Methods of treating breast cancer

Abstract

The present invention relates to a method for treating cancer in a subject receiving a substrate of P-glycoprotein, the method comprising administering to the subject a Compound A having the structure: or a pharmaceutically acceptable salt thereof, and monitoring the subject for an adverse effect during treatment with Compound A or a pharmaceutically acceptable salt thereof. # imgabs0 #

Description

[0001] Cross-reference to related applications

[0002] This application claims priority to and the benefit of U.S. Provisional Application No. 63 / 429,836, filed December 2, 2022, and U.S. Provisional 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 Art

[0003] Certain bifunctional compounds can target specific cellular proteins for degradation via the ubiquitin-proteasome system. Such proteolytically targeted chimeric compounds (i.e., " Examples of bifunctional molecules ("protein degraders") are disclosed in International Publication No. WO 2018 / 102725, which is incorporated herein by reference in its entirety. Such bifunctional molecules exhibit a range of pharmacological activities consistent with the degradation of ER, including but not limited to treating or ameliorating disease conditions such as cancer (e.g., breast cancer, uterine cancer, ovarian cancer, prostate cancer, endometrial cancer) or endometriosis.

[0004] Of particular interest is the bifunctional molecule (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-naphthylphenyl]-4-piperidinyl]methyl]-1-piperazinyl]-2H-isoindol-2-yl]-2,6-piperidinedione (referred to herein as "Compound A"), which has C 45 H 49 The molecular formula of N5O4 and the following structure:

[0005]

[0006] Compound A is being developed as a potential treatment for breast cancer by targeting ER. Protein degraders and have been shown to be useful modulators targeting protein ubiquitination and degradation via the ubiquitin-proteasome pathway.

[0007] Compound A can be administered to a cancer patient who is also being administered a concomitant medication. Concomitant medications include, for example, other prescription or over-the-counter medications that a cancer patient may be taking in addition to Compound A. Concomitant medications may be used by the patient for the same indication or for other indications.

[0008] In a subject, the presence of two drugs simultaneously or almost simultaneously (e.g., accompanying) can change the effect of one or another or both drugs. Such changes are referred to as drug-drug interactions. The concomitant administration or co-administration of two or more drugs means that the drugs are present in the body at the same time. Because the metabolism and / or excretion of each drug may reduce or interfere with the metabolism and / or excretion of other drugs, the effective concentration of these drugs (compared with the effective concentration of these drugs when used alone) is increased thereby, the concomitant administration or co-administration of different drugs usually leads to adverse effects.

[0009] Therefore, there is a need for therapeutic approaches that address and / or minimize drug-drug interactions in cancer treatment. Summary of the Invention

[0010] This 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 a series of concepts further described in the Detailed Description below in a simplified form. This Summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used alone as an aid in determining the scope of the claimed subject matter.

[0011] Provided herein are methods for treating cancer in a subject that receives a substrate for P-glycoprotein, the methods comprising administering to the subject Compound A having the following structure:

[0012]

[0013] or a pharmaceutically acceptable salt thereof, and monitoring the subject for adverse reactions during treatment with Compound A or a pharmaceutically acceptable salt thereof.

[0014] Provided herein are methods for treating cancer in a subject receiving dabigatran etexilate, the methods comprising administering to the subject Compound A having the structure:

[0015]

[0016] or a pharmaceutically acceptable salt thereof, and monitoring the subject for adverse reactions during treatment with Compound A or a pharmaceutically acceptable salt thereof.

[0017] Provided herein are methods for treating cancer comprising administering to a subject a compound A having the following structure:

[0018]

[0019] or a pharmaceutically acceptable salt thereof, wherein Compound A is administered without concomitant administration of a substrate for P-glycoprotein.

[0020] Provided herein are methods for treating cancer comprising administering to a subject a compound A having the following structure:

[0021]

[0022] or a pharmaceutically acceptable salt thereof, wherein Compound A is administered without concomitant administration of dabigatran.

[0023] Additionally, provided herein are methods for treating cancer, comprising administering to a subject a compound A having the following structure:

[0024]

[0025] or a pharmaceutically acceptable salt thereof, wherein instructions are provided to the physician to monitor the subject for adverse reactions during concomitant administration of Compound A, or a pharmaceutically acceptable salt thereof, and a substrate for P-glycoprotein.

[0026] Additionally, provided herein are methods for treating cancer, comprising administering to a subject a compound A having the following structure:

[0027]

[0028] or a pharmaceutically acceptable salt thereof, wherein instructions are provided to the physician for monitoring the subject for adverse reactions during concomitant administration of Compound A, or a pharmaceutically acceptable salt thereof, and dabigatran mesylate.

[0029] Additionally, provided herein are methods for treating cancer, comprising administering to a subject a compound A having the following structure:

[0030]

[0031] or a pharmaceutically acceptable salt thereof, wherein instructions are provided to the physician including a warning that the treatment is not to be administered with concomitant administration of a substrate for P-glycoprotein.

