Dosage regimens of estrogen receptor degraders

Abstract

This article discloses methods for treating cancer that involve administering to an individual a daily dose of a combination of compound A or a medically acceptable salt thereof and a CDK4 / 6 inhibitor.

Description

Technical Field

[0001] This invention relates to a dosing regimen for estrogen receptor degraders. Prior Technology

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

[0003] Of particular note is the bifunctional molecular system vepdegestrant (i.e., (S)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphth-1-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl ... -1-yl)-1-sideoxyisoindoline-2-yl)piperidin-2,6-dione or (3S)-3-[1,3-dihydro-1-sideoxy-5-[4-[[1-[4-[(1R,2S)-1,2,3,4-tetrahydro-6-hydroxy-2-phenyl-1-naphthylphenyl]-4-piperidinyl]methyl]-1-piperidinyl [2H-isoindol-2-yl]-2,6-piperidinedione (referred to as "Compound A" or "Cpd A" in this paper)) has the molecular formula C45H49N5O4 and the following structure: .

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

[0005] Compound A is needed as an appropriate dosing regimen for oral therapy of cancer (e.g., breast cancer) to improve its benefits, including safety and efficacy, as well as convenience for patients, while minimizing adverse events and risks to patients. Summary of the Invention

[0006] This disclosure partially provides a dosing regimen for administering compound A or a pharmaceutically acceptable salt thereof to an individual as a combination therapy for the treatment of cancer. The summary is provided to introduce a series of concepts in a simplified form, which will be further described in the embodiments below. The summary is not intended to identify key or essential features of the claimed subject matter, nor is it intended to be used independently as an aid in determining the scope of the claimed subject matter.

[0007] This article provides a method for treating cancer, which involves administering a daily dose of compound A having the following structure to an individual: , Or a combination of a medically acceptable salt and a CDK4 / 6 inhibitor, wherein the daily dose of compound A is approximately 100 mg or 200 mg.

[0008] This article provides a method for treating cancer, which involves administering a daily dose of compound A having the following structure to an individual: , Combination with CDK4 / 6 inhibitors.

[0009] In one example, the daily dose of compound A is approximately 200 mg. In another example, the daily dose of compound A is approximately 100 mg.

[0010] In the examples, the CDK4 / 6 inhibitor is dalpiciclib, trilaciclib, lerociclib, AT7519M, dinaciclib, ribociclib, abemaciclib, or palbociclib, or a pharmaceutically acceptable salt thereof. In the examples, the CDK4 / 6 inhibitor is abemaciclib, ribociclib, or palbociclib, or a pharmaceutically acceptable salt thereof. In the examples, the CDK4 / 6 inhibitor is abemaciclib or a pharmaceutically acceptable salt thereof. In the examples, the CDK4 / 6 inhibitor is ribociclib or a pharmaceutically acceptable salt thereof. In the examples, the CDK4 / 6 inhibitor is palbociclib or a pharmaceutically acceptable salt thereof.

[0011] In some embodiments, compound A or a pharmaceutically acceptable salt thereof may be administered daily in combination with a CDK4 / 6 inhibitor over a 28-day cycle. In some embodiments, the CDK4 / 6 inhibitor is palbociclib or a pharmaceutically acceptable salt thereof. For example, palbociclib may be administered orally at 125 mg once daily for 21 days in each 28-day cycle, followed by a 7-day treatment break.

[0012] In the embodiments, the daily dose of compound A is administered once daily (QD).

[0013] In the embodiments, the daily dose of compound A was administered orally to the individual.

[0014] In this embodiment, the individual is in a feeding state.

[0015] In the 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.

[0016] In the embodiments, the cancer is breast cancer, lung cancer, prostate cancer, pancreatic cancer, or ovarian cancer.

[0017] In the embodiments, the cancer is breast cancer, lung cancer, or prostate cancer.

[0018] In this embodiment, the cancer is breast cancer. For example, the breast cancer may be metastatic or locally advanced. In this embodiment, the breast cancer may be estrogen receptor-positive (ER+) breast cancer (e.g., human epidermal growth factor receptor 2 negative (HER2-)).

