. The CYP3A4 enzyme is particularly susceptible to enzyme inhibitors, and marked increases in the plasma concentrations of CYP3A4 substrates may occur. CYP3A4 inhibitors are drugs that lower the activity of CYP3A4 by binding with the active site of the enzyme. Itraconazole, a synthetic triazole antifungal agent, and its primary metabolite hydroxy-itraconazole are strong inhibitors of CYP3A4 (Itraconazole. Prescribing information. Janssen Pharmaceuticals, Inc.; 2023.); Itraconazole has been recommended as a probe to investigate CYP3A inhibition by regulatory agencies, (e.g., EMA. Accessed Mar 12, 2024. https: / / www.ema.europa.eu / en / documents / scientific- guideline / guideline-investigation-drug-interactions-revision- l_en.pdf. FDA. M12 drug interaction studies. Accessed Mar 12, 2024. https: / / www.fda.gov / media / 161199 / download.)

[0014] The simultaneous or nearly simultaneous (e.g., concomitant) presence of two drugs in a subject may alter the effects of one or the other, or both, drugs. Such alterations are termed drugdrug interactions. Concomitant administration of different drugs often leads to adverse effects since the metabolism and / or excretion of each drug may reduce or interfere with the metabolism and / or excretion of the other drug(s), thus increasing the effective concentrations of those drugs as compared to effective concentrations of those drugs when administered alone.

[0015] Accordingly, methods of treatment that minimize drug-drug interactions in the treatment of cancer are needed.

[0016] SUMMARY OF THE INVENTION

[0017] The present disclosure provides, in part, methods for administering Compound A, or a pharmaceutically acceptable salt thereof, to a subject, 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.

[0018] Provided herein is a method of treating cancer in a subject who has been administered a CYP3A inhibitor, the method comprising: a) discontinuing the administration of the CYP3A inhibitor to the subject; and b) administering an effective amount of Compound A:

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[0021] Arvinas Docket No.: ARVN0182WO or a pharmaceutically acceptable salt thereof, to the subject.

[0022] Provided herein is a method of treating cancer in a subject who has been administered a CYP3A4 inhibitor, the method comprising: a) discontinuing the administration of the CYP3A4 inhibitor to the subject; and b) administering an effective amount of Compound A: or a pharmaceutically acceptable salt thereof, to the subject.

[0023] In embodiments, the method of treating cancer in a subject who has been administered a CYP3A inhibitor or a CYP3A4 inhibitor, respectively, is further comprising step a’): a') waiting a first time period after step a) before performing step b).

[0024] In embodiments of the method of treating cancer in a subject who has been administered a CYP3A inhibitor or a CYP3A4 inhibitor, respectively, the first time period after step a) is at least 14 days (e.g., about 14 days plus 5 half-lives of the CYP3A inhibitor or the CYP3A4 inhibitor).

[0025] In embodiments of the method of treating cancer in a subject who has been administered a CYP3A inhibitor or a CYP3A4 inhibitor, respectively, the first time period after step a) is about 3 to 5 half-lives of the CYP3A inhibitor or the CYP3A4 inhibitor.

[0026] In embodiments of the method of treating cancer in a subject who has been administered a CYP3A inhibitor or a CYP3A4 inhibitor, respectively, the CYP3A inhibitor or CYP3A4

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[0029] Arvinas Docket No.: ARVN0182WO inhibitor is clarithromycin, diltiazem, erythromycin, itraconazole, ketoconazole, ritonavir, or verapamil, and is preferably, itraconazole.

[0030] In any of the previous embodiments of the method of treating cancer in a subject who has been administered a CYP3A inhibitor or a CYP3A4 inhibitor, respectively, the effective amount of the Compound A, or the pharmaceutically acceptable salt thereof, is administered once per day orally to the subject.

[0031] In any of the previous embodiments of the method of treating cancer in a subject who has been administered a CYP3A inhibitor or a CYP3A4 inhibitor, respectively, the effective amount of the Compound A, or the pharmaceutically acceptable salt thereof, is about 200 mg.

[0032] In any of the previous embodiments of the method of treating cancer in a subject who has been administered a CYP3A inhibitor or a CYP3A4 inhibitor, respectively, the effective amount of the Compound A, or the pharmaceutically acceptable salt thereof, is about 100 mg.

[0033] In any of the previous embodiments of the method of treating cancer in a subject who has been administered a CYP3A inhibitor or a CYP3A4 inhibitor, respectively, the subject is in a fed state.

[0034] In any of the previous embodiments of the method of treating cancer in a subject who has been administered a CYP3A inhibitor or a CYP3A4 inhibitor, respectively, the cancer may be breast cancer; and the breast cancer may be metastatic or locally advanced; the breast cancer may be estrogen positive (ER+) breast cancer; and the estrogen receptor positive (ER+) breast cancer may be human epidermal growth factor receptor 2 negative (HER2-).

[0035] Provided herein is a method of treating cancer in a subject who has been administered a CYP3A inhibitor, the method comprising: a) continuing the administration of the CYP3A inhibitor to the subject; and b) administering an adjusted dose amount of Compound A: or a pharmaceutically acceptable salt thereof, to the subject,

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[0038] Arvinas Docket No.: ARVN0182WO wherein the adjusted dose amount of the Compound A, or the pharmaceutically acceptable salt thereof, is less than an unadjusted dose amount of the Compound A, or the pharmaceutically acceptable salt thereof.

[0039] Provided herein is a method of treating cancer in a subject who has been administered a CYP3A4 inhibitor, the method comprising: c) continuing the administration of the CYP3A4 inhibitor to the subject; and d) administering an adjusted dose amount of Compound A: or a pharmaceutically acceptable salt thereof, to the subject, wherein the adjusted dose amount of the Compound A, or the pharmaceutically acceptable salt thereof, is less than an unadjusted dose amount of the Compound A, or the pharmaceutically acceptable salt thereof.

[0040] In embodiments of the method of treating cancer in a subject who has been administered a CYP3A inhibitor or a CYP3A4 inhibitor, respectively, is further comprising step a’); a’) determining the adjusted dose amount of the Compound A, or the pharmaceutically acceptable salt thereof, as a percentage of the unadjusted dose amount of the Compound A, or the pharmaceutically acceptable salt thereof, after step a) before performing step b).

[0041] In any of the previous embodiments of the method of treating cancer in a subject who has been administered a CYP3A inhibitor or a CYP3A4 inhibitor, respectively, and an adjusted dose is determined, the adjusted dose amount of the Compound A, or the pharmaceutically acceptable salt thereof, is about 50% of the unadjusted dose amount of the Compound A, or the pharmaceutically acceptable salt thereof. In some embodiments, the adjusted dose is less than 60% (e.g., less than 50%, less than 40%, less than 30%, less than 20%) of the unadjusted dose.

[0042] In any of the previous embodiments of the method of treating cancer in a subject who has been administered a CYP3A inhibitor or a CYP3A4 inhibitor, respectively, the unadjusted dose amount of the Compound A, or the pharmaceutically acceptable salt thereof, is about 200 mg.

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[0045] In any of the previous embodiments of the method of treating cancer in a subject who has been administered a CYP3A inhibitor or a CYP3A4 inhibitor, respectively, the adjusted dose amount of the Compound A, or the pharmaceutically acceptable salt thereof, is about 100 mg.

[0046] In any of the previous embodiments of the method of treating cancer in a subject who has been administered a CYP3A inhibitor or a CYP3A4 inhibitor, respectively, the unadjusted dose amount of the Compound A, or the pharmaceutically acceptable salt thereof, is a manufacturer’s recommended dose amount of the Compound A, or the pharmaceutically acceptable salt thereof, in the absence of the administration of the CYP3A inhibitor.

[0047] In any of the previous embodiments of the method of treating cancer in a subject who has been administered a CYP3A inhibitor or a CYP3A4 inhibitor, respectively, the adjusted dose amount of the Compound A, or the pharmaceutically acceptable salt thereof, is about 50% of the manufacturer’s recommended dose amount of the Compound A, or the pharmaceutically acceptable salt thereof, in the absence of the administration of the CYP3A inhibitor.

[0048] In any of the previous embodiments of the method of treating cancer in a subject who has been administered a CYP3A inhibitor or a CYP3A4 inhibitor, respectively, the manufacturer’s recommended dose amount of the Compound A, or the pharmaceutically acceptable salt thereof, is about 200 mg.