[0032] Additionally, provided herein are methods for treating cancer, comprising administering to a subject a compound A having the following structure:

[0033]

[0034] or a pharmaceutically acceptable salt thereof, wherein instructions are provided to the physician including a warning that the treatment is not to be administered with a concomitant administration of dabigatran etexilate.

[0035] In an embodiment, the adverse reaction is selected from the group consisting of diarrhea, nausea, dry skin, hot flashes and headache.

[0036] In embodiments, a daily dose of Compound A or a pharmaceutically acceptable salt thereof is administered to the subject.

[0037] In an embodiment, a daily dose of Compound A or a pharmaceutically acceptable salt thereof is administered to the subject, and the daily dose of Compound A or a pharmaceutically acceptable salt thereof is 200 mg.

[0038] In an embodiment, a daily dose of Compound A or a pharmaceutically acceptable salt thereof is administered to the subject, and the daily dose of Compound A or a pharmaceutically acceptable salt thereof is 100 mg.

[0039] In embodiments, the subject is administered a daily dose of Compound A or a pharmaceutically acceptable salt thereof, and the daily dose of Compound A or a pharmaceutically acceptable salt thereof is administered once a day (QD).

[0040] In an embodiment, a daily dose of Compound A or a pharmaceutically acceptable salt thereof is administered to the subject, and the daily dose of Compound A or a pharmaceutically acceptable salt thereof is administered orally to the subject.

[0041] In embodiments, the subject is in a fed state.

[0042] In embodiments, the daily dose of Compound A or a pharmaceutically acceptable salt thereof is not administered with concomitant administration of a substrate for P-glycoprotein.

[0043] In an embodiment, the substrate of P-glycoprotein is apixaban, colchicine, cyclosporine, dabigatran etexilate mesylate, digoxin, edoxaban, fexofenadine, rivaroxaban, tacrolimus or talinolol.

[0044] In an embodiment, the substrate of P-glycoprotein is dabigatran etexilate mesylate.

[0045] 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.

[0046] In embodiments, the cancer is breast cancer, lung cancer, prostate cancer, pancreatic cancer, or ovarian cancer.

[0047] In embodiments, the cancer is breast cancer, lung cancer, or prostate cancer. In embodiments, the cancer is breast cancer.

[0048] In embodiments, the breast cancer is metastatic or locally advanced. In embodiments, the breast cancer is estrogen receptor positive (ER+) breast cancer.

[0049] In embodiments, the estrogen receptor-positive (ER+) breast cancer is human epidermal growth factor receptor 2-negative (HER2-).

[0050] In embodiments, the subject is a human.

[0051] 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

[0052] The present invention may be understood more readily by reference to the following detailed description of embodiments of the invention and the examples included herein.It should be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0053] P-glycoprotein (P-gp) substrates are substances that use the P-glycoprotein transporter to carry out various activities, including drug absorption, drug excretion, and other important activities, which may lead to changes in the body or changes in the effects of other drugs on 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, administration of 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.

[0054] Thus, provided herein are methods for treating cancer in a subject that receives a substrate for P-glycoprotein, the methods comprising administering to the subject Compound A having the structure:

[0055]

[0056] or a pharmaceutically acceptable salt thereof, and monitoring the subject for adverse reactions during treatment with Compound A or a pharmaceutically acceptable salt thereof.

[0057] definition

[0058] Unless otherwise defined herein, scientific and technical terms used in connection with the present invention have the meanings that are commonly understood by one of ordinary skill in the art.

[0059] The invention described herein may suitably be practiced in the absence of any element or elements not specifically disclosed herein.

[0060] As used herein, the singular forms "a," "an," and "the" include plural referents unless otherwise indicated. For example, "a" or "an" substituent includes one or more substituents.

[0061] As used herein, the term "about" when used to modify a numerically defined parameter (e.g., the dose of Compound A) means that the parameter can vary by up to 10% below or above the stated value of the parameter. For example, a dose of about 200 mg means 200 mg ± 10%, i.e., it can vary between 180 mg and 220 mg.

[0062] As used herein, terms including but not limited to "agent," "compound," "drug," "medication," and "therapeutic agent" are used interchangeably to refer to compounds, specifically Compound A, encompassed within the present disclosure and methods and uses of the present invention.

[0063] Compound A has the following structure:

[0064]

[0065] and pharmaceutically acceptable salts thereof are disclosed in International Publication No. WO 2018 / 102725 and U.S. Pat. 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 entirety.

[0066] Compound A is a Class IV compound (low solubility / low permeability) in the Biopharmaceutical Classification System. Compound A can be interconverted with its diastereomer, Compound B:

[0067]

[0068] Preclinical data indicate that exposure of Compound B is limited compared to Compound A (<26%). Without wishing to be bound by theory, there is evidence that Compound B does not degrade ER; however, Compound B exhibits similar ER-dependent transcriptional antagonism compared to Compound A.

