How to Treat Breast Cancer

Abstract

The present invention relates to a method of treating cancer in a subject receiving a substrate of P-glycoprotein, comprising administering to a subject a compound A having the following structure: [Formula 1] JPEG2025540124000025.jpg47170, or a pharmaceutically acceptable salt thereof to the subject and monitoring the subject for adverse reactions during treatment with Compound A, or a pharmaceutically acceptable salt thereof.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 429,836, filed December 2, 2022, and U.S. Provisional Patent Application No. 63 / 603,606, filed November 28, 2023, the contents of each of which are incorporated by reference in their entirety for all purposes. [Background technology]

[0002] Certain bifunctional compounds can target specific cellular proteins for degradation via the ubiquitin-proteasome system. Examples of such proteolytic targeting chimeric compounds (i.e., "PROTAC® protein degraders") that target estrogen receptor (ER) for ubiquitination and subsequent degradation are disclosed in International Publication No. 2018 / 102725, which is incorporated herein by reference in its entirety. Such bifunctional molecules exhibit a variety of pharmacological activities consistent with ER degradation, including, but not limited to, the treatment or amelioration of disease conditions such as cancer (e.g., breast cancer, uterine cancer, ovarian cancer, prostate cancer, endometrial cancer) or endometriosis.

[0003] A particularly interesting bifunctional molecule is C 45 H 49 Compound A is (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"), having the molecular formula of NO and the following structure: [ka]

[0004] Compound A is being developed as a PROTAC® protein degrader that targets the ER for the potential treatment of breast cancer and has been shown to be a useful regulator of target protein ubiquitination and degradation via the ubiquitin-proteasome pathway.

[0005] Compound A may be administered to a cancer patient who is also receiving a concomitant medication, such as other prescription or over-the-counter medications that the cancer patient may take in addition to Compound A. The concomitant medications may be used by the patient for the same or other indications.

[0006] The simultaneous or near-simultaneous (e.g., simultaneous) presence of two drugs in a subject can change the effects of one or the other, or both, of the drugs. Such changes are called drug-drug interactions. The simultaneous or co-administration of two or more drugs means that the drugs are present in the body at the same time. The simultaneous or co-administration of different drugs often results in adverse effects because the metabolism and / or excretion of each drug can reduce or interfere with the metabolism and / or excretion of the other drug, thus increasing the effective concentration of the drugs compared to the effective concentration of the drugs when administered alone.

[0007] Therefore, there is a need for therapeutic approaches that address and / or minimize drug-drug interactions in the treatment of cancer. Summary of the Invention

[0008] The present disclosure provides, in part, methods for administering Compound A, or a pharmaceutically acceptable salt thereof, to a subject to treat cancer. This Summary is provided to introduce selected 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 solely as an aid in determining the scope of the claimed subject matter.

[0009] Provided herein is a method of treating cancer in a subject receiving a substrate of P-glycoprotein, the method comprising administering to a subject a compound A having the following structure: [ka] , or a pharmaceutically acceptable salt thereof to the subject and monitoring the subject for adverse reactions during treatment with Compound A, or a pharmaceutically acceptable salt thereof.

[0010] Provided herein is a method of treating cancer in a subject receiving dabigatran etexilate mesylate, the method comprising administering to a subject a compound A having the following structure: [ka] , or a pharmaceutically acceptable salt thereof to the subject and monitoring the subject for adverse reactions during treatment with Compound A, or a pharmaceutically acceptable salt thereof.

[0011] As used herein, compound A has the following structure: [ka] , or a pharmaceutically acceptable salt thereof to a subject, wherein Compound A must not be administered in conjunction with a substrate of P-glycoprotein.

[0012] As used herein, compound A has the following structure: [ka] , or a pharmaceutically acceptable salt thereof to a subject, wherein Compound A must not be administered concomitantly with dabigatran.

[0013] As used herein, compound A has the following structure: [ka] , Further provided is a method of treating cancer comprising administering Compound A, or a pharmaceutically acceptable salt thereof, to a subject, wherein a physician is provided with instructions to monitor the subject for adverse reactions during co-administration of Compound A, or a pharmaceutically acceptable salt thereof, and a substrate of P-glycoprotein.

[0014] As used herein, compound A has the following structure: [ka] , or a pharmaceutically acceptable salt thereof to a subject, wherein a physician is provided with instructions to monitor the subject for adverse reactions during co-administration of Compound A, or a pharmaceutically acceptable salt thereof, and dabigatran etexilate mesylate.

[0015] As used herein, compound A has the following structure: [ka] , Further provided is a method of treating cancer comprising administering to a subject or a pharmaceutically acceptable salt thereof, wherein a physician is provided with instructions including a warning that the treatment should not be administered in conjunction with a substrate of P-glycoprotein.

[0016] As used herein, compound A has the following structure: [ka] , or a pharmaceutically acceptable salt thereof to a subject, wherein a physician is provided with instructions including a warning that the treatment should not be administered concomitantly with dabigatran etexilate mesylate.

[0017] In embodiments, the adverse reaction is selected from the group consisting of diarrhea, nausea, dry skin, hot flashes, and headache.

[0018] In embodiments, a daily dose of Compound A, or a pharmaceutically acceptable salt thereof, is administered to the subject.

[0019] In embodiments, a daily dose of Compound A, or a pharmaceutically acceptable salt thereof, is administered to the subject, wherein the daily dose of Compound A, or a pharmaceutically acceptable salt thereof, is 200 mg.

[0020] In embodiments, a daily dose of Compound A, or a pharmaceutically acceptable salt thereof, is administered to the subject, wherein the daily dose of Compound A, or a pharmaceutically acceptable salt thereof, is 100 mg.

[0021] In some embodiments, a daily dose of Compound A, or a pharmaceutically acceptable salt thereof, is administered to the subject, wherein the daily dose of Compound A, or a pharmaceutically acceptable salt thereof, is administered once daily (QD).

