TWI866427B - Dosage regimens of estrogen receptor degraders - Google Patents

Abstract

Disclosed herein are methods for treating cancer comprising administering to a subject a daily dose of Compound A

Description

Dosage regimen of estrogen receptor degraders

The present invention relates to a dosing regimen of an estrogen receptor degrader.

Certain bifunctional compounds target specific cellular proteins that are degraded via the ubiquitin-proteasome system. Examples of such proteolysis-targeted chimeric compounds (i.e., "PROTAC® protein degraders") that target the estrogen receptor (ER) for ubiquitination and subsequent degradation 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 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.

A bifunctional molecule of particular interest is the vepdegestrant (i.e., ( S )-3-(5-(4-((1-(4-((1 R , 2S )-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperidin- -1-yl)-1-oxoisoindolin-2-yl)piperidin-2,6-dione or (3 S )-3-[1,3-dihydro-1-oxo-5-[4-[[1-[4-[(1 R ,2 S )-1,2,3,4-tetrahydro-6-hydroxy-2-phenyl-1-naphthylphenyl]-4-piperidinyl]methyl]-1-piperidin-2,6-dione [0013] -2H -isoindol-2-yl]-2,6 _{- piperidindione (referred to herein as "Compound A" or "Cpd A")) having a molecular formula of C45H49N5O4 and the} following structure: .

Compound A is being developed as a PROTAC® protein degrader targeting the estrogen receptor (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.

There is a need for an appropriate dosing regimen for Compound A as an oral therapy for the treatment of cancer (e.g., breast cancer) to improve its benefits, including safety and efficacy, and convenience to the patient while minimizing adverse events and risks to the patient.

This disclosure provides, in part, a dosing regimen for administering Compound A or a pharmaceutically acceptable salt thereof to an individual in combination therapy for treating cancer. The present disclosure is provided to introduce a series of concepts in a simplified form, which are further described in the following embodiments. The present disclosure is neither intended to identify key features or essential features of the claimed subject matter nor to be used independently as an aid in determining the scope of the claimed subject matter.

Provided herein is a method for treating cancer comprising administering to a subject a daily dose of a compound A having the following structure: , or a pharmaceutically acceptable salt thereof in combination with a CDK4/6 inhibitor, wherein the daily dose of compound A is about 100 mg or 200 mg.

Provided herein is a method for treating cancer comprising administering to a subject a daily dose of a compound A having the following structure: , in combination with CDK4/6 inhibitors.

In an embodiment, the daily dose of Compound A is about 200 mg. In an embodiment, the daily dose of Compound A is about 100 mg.

In an embodiment, the CDK4/6 inhibitor is dalpiciclib, trilaciclib, lerociclib, AT7519M, dinaciclib, ribociclib, abemaciclib or palbociclib, or a pharmaceutically acceptable salt thereof. In an embodiment, the CDK4/6 inhibitor is abemaciclib, ribociclib or palbociclib, or a pharmaceutically acceptable salt thereof. In an embodiment, the CDK4/6 inhibitor is abemaciclib or a pharmaceutically acceptable salt thereof. In an embodiment, the CDK4/6 inhibitor is ribociclib or a pharmaceutically acceptable salt thereof. In an embodiment, the CDK4/6 inhibitor is ribociclib or a pharmaceutically acceptable salt thereof. In one embodiment, the CDK4/6 inhibitor is palbociclib or a pharmaceutically acceptable salt thereof.

In an embodiment, Compound A or a pharmaceutically acceptable salt thereof may be administered daily in combination with a CDK4/6 inhibitor in a 28-day cycle. In an embodiment, Compound A may be administered daily in combination with a CDK4/6 inhibitor in a 28-day cycle. In certain embodiments, the CDK4/6 inhibitor is palbociclib or a pharmaceutically acceptable salt thereof. For example, palbociclib may be administered orally once a day at 125 mg per day for 21 days in each 28-day cycle, followed by 7 days of cessation of treatment.

In an embodiment, the daily dose of Compound A is administered once daily (QD).

In embodiments, the daily dose of Compound A is administered orally to a subject.

In embodiments, the individual is in a feeding state.

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

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

In embodiments, the cancer is breast cancer, lung cancer, or prostate cancer.

In embodiments, the cancer is breast cancer. For example, the breast cancer may be metastatic or locally advanced. In embodiments, the breast cancer may be estrogen receptor positive (ER+) breast cancer ( e.g., human epidermal growth factor receptor 2 negative (HER2-)).

In an embodiment, the subject is a human.

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

Cross-references to related applications

This application claims priority to and the benefits of U.S. Application No. 63/402,651 filed on August 31, 2022, U.S. Application No. 63/443,892 filed on February 7, 2023, U.S. Application No. 63/454,485 filed on March 24, 2023, U.S. Application No. 63/454,422 filed on March 24, 2023, and U.S. Application No. 63/508,503 filed on June 15, 2023, each of which is incorporated herein by reference in its entirety.

The present invention can be more easily understood with reference to the following detailed description of the embodiments of the present invention and the examples included therein. It should also be understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to be limiting.

Widget (i.e., ( S )-3-(5-(4-((1-(4-((1 R , 2 S )-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperidin -1-yl)-1-oxoisoindolin-2-yl)piperidin-2,6-dione or (3 S )-3-[1,3-dihydro-1-oxo-5-[4-[[1-[4-[(1 R ,2 S )-1,2,3,4-tetrahydro-6-hydroxy-2-phenyl-1-naphthylphenyl]-4-piperidinyl]methyl]-1-piperidin-2,6-dione [0013] -2H -isoindol-2-yl]-2,6-piperidindione (also referred to herein as "Compound A")): It is being developed as a PROTAC® protein degrader targeting the estrogen receptor (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.

Compound A and its pharmaceutically acceptable salts are disclosed in International Publication No. WO 2018/102725 and U.S. Patent Nos. 10,647,698, 10,899,742, and 11,104,666; International Publication No. WO 2021/041348; U.S. Serial No. 17/472,847; U.S. Serial No. 17/548,842; and U.S. Serial No. 17/873,748. The contents of each of the aforementioned references are incorporated herein by reference in their entirety.

Cyclin-dependent kinases (CDKs) and related serine/threonine protein kinases are important cellular enzymes that play an essential role in regulating eukaryotic cell division and proliferation. The CDK catalytic unit is activated by regulatory subunits called cyclins. At least sixteen mammalian cyclins have been identified (Johnson DG, Walker CL. Cyclins and Cell Cycle Checkpoints. Annu. Rev. Pharmacol. Toxicol . (1999) 39:295-312). Cyclin B/CDK1, cyclin A/CDK2, cyclin E/CDK2, cyclin D/CDK4, cyclin D/CDK6, and possibly other heterodynes are important regulators of cell cycle progression. Additional functions of cyclin/CDK heterodynes include transcriptional regulation, DNA repair, differentiation, and apoptosis (Morgan DO. Cyclin-dependent kinases: engines, clocks, and microprocessors. Annu. Rev. Cell. Dev. Biol. (1997) 13:261-291).

It has been demonstrated that CDK inhibitors can be used to treat cancer. It has been shown that increased activity or abnormal activation of cyclin-dependent kinases causes the development of human tumors, and human tumor development is often associated with changes in the CDK protein itself or its regulators (Cordon-Cardo C. Mutations of cell cycle regulators: biological and clinical implications for human neoplasia. Am. J. Pathol . (1995) 147:545-560; Karp JE, Broder S. Molecular foundations of cancer: new targets for intervention. Nat. Med . (1995) 1:309-320; Hall M, Peters G. Genetic alterations of cyclins, cyclin-dependent kinases, and Cdk inhibitors in human cancer. Adv. Cancer Res. (1996) 68:67-108).

CDK4 and CDK6 are important regulators of cell cycle progression at the G1-S checkpoint and are controlled by endogenous CDK inhibitors such as D-type cyclin and INK4, such as p16 ^INK4a (CDKN2A). It has been reported that dysregulation of the cyclin D-CDK4/6-INK4 - retinoblastoma (Rb) pathway is associated with the development of resistance to endocrine therapy.

Clinical trials of the CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib are ongoing as monotherapy or in combination with other therapies for breast cancer and other cancers. The combination of CDK4/6 inhibitors and endocrine therapy has demonstrated significant efficacy in the treatment of hormone receptor (HR)-positive, human epidermal growth factor 2 (HER2)-negative advanced or metastatic breast cancer, and CDK4/6 inhibitors, including palbociclib, ribociclib, and abemaciclib, have been approved for use in combination with endocrine therapy in the first-line or second-line setting. Palbociclib, ribociclib, and abemaciclib have been approved for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer in certain patients in combination with aromatase inhibitors such as letrozole in the first-line setting and with fulvestrant in the second or subsequent lines of therapy. (O'Leary et al., Treating cancer with selective CDK4/6 inhibitors. Nature Reviews (2016) 13:417-30).

Palbociclib or 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperidin -1-yl-pyridin-2-ylamino) -8H -pyrido[2,3- d ]pyrimidin-7-one (also known as "PD-0332991") is a potent and selective CDK4 and CDK6 inhibitor with the following structure: .

Palbociclib is described in WHO Drug Information , Vol. 27, No. 2, p. 172 (2013). Palbociclib and its pharmaceutically acceptable salts are disclosed in International Publication No. WO 2003/062236 and U.S. Patent Nos. 6,936,612, 7,456,168 and RE47,739; International Publication No. WO 2005/005426 and U.S. Patent Nos. 7,345,171 and 7,863,278; International Publication No. WO 2008/032157 and U.S. Patent No. 7,781,583; and International Publication No. WO 2014/128588. The contents of each of the aforementioned references are incorporated herein by reference in their entirety.

Abemaciclib, also known as N-(5-((4-ethylpiperidin -1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-amine (sold, for example, under the brand name Verzenio ^® (among others)) is a selective CDK4 and CDK6 inhibitor having the following structure: .

Abemaciclib and its pharmaceutically acceptable salts are disclosed in International Publication No. WO2010/075074 and U.S. Patent No. 7,855,211. The contents of each of the aforementioned references are incorporated herein by reference in their entirety.

Riboxil, 7-cyclopentyl- N , N -dimethyl-2-[(5-piperidin [-1-ylpyridin-2-yl)amino]pyrrolo[2,3-d]pyrimidine-6-carboxamide (sold under the brand names Kisqali ^® and Kryxana ^® , for example) is a cyclin D1/CDK4 and CDK6 inhibitor having the following structure: .

Reboxili and its pharmaceutically acceptable salts are disclosed in International Publication Nos. WO2007140222, WO2010/020675, WO2012/064805 and WO2016/166703, and U.S. Patent Nos. 8,324,225, 8,415,355, 8,685,980, 8,962,630, 9,193,732, 9,416,136, 9,868,739 and 10,799,506. The contents of each of the aforementioned references are incorporated herein by reference in their entirety.

Although CDK4/6 inhibitors have shown significant clinical efficacy in ER-positive metastatic breast cancer, like other kinases, their effects may be limited over time due to the development of primary or acquired resistance. Palbociclib, a selective CDK4/6 inhibitor, has been shown to be clinically effective in breast cancer (DeMichele A, Clark AS, Tan KS et al., CDK4/6 inhibitor palbociclib (PD-0332991) in Rb+ advanced breast cancer: phase II activity, safety, and predictive biomarker assessment. Clin Cancer Res 2015; 21(5):995-1001; Finn RS, Martin M, Rugo HS et al., Palbociclib and Letrozole in Advanced Breast Cancer. New Engl J Med 2016; 375(20):1925-36; Cristofanilli M, Turner NC, Bondarenko I et al., Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy). (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol 2016; 17(4):425-39), however, acquired resistance to palbociclib may develop after the initial clinical benefit (Knudsen Erik S., Witkiewicz Agnieszka K., The Strange Case of CDK4/6 Inhibitors: Mechanisms, Resistance, and Combination Strategies. Trends Cancer (2017) 3(1):39-55). Definition

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

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

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.