[0069] In the Examples, pharmaceutically acceptable salts of the compounds are described herein. Pharmaceutically acceptable salts of the compounds described herein include acid addition salts and base addition salts thereof.

[0070] In the embodiments, pharmaceutically acceptable acid addition salts of the 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, acetates, acid citrates, adipates, aspartates, benzoates, benzenesulfonates, bicarbonates / carbonates, bisulfates / sulfates, bitartrates, borates, camphorsulfonates, citrates, cyclamates, edisylate, ethanesulfonates, ethanesulfonates, formates, fumarates, glucoheptonates, gluconates, glucuronates, hexafluorophosphates, hyphenates, Hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthoate, 2-naphthalenesulfonate, nicotinate, nitrate, lactate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, p-toluenesulfonate, toluenesulfonate, trifluoroacetate, and xinafoate.

[0071] Additional embodiments relate to 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, arginine, benzathine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine, and zinc salts.

[0072] The compounds described herein that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. Acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds described herein are acids that form non-toxic acid addition salts, for example, salts containing 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, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate [i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)] salts. In addition to the acids mentioned above, the compounds described herein that include a basic moiety (eg, amino) can form pharmaceutically acceptable salts with various amino acids.

[0073] Chemical bases that can be used as reagents for preparing pharmaceutically acceptable base salts of the compounds described herein that are acidic in nature are chemical bases 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 other base salts of lower alkanolammonium and pharmaceutically acceptable organic amines.

[0074] Hemisalts of acids and bases can also be formed, for example, hemisulphate and hemicalcium salts.

[0075] For a review of suitable salts, see Stahl and Wermuth, Pharmaceutical Salts: Properties, Selection, and Use (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds described herein are known to those skilled in the art.

[0076] Dabigatran etexilate (dabigatran etexilate) (β-alanine, N-[[2-[[[4-[[[(hexyloxy) carbonyl] amino] iminomethyl] phenyl] amino] methyl]-1-methyl isophthalic acid H-benzimidazole-5-yl] carbonyl]-N-2-pyridyl-, ethyl ester) is the oral prodrug of direct thrombin inhibitor dabigatran (3-[[2-[(4-carbamimidophenylamino) methyl]-1-methylbenzimidazole-5-carbonyl]-pyridin-2-yl amino] propionic acid). Dabigatran mesylate is a kind of anticoagulant, is used for the treatment and prevention of blood clot, and prevents the apoplexy of the patient with atrial fibrillation. In certain embodiments, dabigatran mesylate is with The structures of dabigatran and dabigatran etexilate mesylate are shown below:

[0077]

[0078] Dabigatran mesylate is oral, reversible, competitive and direct thrombin inhibitor, and is substrate in vitro and in vivo of P-glycoprotein (P-gp).Dabigatran mesylate can be used as the probe that intestinal tract P-gp inhibits, and has been recommended as the probe for described purpose by regulatory agencies.

[0079] In addition, P-gp substrates include apixaban, colchicine, cyclosporine, digoxin, edoxaban, fexofenadine, rivaroxaban, tacrolimus, and talinolol.

[0080] Application method

[0081] Provided herein are methods for treating cancer in a subject receiving a substrate of P-glycoprotein, the methods comprising administering Compound A or a pharmaceutically acceptable salt thereof to the subject, and monitoring the subject for adverse effects during treatment with Compound A or a pharmaceutically acceptable salt thereof.

[0082] 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 is administered without concomitant administration of a substrate of P-glycoprotein.

[0083] 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 is administered without concomitant administration of dabigatran etexilate mesylate.

[0084] Additionally, provided herein are methods for treating cancer, comprising administering Compound A, or a pharmaceutically acceptable salt thereof, to a subject, wherein instructions are provided to the physician to monitor the subject for adverse reactions during concomitant administration of Compound A, or a pharmaceutically acceptable salt thereof, and a substrate for P-glycoprotein.

[0085] Additionally, provided herein are methods for treating cancer comprising administering Compound A or a pharmaceutically acceptable salt thereof to a subject, wherein instructions are provided to the physician including a warning that the treatment is not to be administered with concomitant administration of dabigatran mesylate.

[0086] In embodiments, the daily dose of Compound A or a pharmaceutically acceptable salt thereof is administered once a day (QD).

[0087] In embodiments, the daily dose of Compound A or a pharmaceutically acceptable salt thereof is orally administered to the subject.

[0088] In embodiments, the subject is in a fed state.

[0089] In an embodiment, the daily dose of Compound A or a pharmaceutically acceptable salt thereof is about 200 mg or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0090] In an embodiment, the daily dose of Compound A or a pharmaceutically acceptable salt thereof is 200 mg or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0091] In an embodiment, the daily dose of Compound A is about 200 mg.

[0092] In an embodiment, the daily dose of Compound A is 200 mg.

[0093] In an embodiment, the daily dose of Compound A or a pharmaceutically acceptable salt thereof is about 100 mg or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0094] In an embodiment, the daily dose of Compound A or a pharmaceutically acceptable salt thereof is 100 mg or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0095] In an embodiment, the daily dose of Compound A is about 100 mg.