[0022] In embodiments, a daily dose of Compound A, or a pharmaceutically acceptable salt thereof, is administered to the subject, and a daily dose of Compound A, or a pharmaceutically acceptable salt thereof, is administered orally to the subject.

[0023] In embodiments, the subject is in a fed state.

[0024] In embodiments, the daily dose of Compound A, or a pharmaceutically acceptable salt thereof, should not be administered in conjunction with a substrate of P-glycoprotein.

[0025] In embodiments, the P-glycoprotein substrate is apixaban, colchicine, cyclosporine, dabigatran etexilate mesylate, digoxin, edoxaban, fexofenadine, rivaroxaban, tacrolimus, or talinolol.

[0026] In some embodiments, the substrate of P-glycoprotein is dabigatran etexilate mesylate.

[0027] In embodiments, the cancer is breast cancer, lung cancer, colon cancer, brain cancer, head and neck cancer, prostate cancer, gastric cancer, pancreatic cancer, ovarian cancer, melanoma, endocrine cancer, uterine cancer, testicular cancer, or bladder cancer.

[0028] In embodiments, the cancer is breast cancer, lung cancer, prostate cancer, pancreatic cancer, or ovarian cancer.

[0029] In embodiments, the cancer is breast cancer, lung cancer, or prostate cancer. In embodiments, the cancer is breast cancer.

[0030] In embodiments, the breast cancer is metastatic or locally advanced, hi embodiments, the breast cancer is estrogen receptor positive (ER+) breast cancer.

[0031] In embodiments, the estrogen receptor positive (ER+) breast cancer is human epidermal growth factor receptor 2 negative (HER2-).

[0032] In embodiments, the subject is a human.

[0033] 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. DETAILED DESCRIPTION OF THE INVENTION

[0034] The present invention may be understood more readily by reference to the following detailed description of the embodiments of the invention and the examples contained herein. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0035] P-glycoprotein (P-gp) substrates are substances that use the P-glycoprotein transporter for a variety of activities, including drug absorption, drug efflux, and other important activities that may result in changes in the body or alter the effects of other drugs in the body (Lin JH, Yamazaki M: Role of P-glycoprotein in pharmacokinetics: clinical implications. Clin Pharmacokinet. 2003;42(1):59-98). Without wishing to be bound by theory, administering a P-gp substrate with a P-gp inhibitor, or a compound that acts as a P-gp inhibitor, may result in increased plasma exposure of the P-gp substrate.

[0036] Accordingly, provided herein is a method of treating cancer in a subject receiving a substrate of P-glycoprotein, the method comprising administering to a subject a compound A having the following structure: [ka] , or a pharmaceutically acceptable salt thereof to the subject and monitoring the subject for adverse reactions during treatment with Compound A, or a pharmaceutically acceptable salt thereof.

[0037] definition Unless otherwise defined, all technical and scientific terms used in connection with the present invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0038] The invention described herein may suitably be practiced in the absence of any element not specifically disclosed herein.

[0039] As used herein, the singular forms "a," "an," and "the" include plural references unless otherwise indicated. For example, "a" (one) substituent includes one or more substituents.

[0040] As used herein, when used to modify a numerically defined parameter (e.g., a dose of Compound A), the term "about" means that the parameter may vary up to 10% below or above the numerical value stated for that parameter. For example, a dose of about 200 mg means 200 mg ± 10%, i.e., may vary from 180 mg to 220 mg.

[0041] As used herein, terms including, but not limited to, "reagent," "compound," "drug," "drug" and "therapeutic agent" may be used interchangeably to refer to compounds, particularly Compound A, included in the present disclosure and methods and uses of the present invention.

[0042] Compound A having the following structure: JPEG2025540124000012.jpg46170, and pharmaceutically acceptable salts thereof are disclosed in International Publication No. 2018 / 102725 and U.S. Patent Nos. 10,647,698, 10,899,742 and 11,104,666, International Publication No. 2021 / 041348, U.S. Patent Application No. 17 / 472,847, U.S. Patent Application No. 17 / 548,842, and U.S. Patent Application No. 17 / 873,748. The contents of each of the foregoing references are incorporated herein by reference in their entirety.

[0043] Compound A is a Biopharmaceutics Classification System Class IV compound (low solubility / low permeability). Compound A can be interconverted with its epimer, Compound B, below. [ka]

[0044] Preclinical data indicates that Compound B has limited exposure (<26%) compared to Compound A. Without wishing to be bound by theory, evidence indicates that Compound B does not degrade the ER, but Compound B exhibits similar antagonism of ER-dependent transcription compared to Compound A.

[0045] In embodiments, pharmaceutically acceptable salts of the compounds described herein include acid addition and base addition salts thereof.

[0046] In some embodiments, pharmaceutically acceptable acid addition salts of compounds are described herein.Suitable acid addition salts are formed from acids that 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, acetate, citrate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, bitartrate, borate, camsylate, citrate, cyclamate, edisylate, esylate, ethanesulfonate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybenzate, hydrochloride / chloride, bromide, etc. These salts include hydrochloride / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methanesulfonate, methylsulfate, napsylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, p-toluenesulfonate, tosylate, trifluoroacetate, and xinafoate.

[0047] Another embodiment relates to the base addition salts of the compounds described herein.Suitable base addition salts are formed from bases that form non-toxic salts.Non-limiting examples of suitable base salts include aluminum salt, arginine salt, benzathine salt, calcium salt, choline salt, diethylamine salt, diolamine salt, glycine salt, lysine salt, magnesium salt, meglumine salt, olamine salt, potassium salt, sodium salt, tromethamine salt and zinc salt.

[0048] 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 can be used to prepare the pharmaceutically acceptable acid addition salts of such basic compounds described herein are those that form non-toxic acid addition salts, such as those that contain pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonic acid and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoic acid)). 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.