[0049] In any of the previous embodiments of the method of treating cancer in a subject who has been administered a CYP3A inhibitor or a CYP3A4 inhibitor, respectively, the adjusted dose amount of the Compound A, or the pharmaceutically acceptable salt thereof, is administered once per day (QD) orally to the subject.

[0050] In any of the previous embodiments of the method of treating cancer in a subject who has been administered a CYP3A inhibitor or a CYP3A4 inhibitor, respectively, the administration of CYP3A inhibitor is concomitant administration.

[0051] In any of the previous embodiments of the method of treating cancer in a subject who has been administered a CYP3A inhibitor or a CYP3A4 inhibitor, respectively, the CYP3A inhibitor or the CYP3A4 inhibitor is clarithromycin, diltiazem, erythromycin, itraconazole, ketoconazole, ritonavir, or verapamil, and is preferably, itraconazole.

[0052] In any of the previous embodiments of the method of treating cancer in a subject who has been administered a CYP3A inhibitor or a CYP3A4 inhibitor, respectively, a daily dose of the CYP3A inhibitor is administered to the subject.

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[0056] In any of the previous embodiments of the method of treating cancer in a subject who has been administered a CYP3A inhibitor or a CYP3A4 inhibitor, respectively, the CYP3A inhibitor is itraconazole, and wherein the itraconazole is administered in a daily dose of 200 mg.

[0057] In embodiments of the method of treating cancer in a subject who has been administered a CYP3A inhibitor or a CYP3A4 inhibitor, respectively, the CYP3A inhibitor is administered once per day (QD).

[0058] In embodiments of the method of treating cancer in a subject who has been administered a CYP3A inhibitor or a CYP3A4 inhibitor, respectively, the CYP3A inhibitor is administered orally.

[0059] In any of the previous embodiments of the method of treating cancer in a subject who has been administered a CYP3A inhibitor or a CYP3A4 inhibitor, respectively, the subject is human.

[0060] Provided herein are methods for treating cancer comprising administering to a subject Compound A having a structure of: or a pharmaceutically acceptable salt thereof, wherein treatment of the Compound A, or the pharmaceutically acceptable salt thereof, is not to be administered with concomitant administration of a CYP3A inhibitor.

[0061] Provided herein are methods for treating cancer comprising administering to a subject Compound A having a structure of:

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[0064] Arvinas Docket No.: ARVN0182WO or a pharmaceutically acceptable salt thereof, wherein treatment of the Compound A, or the pharmaceutically acceptable salt thereof, is not to be administered with concomitant administration of a CYP3A4 inhibitor.

[0065] Additionally provided herein are methods for treating cancer comprising administering to a subject Compound A having a structure of: or a pharmaceutically acceptable salt thereof, wherein a physician is provided with instructions including a warning that the treatment is not to be administered with concomitant administration of a CYP3A inhibitor.

[0066] Additionally provided herein are methods for treating cancer comprising administering to a subject Compound A having a structure of: or a pharmaceutically acceptable salt thereof, wherein a physician is provided with instructions including a warning that the treatment is not to be administered with concomitant administration of a CYP3A4 inhibitor.

[0067] In any of the previous embodiments of the methods for treating cancer in a subject, wherein treatment of the Compound A, or the pharmaceutically acceptable salt thereof, is not to be administered with concomitant administration of a CYP3A inhibitor or a CYP3A4 inhibitor, respectively, the CYP3A inhibitor or CYP3A4 inhibitor is clarithromycin, diltiazem, erythromycin, itraconazole, ketoconazole, ritonavir, or verapamil , and is preferably, itraconazole.

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[0070] In any of the previous embodiments of the methods for treating cancer in a subject, wherein treatment of the Compound A, or the pharmaceutically acceptable salt thereof, is not to be administered with concomitant administration of a CYP3A inhibitor or a CYP3A4 inhibitor, respectively, the effective amount of the Compound A, or the pharmaceutically acceptable salt thereof, is administered once per day (QD) orally to the subject.

[0071] In any of the previous embodiments of the methods for treating cancer in a subject, wherein treatment of the Compound A, or the pharmaceutically acceptable salt thereof, is not to be administered with concomitant administration of a CYP3A inhibitor or a CYP3A4 inhibitor, respectively, an effective amount of the Compound A, or the pharmaceutically acceptable salt thereof, is about 100 mg.

[0072] In any of the previous embodiments of the methods for treating cancer in a subject, wherein treatment of the Compound A, or the pharmaceutically acceptable salt thereof, is not to be administered with concomitant administration of a CYP3A inhibitor or a CYP3A4 inhibitor, respectively, an effective amount of the Compound A, or the pharmaceutically acceptable salt thereof, is about 200 mg.

[0073] In any of the previous embodiments of the methods for treating cancer in a subject, wherein treatment of the Compound A, or the pharmaceutically acceptable salt thereof, is not to be administered with concomitant administration of a CYP3A inhibitor or a CYP3A4 inhibitor, respectively, the subject is in a fed state.

[0074] In any of the previous embodiments of the methods for treating cancer in a subject, wherein treatment of the Compound A, or the pharmaceutically acceptable salt thereof, is not to be administered with concomitant administration of a CYP3A inhibitor or a CYP3A4 inhibitor, respectively, 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.

[0075] In any of the previous embodiments of the methods for treating cancer in a subject, wherein treatment of the Compound A, or the pharmaceutically acceptable salt thereof, is not to be administered with concomitant administration of a CYP3A inhibitor or a CYP3A4 inhibitor, respectively, the cancer is breast cancer, lung cancer, prostate cancer, pancreatic cancer, or ovarian cancer.

[0076] In any of the previous embodiments of the methods for treating cancer in a subject, wherein treatment of the Compound A, or the pharmaceutically acceptable salt thereof, is not to be

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[0078] 307306062 v3 Attorney Docket No.: 100C-401880-WO Arvinas Docket No.: ARVN0182WO administered with concomitant administration of a CYP3A inhibitor or a CYP3A4 inhibitor, respectively, the cancer is breast cancer, lung cancer, or prostate cancer.

[0079] In any of the previous embodiments of the methods for treating cancer in a subject, wherein treatment of the Compound A, or the pharmaceutically acceptable salt thereof, is not to be administered with concomitant administration of a CYP3A inhibitor or a CYP3A4 inhibitor, respectively, the cancer is breast cancer; and the breast cancer may be metastatic or locally advanced; the breast cancer may be estrogen receptor positive (ER+) breast cancer; and the estrogen receptor positive (ER+) breast cancer may be human epidermal growth factor receptor 2 negative (HER2-).

[0080] In any of the previous embodiments of the methods for treating cancer in a subject, wherein treatment of the Compound A, or the pharmaceutically acceptable salt thereof, is not to be administered with concomitant administration of a CYP3A inhibitor or a CYP3A4 inhibitor, respectively, the subject is human.

[0081] Provided herein is a pharmaceutical product comprising an amount of Compound A, or a pharmaceutically acceptable salt thereof, in an oral dosage form, wherein the pharmaceutical product is packaged, and wherein the package includes an instruction or label that includes a warning that concomitant administration of the Compound A, or the pharmaceutically acceptable salt thereof, is contraindicated with a strong CYP3A inhibitor.

[0082] Provided herein is a pharmaceutical product comprising an amount of Compound A, or a pharmaceutically acceptable salt thereof, in an oral dosage form, wherein the pharmaceutical product is packaged, and wherein the package includes an instruction or label that includes: a) avoiding concomitant use of or co-administration of the Compound A, or the pharmaceutically acceptable salt thereof, with a strong CYP3A inhibitor; b) discontinuing concomitant use of or co-administration of the Compound A, or the pharmaceutically acceptable salt thereof, with a strong CYP3A inhibitor; or c) contraindicating concomitant use of or co-administration of the Compound A, or the pharmaceutically acceptable salt thereof, with a strong CYP3A inhibitor.

[0083] Provided herein is a kit comprising: (a) a pharmaceutical product comprising an amount of Compound A, or a pharmaceutically acceptable salt thereof, in an oral dosage form; and (b) an instruction or label that includes a warning that concomitant administration of the Compound A, or the pharmaceutically acceptable salt thereof, is contraindicated with a strong CYP3A inhibitor.

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[0086] Provided herein is a pharmaceutical product comprising an amount of Compound A, or a pharmaceutically acceptable salt thereof, in an oral dosage form, wherein the pharmaceutical product is packaged, and wherein the package includes an instruction or a label that includes a warning that a reduced amount of the Compound A, or the pharmaceutically acceptable salt thereof, is administered with concomitant use of or co-administration with a strong CYP3A inhibitor.