[0096] In an embodiment, the daily dose of Compound A is 100 mg.

[0097] In the Examples, Compound A was administered as the free base.

[0098] 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.

[0099] In embodiments, the cancer is breast cancer, lung cancer, prostate cancer, pancreatic cancer, or ovarian cancer.

[0100] In embodiments, the cancer is breast cancer, lung cancer, or prostate cancer.

[0101] In embodiments, the cancer is breast cancer.

[0102] In embodiments, the breast cancer is metastatic or locally advanced.

[0103] In embodiments, the breast cancer is estrogen receptor positive (ER+) breast cancer.

[0104] In embodiments, the estrogen receptor-positive (ER+) breast cancer is human epidermal growth factor receptor 2-negative (HER2-).

[0105] In embodiments, the subject is a human.

[0106] Also disclosed herein is a method for treating cancer in a subject receiving a substrate of P-glycoprotein, 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 reaction is selected from the group consisting of diarrhea, nausea, dry skin, hot flashes, and headache.

[0107] Also disclosed herein is a method for treating cancer in a subject receiving a substrate of P-glycoprotein, 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 reaction is selected from the group consisting of diarrhea, nausea, dry skin, hot flashes, and headache; and Compound A or a pharmaceutically acceptable salt thereof is administered once daily (QD).

[0108] Also disclosed herein is a method for treating cancer in a subject receiving a substrate of P-glycoprotein, 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 reaction is selected from the group consisting of diarrhea, nausea, dry skin, hot flashes, and headache; and Compound A or a pharmaceutically acceptable salt thereof is administered orally once a day (QD).

[0109] Also disclosed herein is a method for treating cancer in a subject who receives a substrate of P-glycoprotein, 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 reaction is selected from the group consisting of diarrhea, nausea, dry skin, hot flashes, and headache; and Compound A or a pharmaceutically acceptable salt thereof is orally administered once a day (QD) at a daily dose of about 200 mg or about 100 mg.

[0110] Also disclosed herein is a method for treating cancer in a subject who receives a substrate of P-glycoprotein, 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 reaction is selected from the group consisting of diarrhea, nausea, dry skin, hot flashes, and headache; and Compound A or a pharmaceutically acceptable salt thereof is orally administered once a day (QD) at a daily dose of about 100 mg.

[0111] Also disclosed herein is a method for treating cancer in a subject receiving a substrate of P-glycoprotein, 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).

[0112] Also disclosed herein is a method for treating cancer in a subject receiving a substrate of P-glycoprotein, 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 orally administered once a day (QD) at a daily dose of about 200 mg or about 100 mg.

[0113] Also disclosed herein is a method for treating cancer in a subject receiving a substrate of P-glycoprotein, 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 orally administered once a day (QD) at a daily dose of about 100 mg.

[0114] Also disclosed herein is a method for treating cancer in a subject receiving dabigatran 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 Compound A or a pharmaceutically acceptable salt thereof is administered once daily (QD).

[0115] Also disclosed herein is a method for treating cancer in a subject receiving dabigatran 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 Compound A or a pharmaceutically acceptable salt thereof is orally administered once a day (QD) at a daily dose of about 200 mg or about 100 mg.

[0116] Also disclosed herein is a method for treating cancer in a subject receiving dabigatran 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 Compound A or a pharmaceutically acceptable salt thereof is orally administered once a day (QD) at a daily dose of about 100 mg.

[0117] Also disclosed herein is a method for treating cancer in a subject receiving dabigatran 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 a day (QD).

[0118] Also disclosed herein is a method for treating cancer in a subject receiving dabigatran 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 orally administered once a day (QD) at a daily dose of about 200 mg or about 100 mg.

[0119] Also disclosed herein is a method for treating cancer in a subject receiving dabigatran 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 orally administered once a day (QD) at a daily dose of about 100 mg.

[0120] Also disclosed 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 is administered once a day (QD) and is not concomitantly administered with a substrate of P-glycoprotein.

[0121] Also disclosed 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 is orally administered once a day (QD) and is not concomitantly administered with a substrate of P-glycoprotein.

[0122] Also disclosed 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 is orally administered once a day (QD) at a daily dose of about 200 mg or about 100 mg and is not concomitantly administered with a substrate of P-glycoprotein.

[0123] Also disclosed 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 is orally administered once a day (QD) at a daily dose of about 200 mg or about 100 mg and is not concomitantly administered with a substrate of P-glycoprotein and wherein the subject is a human in a fed state.

[0124] Also disclosed 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 is administered once a day (QD) and is not concomitantly administered with dabigatran mesylate.

[0125] Also disclosed 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 is orally administered once a day (QD) and is not concomitantly administered with dabigatran mesylate.

[0126] Also disclosed 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 is orally administered once a day (QD) at a daily dose of about 200 mg or about 100 mg, and is not concomitantly administered with dabigatran mesylate.