[0019] In this embodiment, the system is human.

[0020] It should be understood that the foregoing general description and the following detailed description are merely illustrative and not limiting of the invention claimed. Simple Explanation of the Diagram

[0021] [ [picture] [1A-1H] shows quantitative figures for live-cell imaging proliferation analysis of MCF7 and T47D cells. Figures 1A and 1C show the relative cell growth kinetics over 120 hours as determined by live-cell imaging of MCF7 and T47D cells treated alone or in combination with abecilibry (40 nM) or fulvestrant (1 nM) at approximately GI50 concentrations. Each figure represents three independent experiments. Figures 1E and 1G show the relative cell growth kinetics over 120 hours as determined by live-cell imaging of MCF7 and T47D cells treated with compound A (10 nM) and / or rebocilibry (40 nM) at approximately GI50 concentrations. Each figure represents three independent experiments, except for the T47D fulvestrant arm in Figures 1A and 1C, which represents the results of two independent experiments. Figures 1B, 1D, 1F, and 1H show the relative differences in MCF7 and T47D cell growth compared to the carboxyl 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 represents the results of two 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 variance analysis test). [ [picture] [2A-2L]] is a graph showing the survival rate and synergistic effect analysis of MCF7 cells given compound A in combination with abecicilline or rebocicilline on day -5 in an 8×8 block matrix. [picture] [2A]、 [2B]、 [2G] and [2H] shows the single-drug curves for compound A, abecitabine, compound A, and reboxil, respectively. [picture] [2C] shows the dose-response change of compound A in the presence of abexilide. [picture] [2I] Shows the dose-response change of compound A with the addition of reboxil. Drug synergy was evaluated using Combenefit software. (BLISS) shows... [2D] and [2J]), Loewe ( [2E] and [2K]) and the highest single drug ( [2F] and [2L]) Model output (representing three independent experiments). [ [picture] [3A] [and] [3B] shows that compound A and the CDK4 / 6 inhibitor abexib were compared using an MCF7 orthotopic xenograft model. [picture] [3A]) and ripocid ( [picture] Figures showing the in vivo efficacy study of the combination of [3B]). Reported mean tumor volume ± SEM. Single-day dosing holidays are indicated by small black arrows. [ [picture] [4A] is a graph showing body weight (±SEM) of the efficacy of MCF7 orthotopic xenograft using the combination of compound A and the CDK4 / 6 inhibitor abexicillin. The compounds were administered as single agents or in combination, 10 mice / arm. [ [picture] [4B] is a graph showing body weight (±SEM) of the efficacy of MCF7 orthotopic xenograft using the combination of compound A and the CDK4 / 6 inhibitor reboxil. The compounds were administered as single agents or in combination, 10 mice / arm. [ [picture] [5] This figure shows the tumor growth inhibition induced by compound A (30 mg / kg, orally [orally; PO]; once daily [QD] × 28) as a single agent or in combination with the CDK4 / 6 inhibitor palbociclib ("Palbo"; 60 mg / kg, PO; QD x 28) or fulvestrant (200 mg / kg, subcutaneously; twice weekly for 2 weeks, followed by once weekly for 2 weeks). MCF7 cells were implanted into female non-obese mice with severe combined immunodeficiency (NOD / scid) and the starting compounds were administered after the tumor reached 200 mm3. Tumor volume was assessed twice weekly for 28 days. At the end of the study, compound A as a single agent and fulvestrant inhibited tumor growth by 105% and 46%, respectively. When combined with palbociclib, growth inhibition using compound A or fulvestrant was 131% and 108%, respectively. Data are presented as mean ± standard error of mean (SEM). Implementation

[0022] Cross-reference to related applications This application claims priority and interest in U.S. Application No. 63 / 402,651, filed August 31, 2022; U.S. Application No. 63 / 443,892, filed February 7, 2023; U.S. Application No. 63 / 454,485, filed March 24, 2023; U.S. Application No. 63 / 454,422, filed March 24, 2023; and U.S. Application No. 63 / 508,503, filed June 15, 2023, the entire contents of which are incorporated herein by reference.