[0087] Provided herein is a pharmaceutical product comprising an amount of Compound A, or a pharmaceutically acceptable salt thereof, in an oral dosage form, wherein the pharmaceutical product is packaged, and wherein the package includes an instruction or a label that includes: a) avoiding concomitant use of or co-administration of the Compound A, or the pharmaceutically acceptable salt thereof, with a strong CYP3A inhibitor; b) discontinuing concomitant use of or co-administration of the Compound A, or the pharmaceutically acceptable salt thereof, with a strong CYP3A inhibitor; c) contraindicating concomitant use of or co-administration of the Compound A, or the pharmaceutically acceptable salt thereof, with a strong CYP3A inhibitor; or d) reducing the amount of the Compound A, or the pharmaceutically acceptable salt thereof, with concomitant use of or co-administration with a strong CYP3A inhibitor.

[0088] Provided herein is a kit comprising: (a) a pharmaceutical product comprising an amount of Compound A, or a pharmaceutically acceptable salt thereof, in an oral dosage form; and (b) an instruction or label that includes a warning that a reduced amount of the Compound A, or the pharmaceutically acceptable salt thereof, is administered with concomitant use of or co- administration with a strong CYP3A inhibitor.

[0089] In any of the previous embodiments of the pharmaceutical product or the kit, the oral dosage form of the Compound A, or the pharmaceutically acceptable salt thereof, is a tablet or capsule; and is preferably a tablet.

[0090] In any of the previous embodiments of the pharmaceutical product or the kit, the strong CYP3A inhibitor is clarithromycin, diltiazem, erythromycin, itraconazole, ketoconazole, ritonavir, or verapamil ; and is preferably itraconazole.

[0091] In any of the previous embodiments of the pharmaceutical product or the kit, the strong CYP3A inhibitor is a strong CYP3A4 inhibitor.

[0092] In any of the previous embodiments of the pharmaceutical product or the kit, the amount of the Compound A, or the pharmaceutically acceptable salt thereof, is about 200 mg.

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[0095] In any of the previous embodiments of the pharmaceutical product or the kit, the amount of the Compound A, or the pharmaceutically acceptable salt thereof, is about 100 mg.

[0096] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.

[0097] BRIEF DESCRIPTION OF THE DRAWINGS

[0098] The accompanying drawings, which are incorporated into and form a part of the specification, illustrate several embodiments of the present disclosure and, together with the description, serve to explain the principles of the disclosure. The drawings are only for the purpose of illustrating an embodiment of the disclosure and are not to be construed as limiting the disclosure. Further objects, features and advantages of the disclosure will become apparent from the following detailed description taken in conjunction with the accompanying figures showing illustrative embodiments of the disclosure, in which:

[0099] FIGs. 1A-B depict median plasma Compound A concentration-time profiles with and without itraconazole. FIG. 1A is linear scale and FIG. IB is semi-log scale. LLOQ = 2.50 ng / mL.

[0100] FIG. 2A depicts individual and geometric mean plasma Compound A AUCinf with and without itraconazole. FIG. 2B depicts individual and geometric mean plasma Compound A Cmax with and without itraconazole. Circles represent individual values and stars represent geometric mean value for each treatment group. Box plot provides median and 25% / 75% quartiles with whiskers to the last point within 1.5 times interquartile range.

[0101] FIGs. 3A-B depict median plasma Compound B concentration-time profiles with and without itraconazole. FIG. 3A is linear scale and FIG. 3B is semi-log scale. LLOQ = 2.50 ng / mL.

[0102] FIG. 4A depicts individual and geometric mean plasma Compound B AUC120 with and without itraconazole. FIG. 4B depicts individual and geometric mean plasma Compound B Cmax with and without itraconazole. Circles represent individual values and stars represent geometric mean value for each treatment group. Box plot provides median and 25% / 75% quartiles with whiskers to the last point within 1.5 times interquartile range.

[0103] DETAILED DESCRIPTION OF THE INVENTION

[0104] The present invention may be understood more readily by reference to the following detailed description of the embodiments of the invention and the Examples included herein. It is

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[0107] Arvinas Docket No.: ARVN0182WO to be also understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to be limiting.

[0108] Definitions

[0109] Unless otherwise defined herein, scientific, and technical terms used in connection with the present invention have the meanings that are commonly understood by those of ordinary skill in the art.

[0110] The invention described herein suitably may be practiced in the absence of any element(s) not specifically disclosed herein.

[0111] As used herein, the singular form “a,” “an,” and “the” include plural references unless indicated otherwise. For example, “a” substituent includes one or more substituents.

[0112] As used herein, the term “about” when used to modify a numerically defined parameter (e.g., the dose of Compound A, a pharmaceutically acceptable salt thereof, or of a CYP3A inhibitor) 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 between 4.5 mg and 5.5 mg.

[0113] As used herein, 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, uses, pharmaceutical products, and kits of the present invention, specifically Compound A and pharmaceutically acceptable salts thereof.

[0114] Compound A, having the structure: and pharmaceutically acceptable salts thereof are disclosed in, e.g., International Publication No. WO 2018 / 102725 and U.S. Patent Nos. 10,647,698, 10,899,742 and 11,104,666; International Publication No. WO 2021 / 041348; U.S. Serial No. 17 / 472,847; U.S. Serial No. 17 / 548,842; and U.S. Serial No. 17 / 873,748. The contents of each of the foregoing references are incorporated herein by reference in their entireties for all purposes.

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[0116] Compound A is a Biopharmaceutics Classification System Class IV compound (low solubility / low permeability). Compound A may interconvert to its epimer, Compound B:

[0117] Without wishing to be bound by theory, preclinical data demonstrates 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.

[0118] Additional 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.

[0119] Another embodiment also relates 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, 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, lactate, malate, maleate, malonate, mesylate, methanesulfonate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, p-toluenesulfonate, tosylate, trifluoroacetate and xinofoate salts.

[0120] Additional embodiments relate to base addition salts of the compounds described herein. Suitable base addition salts are formed from bases which form non-toxic salts. Non-limiting examples of suitable base salts include the aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.

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[0123] The compounds described herein that are basic in nature are capable of forming 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., l,l’-methylene-bis-(2-hydroxy-3- naphthoate)] salts. The compounds described herein that include a basic moiety, such as an amino group, may form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above.

[0124] 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.

[0125] Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.

[0126] For a review on suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002). Methods for making pharmaceutically acceptable salts of compounds described herein are known to one of skill in the art.

[0127] Administration and Dosing

[0128] The terms “treat” and “treating” a cancer or a cancer-associated disease, as used herein, mean to administer an agent, composition, compound, drug, or therapeutic agent 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

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[0130] 307306062 v3 Attorney Docket No.: 100C-401880-WO Arvinas Docket No.: ARVN0182WO 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.

[0131] The terms “treatment” and “therapy,” as used herein, unless otherwise indicated, refer to the act of treating as “treating” is defined immediately above. For the purposes of this disclosure, 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 may be measured in a number of ways (see, for example, W. A. Weber, J. Nucl. Med. (2009) 5O:1S-1OS).

[0132] “Concomitant” as used to describe the administration of two drugs, means that the timing of the administration of the two drugs is simultaneous or nearly simultaneous. In other words, the two drugs are administered either at the same time or almost at the same time. In concomitant administration, the two drugs are present, e.g., being metabolized and / or excreted, in a subject at the same time.

[0133] A “half-life” or a “terminal elimination half-life” of a drug is the time it takes for the amount of a drug’s active pharmaceutical ingredient in a subject to reduce by half. In other words, a drug's half-life is an estimation of the time it takes for the drug's initial concentration in the body of a subject to decrease by half.

[0134] “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.

[0135] As used herein, the terms, “subject”, “participant” and “patient,” are used interchangeably, to refer to a human. Human subjects may be of any gender. In an embodiment, a human is an adult human.

[0136] An “amount” for use and for treating a subject refers to an amount that provides, in single or multiple doses, or 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

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[0139] Arvinas Docket No.: ARVN0182WO 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 (z.e., not worsening) state of the disease, is considered a satisfactory outcome. The term “effective amount” also means an amount of an agent alone or 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. In reference to the treatment of cancer, an 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.

[0140] As used herein, “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.