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 numerical value of the parameter. For example, a dose of about 5 mg means 5 mg ± 10%, i.e., it can vary between 4.5 mg and 5.5 mg.

As used herein, terms including but not limited to "agent," "composition," "compound," "drug," and "therapeutic agent" are used interchangeably to refer to the compounds included in the methods and uses of the present disclosure.

As used herein, the terms "subject," "participant," and "patient" are used interchangeably and refer to any animal, including mammals. Mammals according to the present disclosure include canines, felines, bovines, caprines, equines, ovines, porcines, rodents, lagomorphs, primates, humans, and the like, and encompass unborn mammals. In embodiments, humans are suitable subjects. Human subjects may be of any sex and at any stage of development.

Widget (i.e., ( S )-3-(5-(4-((1-(4-((1 R , 2 S )-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperidin -1-yl)-1-oxoisoindolin-2-yl)piperidin-2,6-dione or (3 S )-3-[1,3-dihydro-1-oxo-5-[4-[[1-[4-[(1 R ,2 S )-1,2,3,4-tetrahydro-6-hydroxy-2-phenyl-1-naphthylphenyl]-4-piperidinyl]methyl]-1-piperidin-2,6-dione [0013] -2H -isoindol-2-yl]-2,6-piperidindione (also referred to herein as "Compound A") is a compound having the following structure: .

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

Without wishing to be bound by theory, preclinical data indicate that exposure to Compound B is limited (<26%) compared to Compound A. There is evidence that Compound B does not degrade ER; however, Compound B exhibits similar antagonism to ER-dependent transcription compared to Compound A.

Cyclic protein-dependent kinases (CDKs) and related serine/threonine kinases are important cellular enzymes that play essential roles in regulating cell division and proliferation. CDK inhibitors include pan-CDK inhibitors that target a broad spectrum of CDKs or selective CDK inhibitors that target one or more specific CDKs.

Examples of CDK4/6 inhibitors include, but are not limited to, abemaciclib, ribociclib, and palbociclib. Additional examples of CDK4/6 inhibitors include leloxicil (also known as G1T38) and trexacil (also known as GTI128).

In an embodiment, the CDK4/6 inhibitor of the present invention includes palbociclib. Unless otherwise indicated herein, palbociclib (also referred to herein as "palbo" or "Palbo") refers to 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperidin- -1-yl-pyridin-2-ylamino) -8H -pyrido[2,3- d ]pyrimidin-7-one: , or its pharmaceutically acceptable salts.

Alternatively, in embodiments, the CDK4/6 inhibitor is abemaciclib or reboxiclib. Unless otherwise indicated, abemaciclib refers to N-(5-((4-ethylpiperidin -1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-amine: , and reboxil refers to 7-cyclopentyl- N , N -dimethyl-2-[(5-piperidin -1-ylpyridin-2-yl)amino]pyrrolo[2,3-d]pyrimidine-6-carboxamide: .

Other embodiments relate to pharmaceutically acceptable salts of the compounds described herein. Pharmaceutically acceptable salts of the compounds described herein include acid addition salts and base addition salts thereof.

Other embodiments also pertain to pharmaceutically acceptable acid addition salts of the compounds 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 a pharmacologically acceptable anion) include, but are not limited to, acetates, citrates, adipates, aspartates, benzoates, benzenesulfonates, bicarbonates/carbonates, bisulfates/sulfates, bitartrates, borates, camphor Cetyl sulfonate, citrate, cyclohexylamine sulfonate (cyclamate), ethanedisulfonate, ethanesulfonate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / Chloride, Hydrobromide/Bromide, Hydroiodide/Iodide, Hydroxyethanesulfonate, Lactate, Apple, Maleate, Malonate, Methanesulfonate, Methanesulfonate, Methylsulfate, Naphthalene dicarboxylate, 2-Naphthalenesulfonate, Nicotinate, Nitrate, Orotate, Oxalate, Palm acid salts, bis(hydroxynaphthoate) salts, phosphates/hydrogenphosphates/dihydrogenphosphates, pyroglutamate, glucarate, stearate, succinate, tannate, tartrate, p-toluenesulfonate, toluenesulfonate, trifluoroacetate, and xinofoate.

Additional embodiments pertain 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, styrene, and zinc salts.

The compounds described herein that are basic in nature can form a 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, such as salts containing pharmacologically acceptable anions, such as hydrochlorides, hydrobromides, hydroiodates, nitrates, sulfates, hydrosulfates, phosphates, acid phosphates, isonicotinates, acetates, lactates, salicylates, citrates, acid citric acid salts. acid salt, tartrate salt, pantothenate salt, hydrogen tartrate salt, ascorbate salt, succinate salt, cismarate salt, gentianate salt, fumarate salt, gluconate salt, glucuronate salt, glucarate salt, formate salt, benzoate salt, glutamine salt, methanesulfonate salt, ethanesulfonate salt, benzenesulfonate salt, p-toluenesulfonate salt and bis(hydroxynaphthoate) salt [i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)] salt. In addition to the acids mentioned above, the compounds described herein that include a basic moiety (such as an amine group) can also form pharmaceutically acceptable salts with various amino acids.

Chemical bases useful as reagents for preparing pharmaceutically acceptable base salts of 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, base salts 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-(methylglucamine), and lower alkanolate ammonium, and other base salts of pharmaceutically acceptable organic amines.

Hemisalts of acids and bases can also be formed, for example hemisulfates and hemicalcium salts.

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

Provided herein is a method for treating cancer, comprising administering to a subject a daily dose of a combination of Compound A having the following structure or a pharmaceutically acceptable salt thereof and a CDK4/6 inhibitor: .

Also provided herein is a method for treating cancer, comprising administering to a subject a daily dose of a combination of Compound A having the following structure and a CDK4/6 inhibitor: .

In an embodiment, the daily dose of Compound A or a pharmaceutically acceptable salt thereof having the following structure is administered once daily (QD): .

In an embodiment, the daily dose is a compound A having the following structure: , or a pharmaceutically acceptable salt thereof is orally administered to a subject.

In embodiments, the individual is in a feeding state.

In the embodiment, compound A: , or a pharmaceutically acceptable salt thereof, in a daily dose of about 200 mg, or an equivalent amount of a pharmaceutically acceptable salt thereof.

In the embodiment, compound A: or its pharmaceutically acceptable salt in a daily dose of 200 mg, or its pharmaceutically acceptable salt equivalent.

In the embodiment, compound A: The daily dose is about 200 mg.

In the embodiment, compound A: The daily dose is 200 mg.

In the embodiment, compound A: , or a pharmaceutically acceptable salt thereof, in a daily dose of about 100 mg, or an equivalent amount of a pharmaceutically acceptable salt thereof.

In the embodiment, compound A: , or its pharmaceutically acceptable salt, the daily dose is 100 mg, or its pharmaceutically acceptable salt equivalent.

In the embodiment, compound A: The daily dose is about 100 mg.

In the embodiment, compound A: The daily dose is 100 mg.

In the embodiment, compound A: It is administered as a free base.

In an embodiment, the CDK4/6 inhibitor is dapicilib, trelaciclib, lelociclib, AT7519M, denacili, ribociclib, abemaciclib or palbociclib, or a pharmaceutically acceptable salt thereof. In an embodiment, the CDK4/6 inhibitor is dapicilib, trelaciclib, lelociclib, AT7519M, denacili, ribociclib, abemaciclib or palbociclib.

In an embodiment, the CDK4/6 inhibitor is abemaciclib, ribociclib or palbociclib, or a pharmaceutically acceptable salt thereof. In an embodiment, the CDK4/6 inhibitor is abemaciclib, ribociclib or palbociclib.

In an embodiment, the CDK4/6 inhibitor is abemaciclib or a pharmaceutically acceptable salt thereof. In an embodiment, the CDK4/6 inhibitor is abemaciclib.

In an embodiment, the CDK4/6 inhibitor is ribociclib or a pharmaceutically acceptable salt thereof. In an embodiment, the CDK4/6 inhibitor is ribociclib.

In an embodiment, the CDK4/6 inhibitor is palbociclib or a pharmaceutically acceptable salt thereof. In an embodiment, the CDK4/6 inhibitor is palbociclib.

In an embodiment, Compound A is administered daily in a 28-day cycle. In certain embodiments, palbociclib or a pharmaceutically acceptable salt thereof is administered orally once a day at 125 mg per day for 21 days in each 28-day cycle, followed by 7 days of resting treatment.

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

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

In embodiments, the cancer is breast cancer, lung cancer, or prostate cancer.

In embodiments, the cancer is breast cancer.

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

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

In an embodiment, the estrogen receptor positive (ER+) breast cancer is human epidermal growth factor receptor 2 negative (HER2-) breast cancer.

In an embodiment, the subject is a human.

Also disclosed herein is compound A: or a pharmaceutically acceptable salt thereof, which is used according to any one of the aforementioned embodiments.

Also disclosed herein is compound A: or a pharmaceutically acceptable salt thereof, which is used according to any one of the aforementioned embodiments.

Also disclosed herein is compound A: Or its pharmaceutically acceptable salt in the manufacture of a medicament according to any one of the aforementioned embodiments.

Also disclosed herein is compound A: Or its pharmaceutically acceptable salt in the manufacture of a medicament according to any one of the aforementioned embodiments.

Each of the embodiments described herein may be combined with any other embodiment described herein that is consistent with the embodiment with which it is combined.

As used herein, "treat" and "treating" cancer or a cancer-related disease means administering a combination therapy according to the present disclosure to an individual, participant or patient having or 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 cells infiltrating into peripheral organs or a decrease in tumor metastasis or tumor growth rate; reversing, alleviating the disease or condition to which such terms apply, or one or more symptoms of such disease or condition; inhibiting the progression of the disease or condition or one or more symptoms of such disease or condition; or preventing the disease or condition or one or more symptoms of such disease or condition. Unless otherwise indicated, as used herein, the terms "treatment" and "therapy" refer to the act of treating, and "treatment" is defined just above. For the purposes of this disclosure, beneficial or desired clinical results include, but are not limited to, one or more of the following: reducing the proliferation of proliferative or cancer cells (destroying proliferative or cancer cells); inhibiting metastasis or proliferative cells; shrinking or reducing tumor size; relieving cancer; reducing symptoms caused by cancer; improving the quality of life of a person suffering from cancer; reducing the dosage of other drugs required to treat cancer; delaying the progression of cancer; curing cancer; overcoming one or more drug resistance mechanisms of cancer; and/or prolonging the survival of cancer patients. Active therapeutic effects on cancer can be measured in a variety of ways (see, e.g., W. A. Weber, J. Nucl. Med. (2009) 50:1S-10S).

As used herein to describe a subject in "fed condition" or "fed state" means that the subject has eaten at a time point of interest, such as less than 4 hours prior to administration of Compound A. In embodiments, the subject in a fed state has eaten within any of 4, 3, 2, 1, or 0.5 hours prior to administration of Compound A.

An "amount" for use and for treating a subject is an amount that provides a detectable response of any duration (short, intermediate or long term), any measurable or detectable degree or for any duration (e.g., for hours, days, months, years, relief or cure) in single or multiple doses in combination with one or more other agents, or a desired outcome or objective or subjective benefit to the subject. Such amounts are typically effective to ameliorate the disease, or one, more or all adverse effects/symptoms, consequences or complications of the disease to a measurable degree, but reducing or inhibiting the progression or worsening of the disease, or providing a stable (i.e., non-worsening) state of the disease is also considered a desirable outcome. The term "therapeutically effective amount" also means an amount of a drug in combination with one or more other drugs that is effective in producing the desired therapeutic effect after administration to an individual, such as preventing the growth of a cancerous tumor or causing the cancerous tumor to shrink. With respect to cancer treatment, a therapeutically effective amount refers to an amount that has the following effects: (1) reducing tumor size; (2) inhibiting (i.e., slowing down to some extent, preferably stopping) the appearance of tumor metastasis; (3) inhibiting (i.e., slowing down to some extent, preferably stopping) tumor growth or tumor invasion; and/or (4) alleviating (or preferably eliminating) to some extent one or more signs or symptoms associated with cancer. The therapeutic or pharmacological effectiveness of a dosage and administration regimen may also be characterized by the ability to induce, enhance, maintain or prolong disease control and/or overall survival, as measured by a prolongation of the time before disease progression, in patients with these particular tumors.