[0049] Chemical bases that can be used as reagents to prepare pharmaceutically acceptable base salts 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, base salts derived from pharmacologically compatible 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 lower alkanolammonium, as well as other base salts of pharmaceutically acceptable organic amines.

[0050] Hemisalts of acids and bases may also be formed, for example, hemisulfate and hemicalcium salts.

[0051] For 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 the compounds described herein are known to those skilled in the art.

[0052] Dabigatran etexilate (β-alanine, N-[[2-[[[4-[[[(hexyloxy)carbonyl]amino]iminomethyl]phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]-N-2-pyridinyl-, ethyl ester) is a direct thrombin inhibitor, dabigatran (3-[[2-[(4-carbamimidoylanilino)methyl]-1-methylbenzimidazole-5-yl]carbonyl). Dabigatran etexilate mesylate is an oral prodrug of [[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[()])]) ... [ka]

[0053] Dabigatran etexilate mesylate is an oral, reversible, competitive, and direct thrombin inhibitor and an in vitro and in vivo substrate of P-glycoprotein (P-gp). It may be used as a probe for intestinal P-gp inhibition and is recommended for this purpose by regulatory authorities.

[0054] Additionally, P-gp substrates include apixaban, colchicine, cyclosporine, digoxin, edoxaban, fexofenadine rivaroxaban, tacrolimus, and talinolol.

[0055] Method of administration Provided herein are methods for treating cancer in a subject receiving a P-glycoprotein substrate, the methods comprising administering Compound A, or a pharmaceutically acceptable salt thereof, to the subject, and monitoring the subject for adverse reactions during treatment with Compound A, or a pharmaceutically acceptable salt thereof.

[0056] Provided herein are methods for treating cancer comprising administering Compound A, or a pharmaceutically acceptable salt thereof, to a subject, wherein Compound A, or a pharmaceutically acceptable salt thereof, should not be administered co-administered with a substrate of P-glycoprotein.

[0057] Provided herein is a method for treating cancer comprising administering Compound A, or a pharmaceutically acceptable salt thereof, to a subject, wherein Compound A, or a pharmaceutically acceptable salt thereof, should not be administered simultaneously with dabigatran etexilate mesylate.

[0058] Further provided herein are methods of treating cancer comprising administering Compound A, or a pharmaceutically acceptable salt thereof, to a subject, wherein a physician is provided with instructions to monitor the subject for adverse reactions during co-administration of Compound A, or a pharmaceutically acceptable salt thereof, with a substrate of P-glycoprotein.

[0059] Further provided herein is a method of treating cancer comprising administering Compound A, or a pharmaceutically acceptable salt thereof, to a subject, wherein a physician is provided with instructions including a warning that the treatment should not be administered concomitantly with dabigatran etexilate mesylate.

[0060] In embodiments, the daily dose of Compound A, or a pharmaceutically acceptable salt thereof, is administered once daily (QD).

[0061] In embodiments, a daily dose of Compound A, or a pharmaceutically acceptable salt thereof, is orally administered to the subject.

[0062] In embodiments, the subject is in a fed state.

[0063] In embodiments, the daily dose of Compound A, or a pharmaceutically acceptable salt thereof, is about 200 mg, or the equivalent of a pharmaceutically acceptable salt thereof.

[0064] In embodiments, the daily dose of Compound A, or a pharmaceutically acceptable salt thereof, is 200 mg, or the equivalent of a pharmaceutically acceptable salt thereof.

[0065] In embodiments, the daily dose of Compound A is about 200 mg.

[0066] In some embodiments, the daily dose of Compound A is 200 mg.

[0067] In embodiments, the daily dose of Compound A, or a pharmaceutically acceptable salt thereof, is about 100 mg, or the equivalent of a pharmaceutically acceptable salt thereof.

[0068] In embodiments, the daily dose of Compound A, or a pharmaceutically acceptable salt thereof, is 100 mg, or the equivalent of a pharmaceutically acceptable salt thereof.

[0069] In embodiments, the daily dose of Compound A is about 100 mg.

[0070] In some embodiments, the daily dose of Compound A is 100 mg.

[0071] In some embodiments, Compound A is administered as the free base.

[0072] In embodiments, the cancer is breast cancer, lung cancer, colon cancer, brain cancer, head and neck cancer, prostate cancer, gastric cancer, pancreatic cancer, ovarian cancer, melanoma, endocrine cancer, uterine cancer, testicular cancer, or bladder cancer.

[0073] In embodiments, the cancer is breast cancer, lung cancer, prostate cancer, pancreatic cancer, or ovarian cancer.

[0074] In embodiments, the cancer is breast cancer, lung cancer, or prostate cancer.

[0075] In embodiments, the cancer is breast cancer.

[0076] In embodiments, the breast cancer is metastatic or locally advanced.

[0077] In embodiments, the breast cancer is estrogen receptor positive (ER+) breast cancer.

[0078] In embodiments, the estrogen receptor positive (ER+) breast cancer is human epidermal growth factor receptor 2 negative (HER2-).

[0079] In embodiments, the subject is a human.

[0080] Also disclosed herein is a method for treating cancer in a subject receiving a P-glycoprotein substrate, the method comprising administering Compound A, or a pharmaceutically acceptable salt thereof, to the subject and monitoring the subject for adverse reactions during treatment with Compound A, or a pharmaceutically acceptable salt thereof, wherein the adverse reactions are selected from the group consisting of diarrhea, nausea, dry skin, hot flashes, and headaches.

[0081] Also disclosed herein is a method for treating cancer in a subject receiving a P-glycoprotein substrate, the method comprising administering Compound A, or a pharmaceutically acceptable salt thereof, to the subject and monitoring the subject for adverse reactions during treatment with Compound A, or a pharmaceutically acceptable salt thereof, wherein the adverse reactions are selected from the group consisting of diarrhea, nausea, dry skin, hot flashes, and headache, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered once daily (QD).