[0141] Compound A is preferably dosed in the form of a free base. The daily dose or daily dosage of Compound A, or a pharmaceutically acceptable salt thereof, is the free base equivalent of Compound A. Dosage amounts provided herein refer to the dose of the free base form of Compound A, or are calculated as the free base equivalent of an administered Compound A salt form. For example, a dosage or amount of Compound A, such as about 100 mg or about 200 mg refers to the free base equivalent.

[0142] As used herein, an “unadjusted dose amount” of the Compound A, or the pharmaceutically acceptable salt thereof, is a dose amount suitable for a subject if the subject were not receiving a concomitant CYP3A, and particularly, a CYP3A4 inhibitor (e.g., itraconazole). An “adjusted dose amount” of Compound A is a dose amount suitable for a subject if the subject were receiving a concomitant CYP3A, and particularly, a CYP3A4 inhibitor (e.g., itraconazole). In embodiments, the unadjusted dose amount of the Compound A, or the pharmaceutically acceptable salt thereof, is a daily dose amount. In embodiments, the adjusted dose amount of the Compound A, or the

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[0144] 307306062 v3 Attorney Docket No.: 100C-401880-WO Arvinas Docket No.: ARVN0182WO pharmaceutically acceptable salt thereof, is a daily dose amount. In embodiments, the unadjusted dose amount of the Compound A, or the pharmaceutically acceptable salt thereof, is about 200 mg. In embodiments, the adjusted dose amount of the Compound A, or the pharmaceutically acceptable salt thereof is about 100 mg.

[0145] As used herein, a “manufacturer’s recommended dose amount” is a dose amount that is of an amount deemed safe and effective for the particular patient under the conditions specified. As used herein and in the claims, the “manufacturer’s recommended dose amount” is determined by following the recommendations of the drug manufacturer's Prescribing Information as approved by the US Food and Drug Administration. In embodiments, the “manufacturer’s recommended dose amount” of the Compound A, or the pharmaceutically acceptable salt thereof, is a daily dose amount. In embodiments, the “manufacturer’s recommended dose amount” of the Compound A, or the pharmaceutically acceptable salt thereof, is about 200 mg.

[0146] 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 effective amount, may be a daily dose of about 100 mg or about 200 mg. In embodiments, a daily dose is about 200 mg. In embodiments, a daily dose is about 100 mg.

[0147] In embodiments, the daily dose of Compound A, or a pharmaceutically acceptable salt thereof, is administered once per day (QD).

[0148] 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. In embodiments, the daily dose of Compound A, or a pharmaceutically acceptable salt thereof, is administered orally.

[0149] 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. The term “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.

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[0152] The compounds of the methods or uses 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.

[0153] 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. In embodiments, the compounds of the present invention may be administered in a continuous dosing schedule. In embodiments, the compounds disclosed herein may be administered concurrently in a continuous dosing schedule.

[0154] In embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is administered once daily to comprise a complete cycle of 28-day s. Repetition of 28-day treatment cycles is continued during treatment in accordance with the methods and uses of the present disclosure.

[0155] Method of Treatment

[0156] In one embodiment, the disclosure provides a method of administering Compound A, or a pharmaceutically acceptable salt thereof, in the treatment of cancer. The references to the methods of treatment of this description are to be interpreted as being also references to the compound(s), pharmaceutical compositions, and medicaments of the present invention for use in those methods.

[0157] The term “locally advanced breast cancer” refers to cancer that has spread from where it started in the breast to nearby tissue or lymph nodes, but not to other parts of the body.

[0158] The term “metastatic breast cancer” refers to cancer that has spread from the breast to other parts of the body, such as the bones, liver, lungs, or brain. Metastatic breast cancer may also be referred to as stage IV breast cancer.

[0159] Provided herein are methods of treating cancer as described in the Summary of the Invention section of this application.

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[0163] In some embodiments, discontinuing administration of a CYP3A inhibitor is to avoid an adverse drug interaction with Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, discontinuing administration of a CYP3A4 inhibitor is to avoid an adverse drug interaction with Compound A, or a pharmaceutically acceptable salt thereof.

[0164] In embodiments, 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. In embodiments, the cancer is breast cancer, lung cancer, prostate cancer, pancreatic cancer, or ovarian cancer. In embodiments, the cancer is breast cancer, lung cancer, or prostate cancer. In embodiments, the cancer is breast cancer. In embodiments, the breast cancer is metastatic or locally advanced. In embodiments, the breast cancer is estrogen receptor positive (ER+) breast cancer. In embodiments, the estrogen receptor positive (ER+) breast cancer is human epidermal growth factor receptor 2 negative (HER2-).

[0165] In embodiments, the subject is human.

[0166] Pharmaceutical Products and Kits

[0167] In embodiments, the invention provides pharmaceutical products comprising Compound A, or a pharmaceutically acceptable salt thereof, formulated for oral administration, wherein the pharmaceutical product is packaged and wherein the package includes an instruction or a label that includes a warning that concomitant administration of the Compound A, or the pharmaceutically acceptable salt thereof, is contraindicated with a strong CYP3A inhibitor, such as a CYP3A4 inhibitor.

[0168] The term “pharmaceutical product” or “drug product” refers to a product that contains an active pharmaceutical ingredient that has been approved for marketing by a governmental authority, e.g., the United States Food and Drug Administration or a similar authority in other countries.

[0169] Similarly, “label” or “drug product label” refers to information provided to a patient or subject which provides relevant information regarding the drug product. Such information includes, without limitation, one or more of the description of the drug, clinical pharmacology, indications (uses for the drug product), contraindication (who should not take the drug product), warnings, precautions, adverse events (side effects), drug abuse and dependence, dosage and administration, use in pregnancy, use in nursing mothers, use in children and older patients, how

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[0171] 307306062 v3 Attorney Docket No.: 100C-401880-WO Arvinas Docket No.: ARVN0182WO the drug is supplied, safety information for the patient, or any combination thereof. In certain embodiments, the label or drug product label provides instructions for treating a cancer.

[0172] Another aspect of the invention provides kits comprising a pharmaceutical product comprising Compound A, or a pharmaceutically acceptable salt thereof, formulated for oral administration. The kit may include an instruction or a label that includes a warning that concomitant administration of Compound A, or a pharmaceutically acceptable salt thereof, is contraindicated with a strong CYP3A inhibitor, such as a CYP3A4 inhibitor. The kit may include instructions for use in a diagnostic or therapeutic method.

[0173] In another embodiment, the invention comprises kits that are suitable for use in performing the methods of treatment described herein. In one embodiment, the kit contains an oral dosage form comprising Compound A, or a pharmaceutically acceptable salt thereof, in quantities sufficient to carry out the methods of the invention.

[0174] Abbreviations

[0175] AE is adverse event;

[0176] AUCextraP% is the percent of AUCinf obtained by forward extrapolation;

[0177] BID is twice a day;

[0178] BMI is Body mass index;

[0179] CI is confidence interval;

[0180] Cmax maximum observed plasma concentration

[0181] CV% is coefficient of variation;

[0182] CYP is cytochrome P450;

[0183] ECG is electrocardiogram;

[0184] ER is estrogen receptor;

[0185] ICD is informed consent document;

[0186] MRCmax is metabolite ratio for Cmax;

[0187] PK is pharmacokinetic(s);

[0188] QD is once per day or once daily;

[0189] SAE is serious adverse event;

[0190] SD is standard deviation;

[0191] SOC is system organ class;

[0192] SOP is standard operating procedure; t> / 2is terminal elimination half-life;

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[0195] TEAE is treatment emergent adverse events;

[0196] TID is three times a day;

[0197] ULN is upper limit of normal; and

[0198] Vz / F is apparent volume of distribution after oral dose.

[0199] EXAMPLE

[0200] In order that this invention may be better understood, the following example is set forth. This example is for purposes of illustration only and is not to be construed as limiting the scope of the invention in any manner.

[0201] A Clinical Study to Understand the Effect of Itraconazole on the Levels of Compound A in Healthy Adults

[0202] Overview:

[0203] Compound A was investigated in an interventional, Phase 1, open-label, fixed sequence, 2-period study to estimate the effect of multiple doses of itraconazole on the PK of a single dose of Compound A in the fed condition in healthy adult males, and females of nonchildbearing potential.