[0127] Also disclosed 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 is orally administered once a day (QD) at a daily dose of about 200 mg or about 100 mg and is not concomitantly administered with dabigatran mesylate and wherein the subject is a human in a fed state.

[0128] In each of the methods described herein, the cancer is preferably breast cancer.

[0129] Also disclosed herein is Compound A or a pharmaceutically acceptable salt thereof, for use according to any of the aforementioned embodiments.

[0130] Also disclosed herein is Compound A or a pharmaceutically acceptable salt thereof, for use according to any of the aforementioned embodiments.

[0131] Also disclosed herein is the use of Compound A or a pharmaceutically acceptable salt thereof for preparing the medicament according to any one of the aforementioned embodiments.

[0132] Also disclosed herein is the use of Compound A or a pharmaceutically acceptable salt thereof for preparing the medicament according to any one of the aforementioned embodiments.

[0133] Each embodiment described herein may be combined with any one or more other embodiments described herein without being inconsistent with the embodiment or embodiments with which it is combined.

[0134] Mode of administration and dosing

[0135] Concomitant administration means giving and applying two or more drugs at or about the same time (e.g., one after another, on the same day, etc.). Co-administration refers to the act of giving or applying (e.g., administering) two or more drugs at the same time.

[0136] As used herein, the terms "treat" and "treating" cancer or a cancer-related disease mean administering a therapy according to the present disclosure to a subject, participant, or patient who has cancer or is diagnosed with cancer to achieve at least one positive therapeutic effect, such as a decrease in the number of cancer cells, a decrease in tumor size, a decrease in the rate of cancer cell infiltration into peripheral organs, or a decrease in the rate of tumor metastasis or tumor growth, reversal, improvement, inhibition of progression of the disorder or condition to which such terms apply, or prevention of the disorder or condition or one or more symptoms of such disorder or condition. As used herein, unless otherwise indicated, the terms "treat" and "therapy" refer to the act of treating as defined immediately above as "treatment." 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 tumor cells or cancer cells (or destroying tumor cells or cancer cells); inhibiting metastasis or tumor cells; shrinking or reducing the size of a tumor; cancer remission; reducing symptoms caused by cancer; increasing the quality of life of a person with cancer; reducing the dose of other drugs required to treat cancer; delaying the progression of cancer; curing cancer; overcoming one or more resistance mechanisms of cancer; and / or prolonging the survival of a patient with cancer. Positive effects of cancer treatment can be measured in a variety of ways (see, eg, WA Weber, J. Nucl. Med. (2009) 50: 1S-10S).

[0137] As used herein, "fed condition" or "fed state" of a subject means that the subject has eaten less than 4 hours prior to the time point of interest (e.g., the time of administration of Compound A). In embodiments, a subject in a fed state has not eaten for any of up to 4 hours, 3 hours, 2 hours, 1 hour, or 0.5 hours prior to administration of Compound A.

[0138] As used herein, the terms "subject," "participant," and "patient" are used interchangeably to refer to a human. A human subject can be of either sex. In an embodiment, the human is an adult.

[0139] An "amount" for use or for treating a subject refers to an amount that provides a detectable response of any duration (short-term, intermediate-term, or long-term), any measurable or detectable degree, or a desired outcome or objective or subjective benefit to the subject for any duration (e.g., hours, days, months, years, remission, or cure) in a single or multiple doses. Such amounts are generally effective to measurably improve the disease or one, multiple, or all adverse effects / symptoms, consequences, or complications of the disease, but reducing or inhibiting the progression or worsening of the disease, or providing a stable (i.e., non-worsening) state of the disease is considered a satisfactory outcome. The term "therapeutically effective amount" or "effective amount" also means an amount of an agent that, when administered to a subject, is effective to produce the desired therapeutic effect (e.g., preventing the growth of a cancerous tumor or shrinking a cancerous tumor). With reference to the treatment of cancer, a therapeutically effective amount is an amount that: (1) reduces the size of a tumor, (2) inhibits (i.e., slows to some extent, preferably stops) the appearance of tumor metastases, (3) inhibits (i.e., slows to some extent, preferably stops) tumor growth or tumor invasiveness, and / or (4) alleviates to some extent (or preferably eliminates) one or more signs or symptoms associated with cancer. The therapeutic or pharmacological effectiveness of a dose and administration regimen can also be characterized by its ability to induce, enhance, maintain or prolong disease control and / or overall survival in patients with these particular tumors, which can be measured as a prolongation of the time before disease progression.

[0140] As used herein, "improvement" refers to any decrease in the extent, severity, frequency, and / or likelihood of symptoms or clinical signs characteristic of a particular disease. "Symptom" refers to any subjective evidence of a disease or condition in a subject.