[0082] Also disclosed herein is a method for treating cancer in a subject receiving a P-glycoprotein substrate, the method comprising administering Compound A, or a pharmaceutically acceptable salt thereof, to the subject and monitoring the subject for adverse reactions during treatment with Compound A, or a pharmaceutically acceptable salt thereof, wherein the adverse reactions are selected from the group consisting of diarrhea, nausea, dry skin, hot flashes, and headache, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered orally once daily (QD).

[0083] Also disclosed herein is a method for treating cancer in a subject receiving a P-glycoprotein substrate, the method comprising administering Compound A, or a pharmaceutically acceptable salt thereof, to the subject and monitoring the subject for adverse reactions during treatment with Compound A, or a pharmaceutically acceptable salt thereof, wherein the adverse reactions are selected from the group consisting of diarrhea, nausea, dry skin, hot flashes, and headache, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered orally in a daily dose of about 200 mg or about 100 mg once daily (QD).

[0084] Also disclosed herein is a method for treating cancer in a subject receiving a P-glycoprotein substrate, the method comprising administering Compound A, or a pharmaceutically acceptable salt thereof, to the subject and monitoring the subject for adverse reactions during treatment with Compound A, or a pharmaceutically acceptable salt thereof, wherein the adverse reactions are selected from the group consisting of diarrhea, nausea, dry skin, hot flashes, and headache, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered orally in a daily dose of about 100 mg once daily (QD).

[0085] Also disclosed herein is a method for treating cancer in a subject receiving a P-glycoprotein substrate, the method comprising administering Compound A, or a pharmaceutically acceptable salt thereof, to the subject and monitoring the subject for adverse reactions during treatment with Compound A, or a pharmaceutically acceptable salt thereof, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered once daily (QD).

[0086] Also disclosed herein is a method for treating cancer in a subject receiving a P-glycoprotein substrate, the method comprising administering Compound A, or a pharmaceutically acceptable salt thereof, to the subject and monitoring the subject for adverse reactions during treatment with Compound A, or a pharmaceutically acceptable salt thereof, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered orally once daily (QD) in a daily dose of about 200 mg or about 100 mg.

[0087] Also disclosed herein is a method for treating cancer in a subject receiving a P-glycoprotein substrate, the method comprising administering Compound A, or a pharmaceutically acceptable salt thereof, to the subject and monitoring the subject for adverse reactions during treatment with Compound A, or a pharmaceutically acceptable salt thereof, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered orally once daily (QD) at a daily dose of about 100 mg.

[0088] Also disclosed herein is a method for treating cancer in a subject receiving dabigatran etexilate mesylate, the method comprising administering Compound A, or a pharmaceutically acceptable salt thereof, to the subject and monitoring the subject for adverse reactions during treatment with Compound A, or a pharmaceutically acceptable salt thereof, wherein the adverse reactions are selected from the group consisting of diarrhea, nausea, dry skin, hot flashes, and headache, and wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered once daily (QD).

[0089] Also disclosed herein is a method for treating cancer in a subject receiving dabigatran etexilate mesylate, the method comprising administering Compound A, or a pharmaceutically acceptable salt thereof, to the subject and monitoring the subject for adverse reactions during treatment with Compound A, or a pharmaceutically acceptable salt thereof, wherein the adverse reactions are selected from the group consisting of diarrhea, nausea, dry skin, hot flashes, and headache, and wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered orally once daily (QD) in a daily dose of about 200 mg or about 100 mg.

[0090] Also disclosed herein is a method for treating cancer in a subject receiving dabigatran etexilate mesylate, the method comprising administering Compound A, or a pharmaceutically acceptable salt thereof, to the subject and monitoring the subject for adverse reactions during treatment with Compound A, or a pharmaceutically acceptable salt thereof, wherein the adverse reactions are selected from the group consisting of diarrhea, nausea, dry skin, hot flashes, and headache, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered orally once daily (QD) at a daily dose of about 100 mg.

[0091] Also disclosed herein is a method for treating cancer in a subject receiving dabigatran etexilate mesylate, the method comprising administering Compound A, or a pharmaceutically acceptable salt thereof, to the subject and monitoring the subject for adverse reactions during treatment with Compound A, or a pharmaceutically acceptable salt thereof, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered once daily (QD).

[0092] Also disclosed herein is a method for treating cancer in a subject receiving dabigatran etexilate mesylate, the method comprising administering Compound A, or a pharmaceutically acceptable salt thereof, to the subject and monitoring the subject for adverse reactions during treatment with Compound A, or a pharmaceutically acceptable salt thereof, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered orally once daily (QD) in a daily dose of about 200 mg or about 100 mg.

[0093] Also disclosed herein is a method for treating cancer in a subject receiving dabigatran etexilate mesylate, the method comprising administering Compound A, or a pharmaceutically acceptable salt thereof, to the subject and monitoring the subject for adverse reactions during treatment with Compound A, or a pharmaceutically acceptable salt thereof, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered orally once daily (QD) at a daily dose of about 100 mg.

[0094] Also disclosed herein are methods for treating cancer comprising administering to a subject Compound A, or a pharmaceutically acceptable salt thereof, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered once daily (QD) and should not be administered simultaneously with a substrate of P-glycoprotein.

[0095] Also disclosed herein are methods for treating cancer, comprising administering to a subject Compound A, or a pharmaceutically acceptable salt thereof, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered orally once daily (QD) and should not be administered simultaneously with a substrate of P-glycoprotein.

[0096] Also disclosed herein are methods for treating cancer, comprising administering to a subject Compound A, or a pharmaceutically acceptable salt thereof, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered orally once daily (QD) at a daily dose of about 200 mg or about 100 mg, and wherein Compound A, or a pharmaceutically acceptable salt thereof, must not be co-administered with a substrate of P-glycoprotein.