As used herein, the term "improvement" refers to any reduction in the extent, severity, frequency and/or likelihood of symptoms or clinical signs characteristic of a particular disease. "Symptom" refers to any subjective sign of a disease or individual's condition.

The embodiments of the present invention provide doses, dosages and dosing regimens, which include administering to a subject an amount or effective amount of Compound A or a pharmaceutically acceptable salt thereof. The amount or the therapeutically effective amount may be a daily dose of about 200 mg. In another embodiment, the daily dose is 200 mg.

In an embodiment, the daily dose of Compound A or a pharmaceutically acceptable salt thereof is administered once a day (QD).

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

In an embodiment, the daily dose of Compound A or a pharmaceutically acceptable salt thereof is administered orally.

Compound A or a pharmaceutically acceptable salt thereof may be present in the form of a pharmaceutical composition, which includes a pharmaceutically acceptable excipient. "Pharmaceutically acceptable excipient" refers to a component that can be included in the composition described herein, is physiologically suitable for pharmaceutical use, and does not cause significant adverse effects and therapeutic effects on an individual. The term "excipient" is used herein to describe any ingredient other than the compound of the present invention. The choice of 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.

The compounds of the methods, uses or combinations of the invention may be formulated prior to administration. The formulation will preferably be adapted to the particular mode of administration. The compounds may be formulated in pharmaceutically acceptable formulations known in the art and administered in a variety of dosage forms known in the art. Unit dosage 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 subdivision into individual doses.

In embodiments, palbociclib or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 125 mg once daily, about 100 mg once daily, about 75 mg once daily, about 50 mg daily, or about 25 mg daily. In embodiments, palbociclib or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 125 mg once daily. For example, palbociclib or a pharmaceutically acceptable salt thereof is administered at a dose of about 100 mg once daily, about 75 mg once daily, or about 50 mg once daily. In one embodiment, palbociclib or a pharmaceutically acceptable salt thereof is administered at a dose of about 100 mg once daily. In embodiments, palbociclib or a pharmaceutically acceptable salt thereof is administered at a dose of about 75 mg once daily. In an embodiment, palbociclib or a pharmaceutically acceptable salt thereof is administered once daily in a dose of about 50 mg. The dosages provided herein refer to the dosage of palbociclib in free base form, or are calculated as the free base equivalent of the palbociclib salt form administered. For example, the dosage or amount of palbociclib, such as 100 mg, 75 mg or 50 mg, refers to the free base equivalent.

In an embodiment, abemaciclib or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 400 mg (e.g., about 200 mg twice a day), about 300 mg (e.g., about 150 mg twice a day), about 200 mg (e.g., about 100 mg twice a day), or about 100 mg (e.g., about 50 mg twice a day). In an embodiment, abemaciclib or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 300 mg (e.g., about 150 mg twice a day), about 200 mg (e.g., about 100 mg twice a day), or about 100 mg (e.g., about 50 mg twice a day). In an embodiment, abemaciclib or a pharmaceutically acceptable salt thereof is administered at a daily dose of 300 mg (e.g., about 150 mg twice a day). In one embodiment, abemaciclib or a pharmaceutically acceptable salt thereof is administered in a dose of about 200 mg (e.g., about 100 mg twice daily). In an embodiment, abemaciclib or a pharmaceutically acceptable salt thereof is administered in a dose of about 50 mg twice daily, i.e., about 100 mg (e.g., about 50 mg twice daily). The dosages provided herein refer to the dosage of abemaciclib in free base form, or are calculated as the free base equivalent of the administered abemaciclib salt form. For example, a dosage or amount of abemaciclib, such as 200 mg, 150 mg, 100 mg, or 50 mg, refers to the free base equivalent.

In an embodiment, Reboxili or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 600 mg once a day, about 400 mg once a day, about 200 mg once a day, or about 50 mg once a day. In an embodiment, Reboxili or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 600 mg once a day. In one embodiment, Reboxili or a pharmaceutically acceptable salt thereof is administered at a dose of about 400 mg once a day. In an embodiment, Reboxili or a pharmaceutically acceptable salt thereof is administered at a dose of about 200 mg once a day. The dosages provided herein refer to the dosage of Reboxili in free base form, or are calculated as the free base equivalent of the administered Reboxili salt form. For example, the dose or amount of riboxil, such as 600 mg, 400 mg, 200 mg, refers to the free base equivalent.

Repetition of the administration or dosing regimen can be performed as needed to obtain the desired reduction or attenuation of cancer cells. As used herein, a "continuous dosing schedule" is a dosing or dosing regimen without dosage interruptions, such as without rest days for treatment. Repetition of 28-day treatment cycles without dosage interruptions between treatment cycles is an example of a continuous dosing schedule. In embodiments, the compounds in the combinations of the present invention can be administered in a continuous dosing schedule. In embodiments, the compounds in the combinations disclosed herein can be administered simultaneously in a continuous dosing schedule.

In an embodiment, Compound A is administered once daily to constitute a complete cycle of 28 days. During treatment according to the methods and uses of the present disclosure, repeated 28-day treatment cycles are continued.

The standard recommended dosing regimen for palbociclib or its pharmaceutically acceptable salt, including the standard dosing schedule, is once daily for 21 consecutive days, followed by 7 days of resting treatment to constitute a complete cycle of 28 days. The 28-day cycle is continued during treatment with the combination of the present invention.

The standard clinical dosing regimen for palbociclib or its pharmaceutically acceptable salt is 125 mg once daily for 21 consecutive days, followed by 7 days of rest for a full cycle of 28 days. The 28-day cycle is repeated continuously during treatment with the combination of the present invention.

The standard clinical dosing regimen for ribociclib or its pharmaceutically acceptable salt is 600 mg once daily for 21 consecutive days, followed by 7 days of cessation of treatment to constitute a complete cycle of 28 days. The 28-day cycle is continued during treatment with the combination of the present invention.

The present invention also relates to kits, which include therapeutic agents of the combination of the present invention and written instructions for administering the therapeutic agents. In embodiments, the written instructions detail and define the mode of administration of the therapeutic agents, such as by administering the therapeutic agents of the present disclosure simultaneously or sequentially. In embodiments, the written instructions detail and define the mode of administration of the therapeutic agents, such as by specifying the days during a 28-day treatment cycle on which each therapeutic agent is administered. Treatment Methods

In an embodiment, provided herein is a method for treating cancer in an individual, comprising administering to the individual an effective amount of Compound A as described herein in combination with an amount of a CDK4/6 inhibitor.

Unless otherwise indicated, as used herein, the term "combination" refers to the use of Compound A and one or more therapeutic agents, wherein Compound A and the one or more therapeutic agents are administered intermittently, simultaneously or sequentially according to the same or different administration routes and according to the same or different dosing schedules.

As used herein, the term "locally advanced" with respect to cancer may or may not be treated with curative intent. For example, locally advanced breast cancer (LABC) is defined by the U.S. National Comprehensive Cancer Network as a small group of breast cancers with the following characteristics: the most advanced tumors without distant metastases, where the tumor is greater than 5 cm in size with local lymph node enlargement; tumors of any size (including ulcers or satellite nodules) that extend directly to the chest wall or skin, or both, regardless of the presence of local lymph node enlargement; the presence of local lymph node enlargement (either clinically fixed or tangled axillary lymph nodes, or subclavian, supraclavicular, or intramammary lymph node enlargement), regardless of tumor stage. (Garg et al., Curr Oncol. 2015 Oct; 22(5): e409-e410; National Comprehensive Cancer Network NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. Fort Washington, PA: NCCN; 2015. Ver. 2.2015.)

As used herein, the term "metastatic" refers to cancer that cannot be treated with curative intent. For example, metastatic breast cancer refers to breast cancer that has spread beyond the breast and nearby lymph nodes to other parts of the body, such as the bones, liver, lungs, and brain. (www.cancer.org/cancer/breast-cancer.)

Those skilled in this technology will be able to identify and diagnose locally advanced and metastatic cancer in patients or individuals.

For convenience, certain well-known abbreviations may be used herein, including: castration-resistant prostate cancer (CRPC), estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-), hormone receptor (HR), human epidermal growth factor receptor 2 positive (HER2+), non-small cell lung cancer (NSCLC), and progesterone receptor (PR).

In embodiments, the cancer is selected from lung cancer, mesothelioma, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, liver cancer, colon cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, disease), esophageal cancer, small intestinal cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, hematological malignancies, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureteral cancer, renal cell cancer, renal pelvic cancer, central nervous system (CNS) tumors, primary CNS lymphoma, spinal tumors, neuroglioblastoma, brain stem neurogliomas, pituitary adenomas, head and neck cancer, and combinations of two or more of the foregoing cancers.

Also disclosed herein are methods of treating cancer in an individual. In embodiments, the methods comprise treating cancer in an individual comprising administering to the individual an amount of a compound described herein effective to treat the cancer.

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

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

In embodiments, the cancer is breast cancer, lung cancer, or prostate cancer.

In embodiments, the cancer is breast cancer.

In embodiments, the breast cancer is metastatic breast cancer.

In embodiments, the breast cancer is locally advanced breast cancer.

In embodiments, the breast cancer is HR+ breast cancer.

In embodiments, the HR+ breast cancer is PR+ and/or ER+ breast cancer.

In embodiments, the breast cancer is PR+ breast cancer.

In embodiments, the breast cancer is ER+ breast cancer.

In embodiments, the breast cancer is ER+HER2- breast cancer.

In embodiments, the breast cancer is ER+HER2+ breast cancer.

In embodiments, the breast cancer is locally advanced or metastatic ER+ breast cancer.

In embodiments, the breast cancer is locally advanced or metastatic ER+HER2- breast cancer.

In embodiments, the breast cancer is locally advanced or metastatic ER+HER2+ breast cancer.

In embodiments, the breast cancer is metastatic ER+HER2- breast cancer.

In embodiments, the breast cancer is metastatic ER+HER2- breast cancer that is also locally advanced.

In an embodiment, the lung cancer is non-small cell lung cancer.

In embodiments, the lung cancer is locally advanced or metastatic non-small cell lung cancer.

In embodiments, the prostate cancer is CRPC.

In embodiments, the prostate cancer is locally advanced or metastatic CRPC.

Also disclosed herein are methods of treating a solid tumor in a subject. In embodiments, disclosed herein are methods of treating a solid tumor in a subject, comprising administering to the subject an amount of a compound described herein effective to treat the solid tumor.

In embodiments, the solid tumor is breast cancer, lung cancer, colon cancer, brain cancer, head and neck cancer, prostate cancer, stomach cancer, pancreatic cancer, ovarian cancer, melanoma, endocrine cancer, uterine cancer, testicular cancer, or bladder cancer.

In embodiments, the solid tumor is breast cancer, lung cancer, prostate cancer, pancreatic cancer, or ovarian cancer.

In embodiments, the solid tumor is breast cancer, lung cancer, or prostate cancer.

In embodiments, the entity tumor is breast cancer. For example, in certain embodiments, the breast cancer is HR+ breast cancer. In other embodiments, the HR+ breast cancer is PR+ and/or ER+ breast cancer.

In embodiments, the solid tumor is breast cancer. For example, in certain embodiments, the breast cancer is ER+HER2- breast cancer.

In embodiments, the solid tumor is breast cancer. For example, in certain embodiments, the breast cancer is ER+HER2+ breast cancer.

In embodiments, the solid tumor is breast cancer. For example, in certain embodiments, the breast cancer is locally advanced or metastatic ER+ HER2- breast cancer.

In embodiments, the solid tumor is breast cancer. For example, in certain embodiments, the breast cancer is locally advanced or metastatic ER+ HER2+ breast cancer.

In embodiments, the solid tumor is lung cancer. For example, in certain embodiments, the lung cancer is non-small cell lung cancer.