[0141] Embodiments of the present invention provide a dosage, dosage, and administration regimen comprising administering to a subject an amount or effective amount of Compound A or a pharmaceutically acceptable salt thereof. The amount, effective amount, or therapeutically effective amount may be a daily dose of about 200 mg. In embodiments, the daily dose is 200 mg. In embodiments, the amount, effective amount, or therapeutically effective amount may be a daily dose of about 100 mg. In embodiments, the daily dose is 100 mg.

[0142] In embodiments, the daily dose of Compound A or a pharmaceutically acceptable salt thereof is administered once a day (QD).

[0143] The compounds disclosed herein can be administered orally. Oral administration can involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration can be employed, whereby the compound enters the bloodstream directly from the mouth.

[0144] In embodiments, the daily dose of Compound A or a pharmaceutically acceptable salt thereof is administered orally.

[0145] Compound A or a pharmaceutically acceptable salt thereof may be present in a pharmaceutical composition comprising at least one pharmaceutically acceptable excipient. A "pharmaceutically acceptable excipient" refers to a component that can be included in the compositions described herein, is physiologically suitable for pharmaceutical use, and does not produce significant adverse effects or therapeutic effects on the subject. The term "excipient" is used herein to describe any ingredient other than one or more compounds of the present invention. The choice of excipient will depend largely on factors such as the mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

[0146] The compound of the method or use of the present invention can be formulated before administration. The formulation is preferably suitable for a specific mode of administration. These compounds can be formulated together with pharmaceutically acceptable excipients as known in the art and administered in a 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 non-aqueous oral solutions and suspensions, packaged in containers suitable for subdividing into individual doses.

[0147] The administration or dosing regimen can be repeated as needed to achieve the desired reduction or decrease in cancer cells. As used herein, a "continuous dosing schedule" is an administration or dosing regimen in which the dose is not interrupted, e.g., without interrupting the treatment days. Repeating a 28-day treatment cycle without dose interruptions between treatment cycles is an example of a continuous dosing schedule. In an embodiment, Compound A of the present invention, or a pharmaceutically acceptable salt thereof, can be administered in a continuous dosing schedule. In an embodiment, Compound A, or a pharmaceutically acceptable salt thereof, disclosed herein, and a substrate for P-gp can be administered concomitantly in a continuous dosing schedule.

[0148] In an embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered once daily to comprise a complete cycle of 28 days. According to the methods and uses of the present disclosure, the 28-day treatment cycle is continuously repeated during the treatment period.

[0149] Treatment

[0150] As used herein, the term "locally advanced" as it relates to cancer may or may not be treated with curative intent. For example, locally advanced breast cancer (LABC) is defined by the US National Comprehensive Cancer Network as a subset of breast cancer characterized by: the most advanced breast tumor in the absence of distant metastases, wherein the tumor is greater than 5 cm in size and has regional lymphadenopathy; tumors of any size (including ulcers or satellite nodules) that extend directly to the chest wall or skin, or both, regardless of regional lymphadenopathy; the presence of regional lymphadenopathy (clinically fixed or tangled axillary lymph nodes, or any of infraclavicular, supraclavicular, or internal mammary lymphadenopathy), regardless of the tumor stage. (Garg et al. Curr Oncol. 2015 Oct;22(5):e409–10; “National Comprehensive Cancer Network NCCN Clinical Practice Guidelines in Oncology: Breast Cancer.” Fort Washington, PA: NCCN; 2015.2.2015.).

[0151] 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.

[0152] In embodiments, the cancer is breast cancer, lung cancer, prostate cancer, pancreatic cancer, or ovarian cancer.

[0153] In embodiments, the cancer is breast cancer, lung cancer, or prostate cancer.

[0154] In embodiments, the cancer is breast cancer.

[0155] In embodiments, the breast cancer is metastatic or locally advanced.

[0156] In embodiments, the breast cancer is estrogen receptor positive (ER+) breast cancer.

[0157] In embodiments, the estrogen receptor-positive (ER+) breast cancer is human epidermal growth factor receptor 2-negative (HER2-).

[0158] Examples

[0159] In order to better understand the present invention, the following examples are described. This example is for illustrative purposes only and should not be construed as limiting the scope of the present invention in any way.

[0160] abbreviation

[0161] AUC inf = area under the plasma concentration-time curve extrapolated from time 0 to infinity;

[0162] AUC last = from time 0 to the last quantifiable concentration (C last )’s area under the plasma concentration-time curve;

[0163] C max =maximum plasma concentration;

[0164] CI = confidence interval;

[0165] hrs = hours;

[0166] ECG = electrocardiogram;

[0167] mins = minutes;

[0168] PE = physical examination;

[0169] TEAE = treatment-emergent adverse event

[0170] A study to understand the effect of compound A on the pharmacokinetics (PK) of dabigatran in healthy adults

[0171] Overview

[0172] Compound A was studied in an interventional, phase 1, open-label, fixed-sequence, 2-period study to evaluate the effect of a single oral dose of Compound A on the PK of dabigatran in healthy participants.