[0023] The invention can be more readily understood by referring to the following detailed description of embodiments of the invention and examples included therein. It should also be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0024] Vidgister (i.e., (S)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphth-1-yl)phenyl)piperidin-4-yl)methyl)piperidin -1-yl)-1-sideoxyisoindoline-2-yl)piperidin-2,6-dione or (3S)-3-[1,3-dihydro-1-sideoxy-5-[4-[[1-[4-[(1R,2S)-1,2,3,4-tetrahydro-6-hydroxy-2-phenyl-1-naphthylphenyl]-4-piperidinyl]methyl]-1-piperidinyl [2H-isoindol-2-yl]-2,6-piperidinedione (also referred to as "compound A" in this paper): PROTAC® protein degrader is being developed as a potential treatment for breast cancer by targeting the estrogen receptor (ER), and has been shown to be a useful regulator of the ubiquitination and degradation of target proteins via the ubiquitin-proteasome pathway.

[0025] Compound A and its pharmaceutically acceptable salts are disclosed in International Publication No. WO 2018 / 102725 and U.S. Patents Nos. 10,647,698, 10,899,742, and 11,104,666; International Publication No. WO 2021 / 041348; U.S. Series No. 17 / 472,847; U.S. Series No. 17 / 548,842; and U.S. Series No. 17 / 873,748. The contents of the foregoing references are incorporated herein by reference in their entirety.

[0026] Cyclin-dependent kinases (CDKs) and related serine / threonine protein kinases are important cellular enzymes that play essential roles in regulating eukaryotic cell division and proliferation. The CDK catalytic unit is activated by a regulatory subunit called a cyclin. 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 heterogenes 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).

[0027] It has been confirmed that CDK inhibitors can be used to treat cancer. Studies have shown that increased activity or temporal aberrations in cyclin-dependent kinases lead to the development of human tumors, and that human tumor development is generally associated with alterations 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).

[0028] CDK4 and CDK6 cell lineages are important regulators of cell cycle progression at the G1-S checkpoint, controlled by D-cyclin and endogenous CDK inhibitors of INK4, such as p16INK4a (CDKN2A). It has been reported that cyclin D-CDK4 / 6-INK4... [-] Dysfunction of the retinoblastoma (Rb) pathway is associated with the development of resistance to endocrine therapy.

[0029] Clinical trials are underway to investigate the CDK4 / 6 inhibitors palbociclib, reboxiclib, and abeciclib as monotherapy or in combination with other therapeutic agents for breast cancer and other cancers. Combinations of CDK4 / 6 inhibitors with endocrine therapy have 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, reboxiclib, and abeciclib, have been approved for use in combination with endocrine therapy as first- or second-line therapy. Palbociclib, reboxiclib, and abeciclib have been approved for use in first-line therapy in combination with aromatase inhibitors such as letrozole and in second- or subsequent-line therapy in combination with fulvestrant for the treatment of certain patients with HR-positive, HER2-negative advanced or metastatic breast cancer. (O'Leary et al., Treating cancer with selective CDK4 / 6 inhibitors. Nature Reviews (2016) 13:417-30).

[0030] Palbociclib or 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazine) -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: . [, , ]

[0031] Palbociclib is described in WHO Drug Information, Volume 27, No. 2, page 172 (2013). Palbociclib and its pharmaceutically acceptable salts are disclosed in International Publication No. WO 2003 / 062236 and U.S. Patents Nos. 6,936,612, 7,456,168, and RE47,739; International Publication No. WO 2005 / 005426 and U.S. Patents 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 the foregoing references are incorporated herein by reference in their entirety.

[0032] Abexilide, namely N-(5-((4-ethylpiperazine) -1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-amine (e.g., sold under the brand name Verzenio® (and other names)) is a selective CDK4 and CDK6 inhibitor having the following structure: .