In embodiments, the solid tumor is lung cancer. For example, in certain embodiments, the lung cancer is locally advanced or metastatic non-small cell lung cancer.

In embodiments, the solid tumor is prostate cancer. For example, in certain embodiments, the prostate cancer is CRPC.

In embodiments, the solid tumor is prostate cancer. For example, in certain embodiments, the prostate cancer is locally advanced or metastatic castration-resistant prostate cancer.

Also disclosed herein are methods of treating a blood tumor in a subject. In embodiments, the method comprises treating a blood tumor in a subject, comprising administering to the subject an amount of a compound described herein effective to treat the blood tumor.

In embodiments, the hematological tumor is leukemia, lymphoma or multiple myeloma.

In embodiments, the hematological tumor is a leukemia or a lymphoma.

Also disclosed herein are methods of treating cancer in an individual with locally advanced or metastatic ER+ HER2- breast cancer, CRPC, or NSCLC whose disease has progressed following or is intolerant to standard therapy.

Also disclosed herein are methods of treating cancer in an individual with locally advanced or metastatic ER+ HER2- breast cancer, CRPC, or NSCLC whose disease has progressed following or is intolerant to standard therapy.

Also disclosed herein are methods of treating cancer in an individual with locally advanced or metastatic 2L+ ER+ HER2 breast cancer who has received prior hormonal/endocrine therapy and chemotherapy in the locally advanced/metastatic setting. In embodiments, the method comprises administering to the individual a combination of Compound A and a CDK4/6 inhibitor.

Also disclosed herein are methods of treating cancer in an individual with locally advanced or metastatic 2L+ ER+ HER2 breast cancer who has received prior treatment with a CDK4/6 inhibitor. In embodiments, the method comprises administering to the individual a combination of Compound A and a CDK4/6 inhibitor.

Also disclosed herein are therapeutic combinations comprising: (i) Compound A: (Compound A), or a pharmaceutically acceptable salt thereof; and (ii) a CDK4/6 inhibitor; the therapeutic combinations are used simultaneously, independently or sequentially in a method for treating cancer; wherein the method comprises administering a daily dose of Compound A or a pharmaceutically acceptable salt thereof.

Also disclosed herein are therapeutic combinations comprising: (i) Compound A: (Compound A); and (ii) a CDK4/6 inhibitor; the therapeutic combinations are used simultaneously, independently or sequentially in a method for treating cancer; wherein the method comprises administering a daily dose of Compound A.

Also disclosed herein is compound A: (Compound A), or a pharmaceutically acceptable salt thereof, for use in a method for treating cancer, wherein the method comprises administering Compound A or a pharmaceutically acceptable salt thereof, and wherein the method further comprises administering a CDK4/6 inhibitor.

Also disclosed herein is compound A: (Compound A) for use in a method for treating cancer, wherein the method comprises administering Compound A, and wherein the method further comprises administering a CDK4/6 inhibitor.

Also disclosed herein is a CDK4/6 inhibitor for use in a method for treating cancer, wherein the method further comprises administering Compound A or a pharmaceutically acceptable salt thereof.

Also disclosed herein is a CDK4/6 inhibitor for use in a method for treating cancer, wherein the method further comprises administering Compound A.

In an embodiment, the method comprises administering a daily dose of about 200 mg of Compound A or an equivalent amount of a pharmaceutically acceptable salt thereof. In an embodiment, the method comprises administering a daily dose of about 200 mg of Compound A. In an embodiment, the method comprises administering a daily dose of about 100 mg of Compound A. Example

In order to better understand the present invention, the following examples are described. These examples are only for illustrative purposes and should not be interpreted as limiting the scope of the present invention in any way.

Abbreviations used in this article include: ● AUC _0-8 = area under the plasma concentration-time curve from zero to 8 hours; ● AUC _0-12 = area under the plasma concentration-time curve from 0 to 12 hours; ● AUC _τ = area under the plasma concentration-time curve during the dosing interval, where τ = 24 hours for once-daily dosing and 12 hours for twice-daily dosing; ● BID = twice daily; ● BMI = body mass index; ● CI = confidence interval; ● CR = complete response ● CBR = clinical benefit rate; ● C _max = maximum plasma concentration; ● DDI = drug-drug interaction; ● ER = estrogen receptor; ● GCV = geometric coefficient of variation; ● HER2 = human epidermal growth factor receptor 2; ● FIH=First in Human; ● IR=Immediate Release; ● mBC=Metastatic Breast Cancer; ● MTD=Maximum Tolerated Dose; ● ORR=Overall Response Rate; ● PPI=Proton Pump Inhibitor; ● PR=Partial Response● rBA=Relative Bioavailability Rate; ● RP2D=Recommended Phase 2 Dose; ● QD=Once Daily; ● SA=Single Agent; ● SD=Stable Disease; and ● TRAE=Treatment Related Adverse Event. Compound A Clinical Trials ( “ FIH Studies” and “ Clinical Pharmacology Studies” ) First in Human (“FIH”) Studies

Compound A is being studied in an ongoing Phase 1/2, open-label, dose-escalation and cohort expansion study to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of the combination of Compound A and palbociclib (IBRANCE®) in patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+/HER2-) locally advanced or metastatic breast cancer who have received prior hormonal therapy and chemotherapy in the locally advanced/metastatic setting. An overview of the FIH study is provided in Table 1 below.

The FIH study will evaluate the safety and tolerability of the combination of Compound A and Palbociclib in patients with locally advanced or mBC and determine its MTD and/or RP2D. The study will also evaluate the clinical activity of Compound A at the RP2D in combination with Palbociclib. Additional evaluations will include single-dose and multiple-dose pharmacokinetic and biochemical activity.

Study Design: Part C of the FIH study is a Phase 1b study evaluating the combination of Compound A and Palbociclib. Administration Methods

The combination of Compound A and palbociclib (Part C) was administered orally in a 28-day cycle at the doses shown in Table 1. Compound A was supplied as immediate-release tablets in 10 mg, 50 mg, and 100 mg strengths. The tablet formulation was an inert pharmacopoeial component commonly used in oral formulations, including lactose monohydrate and sodium stearyl fumarate.

Palbociclib was administered orally at 125 mg once daily for 21 days of each 28-day cycle according to the product label and in accordance with local prescribing information, followed by 7 days of treatment cessation.

As of the data cutoff date of June 6, 2022, 176 patients have been treated in the FIH study (Part C, n=27) and preliminary evidence of clinical activity has been observed. Table 1. Overview of Part C FIH study Research Title Study Design Research Group Evaluation of Compound A treatment group Phase 1/2, open-label, dose-escalation and cohort expansion trial evaluating the safety, tolerability, and pharmacokinetics of Compound A alone and in combination with palbociclib (IBRANCE®) in patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+/HER2-) locally advanced or metastatic breast cancer who have received prior hormonal therapy and chemotherapy in the locally advanced/metastatic setting FIH, open label, continuous arm, dose escalation 3+3 and cohort expansion consist of the following: Part C - Phase 1b Compound A + Palbociclib combination Patients with histologically or cytologically confirmed ER+/HER2- metastatic, recurrent or locally advanced unresectable breast cancer for which standard curative therapy is no longer effective or does not exist Age: ≥18 years Part C - Phase 1b Combination with Palbociclib: ● 180 mg ^a , 200 mg, 400 mg or 500 mg QD Compound A + Palbociclib: 125 mg QD orally for 21 days, followed by a 7-day off-treatment period a Patients initially enrolled in this cohort received 180 mg QD, but this dose was rounded up to 200 mg QD based on the availability of 100 mg tablets.

Compound A is being studied in an ongoing Phase 1 clinical pharmacology study to evaluate the effects of food or PPI (esomeprazole) on the single-dose PK and safety of Compound A in healthy postmenopausal female volunteers ("Participants"). A summary of the clinical pharmacology study is provided in Table 2 below.

Study Design: The clinical pharmacology study consisted of 3 independent cohorts: 1) an open-label, randomized, 2-period crossover fed/fasted cohort to determine food effects; 2) an open-label, 2-period, fixed-sequence PPI cohort to evaluate interactions with esomeprazole; and 3) an open-label, randomized, 2-period crossover rBA cohort to evaluate 2 tablet formulations.

As of the data cutoff date of June 16, 2022, 47 participants have been treated in 3 clinical pharmacology study cohorts. (14 participants in the fed/fasted cohort, 17 participants in the PPI cohort, and 16 participants in the rBA cohort). Each participant received 2 doses of 200 mg of Compound A, 1 dose in each of 2 phases, and Compound A treatments were separated by a washout period of at least 14 days.

Compound A at a dose of 200 mg was well tolerated by participants, and no TRAEs of grade 2 or higher were reported. Table 2. Summary of Clinical Pharmacology Studies Research Title Study Design Research Group Evaluation of Compound A treatment group A Phase 1, multipart, open-label study to evaluate the effects of food or a proton pump inhibitor (esomeprazole) on the pharmacokinetics and safety of a single dose of Compound A and to evaluate the relative bioavailability of different tablet formulations in healthy postmenopausal female volunteers Open label study with 3 separate parts: Fasting/Fed: 2-period, crossover fed/fasting cohort to determine food effects PPI: 2-period, fixed sequence PPI cohort to evaluate interactions with esomeprazole rBA: Randomized, 2-period, crossover rBA cohort to evaluate 2 tablet formulations Healthy postmenopausal women with a BMI of 18.5 to 35.0 kg/ ^m2 and a weight of 50 to 120 kg (inclusive). Age: 18 to 70 years old Each dose cohort received 200 mg of Compound A after a 10-hour overnight fast. Fed/Fasting Cohort: Compound A was administered on Days 1 and 15: ● Fasting Phase: Continue fasting for at least 4 hours after dosing ● Fed Phase: Compound A was administered 30 minutes after the start of a high-fat meal, followed by a fast of at least 4 hours after Compound A administration PPI Cohort: ● Single-Dose Phase: ^Compound A was administered in the fed state on Days 1 and 19 ● Continuous Dosing Phase: Esomeprazole delayed-release capsules (40 mg QD) were taken at least 1 hour before meals for 5 days from Days 15 to 19. On Day 19, Compound A was administered at least 90 minutes after esomeprazole in the fed state. ^rBA Cohort: On Days 1 and 15, 200 mg of Compound ^A was administered in the fed state at 20% (reference) or 42% (test) drug loading. c Study drug was administered 30 minutes after the start of a moderate fat meal, followed by a fast of at least 4 hours after Compound A administration. Example 1 : Pharmacokinetics (PK) in Breast Cancer Patients (FIH Study )

Preliminary PK data from Part C of the FIH study (Compound A administered together with palbociclib) were obtained at dose levels ranging from 180 mg to 500 mg QD. Preliminary results indicate that there was a dose-dependent increase _{in Cmax} and _AUCτ for Compound A, Compound B, and the sum of Compound A+Compound B administered up to 500 mg QD on Day 1 and Day 15 of Cycle 1. The clinical DDI potential between Compound A and palbociclib was evaluated by comparing the plasma PK exposure parameters ( _Cmax and _AUCτ ) of palbociclib and Compound A obtained in Part C on Day 15 of Cycle 1 with the relevant PK data observed in previously completed studies administering palbociclib or Compound A as a single agent. The PK data obtained from Part C indicated that palbociclib had no effect on Compound A exposure, as evidenced by the C _max and AUC _τ of Compound A in patients receiving Compound A plus palbociclib being similar to those parameters in patients receiving Compound A monotherapy. On the other hand, the preliminary _Cmax and _AUCτ of palbociclib after administration of 125 mg QD palbociclib in combination with 500 mg QD Compound A on Day 15 of Cycle 1 were approximately 18% to 25% and 34%, respectively, which were higher than those observed with 125 mg QD palbociclib in Studies PALOMA-1 and PALOMA-2 (Pfizer. IBRANCE ^® (palbociclib). Product Monograph Including Patient Medication Information. Kirkland, Quebec: Pfizer Canada ULC; Revised: July 15, 2021. Available at: www.pfizer.ca/sites/default/files/202107/Ibrance_PM_EN_243405_15-Jul-2021.pdf; Durairaj C, Ruiz-Garcia A, Gauthier ER et al., Palbociclib has no clinically relevant effect on the QTc interval in patients with advanced breast cancer. Anticancer Drugs. 2018 Mar;29(3):271280). Further evaluation of the DDI potential between palbociclib and compound A is ongoing. Example 2 : Pharmacokinetics (PK) in healthy volunteers ( clinical pharmacology study )

In the clinical pharmacology study, preliminary PK parameters were calculated for all three cohorts after administration of a single dose of 200 mg of Compound A. The median _Tmax for each cohort ranged from 6.0 hours to 8.0 hours. The geometric mean T1 _/2 after administration of a single dose of 200 mg was approximately 40 hours under fed conditions.