[0097] Also disclosed herein is a method for treating cancer, comprising administering to a subject Compound A or a pharmaceutically acceptable salt thereof, wherein Compound A, or a pharmaceutically acceptable salt thereof, is orally administered once daily (QD) at a daily dose of about 200 mg or about 100 mg, and wherein Compound A, or a pharmaceutically acceptable salt thereof, is not co-administered with a substrate of P-glycoprotein, and wherein the subject is a human in a fed state.

[0098] Also disclosed herein is a method for treating cancer, comprising administering to a subject Compound A or a pharmaceutically acceptable salt thereof, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered once daily (QD) and should not be administered simultaneously with dabigatran etexilate mesylate.

[0099] Also disclosed herein is a method for treating cancer, comprising administering to a subject Compound A or a pharmaceutically acceptable salt thereof, wherein Compound A, or a pharmaceutically acceptable salt thereof, is orally administered once daily (QD) and should not be administered simultaneously with dabigatran etexilate mesylate.

[0100] Also disclosed herein is a method for treating cancer, comprising administering to a subject Compound A or a pharmaceutically acceptable salt thereof, wherein Compound A, or a pharmaceutically acceptable salt thereof, is orally administered once daily (QD) at a daily dose of about 200 mg or about 100 mg, and wherein Compound A, or a pharmaceutically acceptable salt thereof, should not be administered simultaneously with dabigatran etexilate mesylate.

[0101] Also disclosed herein is a method for treating cancer, comprising administering to a subject Compound A or a pharmaceutically acceptable salt thereof, wherein Compound A, or a pharmaceutically acceptable salt thereof, is orally administered once daily (QD) at a daily dose of about 200 mg or about 100 mg, and wherein Compound A, or a pharmaceutically acceptable salt thereof, is not co-administered with dabigatran etexilate mesylate, and wherein the subject is a human being in a fed state.

[0102] In each of the methods described herein, the cancer is preferably breast cancer.

[0103] Also disclosed herein is Compound A, or a pharmaceutically acceptable salt thereof, for use according to any of the preceding embodiments.

[0104] Also disclosed herein is Compound A, or a pharmaceutically acceptable salt thereof, for use according to any of the preceding embodiments.

[0105] Also disclosed herein is the use of Compound A, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament according to any one of the preceding embodiments.

[0106] Also disclosed herein is the use of Compound A, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament according to any one of the preceding embodiments.

[0107] Each of the embodiments described herein may be combined with any other embodiment described herein that is not inconsistent with the embodiment with which it is combined.

[0108] Mode of administration and dosage Co-administration means that two or more agents are given and administered at the same time or about the same time (e.g., one after the other, on the same day, etc.). Concomitant administration means the act of giving or administering (e.g., administering) two or more agents at the same time.

[0109] As used herein, the terms "treat" and "treating" cancer or a cancer-related disease mean administering a therapy as described herein to a subject, participant, or patient who has or has been diagnosed with cancer in order to achieve at least one positive therapeutic effect, such as reversing, alleviating, inhibiting the progression of, or preventing the disorder or condition to which the following term applies, or one or more symptoms of such disorder or condition, e.g., a reduction in the number of cancer cells, a reduction in tumor size, a decrease in the rate of cancer cell invasion into peripheral organs, or a decrease in the rate of tumor metastasis or tumor growth. As used herein, the terms "treatment" and "therapy," unless otherwise indicated, refer to the act of treating, where "treating" is as defined immediately above. For purposes of this disclosure, beneficial or desirable clinical results include, but are not limited to, one or more of the following: reducing (or destroying) the proliferation of neoplastic or cancerous cells, inhibiting metastasis or neoplastic cells, shrinking or reducing tumor size, cancer remission, reducing symptoms resulting from cancer, improving the quality of life of those suffering from cancer, reducing the dose of other drugs needed to treat cancer, slowing the progression of cancer, curing cancer, overcoming one or more resistance mechanisms of cancer, and / or extending the survival of cancer patients. Positive therapeutic effects in cancer can be measured in many ways (see, e.g., W.A. Weber, J. Nucl. Med. (2009) 50:1S-10S).

[0110] "Fed conditions" or "fed state" as used herein to describe a subject means that the subject has consumed food within at least 4 hours prior to the time of interest, such as the time of administration of Compound A. In embodiments, a subject in a fed state has not consumed food for up to 4, 3, 2, 1, or 0.5 hours prior to administration of Compound A.

[0111] As used herein, the terms "subject," "participant," and "patient" are used interchangeably to refer to a human. A human subject may be of any gender. In embodiments, the human is an adult human.

[0112] An "amount" for use and for treating a subject refers to an amount, in a single dose or multiple doses, that provides the desired result of a detectable response of any duration (temporary, moderate, or long-term), any measurable or detectable degree, or objective or subjective benefit to the subject for any duration (e.g., hours, days, months, years, remission, or cure). Such an amount is typically effective to measurably improve the disease, or one, several, or all adverse effects / symptoms, consequences, or complications of the disease, although reducing or inhibiting the progression or worsening of the disease, or bringing the disease to a stable (i.e., non-worsening) state, is considered a satisfactory outcome. The term "therapeutically effective amount" or "effective amount" also refers to the amount of an agent that is effective to produce a desired therapeutic effect when administered to a subject, for example, to stop the growth of or cause the shrinkage of a cancerous tumor. With respect to the treatment of cancer, a therapeutically effective amount refers to an amount effective to (1) reduce tumor size, (2) inhibit (i.e., slow to some extent, and preferably stop) the development of tumor metastasis, (3) inhibit to some extent (i.e., slow to some extent, and preferably stop) tumor growth or tumor invasiveness, and / or (4) alleviate to some extent (or preferably eliminate) one or more signs or symptoms associated with cancer. The therapeutic or pharmacological effectiveness of doses and administration regimens may also be characterized as their ability to induce, enhance, maintain, or prolong disease control and / or overall survival, which may be measured as the extension of the time to disease progression, in patients with these particular tumors.