[0204] Background: Nonclinical Pharmacokinetics and Metabolism

[0205] The PK profile of Compound A in the nonclinical species (mouse, rat, dog, and monkey) was characterized by a low to moderate clearance (13.8% to 33.8% of hepatic blood flow), extensive tissue distribution (2.1 to 6.0 L / kg), short to moderate t> / 2(2.1 to 8.2 hours), and moderate to good oral bioavailability (27% to 65%).

[0206] A dose-dependent increase in Compound A exposure was observed when Compound A was administered as an oral solution in the mouse (10, 30, 100 mg / kg), rat (30, 100, 300 mg / kg), dog (15, 45, 90, 200, and 400 mg / kg), and monkey (1 and 3 mg / kg).

[0207] A 3-fold increase in AUC and reduced inter-animal variability were observed in fed dogs; as such, the data indicated that the tablets should be administered with food in clinical trials.

[0208] A CYP reaction phenotyping study was conducted using 2 orthogonal methods in human liver microsomes and recombinant CYP isoforms. This study indicated CYP3A4 as the principal isoform responsible for CYP metabolism of Compound A (accounting for 85%).

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[0211] Rationale:

[0212] A CYP reaction phenotyping study indicated CYP3A4 as the principal isoform responsible for CYP metabolism of Compound A. Itraconazole and its primary metabolite (hydroxyitraconazole) are strong inhibitors of CYP3A. Since Compound A is a substrate for CYP3A, concomitant administration of multiple doses of itraconazole along with Compound A may lead to increased systemic exposure (i.e., increase the exposure) of Compound A.

[0213] The epimer of Compound A, Compound B, was found in plasma (32% of Compound A exposure) after Compound A was administered in patients. Preclinical data showed Compound A has both antagonist and degradation activities against ER, whereas Compound B displays only antagonist activity.

[0214] The objective of this study is to estimate the effect of multiple doses of itraconazole on the PK of Compound A.

[0215] Overall Study Design:

[0216] This was a Phase 1, open-label, 2-period fixed-sequence crossover study to estimate the effect of multiple doses of the strong CYP3A inhibitor, itraconazole, on Compound A and Compound B PK in healthy males and healthy females of nonchildbearing potential. The study consisted of 2 periods; Period 1 = single dose of Compound A alone and Period 2 = multiple doses of itraconazole + single dose of Compound A. Following Period 1, a washout period of at least 10 days must occur between the 2 single doses of Compound A. Following administration of Compound A in each period, participants underwent serial PK sampling.

[0217] Estimated Enrollment:

[0218] A total of approximately 12 participants were planned to be enrolled in the study. Participants who withdrew may be replaced at the discretion of the sponsor.

[0219] Study Arms and Duration:

[0220] Period 1 Day 1: Following an overnight fast of least 10 hours and after the collection of the pre-dose Compound A PK sample, participants started the recommended high fat, high-calorie breakfast consumed prior to administration of Compound A 200 mg as two 100 mg tablets. Participants received study medication at approximately 8 hours (plus or minus 2 hours). Investigator site personnel administered study medication with ambient temperature water to a

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[0222] 307306062 v3 Attorney Docket No.: 100C-401880-WO Arvinas Docket No.: ARVN0182WO total volume of 240 mL. Participants swallowed the study medication whole without manipulating or chewing the medication prior to swallowing. No additional food was allowed for at least 4 hours post dose.

[0223] Period 2 Days 1-4 and 6-11: Following an overnight fast of at least 10 hours, participants were administered 200 mg itraconazole (as 20 mL Sporanox 10 mg / mL oral solution) once daily under fasted conditions with approximately 220 mL of water. No food was allowed for at least 1 hour post itraconazole dose.

[0224] Period 2 Day 5: Following an overnight fast of at least 10 hours and after the collection of the pre-dose Compound A PK sample, participants started the recommended high fat, high-calorie breakfast (approximately 800-1000 calories with 150, 250, and 500-600 calories from protein, carbohydrate and fat, respectively) consumed prior to the concomitant administration of itraconazole and Compound A. Participants received study medications at approximately 8 hours (plus or minus 2 hours). Itraconazole 200 mg, as 20 mL Sporanox 10 mg / mL oral solution were administered first, immediately followed by the two 100 mg tablets of Compound A. The study drugs (itraconazole and Compound A) were administered with approximately 220 mL of ambient temperature water. Participants swallowed the Compound A tablets whole without manipulating or chewing the medication prior to swallowing. No additional food was allowed for at least 4 hours post dose of both drugs.

[0225] Study Objectives and Endpoints:

[0226] The objectives and endpoints of the clinical study are shown below in Table 1 and associated definitions of PK parameters are shown in Table 2.

[0227] Table 1.

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[0231] Calculation of PK Parameters:

[0232] The following Compound A and Compound B PK parameters in Table 2 were calculated for each participant and treatment, as appropriate, and as data permitted, using noncompartmental analysis of plasma concentration-time data. Samples below the lower limit of quantitation (LLOQ) were set to zero for the PK analysis. Actual sample collection times were used for the PK analysis.

[0233] Table 2.

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[0237] The following supporting data from the estimation of t> / 2were also reported: the terminal phase rate constant (kei); the first, last, and number of time points used for the log-linear regression (kei,t(lo), kei,t(hi), and kei,t(n)); the goodness-of-fit statistic from the regression (r2); and the percent of the area under the plasma concentration-time curve from time zero to infinite time, AUCinf, obtained by forward extrapolation (AUCetraP%).

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[0240] Unless otherwise noted, parameters marked “if data permit” were reported only where a well-characterized terminal phase was observed. A well-characterized terminal phase is defined as one with at least 3 data points, r2>0.9, and AUCextrap % <20.

[0241] Clinical Study Results: Study Participants

[0242] 1. Disposition of Participants

[0243] A total of 12 participants were screened and enrolled into the study. All enrolled participants were treated and completed the study.

[0244] 2. Exposure

[0245] In Period 1, the participants received Compound A as two 100 mg tablets on Day 1 with a washout period of at least 10 days.

[0246] In Period 2, the participants received an itraconazole oral solution dose of 200 mg once daily from Day 1 to Day 11 (except for Day 5). On Day 5, itraconazole 200 mg, as 20 mL Sporanox 10 mg / mL oral solution was administered first, immediately followed by two 100 mg tablets of Compound A (200 mg).

[0247] Clinical Study Results: Evaluation Of Response To Study Intervention

[0248] 1. Safety

[0249] Brief Summary of Adverse Events

[0250] A total of 3 TEAEs were reported in 2 (16.7%) participants following a single dose administration of Compound A 200 mg on Day 1 of Period 1, 2 TEAEs of which in 1 (8.3%) participant were assessed as treatment-related; 4 TEAEs were reported in 3 (25.0%) participants following the administration of itraconazole 200 mg daily alone over a period of 4 days in Period 2; 3 TEAEs in 2 (16.7%) participants after the administration of a single dose of Compound A 200 mg + itraconazole 200 mg daily starting on Day 5 of Period 2. No severe TEAEs, SAEs, discontinuation, or dose reduction due to TEAEs were reported.

[0251] Following the administration of single dose Compound A 200 mg on Day 1 of Period 1, mild AEs of abdominal pain and diarrhea were both reported in 1 (8.3%) participant, of which both events were considered as treatment-related, back pain was reported in 1 (8.3%) participant and was not assessed as treatment-related.

[0252] Following the administration of itraconazole 200 mg alone over a period of four days in Period 2, moderate AEs of abdominal pain, diarrhea were both reported in 1 (8.3%) participant, a

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[0254] 307306062 v3 Attorney Docket No.: 100C-401880-WO Arvinas Docket No.: ARVN0182WO moderate AE of gingival discomfort and a mild AE of nasal congestion was reported in 1 (8.3%) participant each. None were assessed as treatment-related.

[0255] Following the administration of a single dose of Compound A 200 mg on Day 5 of Period 2 co-administered with itraconazole 200 mg daily in Period 2, mild AEs of diarrhea, fatigue were both reported in 1 (8.3%) participant, and a mild AE of somnolence was reported in 1 (8.3%) participant. None were assessed as treatment-related.

[0256] The most commonly reported SOC among all study intervention regimens was gastrointestinal disorder and the most frequently reported PT among all study intervention regimens was diarrhea.

[0257] 2. Pharmacokinetics

[0258] Compound A Pharmacokinetics

[0259] Median plasma Compound A concentration-time profiles with and without itraconazole are presented in FIG.s 1 A-B (linear and semi-log plots). Plasma PK parameters are summarized in Table 3. Statistical comparisons of plasma exposures after a single dose of Compound A with and without itraconazole are summarized in Table 4. Box plots of individual and geometric mean AUCinf and Cmax are presented by treatment in FIG.s 2A-B.