Statistical analysis showed that food intake significantly increased the C _max and AUC _inf of Compound A by 3 to 2 times, respectively, compared to fasting conditions. Therefore, patients should be instructed to take Compound A with food. The AUC values of Compound A were similar when administered with or without PPI, but PPI reduced the median C _max of Compound A by approximately 18%, which is not considered clinically significant. This indicates that PPI has no effect on the exposure of Compound A when administered with a moderate fat meal. Example 3 : Safety in healthy volunteers ( clinical pharmacology study )

Adverse events (AEs) were coded according to the Medical Dictionary for Regulatory Activities (MedDRA), version 24.1, for system organ class and preferred terminology. The severity of AEs was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.0.

Treatment-emergent adverse events (TEAEs) were AEs occurring after the first dose of Compound A and within 30 days of the last dose of Compound A, regardless of study drug attribution or grade.

Treatment-related adverse events (TRAEs) were AEs assessed by the investigator as “possibly related”, “probably related”, or “related” to Compound A. Treatment-emergent adverse events (TEAEs)

In the ongoing clinical pharmacology studies (all cohorts), TEAEs were observed in 15 of 47 participants treated with 200 mg Compound A, regardless of study drug attribution and class.

Fasting/Feeding Cohort (n=14): The most common TEAE observed in ≥10% of participants (regardless of whether it was attributed to study medication) was ligament sprain (2 participants, 14.3%). All other TEAEs were reported in <10% of participants.

All participants in the fasting/fed cohort who reported TEAEs experienced Grade 1 (21.4%) or 2 (14.3%) TEAEs. No participant reported Grade 3 or higher TEAEs.

There were no clinically significant differences in TEAEs reported between participants treated with Compound A under fasting and fed conditions.

PPI Cohort (n=17): The most common TEAEs observed in ≥10% of participants (regardless of whether attributed to study drug) were headache (5 participants, 29.4%) and COVID-19 (2 participants, 11.8%).

All participants in the PPI cohort who reported TEAEs experienced Grade 1 (47.1%) or Grade 2 (5.9%) TEAEs. No participant reported Grade 3 or higher TEAEs.

There were no clinically significant differences in TEAEs reported in participants treated with Compound A and a PPI and those treated with Compound A and no PPI.

rBA Cohort (n=16): Only 1 participant (6.3%) reported a TEAE (dizziness, Grade 1). There were no clinically significant differences in TEAEs reported in participants treated with 20% of the drug load and those treated with 42% of the drug load. Treatment-Related Adverse Events (TRAEs)

A total of 3 of the 47 participants experienced at least 1 TEAE (regardless of severity) that was considered possibly related to Compound A.

Fasting/Fed Cohort (n=14): TRAE frequency of urine was reported by 1 participant (7.1%).

PPI cohort (n=17): 2 participants (11.8%) reported at least 1 TRAE. Reported TRAEs included nausea, headache, and itching (1 participant [5.9%] each).

rBA cohort (n=16): No participant reported TRAEs. Serious adverse events (SAEs) , serious adverse drug reactions (SARs) , and deaths

No SAEs, SARs, or deaths were reported in the clinical pharmacology studies (all cohorts). Treatment-emergent adverse events (TEAEs) leading to study discontinuation

One healthy participant reported a TEAE that led to discontinuation of the clinical pharmacology study. This participant was in the PPI cohort, treated with 200 mg of Compound A and was not on PPI therapy, and was unable to receive a second dose of Compound A and a PPI due to COVID. Example 4 : Safety and Efficacy in Breast Cancer Patients (FIH Study ) I. Safety in Breast Cancer Patients (FIH Study )

TEAEs and TRAEs in the clinical research database were coded using MedDRA version 22.0 for system organ class and preferred terminology, and SAEs in the centralized safety database were coded using MedDRA version 25.0. The severity of adverse events was graded according to NCI CTCAE version 5.0.

TEAEs were AEs occurring after the first dose of Compound A and within 30 days of the last dose of Compound A, regardless of study drug attribution or grade.

TRAEs were assessed by the investigator as “possibly related,” “probably related,” or “related” to Compound A.

Preliminary safety data from the FIH study are presented below. Part C continues to enroll. Adverse Event Summary

Based on the data cutoff date of June 6, 2022, TEAEs were observed in 157 of a total of 176 patients treated with Compound A in the ongoing FIH study (all parts), regardless of study drug attribution and grade. Compound A Combination Therapy - Part C

Preliminary safety data obtained from evaluating patients treated with the combination of Compound A and palbociclib showed TEAEs consistent with those observed following treatment with Compound A and palbociclib alone (Pfizer. IBRANCE ^® (palbociclib). US FDA Package Insert. Capsules, for oral use: Full Prescribing Information. New York, NY: Pfizer Laboratories; Revised: 04/2019. Available at: www.accessdata.fda.gov/drugsatfda_docs/label/2019/207103s008lbl.pdf).

Based on the data cutoff date of June 6, 2022, a total of 24 of 27 patients (88.9%) reported at least 1 TEAE in Part C.

The most common TEAEs observed in ≥20% of patients (regardless of whether attributed to study drug) included decreased neutrophil count (51.9%), fatigue (44.4%), decreased neutrophil count (37.0%), decreased platelet count (33.3%), anemia (29.6%), nausea (25.9%), cough (22.2%), diarrhea (22.2%), and leukocytopenia (22.2%). Compound A Combination Therapy—Part C—Combination of Compound A + Palbociclib:

Based on the data cutoff date of June 6, 2022, a total of 7 SAEs were reported by 5 of 27 patients. All SAEs reported in Part C were assessed by the investigator as not related to Compound A. One Grade 3 bacteremia SAE was assessed by the investigator as possibly related to palbociclib treatment. II. Efficacy in Breast Cancer Patients (FIH Study )

For Part C, efficacy data collection continues .

Without wishing to be bound by theory, based on the foregoing examples, a 200 mg daily dose may be beneficial for Compound A administered in combination with a CDK4/6 inhibitor. Example 5 : TACTIVE-U : A Phase 1b /2 Comprehensive Study of Compound A as a Proteolytic Targeting Chimera (PROTAC) Estrogen Receptor (ER) Degrader in Combination with Other Anticancer Therapies in ER+ Advanced or Metastatic Breast Cancer

Eligible patients for Substudies A and B are ≥18 years of age with histologically or cytologically confirmed ER+/HER2- advanced or metastatic breast cancer that is not amenable to surgical resection and has ≥1 measurable lesion and has received ≤2 lines of prior therapy for advanced or metastatic disease, including 1 line of any CDK4/6 inhibitor-based regimen. In Substudy A, patients will receive Compound A orally administered once daily (QD) and abemaciclib orally administered twice daily (BID) continuously in a dose-escalating/de-escalating regimen. In Substudy B, patients will receive Compound A administered orally QD and reboxil administered orally QD in a dose-escalating/decreasing regimen; Compound A will be given continuously, while reboxil will be given for 21 days, followed by a 7-day treatment break. For both substudies, the primary endpoint of the Phase 1b portion is dose-limiting toxicity, which will be used to determine the recommended Phase 2 dose for the combination of Compound A with either abemaciclib or reboxil. Secondary endpoints for Phase 1b are progression-free survival (PFS), antitumor activity (overall response rate [ORR], clinical benefit rate [CBR], and duration of response [DOR]), safety (type, frequency, and severity of adverse events and laboratory abnormalities), and plasma concentrations of study drug; AUC _τ and C _max of Compound A +/- Riboxil will be measured in Substudy B. Phase 2 further evaluates the antitumor activity of these combinations; the primary endpoint is ORR and secondary endpoints include overall survival, PFS, antitumor activity (CBR and DOR), safety, plasma concentrations of study drug, and changes in circulating tumor DNA.

As of the data cutoff date of June 6, 2023, 4 patients received 200 mg QD Compound A and 150 mg BID abemaciclib in Substudy A and 2 patients received 100 mg QD Compound A and 600 mg QD ribociclib in Substudy B. Example 6 : Potentiation of the Combination of Compound A and CDK4/6 Inhibitors in ER+ Breast Cancer Models Methods Live Cell Imaging Proliferation Assay

MCF7 or T47D cells were seeded in 6-well plates and treated with the indicated concentrations of compounds. The plates were then placed in the Incucyte® S3 Live Cell Analysis System and images were acquired every 4 hours for a total of 5 days. Data were analyzed using Incucyte® Software v2020C, whereby cell surface area coverage was quantified as confluence values. Relative growth was calculated for all time points under all growth conditions relative to the confluence values observed for the control at 120 hours ( Figures 1A and 1C ). GraphPad Prism (GraphPad Software) was used for plotting and statistical analysis.

In MCF7 and T47D cells treated for 5 days with Compound A or Fulvestrant at concentrations close to their respective GI _50s as monotherapy or in combination with abemaciclib, Compound A, abemaciclib, and the combination caused a mean reduction in MCF7 cell growth of 41%, 49%, and 65%, respectively, relative to control cells (Figures 1A-1B). The mean reduction in MCF7 cell growth was 48% and 68% for Fulvestrant and Fulvestrant + abemaciclib, respectively. The mean reduction in T47D cell growth caused by Compound A, abemaciclib, and the combination was 42%, 32%, and 63%, respectively, and Fulvestrant and Fulvestrant + abemaciclib caused a mean reduction of 16% and 50%, respectively (Figures 1C-1D). Similar results were produced by treatment with Compound A and Reboxil as single agents or in combination. After 5 days of treatment at concentrations close to their respective GI _50s , Compound A, Reboxil and their combination caused an average decrease in MCF7 cell growth of 41%, 44% and 63%, respectively (Figures 1E-1F); Compound A, Reboxil and their combination caused an average change in T47D cell growth of 41%, 32% and 61%, respectively (Figures 1G-1H). When compared to either single agent alone, the combination of Compound A with Abemaciclib or Reboxil showed significantly stronger inhibitory effects on the growth of MCF7 and T47D cells. These results were similar to those observed with fulvestrant when combined with abemaciclib or ribociclib.

When compared to single-agent Compound A activity (105% TGI) in this model ( Figure 5 ), the combination of Compound A and palbociclib caused tumor regression (131% TGI). In contrast, subcutaneously administered single-agent fulvestrant caused only a modest TGI (46% TGI), while the combination of fulvestrant and palbociclib caused increased tumor growth inhibition (108% TGI), but not to the level achieved with Compound A and palbociclib. Similar results were observed in a tamoxifen-resistant xenograft model, where the combination of Compound A and palbociclib caused a stronger TGI compared to either single agent alone.

The in vivo effects of the combination of Compound A or Fulvestrant and Abemaciclib were also evaluated in mice bearing MCF7 tumors. As single agents, Compound A and Abemaciclib treatment caused 88% and 50% TGI, respectively, while their combination caused a higher growth inhibition (111% TGI) than either single agent alone ( Figure 3A ). Fulvestrant showed a moderate TGI (42%) as a single agent and an enhanced TGI (77%) when combined with Abemaciclib. However, the TGI observed with the combination of Fulvestrant and Abemaciclib did not reach the level observed with the combination of Compound A and Abemaciclib.