[0173] Target

[0174] The goal of this drug-drug interaction study was to evaluate the effect of Compound A on the PK of dabigatran etexilate, a model substrate of P-gp, in healthy adults (NCT05673889).

[0175] Popular Science Summary

[0176] The study aimed to see whether Compound A affects how the body absorbs or processes a drug called dabigatran in healthy adults.

[0177] In the 1st period, all participants of this research were orally administered a single dose of dabigatran etcxilate. In the 2nd period, approximately 90 minutes after oral administration of a dose of Compound A, each person was orally administered a single dose of dabigatran etcxilate. The dabigatran level in the 1st period was compared with the dabigatran level in the 2nd period. This research design is used to determine whether and how Compound A affects the absorption of dabigatran in healthy adults.

[0178] All participants stayed at the study clinic for approximately 8 days and 7 nights.

[0179] method

[0180] This was a phase 1, open-label, 2-period, fixed-sequence study designed to evaluate the effect of a single oral dose of Compound A on the PK of the P-gp substrate dabigatran etexilate (as the mesylate) in healthy male and female participants of non-reproductive potential.

[0181] This study consisted of 2 periods with a fixed-sequence treatment design.

[0182] The 1st day in the 1st period, before administration, provide standard breakfast (about 700 calories, fat content is about 35%).Standard breakfast need all edible in the period of about 20 minutes.After starting standard breakfast, about 2 hours (120 minutes) used the 75mg dabigatran etcxilate (with the form of mesylate) (with 1 capsule, 75mg) of single dose.In order to fully remove any drug influence of dabigatran, after using dabigatran etcxilate (with the form of mesylate) on the 1st day in the 1st period, need at least 4 days clearance phase.After single dose is used, reach a series of PK samples collected in 48 hours to determine dabigatran PK parameter (total).

[0183] The 1st day in the 2nd period, before Compd A and dabigatran etcxilate (with the form of mesylate) administration, standard breakfast (about 700 calories, fat content is about 35%) is provided.The standard breakfast requirement is identical with the 1st day that provides in the 1st period, and requires all to eat in the period of about 20 minutes.After completing breakfast, about 10 minutes, used the 200mg Compd A (with 2, 100mg) of single dose.After starting Compd A administration about 1.5 hours (90 minutes), namely started after breakfast about 2 hours (120 minutes), used the 75mg dabigatran etcxilate (with the form of mesylate) (with 1 capsule, 75mg) of single dose.After dabigatran etcxilate (with the form of mesylate) administration, reach a series of PK samples collected in 48 hours, to determine the single dose PK parameter of Compd A and dabigatran (total).

[0184] Blind: Unblinded (open label)

[0185] Number of recruits: 24

[0186] Goals and End Points

[0187] The objectives and endpoints of this clinical study are shown in Table 1 below.

[0188] Table 1:

[0189]

[0190] Statistical methods

[0191] The natural logarithm-transformed parameter (AUC) of total dabigatran was analyzed using a mixed-effects model. inf [if data permits], AUC last and C max ), with treatment as a fixed effect and participant as a random effect. Note that time zero to 24 hours (AUC 24 ) is the area under the concentration-time curve rather than the AUC last The time of the last measurable concentration across the participant is different.From model, obtained the estimated value and corresponding 90%CI through adjusting mean difference (test-reference).The adjusted mean difference and 90%CI of difference are carried out indexation, so that the estimated value and 90%CI of the ratio through adjusting geometric mean (test / reference) ratio are provided. Using dabigatran mesylate separately is reference treatment, and Compound A and dabigatran mesylate use altogether and are test treatment.All safety analyses are carried out on the safety analysis set.According to the standard of Clinical Data Exchange Standard Association (CaPS), safety data presents with table and / or graphic format, and carries out descriptive summary when appropriate.

[0192] intervention

[0193] The individual arms of this clinical study are shown in Table 2 below.

[0194] Table 2:

[0195]

[0196] The drug interferences explored in the study are shown in Table 3.

[0197] Table 3:

[0198]

[0199] The outcome measures in the study are shown in Table 4.

[0200] Table 4:

[0201]

[0202]

[0203] 1 When referring to pharmacokinetic results, dabigatran refers to the sum of unconjugated dabigatran and glucuronide-conjugated dabigatran.

[0204] The secondary outcome measures in the study are shown in Table 5.

[0205] Table 5:

[0206]

[0207]

[0208] Study eligibility is shown in Table 6.

[0209] Table 6:

[0210]

[0211]

[0212] Safety results

[0213] After single dose dabigatran mesylate 75mg (the 1st treatment period), 6 (25.0%) participants reported 9 totally causal adverse events (AE) altogether, and wherein 4 AE that 3 (12.5%) participants reported were considered to treatment-related. After single dose compound A200mg and dabigatran mesylate 75mg (the 2nd treatment period), 6 (25.0%) participants reported 7 totally causal AE altogether, and wherein 1 AE that 1 (4.2%) participant reported was considered to treatment-related.Do not report serious adverse events (SAE), severe AE, stop or dosage reduction owing to AE in this research.