[0260] The median Compound A concentration-time profile was generally higher when a single dose of Compound A 200 mg orally was co-administered with multiple daily doses of itraconazole 200 mg orally than that observed when Compound A was administered alone (FIG.s 1A-B and FIG.s 2A-B). Median Tmax was 6.00 hours when Compound A was administered alone and when administered with itraconazole. Following attainment of Cmax, the mean terminal half-life (t> / 2) was longer when Compound A was co-administered with itraconazole (61.57 hours) than when Compound A was administered alone (42.64 hours). The apparent oral clearance of Compound A was 10.54 E / hr when Compound A was administered alone and 6.245 E / hr when Compound A was co-administered with itraconazole. Predose Compound A concentrations on Day 5 of Period 2 were quantifiable and were <5% of Cmax for all 12 participants.

[0261] Co-administration with multiple daily doses of itraconazole solution 200 mg orally with a single dose of Compound A 200 mg increased Compound A plasma AUCinf and Cmax by approximately 69% and 52%, respectively. The test / reference ratios of the adjusted geometric means (90% CI) for Compound A AUCinf and Cmax were 168.90% (157.66%, 180.94%) and

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[0264] 152.19% (136.90%, 169.18%), respectively, following Compound A administration with itraconazole (Test) as compared to administration alone (Reference).

[0265] Similar inter-participant variability for AUC and Cmax was observed when Compound A was administered alone compared to when Compound A was co-administered with itraconazole. Geometric CV% of AUCinf and Cmax was 23% and 22% when Compound A was administered alone and geometric CV% of AUCinf and Cmax was 24% and 19%, respectively, following coadministration with itraconazole.

[0266] Table 3. Descriptive Summary of Plasma Compound A PK Parameters - PK Parameter Analysis Set

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[0270] Table 4. Statistical Summary of Natural Log Transformed Plasma Compound A PK

[0271] Parameters (AUCinf, AUCiast, AUC120 and Cmax) - PK Parameter Analysis Set Compound B Pharmacokinetics

[0272] Median plasma Compound B concentration-time profiles following Compound A administration alone and when Compound A was co-administered with itraconazole are presented in FIGs. 3A-B (linear and semi-log plots). Plasma PK parameters are summarized in Table 5. Statistical comparisons of Compound B plasma exposures after a single dose of Compound A with and without itraconazole are summarized in Table 6. Box plots of individual and geometric mean AUC120 and Cmax are presented by treatment in FIGs. 4A-B.

[0273] Predose residual Compound B concentrations were observed in 8 out of the 12 participants in the Test Treatment (Period 2; Compound A 200 mg + itraconazole 200 mg) that were >5% of Cmax due to carryover from dosing in the Reference Treatment (Period 1; Compound A 200 mg alone). To account for the residual Compound B concentrations in the 8 predose samples on Day 5 of Period 2, corrected PK parameters for AUC120, and Cmax were reported. AUCinf for Compound B could only be reported for 2 of 12 participants in Period 1 (Compound A alone) and 6 of 12 participants in Period 2 (Compound A + itraconazole) based on prespecified criteria (AUCextraP% 30

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[0275] <20), therefore was not used as the primary endpoint for Compound B. Furthermore, AUC120, was selected as the primary endpoint for Compound B in lieu of AUCiast to account for the difference in sampling intervals between Test Treatment (0-168 hours) and Reference Treatment (0-120 hours).

[0276] The median Compound B concentration-time profile was generally higher when a single oral dose of Compound A 200 mg was co-administered with multiple 200-mg oral daily doses of itraconazole than that observed when Compound A was administered alone (FIGs. 3A-B and FIGs. 4A-B). Median Tmax of Compound B was 24.0 hours when Compound A was administered alone and 35.9 hours when Compound A was co-administered with itraconazole.

[0277] Co-administration with multiple 200 mg oral daily doses of itraconazole solution increased Compound B plasma exposure to a similar extent as for the Compound A exposure. The Compound B test / reference ratios of the adjusted geometric means (90% CI) for AUC120 and Cmax were 161.99% (148.70%, 176.47%) and 153.13% (138.51%, 169.30%), respectively, following Compound A administration with itraconazole (Test) as compared to administration alone (Reference).

[0278] Similar inter-participant variability for AUC and Cmax of Compound B was observed when Compound A was administered alone compared to when Compound A was co-administered with itraconazole. Geometric CV% of AUC120 and Cmax was 30% and 26% when Compound A was administered alone and geometric CV% of AUC120 and Cmax was 28% and 27%, respectively, following co-administration with itraconazole.

[0279] Table 5. Descriptive Summary of Plasma Compound B PK Parameters - PK Parameter Analysis Set

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[0286] Table 6. Statistical Summary of Natural Log Transformed Plasma Compound B PK

[0287] Parameters (AUCinf, AUCiast, AUC120 and Cmax) - PK Parameter Analysis Set

[0288] CONCLUSIONS

[0289] Discussion The primary endpoints are plasma AUCinf and Cmax of Compound A and Compound B, and AUCiast if AUCinf cannot be estimated. The AUCinf of Compound A has been adequately estimated for all 12 treated participants and therefore AUCinf is reported as the primary endpoint for Compound A. AUCinf for Compound B could only be reported for 2 of 12 participants in Period 1 (Compound A alone) and 6 of 12 participants in Period 2 (Compound A + itraconazole) based on prespecified criteria (AUCextraP% <20), therefore was not used as the primary endpoint for Compound B. Furthermore, AUC120, was selected as the primary endpoint for Compound B in lieu of AUCiast to account for the difference in sampling intervals between Test Treatment (0-168 hours) and Reference Treatment (0-120 hours).

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[0293] Predose residual Compound B concentrations were observed in 8 out of the 12 participants in the Test Treatment (Period 2; Compound A 200 mg + itraconazole 200 mg) that were >5% of Cmax due to carryover from dosing in the Reference Treatment (Period 1; Compound A 200 mg alone). In order to adequately estimate the treatment effect, i.e., the test / reference ratio of geometric mean, manual correction of PK parameters (AUCinf, AUCiast, AUC120, and Cmax) on Period 2 are applied for the 8 participants to remove the carryover effect. By this correction approach, PK parameters for all participants were included in the statistical analysis without dropping any affected participants. Predose Compound A concentrations on Day 5 of Period 2 were quantifiable and <5% of Cmax in all 12 participants. They are considered minimal carryover effects, therefore correction of Compound A PK parameters in Period 2 was not applied.

[0294] Pharmacokinetics

[0295] Co-administration of multiple 200 mg oral daily doses of itraconazole solution (strong inhibitor of CYP3A) with a single 200 mg dose of Compound A increased Compound A plasma AUCinf and Cmax by approximately 69% and 52%, respectively. The Compound A test / reference ratios of the adjusted geometric means (90% CI) for AUCinf and Cmax were 168.90% (157.66%, 180.94%) and 152.19% (136.90%, 169.18%), respectively, following Compound A administration with itraconazole (Test) as compared to administration alone (Reference).

[0296] The exposure of Compound B, the epimer metabolite of Compound A, was increased to a similar extent as for Compound A, following Compound A co-administration with multiple doses of itraconazole. The Compound B test / reference ratios of the adjusted geometric means (90% CI) for AUC120 and Cmax were 161.99% (148.70%, 176.47%) and 153.13% (138.51%, 169.30%), respectively, following Compound A administration with itraconazole (Test) as compared to administration alone (Reference).

[0297] Safety

[0298] The study interventions were safe and well-tolerated in healthy adult participants, and no death, SAE, or discontinuation due to AEs were identified.

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[0301] EQUIVALENTS

[0302] Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described specifically herein. Such equivalents are intended to be encompassed in the scope of the following claims.

[0303] The methods of the disclosure have been described herein by reference to certain preferred embodiments. However, as particular variations thereon will become apparent to those skilled in the art, based on the disclosure set forth herein, the disclosure is not to be considered as limited thereto.

[0304] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the specification and claims, the singular forms also include the plural unless the context clearly dictates otherwise.

[0305] It is to be understood that at least some of the descriptions of the disclosure have been simplified to focus on elements that are relevant for a clear understanding of the disclosure, while eliminating, for purposes of clarity, other elements that those of ordinary skill in the art will appreciate may also comprise a portion of the disclosure. However, because such elements are well known in the art, and because they do not necessarily facilitate a better understanding of the disclosure, a description of such elements is not provided herein.