Compound A and ribociclib used as single agents induced 87% TGI and 58% TGI, respectively, in treating MCF7 tumor-bearing mice, while their combination induced a higher TGI (124%) than either agent alone ( Figure 3B ). Fulvestrant showed a modest TGI (31%) as a single agent and an enhanced TGI (76%) when combined with ribociclib, but did not reach the levels achieved with the combination of Compound A and ribociclib, similar to the observations with the combination of fulvestrant and abemaciclib.

In summary, these results show that in the BC tumor model, Compound A exhibited antitumor activity as a single agent and in combination with the CDK4/6 inhibitors abemaciclib and ribociclib exhibited higher antitumor activity, and exhibited higher antitumor effects than those observed with the combination of fulvestrant and any of these CDK4/6 inhibitors. Dose - Response Matrix Analysis

Cells were seeded in 96-well plates at 2×10 ³ cells in 200 μl of medium per well and incubated overnight at 37°C. Compound A and abemaciclib concentration curves were 8-point concentration curves starting at 100 nM and ranging from 100 nM to 0.046 nM ( Figures 2A , 2C , and B ). Reboxil concentration curves were 8-point concentration curves starting at 3000 nM and ranging from 3000 nM to 1.37 nM ( Figure 2B ). On day 5, cell viability was measured using Cell-Titer Glo and CTG data were analyzed using Combenefit software (Veroli GYD, Fornari C, Wang D, Mollard S, Bramhall JL, Richards FM et al., Combenefit: an interactive platform for the analysis and visualization of drug combinations. Bioinformatics. 2016;32:2866-8). Combinations of abemaciclib or reboxiclib with Compound A showed enhanced cell growth inhibition compared to single-agent treatment and induced synergistic effects in the Brise, Lowy, and HSA models, except for the Brise model used in T47D cells. MCF7 xenograft model

Briefly, MCF7 cells were orthotopically implanted into the mammary fat pad of NOD/SCID female mice. 2-3 days prior to implantation of MCF7 cells, 0.72 mg of a 90-day timed-release 17β-estradiol pellet (Innovative Research of America) was implanted. For the combination arm, Compound A was administered first, followed by the combination partner 1 hour later. Compound A-treated mice and/or combination partner-treated mice were orally dosed once daily. Fulvestrant-treated mice were subcutaneously dosed twice a week for 2 weeks, followed by once a week for 2 weeks.

More specifically, the synergistic effects of Compound A with abemaciclib and reboxiclib were followed in vivo using the MCF7 orthotopic xenograft model. Female NOD/SCID mice, eight to ten weeks of age, were surgically implanted subcutaneously with a 0.36 mg 90-day time-release 17β-estradiol pellet. One to two days later, 5×10 6/200 µL MCF7 cells were injected into one mammary fat pad of each mouse. Cells were prepared at 25× ^{10 6 cells} /mL in a 50/50 mixture of phenol red-free RPMI-1640 medium/Corning Matrigel membrane matrix. Dosing was initiated after tumors reached an average of 200 mm ³ . In the case of oral combination administration, Compound A (30 mg/kg) was administered first and abemaciclib (30 mg/kg) and reboxiclib (75 mg/kg) were administered 30-60 minutes later. Fulvestrant (200 mg/kg, subcutaneous; twice a week for 2 weeks, then once a week for 2 weeks) as a single agent and in combination with abemaciclib and reboxiclib were also evaluated. The designated drugs were administered to 10 mice/arm as a single agent or in combination. Compound A and abemaciclib and reboxiclib were administered once daily for 28 days (qdx28) in a volume of 5 ml/kg. The vehicle used for Compound A was 2% Tween 80/PEG400. The vehicle for abemaciclib was 1% hydroxymethylcellulose (HEC) in 20 mM HCl pH 2. The vehicle for ribociclib was 0.5% methylcellulose. The vehicle for fulvestrant was 10% w/v ethanol, 10% w/v benzyl alcohol, 15% w/v benzyl benzoate, made 100% w/v with castor oil. A one-day dosing holiday was implemented for all arms if any weight loss approached 10% (Days 11, 12, 19, and 20 for the ribociclib study). Weight was well maintained during the one-day dosing holiday ( Figures 4A and 4B ). In the efficacy study, tumor volume was measured twice a week and calculated using ( ^width2 × length)/2, where all measurements are in millimeters (mm) and tumor volume is in ^mm3 . Body weight was recorded twice a week. At study termination, mice were euthanized 18 hours after the last dose and the collected tissues were snap-frozen on dry ice. Tumor growth inhibition (TGI) was calculated as follows, where tumor volume is in ^mm3 : TGI (%) = [ 1- ( Tumor volume on day X , compound ) - ( Tumor volume on day 0 , compound ) ] × 100 ( Tumor volume on day X , vehicle ) - ( Tumor volume on day 0 , vehicle )

At the end of the abemaciclib study, single-agent Compound A and abemaciclib inhibited tumor growth by 88% and 50%, respectively. The combination of Compound A and abemaciclib caused a growth inhibition rate of 111%. Fulvestrant inhibited tumor growth by 42% as a single agent and 77% in combination with abemaciclib.

At the end of the ribociclib study, single-agent Compound A and ribociclib inhibited tumor growth by 87% and 58%, respectively. The combination of Compound A and ribociclib caused a growth inhibition rate of 124%. Fulvestrant inhibited tumor growth by 31% as a single agent and 76% in combination with ribociclib.

Data are presented as mean ± standard error of the mean .

In vitro studies revealed evidence of synergistic interactions between Compound A and the CDK4/6 inhibitors abemaciclib and reboxiclib. Figures 1 and 2 show that the combination of Compound A and CDK4/6 inhibitors ( i.e. , abemaciclib and reboxiclib) exhibited enhanced efficacy and evidence of in vitro synergy.

The combination of Compound A and the CDK4/6 inhibitors abemaciclib and ribociclib caused enhanced tumor regression in MCF7 xenografts compared to either agent alone.

Compound A, when combined with abemaciclib or ribociclib, exhibited anti-tumor activity greater than that observed with the combination of fulvestrant with these agents.

Overall, these data highlight the potential utility of Compound A as a combination partner with clinically relevant targeted agents for the treatment of both early and advanced ER+ disease. Example 6 : Brief summary of studies conducted in China studying Compound 1 in individuals with ER+/HER2- advanced breast cancer

The purpose of this clinical trial is to study the pharmacokinetics, safety and tolerability of compound 1 for the potential treatment of advanced estrogen receptor-positive and human epidermal growth factor receptor 2-negative breast cancer.

This study seeks participants who: - Have ER+/HER2- advanced breast cancer - Received at least 1 line of endocrine therapy with or without CDK4/6 inhibitors - Received up to 2 prior chemotherapy regimens in the advanced setting

All participants in this study will receive Compound A.

Compound A will be administered orally once a day at home.

The experiences of the individuals who received the study drug will be examined. This will help determine if the study drug is safe and effective.

Participants will be in this study until their cancer no longer responds. During this time, they will visit the study clinic approximately every 4 weeks.

All participants will stay in the research clinic for 10 days and 9 nights. Study Type: Interventional Study Phase: Phase 1 Study Arm: One Study Arm Blind: Unblinded Number of Enrolled: 9 Interventional Arm Title Type describe Rosuvastatin, with and without Compound A Experimental Intervention Name Type Related Arm describe Other Names Compound A Drugs Compound A For monotherapy as defined in Study ARV-471-mBC-101, Compound A will be administered orally once daily at RP3D with food (e.g., a light meal of approximately 400 to 600 calories, including a mixture of fat, carbohydrate, and protein) for continuous dosing over a 28-day cycle. Result measurement Result measurement Time range describe Single dose Cmax (maximum plasma concentration) 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours after administration, until day 71 Maximum plasma concentration Single dose AUCτ 0, 1, 2, 3, 4, 6, 8, 12 hours after administration, until day 71 The area under the concentration-time curve from time zero to the dosing interval τ (tau), where τ = 24 hours (QD dosing) Multiple dose Cmax 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours after administration Maximum observed plasma concentration (Cmax) Multiple dose AUCτ 0, 1, 2, 3, 4, 6, 8, 12 hours after administration The area under the concentration curve (AUCτ) from time 0 to the end of the dosing interval, where the dosing interval is 12 hours. Secondary outcome measures Result measurement Time range describe Objective response rate - the percentage of participants who responded objectively Baseline to 24 weeks Percentage of participants with an objective response based on confirmed complete response (CR) or confirmed partial response (PR) as assessed by Response Evaluation Criteria in Solid Tumors (RECIST). Confirmed response is based on a response maintained for at least 4 weeks after the initial documented response on repeat imaging studies. Per RECIST v1.1: CR defined as complete disappearance of all target lesions and non-target disease, excluding nodular disease. All target and non-target nodules must be reduced to normal (<10 mm in the short axis). No new lesions. PR defined as a >= 30% decrease from baseline in the percentage of participants with an objective response based on a complete response (CR) or partial response (PR) as assessed by Response Evaluation Criteria in Solid Tumors (RECIST). Percentage of participants with clinical benefit Baseline to 24 weeks Percentage of participants with complete response (CR), partial response (PR), or stable disease (SD) confirmed by RECIST for at least 24 weeks on study. Per RECIST v1.1: CR defined as complete disappearance of all target lesions and non-target disease, excluding nodular disease. All target and non-target nodules must be reduced to normal (short axis <10 mm). No new lesions. PR defined as >= 30% reduction in the sum of the diameters of all target lesions compared to baseline. The short axis is used in the sum of target nodules, while the longest diameter is used in the sum of all other target lesions. No significant progression of non-target disease. No new lesions. SD defined as not meeting CR, PR, progressive disease (PD). Duration of objective response (DOR) From the date of first recorded response (CR or PR) to the date of first recorded progression or death DOR: The time from the date of the first recorded response (CR or PR) to the first recorded progression or death caused by the underlying cancer. RECIST V1.1, a) CR: All lesions disappear; the short axis of any pathological lymph node (TL) or non-pathological lymph node (non-TL) must be reduced to <10 mm; for non-TL, the level of tumor markers returns to normal; b) PR: With reference to the sum of baseline diameters, the sum of the diameters (dia) of all TLs has a ≥=30% decrease; c) PD: The sum of the diameters of all measured target lesions has a ≥=20% increase, with the sum of the smallest diameters of all target lesions recorded at or after baseline as a reference, and the sum must also have an absolute increase of ≥=5 mm. Significant progression of existing non-target lesions. Appearance of at least 1 new lesion. Participants with a CR or PR were censored at the last appropriate tumor assessment date if they had no PD or death due to the underlying cancer. Presence (ratio) or absence of blood biomarkers Baseline until end of treatment Identify biomarkers for complete response and progression (if present) (ESR1 mutation) Number of participants with noteworthy electrocardiogram (ECG) values From baseline until 28 days after the last dose of study drug The criteria for noteworthy ECG values are as follows: new (newly occurring post-baseline) QT interval (in milliseconds [msec]) greater than (>) 450, 480, 500, increase >30 from baseline, increase >60 from baseline; new (newly occurring post-baseline) QT interval in msec (QTcF) corrected by Fredericia formula >450, 480, 500, increase >30 from baseline, increase >60 from baseline; new (newly occurring post-baseline) QT interval in msec (QTcF) corrected by Bazett's formula >450, 480, 500, increase >30 from baseline, increase >60 from baseline; The new (new post-baseline) QT interval (QTcB) in msec corrected by the formula is >450, 480, 500, the increase relative to baseline is >30, the increase relative to baseline is >60; the new (new post-baseline) heart rate in bpm is <60 and >100. Number of participants with laboratory abnormalities Baseline (Day 1) until 28 days after the last dose of study drug Hemoglobin (HGB), hematocrit, erythrocyte (ery.), HDL cholesterol (chl.) <0.8*lower limit of normal (LLN); reticulocyte (ret.), ret./ery. (%) <0.5*LLN, >1.5*upper limit of normal (ULN); mean corpuscular volume (EMC), EMC HGB, EMC HGB Number of participants with clinically significant changes from baseline in vital signs Baseline until 28 days after last dose of study drug Vital signs (temperature, respiratory rate, pulse, systolic and diastolic blood pressure) were obtained with participants in an upright position after they had sat quietly for at least 5 minutes. The clinical significance of the vital signs was determined at the discretion of the investigator. Number of participants with adverse events classified by type, frequency, severity (according to NCI CTCAE grading version 5.0), timing, severity, and relationship to study treatment Baseline until 28 days after last dose of study drug Count of participants with treatment-emergent adverse events (TEAEs), defined as new onset or worsening after the first dose. Relevance to [study drug] was assessed by the Investigator. Participants with multiple AEs within a category were counted once within that category. An adverse event (AE) is any untoward medical occurrence in a participant receiving study drug, regardless of the possibility of a causal relationship. According to the 4th edition of CTCAE, Grade 1 = mild AE; Grade 2 = moderate AE; Grade 3 = severe AE; Grade 4 = life-threatening or disabling AE; Grade 5 = death related to the AE. Single dose T _max 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours after administration Time of Cmax Single dose AUC _last Until the last quantifiable concentration The area under the concentration-time curve from time zero to the time of the last quantifiable concentration (Clast) Single dose MRC _max Until Day 71 Cmax ratio of compound 2 to compound 1 Single dose AUCinf 0 (before administration), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 and 72 hours after administration The area under the concentration-time curve extrapolated from time zero to infinity Single dose CL/F Week X The clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. The clearance obtained after oral administration (apparent oral clearance) is affected by the fraction of the dose absorbed. Clearance is estimated by population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. Single dose Vz/F 0 (before medication), 1, 2, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96 and 144 hours after medication Apparent distribution volume Single dose t½ 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours after administration Terminal half-life Multiple dose Tmax 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours after administration Time to maximum observed plasma concentration Multiple dose Tmax 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours after administration Time of Cmax Multi-dose MRCmax Until Day 71 Cmax ratio of compound 2 to compound 1 Rac Until Day 71 Based on the cumulative ratio of AUC (observation value) t½eff Until Day 71 Effective half-life based on cumulative rate (t½eff) Multi-dose CL/F Until Day 71 The clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. The clearance obtained after oral administration (apparent oral clearance) is affected by the fraction of the dose absorbed. Clearance is estimated by population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. Multiple dose t½ 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours after administration Terminal half-life Qualifications Age all Age restriction Minimum age: 18 Maximum age: N/A Accepting healthy volunteers no Eligibility criteria Inclusion Criteria: - Histological or cytological diagnosis of breast cancer and evidence of ER+/HER2- locally advanced or metastatic disease, not amenable to surgical resection or radiation therapy with curative intent. - SOC receiving at least 1 line of endocrine therapy with or without CDK4/6 inhibitors for locally advanced or metastatic disease. - Up to 2 prior chemotherapy regimens in the setting of advanced or metastatic disease are permitted. Exclusion Criteria: - Known active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis or meningeal disease indicated by clinical symptoms, brain edema and/or progressive growth. Participants with a history of CNS metastases or spinal cord compression were eligible if they had received definitive treatment (e.g., radiation therapy, stereotactic surgery) prior to the first dose of study drug and were clinically stable for at least 28 days after discontinuation of enzyme-inducing anticonvulsants and steroids (including patients with residual CNS symptoms/deficits). - Any of the following in the past 6 months: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure (New York Heart Association Class III or IV), cerebrovascular accident, transient ischemic attack, or symptomatic pulmonary embolism or other clinically significant episode of thromboembolic disease, congenital long QT syndrome, polymorphic ventricular tachycardia, serious conduction system abnormality (e.g., bifascicular block defined as right bundle branch and left anterior or left posterior hemiblock, 3rd degree AV block), clinically significant arrhythmia, left anterior hemiblock (bifascicular block), NCI CTCAE Persistent dysrhythmia of grade ≥2, atrial fibrillation of any grade. Example 6 : Treatment-emergent AE (TEAE)