[0113] As used herein, "amelioration" refers to any decrease in the degree, severity, frequency, and / or likelihood of a symptom or clinical sign characteristic of a particular disease. "Symptom" refers to any subjective evidence of a disease or condition in a subject.

[0114] Embodiments of the present invention provide doses, administration amounts, and dosing regimens that include administering an amount, or effective amount, of Compound A, or a pharmaceutically acceptable salt thereof, to a subject. The amount, effective amount, or therapeutically effective amount can be a daily amount of about 200 mg. In some embodiments, the daily amount is 200 mg. In some embodiments, the amount, effective amount, or therapeutically effective amount can be a daily amount of about 100 mg. In some embodiments, the daily amount is 100 mg.

[0115] In embodiments, the daily dose of Compound A, or a pharmaceutically acceptable salt thereof, is administered once daily (QD).

[0116] The compounds disclosed herein can be administered orally, which may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed, whereby the compound enters the blood stream directly from the mouth.

[0117] In embodiments, the daily dose of Compound A, or a pharmaceutically acceptable salt thereof, is administered orally.

[0118] Compound A, or a pharmaceutically acceptable salt thereof, may be present in a pharmaceutical composition, which includes at least one pharmaceutically acceptable excipient. A "pharmaceutically acceptable excipient" refers to a component that may be included in the compositions described herein, which is physiologically suitable for pharmaceutical use and does not cause any significant adverse or therapeutic effects in the subject. The term "excipient" is used herein to describe any component other than the compound of the present invention. The selection of an excipient will largely 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.

[0119] The compound of the method or use of the present invention can be formulated before administration.Preferably, the formulation is adapted to a specific mode of administration.These compounds can be formulated with pharmaceutically acceptable excipients known in the art and administered in a variety of dosage forms known in the art.The dosage unit form or pharmaceutical composition suitable for oral administration includes, but is not limited to, tablets, capsules, such as gelatin capsules, pills, powders, granules, aqueous solutions, and non-aqueous oral solutions and suspensions, packaged in a container suitable for subdivision into individual doses.

[0120] Repeated administration or dosing schedules may be performed as necessary to achieve the desired reduction or reduction of cancer cells. As used herein, a "continuous dosing schedule" refers to an administration or dosing schedule without dose interruptions, e.g., without treatment breaks. Repeated 28-day treatment cycles without interruptions in administration between treatment cycles is an example of a continuous dosing schedule. In some embodiments, compound A of the present invention, or a pharmaceutically acceptable salt thereof, can be administered in a continuous dosing schedule. In some embodiments, compound A disclosed herein, or a pharmaceutically acceptable salt thereof, and a P-gp substrate can be administered simultaneously in a continuous dosing schedule.

[0121] In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is administered once daily (QD) to constitute a complete 28-day cycle. Repeated 28-day treatment cycles are continued during treatment according to the methods and uses of the present disclosure.

[0122] Treatment methods As used herein, the term "locally advanced" in relation to cancer may or may not be treated with curative intent. For example, locally advanced breast cancer (LABC) is defined by the National Comprehensive Cancer Network as a subset of breast cancer characterized by the absence of distant metastasis and the most advanced breast tumor, where the tumor is greater than 5 cm in size with regional lymphadenopathy; tumors of any size with direct extension to the chest wall or skin, or both (including ulcers or satellite nodules), regardless of regional lymphadenopathy; regardless of tumor stage, regional lymphadenopathy (either clinically fixed or matted axillary lymph nodes, or infraclavicular, supraclavicular, or internal mammary lymphadenopathy) is present. (Garg et al.Curr Oncol.2015 Oct;22(5):e409-10;National Comprehensive Cancer Network NCCN Clinical Practice Guidelines in Oncology:Breast Cancer.Fort Washington,PA:NCCN;2015.Ver.2.2015.)

[0123] In embodiments, the cancer is breast cancer, lung cancer, colon cancer, brain cancer, head and neck cancer, prostate cancer, gastric cancer, pancreatic cancer, ovarian cancer, melanoma, endocrine cancer, uterine cancer, testicular cancer, or bladder cancer.

[0124] In embodiments, the cancer is breast cancer, lung cancer, prostate cancer, pancreatic cancer, or ovarian cancer.

[0125] In embodiments, the cancer is breast cancer, lung cancer, or prostate cancer.

[0126] In embodiments, the cancer is breast cancer.

[0127] In embodiments, the breast cancer is metastatic or locally advanced.

[0128] In embodiments, the breast cancer is estrogen receptor positive (ER+) breast cancer.

[0129] In embodiments, the estrogen receptor positive (ER+) breast cancer is human epidermal growth factor receptor 2 negative (HER2-). [Example]

[0130] In order that this invention may be better understood, the following examples are set forth, which are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way.

[0131] Abbreviation AUC inf = area under the plasma concentration-time curve extrapolated from time 0 to infinity; AUC last = time 0 to final quantifiable concentration (C last ) area under the plasma concentration-time profile up to C max = maximum plasma concentration; CI = confidence interval; hrs=hours; ECG = electrocardiogram; mins=minutes; PE = physical examination; TEAE = treatment-emergent adverse event

[0132] A study to understand the effect of Compound A on dabigatran etexilate pharmacokinetics (PK) in healthy adults overview Compound A was investigated in an interventional, phase 1, open-label, fixed-sequence, two-period study to evaluate the effect of a single oral dose of Compound A on the PK of dabigatran in healthy participants.