[0306] Further, to the extent that a method does not rely on the particular order of steps set forth herein, the particular order of the steps recited in a claim should not be construed as a limitation on that claim.

[0307] All patents, patent applications, references and publications cited herein are fully and completely incorporated by reference as if set forth in their entirety. Such documents are not admitted to be prior art to the present disclosure.

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[0311] Embodiments:

[0312] Embodiment 1. A method of treating cancer in a subject who has been administered a

[0313] CYP3A inhibitor, the method comprising: a) discontinuing the administration of the CYP3A inhibitor to the subject; and b) administering an effective amount of Compound A: or a pharmaceutically acceptable salt thereof, to the subject.

[0314] Embodiment 2. The method of embodiment 1, further comprising step a’): a’) waiting a first time period after step a) before performing step b).

[0315] Embodiment 3. The method of embodiment 2, wherein the first time period is about 14 days plus 5 half-lives of the CYP3A inhibitor.

[0316] Embodiment 4. The method of embodiment 2, wherein the first time period is about 3 to 5 half-lives of the CYP3A inhibitor.

[0317] Embodiment 5. The method of any one of embodiments 1-4, wherein the CYP3A inhibitor is clarithromycin, diltiazem, erythromycin, itraconazole, ketoconazole, ritonavir, or verapamil.

[0318] Embodiment 6. The method of embodiment 5, wherein the CYP3A inhibitor is itraconazole.

[0319] Embodiment 7. The method of any one of embodiments 1-6, wherein the CYP3A inhibitor is a CYP3A4 inhibitor.

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[0323] Embodiment 8. The method of any one of embodiments 1-7, wherein the effective amount of the Compound A, or the pharmaceutically acceptable salt thereof, is administered once per day orally to the subject.

[0324] Embodiment 9. The method of any one of embodiments 1-8, wherein the effective amount of the Compound A, or the pharmaceutically acceptable salt thereof, is a daily dose of about 200 mg.

[0325] Embodiment 10. The method of any one of embodiments 1-8, wherein the effective amount of the Compound A, or the pharmaceutically acceptable salt thereof, is a daily dose of about 100 mg.

[0326] Embodiment 11. The method of any one of embodiments 1-10, wherein the subject is in a fed state.

[0327] Embodiment 12. The method of any one of embodiments 1-11, wherein the cancer is breast cancer.

[0328] Embodiment 13. The method of embodiment 12, wherein the breast cancer is metastatic or locally advanced.

[0329] Embodiment 14. The method of embodiment 12 or 13, wherein the breast cancer is estrogen receptor positive (ER+) breast cancer.

[0330] Embodiment 15. The method of embodiment 14, wherein the estrogen receptor positive (ER+) breast cancer is human epidermal growth factor receptor 2 negative (HER2-).

[0331] Embodiment 16. The method of any one of embodiments 1-15, wherein the subject is human.

[0332] Embodiment 17. A method of treating cancer in a subject who has been administered a

[0333] CYP3A inhibitor, the method comprising: a) continuing the administration of the CYP3A inhibitor to the subject; and b) administering an adjusted dose amount of Compound A:

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[0336] Arvinas Docket No.: ARVN0182WO or a pharmaceutically acceptable salt thereof, to the subject, wherein the adjusted dose amount of the Compound A, or the pharmaceutically acceptable salt thereof, is less than an unadjusted dose amount of the Compound A, or the pharmaceutically acceptable salt thereof.

[0337] Embodiment 18. The method of embodiment 17, further comprising step a’); a’) determining the adjusted dose amount of the Compound A, or the pharmaceutically acceptable salt thereof, as a percentage of the unadjusted dose amount of the Compound A, or the pharmaceutically acceptable salt thereof, after step a) before performing step b).

[0338] Embodiment 19. The method of embodiment 17 or 18, wherein the adjusted dose amount of the Compound A, or the pharmaceutically acceptable salt thereof, is about 50% of the unadjusted dose amount of the Compound A, or the pharmaceutically acceptable salt thereof.

[0339] Embodiment 20. The method of any one of embodiments 17-19, wherein the unadjusted dose amount of the Compound A, or the pharmaceutically acceptable salt thereof, is about 200 mg.

[0340] Embodiment 21. The method of any one of embodiments 17-20, wherein the adjusted dose amount of the Compound A, or the pharmaceutically acceptable salt thereof, is about 100 mg.

[0341] Embodiment 22. The method of embodiment 17 or embodiment 18, wherein the unadjusted dose amount of the Compound A, or the pharmaceutically acceptable salt thereof, is a manufacturer’s recommended dose amount of the Compound A, or the pharmaceutically acceptable salt thereof, in the absence of the administration of the CYP3A inhibitor.

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[0345] Embodiment 23. The method of embodiment 17 or embodiment 18, wherein the adjusted dose amount of the Compound A, or the pharmaceutically acceptable salt thereof, is about 50% of the manufacturer’s recommended dose amount of the Compound A, or the pharmaceutically acceptable salt thereof, in the absence of the administration of the CYP3A inhibitor.

[0346] Embodiment 24. The method of embodiment 22 or embodiment 23, wherein the manufacturer’s recommended dose amount of the Compound A, or the pharmaceutically acceptable salt thereof, is about 200 mg.

[0347] Embodiment 25. The method of any one of embodiments 17-24, wherein the adjusted dose amount of the Compound A, or the pharmaceutically acceptable salt thereof, is administered once per day (QD) orally to the subject.

[0348] Embodiment 26. The method of any one of embodiments 17-25, where the administration of CYP3A inhibitor is concomitant administration.

[0349] Embodiment 27. The method of any one of embodiments 17-26, wherein the CYP3A inhibitor is clarithromycin, diltiazem, erythromycin, itraconazole, ketoconazole, ritonavir, or verapamil.

[0350] Embodiment 28. The method of embodiment 27, wherein the CYP3A inhibitor is itraconazole.

[0351] Embodiment 29. The method of any one of embodiments 17-28, wherein a daily dose of the CYP3A inhibitor is administered to the subject.

[0352] Embodiment 30. The method of embodiment 17, wherein the CYP3A inhibitor is itraconazole, and wherein the itraconazole is administered in a daily dose of 200 mg.

[0353] Embodiment 31. The method of any one of embodiments 17-30, wherein the CYP3A inhibitor is administered once per day (QD).

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[0357] Embodiment 32. The method of any one of embodiments 17-31, wherein the CYP3A inhibitor is administered orally.

[0358] Embodiment 33. The method of any one of embodiments 17-32, wherein the CYP3A inhibitor is a CYP3A4 inhibitor.

[0359] Embodiment 34. The method of any one of embodiments 17-33, wherein the subject is human.

[0360] Embodiment 35. A pharmaceutical product comprising an amount of Compound A, or a pharmaceutically acceptable salt thereof, in an oral dosage form, wherein the pharmaceutical product is packaged, and wherein the package includes an instruction or a label that includes a warning that concomitant administration of the Compound A, or the pharmaceutically acceptable salt thereof, is contraindicated with a strong CYP3A inhibitor.

[0361] Embodiment 36. A pharmaceutical product comprising an amount of Compound A, or a pharmaceutically acceptable salt thereof, in an oral dosage form, wherein the pharmaceutical product is packaged, and wherein the package includes an instruction or a label that includes: a) avoiding concomitant use of or co-administration of the Compound A, or the pharmaceutically acceptable salt thereof, with a strong CYP3A inhibitor; b) discontinuing concomitant use of or co-administration of the Compound A, or the pharmaceutically acceptable salt thereof, with a strong CYP3A inhibitor; or c) contraindicating concomitant use of or co-administration of the Compound A, or the pharmaceutically acceptable salt thereof, with a strong CYP3A inhibitor.

[0362] Embodiment 37. A kit comprising: (a) a pharmaceutical product comprising an amount of Compound A, or a pharmaceutically acceptable salt thereof, in an oral dosage form; and (b) an instruction or label that includes a warning that concomitant administration of the Compound A, or the pharmaceutically acceptable salt thereof, is contraindicated with a strong CYP3A inhibitor.