As of June 6, 2023, a total of 46 participants (100%) receiving the combination of Compound A and 125 mg palbociclib reported at least 1 TEAE.

For all Compound A doses combined with 125 mg palbociclib, the most common TEAEs observed in ≥20% of patients were as follows in decreasing order of frequency: neutropenia, fatigue, decreased platelet count, anemia, constipation, nausea, decreased white blood cell count, diarrhea, and electrocardiogram QT prolongation (Table 4). Grade 3 and 4 TEAEs occurred in 23 (50%) and 19 (41.3%) participants, respectively. Neutropenia was the most common Grade 3 or 4 TEAE and occurred in 47.8% (Grade 3) and 41.3% (Grade 4) of participants, respectively. Table 3. TEAEs ≥ 5% by Preferred Term and CTCAE Highest Grade 3 and Above — Study ARV -471-mbc-101 ( Part C ) Dosage group AE preferred term [n(%)] Any level Level 3 Level 4 Level 5 Any treatment-emergent AE 46 (100.0) 23 (50.0) 19 (41.3) 0 All doses of compound A + palbociclib 125 mg (TEAE) Neutropenia 46 (100.0) 22 (47.8) 19 (41.3) 0 Compound A 200 mg + Palbociclib 125 mg (TRAE) Neutropenia 21 (100.0) 10 (47.6) 8 (38.1) 0 *Neutropenia is categorized according to the MedDRA preferred terms neutropenia and decreased neutrophil count. NOTE: Treatment-emergent AEs were defined as occurring on/after the day of first study dose and within 30 days of last study dose. NOTE: Patients were counted only once for each preferred term. NOTE: Adverse events were coded using MedDRA version 22.0. Source: BDM TAE04C: TEAEs by Preferred Term and Highest CTCAE Grade (Part C)—All Dose Groups All-As-Treatment Analysis Set and BDM TAE04RELC2: Compound A or Palbociclib TRAEs by Preferred Term and Highest CTCAE Grade (Part C)—200 mg All-As-Treatment Analysis Set Data Cutoff: June 6, 2023

In patients treated with 200 mg Compound A and 125 mg palbociclib, the most common TEAEs observed in ≥20% of patients included neutropenia (100.0%), fatigue (66.7%), decreased platelet count (52.4%), anemia (42.9%), constipation (33.3%), increased alanine aminotransferase (23.8%), increased aspartate aminotransferase (23.8%), back pain (23.8%), dizziness (23.8%), and decreased white blood cell count (23.8%).

All patients in the 200 mg Compound A and 125 mg palbociclib cohorts experienced neutropenia, with 8 participants (38.1%) reporting G4 neutropenia. The median time to first onset of any grade neutropenic episode in patients treated with the 200 mg Compound A plus palbociclib combination was 14.5 days and consistent with IBRANCE USPI. All neutropenic episodes were reversible, non-cumulative, and medically manageable with or without supportive care and/or dose reductions. Dose reductions of palbociclib were reported in 13 participants (61.9%). Table 4. Treatment-emergent adverse events ≥ 10% by preferred terminology ( Part C )—Full treatment analysis set (ARV-471-mBC-101) AE preferred term [n(%)] 180 mg + Palbo (N=2) 200 mg + Palbo (N=21) 400 mg + Palbo (N=3) 500 mg + Palbo (N=20) Total (N=46) Any adverse events that occur during treatment 2 (100) 21 (100) 3 (100) 20 (100) 46 (100) Neutropenia* 2 (100) 21 (100) 3 (100) 20 (100) 46 (100) Fatigue 2 (100) 14 (66.7) 1 (33.3) 12 (60.0) 29 (63.0) Decreased platelet count 0 11 (52.4) 2 (66.7) 10 (50.0) 23 (50.0) Anemia 0 9 (42.9) 2 (66.7) 8 (40.0) 19 (41.3) constipate 0 7 (33.3) 0 6 (30.0) 13 (28.3) Nausea 1 (50.0) 4 (19.0) 1 (33.3) 7 (35.0) 13 (28.3) Decreased white blood cell count 0 5 (23.8) 2 (66.7) 6 (30.0) 13 (28.3) Diarrhea 1 (50.0) 4 (19.0) 1 (33.3) 4 (20.0) 10 (21.7) QT prolongation on electrocardiogram 0 4 (19.0) 0 6 (30.0) 10 (21.7) Dizziness 0 5 (23.8) 2 (66.7) 2 (10.0) 9 (19.6) Hot flashes 0 4 (19.0) 2 (66.7) 3 (15.0) 9 (19.6) Joint pain 0 4 (19.0) 0 4 (20.0) 8 (17.4) Aspartate aminotransferase elevated 0 5 (23.8) 0 3 (15.0) 8 (17.4) cough 1 (50.0) 2 (9.5) 0 5 (25.0) 8 (17.4) Difficulty breathing 0 4 (19.0) 0 4 (20.0) 8 (17.4) Vomiting 0 3 (14.3) 0 5 (25.0) 8 (17.4) Elevated alanine transaminase 0 5 (23.8) 0 2 (10.0) 7 (15.2) Back pain 0 5 (23.8) 0 2 (10.0) 7 (15.2) Hair loss 1 (50.0) 2 (9.5) 0 3 (15.0) 6 (13.0) Hyponatremia 0 3 (14.3) 0 3 (15.0) 6 (13.0) Fever 1 (50.0) 3 (14.3) 0 2 (10.0) 6 (13.0) Coronavirus infection 2 (100) 1 (4.8) 0 2 (10.0) 5 (10.9) Decreased appetite 0 1 (4.8) 1 (33.3) 3 (15.0) 5 (10.9) headache 0 3 (14.3) 0 2 (10.0) 5 (10.9) High blood sugar 0 0 1 (33.3) 4 (20.0) 5 (10.9) Insomnia 0 0 1 (33.3) 4 (20.0) 5 (10.9) Stomatitis 1 (50.0) 4 (19.0) 0 0 5 (10.9) *Neutropenia is categorized according to the MedDRA preferred terms Neutropenia and Decreased neutrophil count. NOTE: Treatment-emergent is defined as an AE occurring on the day of/after the first study dose and within 30 days of the last study dose. NOTE: For each preferred term, patients are counted only once. NOTE: Adverse events are coded using MedDRA version 22.0. Data Cutoff: June 6, 2023 Source: BDM TAE02C3: Treatment-emergent adverse events ≥ 10% according to the preferred term (Part C) - Full As-Treated Analysis Set

All 46 participants (100%) experienced at least one adverse event related to Compound A or palbociclib, with neutropenia, fatigue, and decreased platelet count being the most frequently reported TRAEs (Table 5).

Thirty-nine (39) of the 46 participants (84.8%) reported Compound A treatment-related TEAEs (Table 6). The most common Compound A treatment-related TEAEs observed in ≥10% of patients (all doses) included fatigue (47.8%), neutropenia (28.3%), constipation (21.7%), electrocardiogram QT prolongation (19.6%), diarrhea (17.4%), hot flashes (15.2%), arthralgia (13%), nausea (13%), decreased platelet count (13%), and alopecia (10.9%). Neutropenia was the most common Grade 3 or 4 TRAE and occurred in 47.6% (Grade 3) and 38.1% (Grade 4) of participants, respectively.

The most common palbociclib treatment-related TEAEs observed in ≥10% of patients treated with all doses of Compound A and 125 mg palbociclib included neutropenia (100%), fatigue (60.9%), decreased platelet count (45.7%), anemia (34.8%) and decreased white blood cell count (26.1%), constipation (17.4%), diarrhea (17.4%), and nausea (17.4%) for all patients.

A total of 5 deaths (10.9%) were reported among the 46 participants. Of these, 3 deaths (6.5%) were found to be related to the disease under study or its complications, and the remaining 2 deaths (4.3%) were reported as being related to "other".