[0133] the purpose The objective of this drug-drug interaction study was to evaluate the effect of Compound A on the PK of dabigatran etexilate (a model substrate for P-gp) in healthy adults (NCT05673889).

[0134] A concise, plain language summary The goal of the study was to understand whether Compound A affected the way a medicine called dabigatran etexilate was absorbed or processed by the bodies of healthy adults.

[0135] All participants in this study received a single oral dose of dabigatran etexilate mesylate alone during the first period. In the second period, all participants received a single oral dose of dabigatran etexilate mesylate approximately 90 minutes after receiving a single dose of Compound A. Dabigatran levels during the first period were compared with those during the second period. This study design was used to determine whether and how Compound A affects dabigatran absorption in healthy adults.

[0136] All participants will stay at the study site for approximately eight days and seven nights.

[0137] method This was a phase 1, open-label, two-period, fixed-sequence study to estimate the effect of a single oral dose of Compound A on the PK of the P-gp substrate, dabigatran etexilate (as the mesylate salt), in healthy male and female participants of non-childbearing potential.

[0138] The study consisted of two periods with a fixed sequence treatment design.

[0139] On Day 1 of Period 1, a standard breakfast (approximately 700 calories with approximately 35% fat content) was provided prior to dosing. The standard breakfast was required to be consumed completely within approximately 20 minutes. A single dose of 75 mg of dabigatran etexilate (as mesylate) (as one 75 mg capsule) was administered approximately 2 hours (120 minutes) after the start of the standard breakfast. A minimum washout period of 4 days was required to allow adequate clearance of the dabigatran drug effect.

[0140] This was required after administration of dabigatran etexilate (as mesylate) on Day 1 of Period 1. Serial PK samples were collected up to 48 hours after the single dose to determine dabigatran PK parameters (total).

[0141] On Day 1 of Period 2, a standard breakfast (approximately 700 calories with approximately 35% fat content) was provided prior to administration of Compound A and dabigatran etexilate (as mesylate). The standard breakfast was required to be the same as that provided on Day 1 of Period 1 and was required to be consumed completely within approximately 20 minutes. A single dose of 200 mg of Compound A (as two 100 mg tablets) was administered approximately 10 minutes after the completion of breakfast. 75 mg of dabigatran etexilate

[0142] A single dose of dabigatran (as mesylate) (as one 75 mg capsule) was administered approximately 1.5 hours (90 minutes) after the start of Compound A administration, which was approximately 2 hours (120 minutes) after the start of breakfast. Serial PK samples were collected up to 48 hours after dabigatran etexilate (as mesylate) administration to determine single-dose PK parameters (combined) of Compound A and dabigatran. Masking: Unmasked (unblinded) Registration number: 24

[0143] Objectives and evaluation items The clinical trial objectives and endpoints are shown in Table 1 below. [Table 1]

[0144] statistical methods Natural log-transformed parameters of total dabigatran (AUC inf [If data permits], AUC last , and C max ) was analyzed using a mixed-effects model with treatment as a fixed effect and participant as a random effect. AUC last instead of 24-hour (AUC 24Note that the area under the concentration-time curve up to 10 min (≤10 min) was used for statistical analysis due to variability in the time of the last measurable concentration between participants. The adjusted mean difference (test-reference) estimates and the corresponding 90% CI were obtained from the model. The adjusted mean difference and the 90% CI of the difference were exponentiated to obtain estimates of the adjusted geometric mean (test / reference) ratio and the 90% CI of the ratio. Dabigatran etexilate mesylate administered alone was the reference treatment, and Compound A administered in combination with dabigatran etexilate mesylate was the test treatment. All safety analyses were performed on the safety analysis set. Safety data were presented in tabular and / or graphical form and summarized narratively as appropriate according to the Consortium for Clinical Data Exchange Standards (CaPS).

[0145] intervention The single arms of the clinical trial are shown in Table 2 below. [Table 2]

[0146] The drug interventions investigated in the studies are shown in Table 3 . [Table 3]

[0147] The outcome measures of the study are shown in Table 4. [Table 4]

[0148] Secondary outcome measures in this study are shown in Table 5. [Table 5-1] [Table 5-2]

[0149] Study eligibility is shown in Table 6. [Table 6-1] [Table 6-2]

[0150] safety results After a single dose of dabigatran etexilate mesylate 75 mg (treatment period 1), a total of nine all-cause adverse events (AEs) were reported in six (25.0%) participants, of which four AEs reported in three (12.5%) participants were considered treatment-related.After a single dose of compound A 200 mg and dabigatran etexilate mesylate 75 mg (treatment period 2), a total of seven all-cause AEs were reported in six (25.0%) participants, of which one AE reported in one (4.2%) participant was considered treatment-related.No serious adverse events (SAEs), severe AEs, or discontinuations or dose reductions due to AEs were reported in this study.

[0151] After a single dose of dabigatran etexilate mesylate 75 mg, mild AEs of diarrhea, dry mouth, nausea, dry throat, dry skin, and hot flashes were reported in one (4.2%) participant each, of which diarrhea, nausea, dry skin, and hot flashes were considered treatment-related. Moderate AEs of hematoma and myalgia were reported in two (8.3%) and one (4.2%) participants, respectively, and were not considered treatment-related. After a single dose of Compound A 200 mg and dabigatran etexilate mesylate 75 mg, mild AEs of influenza, bruising, wound, oropharyngeal pain, and rhinorrhea were reported in one (4.2%) participant each, and were not considered treatment-related. Moderate AEs of bruising and headache were reported in one (4.2%) participant each, of which headache was considered treatment-related.

[0152] After a single dose of dabigatran etexilate mesylate 75 mg, two (8.3%) participants had monocytes / white blood cells >1.2 × ULN. After a single dose of compound A 200 mg and dabigatran etexilate mesylate 75 mg, two (8.3%) participants had monocytes / white blood cells >1.2 × ULN and one (4.2%) participant had leukocyte esterase ≥1.