[0033] Abecilib and its medically acceptable salts are disclosed in International Publication No. WO2010 / 075074 and U.S. Patent No. 7,855,211. The contents of the foregoing references are incorporated herein by reference in their entirety.

[0034] Ripocidil, i.e., 7-cyclopentyl-N,N-dimethyl-2-[(5-piperazine)] [-1-ylpyridin-2-yl)amino]pyrrolo[2,3-d]pyrimidin-6-methamide (e.g., marketed under the brand names Kisqali® and Kryxana®) is a cyclin D1 / CDK4 and CDK6 inhibitor with the following structure: .

[0035] Reboxil and its medically acceptable salts are disclosed in International Publications Nos. WO2007140222, WO2010 / 020675, WO2012 / 064805 and WO2016 / 166703, and U.S. Patents 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 foregoing references are incorporated herein by reference in their entirety.

[0036] 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. It has been confirmed that the selective CDK4 / 6 inhibitor palbociclib is effective in clinical practice for 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 occur 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 [] []

[0037] Unless otherwise defined herein, scientific and technical terms used in connection with this invention shall have the meanings commonly understood by one of ordinary skill in the art.

[0038] The invention described herein can be practiced appropriately without any elements not specifically disclosed herein.

[0039] Unless otherwise specified, as used herein, the singular forms "a", "an" and "the" include a plurality of indicators. For example, an "a" substituent includes one or more substituents.

[0040] 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 value of the parameter. For example, about 5 mg means 5 mg ± 10%, that is, it can vary between 4.5 mg and 5.5 mg.

[0041] As used herein, the terms, including but not limited to "pharmaceutical", "composition", "compound", "drug" and "therapeutic agent", are used interchangeably to refer to the compounds included in the methods and uses of this disclosure.

[0042] As used herein, the terms "individual," "participant," and "patient" are used interchangeably to mean any animal, including mammals. Mammals according to this disclosure include canines, felines, cattle, goats, equines, sheep, pigs, rodents, rabbits, primates, humans, and similar animals, and include unborn mammals. In this embodiment, a human is a suitable individual. A human individual can be of any sex and at any developmental stage.

[0043] Vidgister (i.e., (S)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphth-1-yl)phenyl)piperidin-4-yl)methyl)piperidin -1-yl)-1-sideoxyisoindoline-2-yl)piperidin-2,6-dione or (3S)-3-[1,3-dihydro-1-sideoxy-5-[4-[[1-[4-[(1R,2S)-1,2,3,4-tetrahydro-6-hydroxy-2-phenyl-1-naphthylphenyl]-4-piperidinyl]methyl]-1-piperidinyl [2H-isoindol-2-yl]-2,6-piperidinedione (also referred to as "compound A" in this paper) is a compound having the following structure: .

[0044] Compound A belongs to Class IV (low solubility / low permeability) in the Biopharmaceutics Classification System. Compound A can interconvert with its epimeric compound B. .

[0045] To avoid being bound by theoretical considerations, preclinical data indicate that the exposure to compound B is limited (<26%) compared to compound A. There is evidence that compound B does not degrade ER; however, compared to compound A, compound B shows similar antagonistic effects on ER-dependent transcription.

[0046] Cyclin-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.

[0047] Examples of CDK4 / 6 inhibitors include, but are not limited to, abecicilline, reboxil, and palbociclib. Additional examples of CDK4 / 6 inhibitors include leroxicillin (also known as G1T38) and trelashicillin (also known as GTI128).

[0048] In the embodiments, 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-piperazine) -1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one: , Or a medically acceptable salt.

[0049] Alternatively, in the examples, the CDK4 / 6 inhibitor is abexicillin or reboxil. Unless otherwise indicated, abexicillin refers to N-(5-(4-ethylpiperazine) -1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-amine: , Furthermore, ripocidil refers to 7-cyclopentyl-N,N-dimethyl-2-[(5-piperazine)] -1-pyridin-2-yl)amino]pyrrolo[2,3-d]pyrimidin-6-methamide: .