[0363] Embodiment 38. A pharmaceutical product comprising an amount of Compound A, or a pharmaceutically acceptable salt thereof, in an oral dosage form, wherein the pharmaceutical product is packaged, and wherein the package includes an instruction or a label that includes a

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[0366] Arvinas Docket No.: ARVN0182WO warning that a reduced amount of the Compound A, or the pharmaceutically acceptable salt thereof, is administered with concomitant use of or co-administration with a strong CYP3A inhibitor.

[0367] Embodiment 39. A pharmaceutical product comprising an amount of Compound A, or a pharmaceutically acceptable salt thereof, in an oral dosage form, wherein the pharmaceutical product is packaged, and wherein the package includes an instruction or a label that includes: a) avoiding concomitant use of or co-administration of the Compound A, or the pharmaceutically acceptable salt thereof, with a strong CYP3A inhibitor; b) discontinuing concomitant use of or co-administration of the Compound A, or the pharmaceutically acceptable salt thereof, with a strong CYP3A inhibitor; c) contraindicating concomitant use of or co-administration of the Compound A, or the pharmaceutically acceptable salt thereof, with a strong CYP3A inhibitor; or d) reducing the amount of the Compound A, or the pharmaceutically acceptable salt thereof, with concomitant use of or co-administration with a strong CYP3A inhibitor.

[0368] Embodiment 40. A kit comprising: (a) a pharmaceutical product comprising an amount of Compound A, or a pharmaceutically acceptable salt thereof, in an oral dosage form; and (b) an instruction or label that includes a warning that a reduced amount of the Compound A, or the pharmaceutically acceptable salt thereof, is administered with concomitant use of or co- administration with a strong CYP3A inhibitor.

[0369] Embodiment 41. The pharmaceutical product or the kit of any one of embodiments 35-40, wherein the oral dosage form is a tablet or capsule.

[0370] Embodiment 42. The pharmaceutical product or the kit of embodiment 41, wherein the oral dosage form is a tablet.

[0371] Embodiment 43. The pharmaceutical product or the kit of any one of embodiments 35-42, wherein the strong CYP3A inhibitor is clarithromycin, diltiazem, erythromycin, itraconazole, ketoconazole, ritonavir, or verapamil.

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[0375] Embodiment 44. The pharmaceutical product or the kit of embodiment 43, wherein the strong CYP3A inhibitor is itraconazole.

[0376] Embodiment 45. The pharmaceutical product or the kit of any one of embodiments 35-44, wherein the strong CYP3A inhibitor is a strong CYP3A4 inhibitor.

[0377] Embodiment 46. The pharmaceutical product or the kit of any one of embodiments 35-45, wherein the amount of the Compound A, or the pharmaceutically acceptable salt thereof, is about 200 mg.

[0378] Embodiment 47. The pharmaceutical product or the kit of any one of embodiments 35-46, wherein the amount of the Compound A, or the pharmaceutically acceptable salt thereof, is about 100 mg.

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Claims

Attorney Docket No.: 100C-401880-WOArvinas Docket No.: ARVN0182WOCLAIMSWe claim:

1. A method of treating cancer in a subject who has been administered a CYP3A inhibitor, the method comprising: a) discontinuing the administration of the CYP3A inhibitor to the subject; and b) administering an effective amount of Compound A:or a pharmaceutically acceptable salt thereof, to the subject.

2. The method of claim 1, further comprising step a’): a’) waiting a first time period after step a) before performing step b).

3. The method of claim 2, wherein the first time period is about 14 days plus 5 half-lives of the CYP3A inhibitor.

4. The method of claim 2, wherein the first time period is about 3 to 5 half-lives of the CYP3A inhibitor.

5. The method of any one of claims 1-4, wherein the effective amount of the Compound A, or the pharmaceutically acceptable salt thereof, is administered once per day orally to the subject.

6. The method of any one of claims 1-5, wherein the effective amount of the Compound A, or the pharmaceutically acceptable salt thereof, is a daily dose of about 200 mg or a daily dose of about 100 mg.43307306062 v3Attorney Docket No.: 100C-401880-WOArvinas Docket No.: ARVN0182WO7. The method of any one of claims 1-6, wherein the subject is in a fed state.

8. The method of any one of claims 1-7, wherein the cancer is breast cancer.

9. The method of claim 8, wherein the breast cancer is metastatic or locally advanced.

10. The method of claim 8 or 9, wherein the breast cancer is estrogen receptor positive (ER+) breast cancer, optionally wherein the estrogen receptor positive (ER+) breast cancer is human epidermal growth factor receptor 2 negative (HER2-).

11. A method of treating cancer in a subject who has been administered a CYP3A inhibitor, the method comprising: a) continuing the administration of the CYP3A inhibitor to the subject; and b) administering an adjusted dose amount of Compound A:or a pharmaceutically acceptable salt thereof, to the subject, wherein the adjusted dose amount of the Compound A, or the pharmaceutically acceptable salt thereof, is less than an unadjusted dose amount of the Compound A, or the pharmaceutically acceptable salt thereof.

12. The method of claim 11, further comprising step a’); a’) determining the adjusted dose amount of the Compound A, or the pharmaceutically acceptable salt thereof, as a percentage of the unadjusted dose amount of the Compound A, or the pharmaceutically acceptable salt thereof, after step a) before performing step b).44307306062 v3Attorney Docket No.: 100C-401880-WOArvinas Docket No.: ARVN0182WO13. The method of claim 11 or 12, wherein the adjusted dose amount of the Compound A, or the pharmaceutically acceptable salt thereof, is about 50% of the unadjusted dose amount of the Compound A, or the pharmaceutically acceptable salt thereof.

14. The method of any one of claims 11-13, wherein the unadjusted dose amount of the Compound A, or the pharmaceutically acceptable salt thereof, is about 200 mg; and / or the adjusted dose amount of the Compound A, or the pharmaceutically acceptable salt thereof, is about 100 mg.

15. The method of claim 11 or claim 12, wherein the unadjusted dose amount of the Compound A, or the pharmaceutically acceptable salt thereof, is a manufacturer’s recommended dose amount of the Compound A, or the pharmaceutically acceptable salt thereof, in the absence of the administration of the CYP3A inhibitor; and / or the adjusted dose amount of the Compound A, or the pharmaceutically acceptable salt thereof, is about 50% of the manufacturer’s recommended dose amount of the Compound A, or the pharmaceutically acceptable salt thereof, in the absence of the administration of the CYP3A inhibitor.

16. The method of claim 15, wherein the manufacturer’s recommended dose amount of the Compound A, or the pharmaceutically acceptable salt thereof, is about 200 mg.

17. The method of any one of claims 11-16, wherein the adjusted dose amount of the Compound A, or the pharmaceutically acceptable salt thereof, is administered once per day (QD) orally to the subject.

18. The method of any one of claims 11-17, where the administration of CYP3A inhibitor is concomitant administration.

19. The method of any one of claims 11-18, wherein a daily dose of the CYP3A inhibitor is administered to the subject.

20. The method of claim 11, wherein the CYP3A inhibitor is itraconazole, and wherein the itraconazole is administered in a daily dose of 200 mg.45307306062 v3Attorney Docket No.: 100C-401880-WOArvinas Docket No.: ARVN0182WO21. The method of any one of claims 11-20, wherein the CYP3A inhibitor is administered once per day (QD) orally to the subject.

22. The method of any one of claims 1-21, wherein the CYP3A inhibitor is clarithromycin, diltiazem, erythromycin, itraconazole, ketoconazole, ritonavir, or verapamil; optionally wherein the CYP3A inhibitor is itraconazole.

23. The method of any one of claims 1-22, wherein the CYP3A inhibitor is a CYP3A4 inhibitor.

24. The method of any one of claims 1-23, wherein the subject is human.

25. A pharmaceutical product comprising an amount of Compound A, or a pharmaceutically acceptable salt thereof, in an oral dosage form, wherein the pharmaceutical product is packaged, and wherein the package includes an instruction or a label that includes: a) avoiding concomitant use of or co-administration of the Compound A, or the pharmaceutically acceptable salt thereof, with a strong CYP3A inhibitor; b) discontinuing concomitant use of or co-administration of the Compound A, or the pharmaceutically acceptable salt thereof, with a strong CYP3A inhibitor; c) contraindicating concomitant use of or co-administration of the Compound A, or the pharmaceutically acceptable salt thereof, with a strong CYP3A inhibitor; or d) reducing the amount of the Compound A, or the pharmaceutically acceptable salt thereof, with concomitant use of or co-administration with a strong CYP3A inhibitor.46307306062 v3

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