Four patients (8.7%) experienced TEAEs that led to study discontinuation for both Compound A and Palbociclib: ●  One patient given 200 mg Compound A + 125 mg Palbociclib QD experienced Grade 1 weight loss, which was considered by the investigator to be related to both Compound A and Palbociclib. ●  One patient given 200 mg Compound A + 125 mg Palbociclib QD experienced Grade 1 cough, which was considered unrelated to Compound A or Palbociclib. The patient withdrew from the study and the reason for discontinuation was individual withdrawal. ●  One patient given 200 mg Compound A + 125 mg Palbociclib QD experienced Grade 1 dizziness, which was considered unrelated to Compound A or Palbociclib. ●  One patient who was given 500 mg Compound A + 125 mg Palbociclib QD experienced Grade 3 fatigue, which was considered by the investigator to be unrelated to Compound A and related to Palbociclib. The patient withdrew from the study and the reason for discontinuation was individual withdrawal.

Four patients (8.7%) experienced TEAEs leading to discontinuation of palbociclib only: ● One patient given 200 mg Compound A + 125 mg palbociclib QD experienced a Grade 4 decreased neutrophil count, which was considered by the investigator to be related to both Compound A and palbociclib. ● One patient given 200 mg Compound A + 125 mg palbociclib QD experienced a Grade 3 cerebrovascular accident, which was considered not related to Compound A or palbociclib. ● One patient given 500 mg Compound A + 125 mg palbociclib QD experienced a Grade 4 decreased neutrophil count, which was considered by the investigator to be related to palbociclib only. ● One patient given 500 mg Compound A + 125 mg palbociclib QD experienced a Grade 3 decrease in neutrophil count, which was considered by the investigator to be related solely to palbociclib. Table 5. Compound A or palbociclib treatment-related adverse events ≥ 10% based on preferred terminology ( Part C ) —All-As-Treatment Analysis Set (ARV-471-mBC-101) AE preferred term [n (%)] 180 mg + Palbo (N=2) 200 mg + Palbo (N=21) 400 mg + Palbo (N=3) 500 mg + Palbo (N=20) Total (N=46) Any adverse events related to Compound A or palbociclib treatment 2 (100) 21 (100) 3 (100) 20 (100) 46 (100) Neutropenia* 2 (100) 21 (100) 3 (100) 20 (100) 46 (100) Fatigue 2 (100) 13 (61.9) 1 (33.3) 12 (60.0) 28 (60.9) Decreased platelet count 0 11 (52.4) 2 (66.7) 10 (50.0) 23 (50.0) Anemia 0 7 (33.3) 2 (66.7) 7 (35.0) 16 (34.8) Decreased white blood cell count 0 5 (23.8) 2 (66.7) 5 (25.0) 12 (26.1) constipate 0 5 (23.8) 0 6 (30.0) 11 (23.9) QT prolongation on electrocardiogram 0 4 (19.0) 0 6 (30.0) 10 (21.7) Diarrhea 1 (50.0) 2 (9.5) 1 (33.3) 4 (20.0) 8 (17.4) Nausea 1 (50.0) 2 (9.5) 0 5 (25.0) 8 (17.4) Hot flashes 0 2 (9.5) 2 (66.7) 3 (15.0) 7 (15.2) Hair loss 1 (50.0) 2 (9.5) 0 3 (15.0) 6 (13.0) Joint pain 0 3 (14.3) 0 3 (15.0) 6 (13.0) Decreased appetite 0 1 (4.8) 1 (33.3) 3 (15.0) 5 (10.9) Vomiting 0 3 (14.3) 0 2 (10.0) 5 (10.9) Note: Adverse events are coded using MedDRA version 22.0. Data cutoff: June 6, 2023 Source: BDM TAE03C: Adverse events related to Compound A or palbociclib treatment ≥ 10% based on preferred terminology (Part C) - All-As-Treatment Analysis Set Table 6. Compound A Treatment-Related Adverse Events in ≥ 10% of Patients by Preferred Terminology ( Part C ) —All-As-Treatment Analysis Set ( ARV-471-mBC-101) AE preferred term [n (%)] 180 mg + Palbo (N=2) 200 mg + Palbo (N=21) 400 mg + Palbo (N=3) 500 mg + Palbo (N=20) Total (N=46) Any adverse events related to Compound A treatment 2 (100) 17 (81.0) 3 (100) 17 (85.0) 39 (84.8) Fatigue 2 (100) 10 (47.6) 1 (33.3) 9 (45.0) 22 (47.8) Neutropenia* 2 (100) 4 (19.0) 1 (33.3) 6 (30.0) 13 (28.3) constipate 0 5 (23.8) 0 5 (25.0) 10 (21.7) QT prolongation on electrocardiogram 0 3 (14.3) 0 6 (30.0) 9 (19.6) Diarrhea 1 (50.0) 2 (9.5) 1 (33.3) 4 (20.0) 8 (17.4) Hot flashes 0 2 (9.5) 2 (66.7) 3 (15.0) 7 (15.2) Joint pain 0 3 (14.3) 0 3 (15.0) 6 (13.0) Nausea 1 (50.0) 2 (9.5) 0 3 (15.0) 6 (13.0) Decreased platelet count 0 3 (14.3) 1 (33.3) 2 (10.0) 6 (13.0) Hair loss 1 (50.0) 1 (4.8) 0 3 (15.0) 5 (10.9) Note: Adverse events are coded using MedDRA version 22.0. Data cutoff: June 6, 2023 Source: BDM TAE03C1: Compound A treatment-related adverse events ≥ 10% based on preferred terms (Part C) - all-treatment analysis set Equivalent content

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

The method of the present disclosure has been described herein with reference to certain preferred embodiments. However, based on the disclosure described herein, relevant specific changes will become apparent to those skilled in the art, and therefore the present disclosure should not be considered limited thereto.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. Unless the context clearly indicates otherwise, in the specification and patent application, the singular also includes the plural.

It should be understood that at least some of the descriptions of the present disclosure have been simplified in order to focus on the elements relevant to a clear understanding of the present disclosure, and that other elements that should be understood by a person skilled in the art may also constitute part of the present disclosure for the sake of clarity. However, since such elements are well known in the art and since they may not be helpful for a better understanding of the present invention, descriptions of such elements are not provided herein.

Furthermore, to the extent a method does not rely on the specific order of steps recited herein, the specific order of steps recited in the claims should not be construed as a limitation on the claims.

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

[ FIGS. 1A-1H ] are graphs showing quantification of MCF7 and T47D live cell imaging proliferation assays. FIGs. 1A and 1C show relative cell growth kinetics over 120 hours as determined by live cell imaging of MCF7 and T47D cells given Compound A (10 nM) or fulvestrant (1 nM) alone or in combination with abemaciclib (40 nM) at concentrations approximating GI ₅₀ , respectively. Each graph represents three independent experiments. FIGs. 1E and 1G show relative cell growth kinetics over 120 hours as determined by live cell imaging of MCF7 and T47D cells given Compound A (10 nM) and/or reboxiclib (40 nM) at concentrations approximating GI ₅₀ , respectively. Each figure represents three independent experiments, except for the T47D fulvestrant arm in Figures 1A and 1C, which is the result of 2 independent experiments). Figures 1B, 1D, 1F, and 1H show relative MCF7 and T47D cell growth differences compared to vehicle control at 120 hours of treatment. Each figure shows the mean of three independent experiments, except for the T47D fulvestrant arm in Figures 1B and 1D, which is the result of 2 independent experiments). Error bars = standard error of the mean (SEM). *p < 0.025, **p ≤ 0.008, ***p ≤ 0.0006, ****p < 0.0001, ns = not significant (one-way ANOVA test). [ Figures 2A-2L ] are graphs showing the viability and synergy analysis of MCF7 cells given a combination of Compound A and abemaciclib or ribociclib on day -5 in an 8×8 block matrix. Figures 2A , 2B , 2G , and 2H show the single-dose curves of Compound A, abemaciclib, Compound A, and ribociclib, respectively. Figure 2C shows the dose-response change of Compound A with the addition of abemaciclib. Figure 2I shows the dose-response change of Compound A with the addition of ribociclib. Drug synergy was evaluated using Combenefit software. BLISS ( 2D and 2J ), Loewe ( 2E and 2K ) and top single agent ( 2F and 2L ) model outputs are shown (representative of three independent experiments). [ Figures 3A and 3B ] are graphs showing in vivo efficacy studies of the combination of Compound A with the CDK4/6 inhibitors abemaciclib ( Figure 3A ) and ribociclib ( Figure 3B ) using the MCF7 orthotopic xenograft model. Mean tumor volumes ± SEM are reported. Single-day dosing breaks are indicated by small black arrows. [ Figure 4A ] is a graph showing body weight (± SEM) of MCF7 orthotopic xenograft efficacy using the combination of Compound A with the CDK4/6 inhibitor abemaciclib. Compounds were given as single agents or in combination, 10 mice/arm. [ FIG. 4B ] is a graph showing the body weight (±SEM) of the efficacy of MCF7 orthotopic xenografts using a combination of Compound A and the CDK4/6 inhibitor Riboxil. Compounds were administered as single agents or in combination, 10 mice/arm. [ FIG. 5 ] is a graph showing the inhibition of tumor growth caused by Compound A (30 mg/kg, oral [administered orally; PO]; once daily [QD]×28) or Fulvestrant (200 mg/kg, subcutaneous; twice a week for 2 weeks, then once a week for 2 weeks) as a single agent or in combination with the CDK4/6 inhibitor Palbociclib (“Palbo”; 60 mg/kg, PO; QDx28). Female severely confluent immunodeficient mice (NOD/scid) in a non-obese background were implanted with MCF7 cells and compound administration was initiated after tumors reached 200 mm ^3. Tumor volume was assessed twice a week for 28 days. At the end of the study, single-agent Compound A and Fulvestrant inhibited tumor growth by 105% and 46%, respectively. When combined with palbociclib, growth inhibition with Compound A or Fulvestrant was 131% and 108%, respectively. Data are presented as mean ± standard error of the mean (SEM).

Claims (17)

A compound A

The invention relates to a method for preparing a medicament for treating cancer, wherein the medicament is administered to an individual in the form of a daily dose of a combination of compound A or a pharmaceutically acceptable salt thereof and a CDK4/6 inhibitor, wherein the daily dose of compound A or a pharmaceutically acceptable salt thereof is about 100 mg or about 200 mg; and wherein the CDK4/6 inhibitor is ribociclib or a pharmaceutically acceptable salt thereof. The use of claim 1, wherein compound A or a pharmaceutically acceptable salt thereof and the CDK4/6 inhibitor are administered simultaneously or sequentially. For use as claimed in claim 1 or 2, the daily dose of compound A or its pharmaceutically acceptable salt is about 200 mg. For use as claimed in claim 1 or 2, the daily dose of compound A or its pharmaceutically acceptable salt is about 100 mg. For use as claimed in claim 1 or 2, wherein the daily dose of compound A or a pharmaceutically acceptable salt thereof is administered once a day (QD). For the use of claim 1 or 2, the daily dose of compound A or a pharmaceutically acceptable salt thereof is orally administered to the subject. For use as claimed in claim 1 or 2, wherein the individual is in a feeding state. For use as claimed in claim 1, wherein compound A or its pharmaceutically acceptable salt is administered daily in a 28-day cycle, and reboxil or its pharmaceutically acceptable salt is orally administered once daily in a daily dose of about 600 mg for 21 days in each 28-day cycle, followed by cessation of treatment for 7 days. For use as claimed in claim 1, the daily dose of compound A or its pharmaceutically acceptable salt combined with reboxil or its pharmaceutically acceptable salt is about 100 mg, and the reboxil or its pharmaceutically acceptable salt is administered at a daily dose of about 600 mg. For use as claimed in claim 1, 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. For use as claimed in claim 10, wherein the cancer is breast cancer, lung cancer, prostate cancer, pancreatic cancer or ovarian cancer. For use as claimed in claim 11, wherein the cancer is breast cancer, lung cancer or prostate cancer. For use as claimed in claim 12, wherein the cancer is breast cancer. The use as claimed in claim 13, wherein the breast cancer is metastatic or locally advanced. The use of claim 13 or 14, wherein the breast cancer is estrogen receptor positive (ER+) breast cancer. The use of claim 15, wherein the estrogen receptor positive (ER+) breast cancer is human epidermal growth factor receptor 2 negative (HER2-). For the purpose of claim 1, where the individual is a human being.