[0050] Other examples relate to pharmaceutically acceptable salts of the compounds described herein. Pharmaceutically acceptable salts of the compounds described herein include their acid addition salts and base addition salts.

[0051] Other embodiments also relate 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 pharmacologically acceptable anions) include, but are not limited to, acetates, acid citrates, adipates, aspartate, benzoates, benzenesulfonates, bicarbonates / carbonates, bisulfates / sulfates, tartrates, borates, camphor sulfonates, citrates, cyclamate, ethanedisulfonates, ethanesulfonates, ethanesulfonates, formates, fumarates, glucohepanoates, glucuronates, glucuronates, hexafluorophosphates, hibenzates, and hydrochlorides. Chloride, hydrobromide / bromide, hydroiodide / iodide, hydroxyethanesulfonate, lactate, malate, maleate, malonate, methanesulfonate, methanesulfonate, methyl sulfate, naphthalene dicarboxylate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, dihydroxynaphthalate, phosphate / hydrogen phosphate / dihydrogen phosphate, pyroglutamate, gluconate, stearate, succinate, tannate, tartrate, p-toluenesulfonate, toluenesulfonate, trifluoroacetate, and xinofoate.

[0052] Additional examples relate to base addition salts of the compounds described herein. Suitable base addition salts are formed from bases that form non-toxic salts. Non-limiting examples of suitable base salts include aluminum, arginine, benzathine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, thiazoline, and zinc salts.

[0053] The compounds described in this article are essentially alkaline and 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, forming non-toxic acid addition salts, are, for example, salts containing pharmacologically acceptable anions, such as hydrochlorides, hydrobromides, hydroiodides, nitrates, sulfates, hydrogen sulfates, phosphates, acid phosphates, isonicotinates, acetates, lactates, salicylates, citrates, acid citrates, tartrates, pantothenates, hydrogen tartrates, ascorbic acid salts, succinates, maleate, gentianate, fumarate, gluconate, glucuronide, glucosidate, formate, benzoate, glutamates, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and bis(hydroxynaphthyl)ate [i.e., 1,1'-methylene-bis(2-hydroxy-3-naphthylcarbamate)]. In addition to the acids mentioned above, compounds described herein, including those with basic moieties (such as amino groups), can also form medically acceptable salts with various amino acids.

[0054] Chemical bases that can be used as reagents to prepare pharmaceutically acceptable base salts of inherently acidic compounds described herein, forming non-toxic base salts with these 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-methylglucosamine-(glucosamine), and lower alkanol ammonium, as well as other base salts of pharmaceutically acceptable organic amines.

[0055] It can also form half-salts of acids and bases, such as half-sulfates and half-calcium salts.

[0056] 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 regimen

[0057] This article provides a method for treating cancer, which involves administering to an individual a daily dose of a compound A having the following structure or a pharmaceutically acceptable salt thereof, in combination with a CDK4 / 6 inhibitor: .

[0058] This article also provides a method for treating cancer, which involves administering a daily dose to an individual a combination of compound A having the following structure and a CDK4 / 6 inhibitor: .

[0059] In the embodiment, the daily dose of compound A having the following structure or a pharmaceutically acceptable salt thereof is administered once daily (QD): .

[0060] In an embodiment, the daily dose comprises compound A having the following structure: Oral administration of a saline solution or other medically acceptable salt to an individual.

[0061] In this embodiment, the individual is in a feeding state.

[0062] In the examples, compound A: The daily dose of its medically acceptable salt is approximately 200 mg, or an equivalent amount of its medically acceptable salt.

[0063] In the examples, compound A: Or the daily dose of its medically acceptable salt is 200 mg, or an equivalent amount of its medically acceptable salt.

[0064] In the examples, compound A: The daily dose is approximately 200 mg.

[0065] In the examples, compound A: The daily dose is 200 mg.

[0066] In the examples, compound A: The daily dose of its medically acceptable salt is approximately 100 mg, or an equivalent amount of its medically acceptable salt.