[0214] After single dose of dabigatran mesylate 75mg, respectively have 1 (4.2%) participant to report the mild AE of diarrhoea, dry lips, nausea, dry throat, xerostomia and hot flashes, and wherein diarrhoea, nausea, xerostomia and hot flashes are considered to be relevant to treatment.2 (8.3%) and 1 (4.2%) participants have reported the moderate AE of hematoma and myalgia respectively, and these are not considered to be relevant to treatment.After single dose of compound A 200mg and dabigatran mesylate 75mg, respectively have 1 (4.2%) participant to report the mild AE of influenza, contusion, wound, oropharyngeal pain and rhinorrhea, and these are not considered to be relevant to treatment.Respectively have 1 (4.2%) participant to report the moderate AE of contusion and headache, and wherein headache is considered to be relevant to treatment.

[0215] After single dose of dabigatran mesylate 75mg, monocyte / leukocyte of 2 (8.3%) participants>1.2×upper limit of normal (ULN).After single dose of Compound A 200mg and dabigatran mesylate 75mg, monocyte / leukocyte of 2 (8.3%) participants>1.2×ULN, leukocyte esterase of 1 (4.2%) participant>=1.

[0216] No participant had a laboratory abnormality that met predefined clinical chemistry analysis criteria. No laboratory abnormality was reported as an AE by the investigator or sponsor.

[0217] In this study, no clinically relevant changes in vital sign measurements, ECGs, or other safety-related observations were observed.

[0218] Safety Conclusion

[0219] All study interventions were safe and well tolerated in healthy adult participants. No new safety concerns were identified. All adverse events (AEs) were mild or moderate. No serious or severe AEs occurred, and no discontinuations or dose reductions / modifications due to AEs were reported.

[0220] Pharmacokinetic results

[0221] Dabigatran (total) pharmacokinetics

[0222] Co-administration with a single dose of Compound A (200 mg) increased dabigatran (75 mg) plasma exposure AUC inf Increased by 98% and C max An increase of 92%.

[0223] Following co-administration of dabigatran with Compound A (Test), the AUC of dabigatran was significantly decreased compared to that of Compound A alone (Reference). inf , AUC 24 and C max The adjusted geometric mean ratios (90% CI) for the 2-HRP-positive control group and the 2-HRP-positive control group were 197.81% (177.32%, 220.66%), 209.42% (185.03%, 237.03%), and 192.20% (166.56%, 221.79%), respectively.

[0224] Results Summary

[0225] A total of 24 participants were recruited and treated in this study. Co-administration of dabigatran and Compound A was extrapolated from the time of dosing (time 0) to infinity (AUC inf ) and the maximum plasma concentration of dabigatran (C max) increased by 98% and 92% (primary endpoint). After administration of dabigatran with Compound A (test), dabigatran AUC increased by 98% and 92% (primary endpoint) compared to administration alone (reference). inf and C max The ratios of the adjusted geometric means (90% CI) for the dabigatran group and the dabigatran group were 197.81% (177.32%–220.66%) and 192.20% (166.56%–221.79%), respectively. After dabigatran treatment and after co-administration of dabigatran and compound A, 6 (25.0%) participants each experienced a treatment-induced adverse event (TEAE). After dabigatran treatment, 3 (12.5%) participants experienced a treatment-related AE (diarrhea, dry skin, hot flashes, and nausea; 1 [4.2%] each) and after co-administration of dabigatran and compound A, 1 (4.2%) participant experienced a treatment-related AE (headache). All AEs were mild or moderate; no serious or severe AEs occurred, and no discontinuation or dose modification due to AEs was reported.

[0226] in conclusion

[0227] Without wishing to be bound by theory, co-administration of Compound A increased dabigatran exposure, suggesting that Compound A is a P-gp inhibitor. Caution is advised when administering Compound A to cancer patients with sensitive P-gp substrates such as dabigatran.

Claims

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

2. A method for treating cancer, comprising administering to a subject a compound A having the following structure: or a pharmaceutically acceptable salt thereof, wherein instructions are provided to the physician to monitor the subject for adverse reactions during concomitant administration of Compound A, or a pharmaceutically acceptable salt thereof, and a substrate for P-glycoprotein.

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

4. The method according to 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 . The method according to claim 4 , wherein the daily dose of Compound A or a pharmaceutically acceptable salt thereof is 200 mg. 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. The method according to 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. The method according to 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 according to any one of claims 1 to 8, wherein the subject is in a fed state.

10. The method of claim 3, wherein the daily dose of Compound A or a pharmaceutically acceptable salt thereof is administered without concomitant administration of a substrate for P-glycoprotein.

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

12. method according to claim 11, the substrate of wherein said P-glycoprotein is dabigatran etcxilate.

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, stomach cancer, pancreatic cancer, ovarian cancer, melanoma, endocrine cancer, uterine cancer, testicular cancer, or bladder cancer.

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

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

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

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

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

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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