[0153] No participant had laboratory abnormalities that met the predefined criteria for clinical chemistry analysis. No laboratory abnormalities were reported as AEs by the investigator or sponsor.

[0154] No clinically significant changes in vital sign measurements, ECGs, or other observations related to safety were observed in this study.

[0155] Safety Conclusions All study interventions were safe and well-tolerated in healthy adult participants. No new safety issues were identified. All AEs were mild or moderate in severity. No serious or severe AEs occurred, and no discontinuations or dose reductions / modifications due to AEs were reported.

[0156] Pharmacokinetic results Dabigatran (total) pharmacokinetics Coadministration of a single dose of Compound A (200 mg) significantly reduced the plasma exposure AUC of dabigatran (75 mg). inf 98% C max increased by 92%.

[0157] Adjusted geometric mean (90% CI) dabigatran AUC inf , AUC 24 , and C max The ratios to were 197.81% (177.32%, 220.66%), 209.42% (185.03%, 237.03%), and 192.20% (166.56%, 221.79%), respectively, after dabigatran co-administration with Compound A (test) compared to administration alone (reference).

[0158] Summary of results A total of 24 participants were enrolled and treated in this study. The combined administration of dabigatran and Compound A was evaluated using the area under inf ) and the area under the plasma concentration-time curve up to the maximum plasma concentration of dabigatran (C max ) by 98% and 92%, respectively (primary endpoint). Adjusted geometric mean (90% CI) dabigatran AUC inf and C max The ratios of dabigatran to Compound A were 197.81% (177.32% to 220.66%) and 192.20% (166.56% to 221.79%) after dabigatran administration with Compound A (test) compared with monotherapy (reference), respectively. Treatment-emergent adverse events (TEAEs) occurred in 6 (25.0%) participants after dabigatran treatment and after coadministration of dabigatran with Compound A. Treatment-related AEs occurred in 3 (12.5%) participants after dabigatran treatment (diarrhea, dry skin, hot flashes, and nausea, 1 patient each [4.2%]) and 1 (4.2%) participant after coadministration of dabigatran and Compound A (headache). All AEs were mild or moderate; no serious or severe AEs occurred, and no discontinuations or dose modifications due to AEs were reported.

[0159] conclusion Without wishing to be bound by theory, co-administration of Compound A increases dabigatran exposure, indicating that Compound A is a P-gp inhibitor. Caution is recommended when administering Compound A together with sensitive substrates of P-gp, such as dabigatran, to cancer patients.

Claims

1. 1. A method of treating cancer in a subject receiving a substrate of P-glycoprotein, comprising administering to a subject a compound A having the following structure: 【Chemistry 1】 、 or a pharmaceutically acceptable salt thereof to said subject; and monitoring said subject for adverse reactions during treatment with Compound A, or a pharmaceutically acceptable salt thereof.

2. Compound A having the following structure: 【Chemistry 2】 、 1. A method of treating cancer comprising administering Compound A, or a pharmaceutically acceptable salt thereof, to a subject, wherein a physician is provided with instructions to monitor the subject for adverse reactions during co-administration of Compound A, or a pharmaceutically acceptable salt thereof, with a substrate of P-glycoprotein.

3. 3. The method of claim 1 or 2, wherein the adverse reaction is selected from the group consisting of diarrhea, nausea, dry skin, hot flashes, and headache.

4. 4. The method of any one of claims 1 to 3, wherein a daily dose of Compound A, or a pharmaceutically acceptable salt thereof, is administered to the subject.

5. 5. The method of claim 4, wherein the daily dose of Compound A, or a pharmaceutically acceptable salt thereof, is 200 mg.

6. 6. The method of claim 5, wherein the daily dose of Compound A, or a pharmaceutically acceptable salt thereof, is reduced to 100 mg.

7. 7. The method of any one of claims 4 to 6, wherein the daily dose of Compound A, or a pharmaceutically acceptable salt thereof, is administered once a day.

8. 8. The method of any one of claims 4 to 7, wherein the daily dose of Compound A, or a pharmaceutically acceptable salt thereof, is administered orally to the subject.

9. The method of any one of claims 1 to 8, wherein the subject is in a fed state.

10. 4. The method of claim 3, wherein the daily dose of Compound A, or a pharmaceutically acceptable salt thereof, cannot be administered in conjunction with a substrate of P-glycoprotein.

11. 11. The method of claim 1, 2, or 10, wherein the P-glycoprotein substrate is apixaban, colchicine, cyclosporine, dabigatran etexilate mesylate, digoxin, edoxaban, fexofenadine, rivaroxaban, tacrolimus, or talinolol.

12. The method according to claim 11, wherein the substrate of P-glycoprotein is dabigatran etexilate mesylate.

13. 13. The method of any one of claims 1 to 12, wherein the cancer is breast cancer, lung cancer, colon cancer, brain cancer, head and neck cancer, prostate cancer, gastric cancer, pancreatic cancer, ovarian cancer, melanoma, endocrine cancer, uterine cancer, testicular cancer, or bladder cancer.

14. 14. The method of claim 13, wherein the cancer is breast cancer, lung cancer, prostate cancer, pancreatic cancer, or ovarian cancer.

15. 15. The method of claim 14, wherein the cancer is breast cancer, lung cancer, or prostate cancer.

16. 16. The method of claim 15, wherein the cancer is breast cancer.

17. 17. The method of claim 16, wherein the breast cancer is metastatic or locally advanced.

18. 18. The method of claim 16 or 17, wherein the breast cancer is estrogen receptor positive (ER+) breast cancer.

19. 19. The method of claim 18, wherein the estrogen receptor positive (ER+) breast cancer is human epidermal growth factor receptor 2 negative (HER2-).

20. The method of any one of claims 1 to 19, wherein the subject is a human.

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