[0067] In the examples, compound A: The daily dose of its medically acceptable salt is 100 mg, or an equivalent amount of its medically acceptable salt.

[0068] In the examples, compound A: The daily dose is approximately 100 mg.

[0069] In the examples, compound A: The daily dose is 100 mg.

[0070] In the examples, compound A: It is administered in the form of free alkali.

[0071] In the examples, the CDK4 / 6 inhibitor is dapoxetine, triprazine, lerosicillin, AT7519M, dinasicillin, reboxicillin, abecilide, or palbocicillin, or a pharmaceutically acceptable salt thereof. In the examples, the CDK4 / 6 inhibitor is dapoxetine, triprazine, lerosicillin, AT7519M, dinasicillin, reboxicillin, abecilide, or palbocicillin.

[0072] In the examples, the CDK4 / 6 inhibitor is abeciclib, reboxil, or palbociclib, or a pharmaceutically acceptable salt thereof. In the examples, the CDK4 / 6 inhibitor is abeciclib, reboxil, or palbociclib.

[0073] In the examples, the CDK4 / 6 inhibitor is abexicillin or a pharmaceutically acceptable salt thereof. In the examples, the CDK4 / 6 inhibitor is abexicillin.

[0074] In the examples, the CDK4 / 6 inhibitor is reboxil or a pharmaceutically acceptable salt thereof. In the examples, the CDK4 / 6 inhibitor is reboxil.

[0075] In the examples, the CDK4 / 6 inhibitor is palbociclib or a pharmaceutically acceptable salt thereof. In the examples, the CDK4 / 6 inhibitor is palbociclib.

[0076] In the examples, compound A was administered daily for 28-day cycles. In some examples, palbociclib or a pharmaceutically acceptable salt thereof was administered orally at 125 mg once daily for 21 days in each 28-day cycle, followed by a 7-day treatment break.

[0077] In the embodiments, the cancers are 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.

[0078] In the embodiments, the cancer is breast cancer, lung cancer, prostate cancer, pancreatic cancer, or ovarian cancer.

[0079] In the embodiments, the cancer is breast cancer, lung cancer, or prostate cancer.

[0080] In this embodiment, the cancer is breast cancer.

[0081] In the examples, the breast cancer is metastatic or locally advanced.

[0082] In this embodiment, the breast cancer is an estrogen receptor-positive (ER+) breast cancer.

[0083] In this embodiment, the estrogen receptor-positive (ER+) breast cancer is a human epidermal growth factor receptor 2-negative (HER2-) breast cancer.

[0084] In this embodiment, the system is human.

[0085] This article also reveals compound A: Or a medically acceptable salt thereof, which is used according to any of the foregoing embodiments.

[0086] This article also reveals compound A: Or a medically acceptable salt thereof, which is used according to any of the foregoing embodiments.

[0087] This article also reveals compound A: Or the use of its pharmaceutically acceptable salt in the manufacture of a pharmaceutical preparation according to any of the foregoing embodiments.

[0088] This article also reveals compound A: Or the use of its pharmaceutically acceptable salt in the manufacture of a pharmaceutical preparation according to any of the foregoing embodiments.

[0089] Each of the embodiments described herein may be combined with any other embodiment described herein, which is consistent with the embodiments in which they are combined. Administration and administration

[0090] As used herein, “treat” and “treating” cancer or cancer-related diseases mean administering, to an individual, participant, or patient who has cancer or has been diagnosed with cancer, a combination of therapies according to this disclosure to achieve at least one positive therapeutic effect, such as a reduction in the number of cancer cells; a reduction in tumor size; a reduction in the rate of cancer cells infiltrating surrounding organs or a decrease in tumor metastasis or tumor growth rate; reversal or relief of the condition or disease to which such terms apply, or one or more symptoms of such condition or disease; inhibition of the progression of the condition or disease, or one or more symptoms of such condition or disease; or prevention of the condition or disease, or one or more symptoms of such condition or disease. Unless otherwise indicated, as used herein, the terms “treat” and “therapy” mean the act of treatment, as defined above. For the purposes of this disclosure, beneficial or desired clinical outcomes include, but are not limited to, one or more of the following: reduction of the proliferation of neoplastic or cancerous cells (destruction of neoplastic or cancerous cells); inhibition of metastatic or neoplastic cells; reduction or shrinkage of tumor size; cancer relief; alleviation of cancer-related symptoms; improvement of the quality of life of cancer patients; reduction of the dosage of other drugs required to treat cancer; delay of cancer progression; cure of cancer; overcoming one or more drug resistance mechanisms in cancer; and / or prolongation of survival in cancer patients. The positive therapeutic effect on cancer can be measured in various ways (see, for example, WA Weber, J. Nucl. Med. (2009) 50:1S-10S).

[0091] The term "feeding condition" or "feeding state" used to describe individuals in this document means that the individual had eaten at a point in time of interest, such as less than 4 hours before the administration of compound A. In the embodiments, an individual in a feeding state had eaten within any of 4, 3, 2, 1, or 0.5 hours before the administration of compound A.

[0092] The term "amount" for use and treatment of an individual refers to the amount, in combination with one or more other agents, administered in single or multiple doses to provide a detectable response of any duration (transient, intermediate, or long-term), any measurable or detectable degree, or any duration of remission or cure for the desired outcome or objective or subjective benefit to the individual. Such amounts are typically effective in improving the disease, or one, several, or all adverse effects / symptoms, consequences, or complications of the disease to a measurable degree, but are also considered satisfactory to reduce or inhibit the progression or worsening of the disease, or to provide a stable (i.e., non-worsening) state of the disease. The term "therapeuticly effective amount" also means the amount of a combination of one or more other agents that, when administered to an individual, effectively produces the desired therapeutic effect, such as inhibiting the growth of a cancerous tumor or shrinking a cancerous tumor. Regarding cancer treatment, a therapeutically effective dose refers to a dose that has the following effects: (1) reducing tumor size; (2) inhibiting (i.e., slowing down, or preferably stopping) the occurrence of tumor metastasis; (3) inhibiting (i.e., slowing down, or preferably stopping) tumor growth or tumor invasion to some extent; and / or (4) alleviating (or preferably eliminating) one or more signs or symptoms associated with cancer to some extent. The therapeutic or pharmacological effectiveness of the dosage and administration regimen is also characterized by the ability to induce, enhance, maintain, or prolong disease control and / or overall survival in patients with such specific tumors, which can be measured by the extension of time before disease progression.

[0093] 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. "Symptoms" refers to any subjective indication of a disease or an individual's condition.

[0094] Embodiments of the present invention provide a dose, dosage, and administration regimen comprising administering to an individual a quantity or effective amount of compound A or its pharmaceutically acceptable salt. This quantity or therapeutically effective amount may be a daily dose of about 200 mg. In another embodiment, the daily dose is 200 mg.

[0095] In the embodiments, the daily dose of compound A or its pharmaceutically acceptable salt is administered once daily (QD).

[0096] The compounds described in this article can be administered orally. Oral administration may involve swallowing to allow the compounds to enter the gastrointestinal tract, or it may be administered via the cheek or under the tongue, thereby allowing the compounds to enter the bloodstream directly from the mouth.

[0097] In the embodiments, the daily dose of compound A or its pharmaceutically acceptable salt is administered orally.

[0098] Compound A or a pharmaceutically acceptable salt thereof may be present in the form of a pharmaceutical composition comprising pharmaceutically acceptable excipients. "Pharmaceutically acceptable excipients" refers to components that may be included in the compositions described herein, are physiologically suitable for pharmaceutical use, and will not cause significant adverse effects or therapeutic effects in an individual. The term "excipient" is used herein to describe any component other than the compounds of the present invention. The selection of excipients will depend considerably on factors such as the mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

[0099] The compounds of the methods, uses, or combinations of the present invention can be formulated prior to administration. The formulation is preferably suited to a particular mode of administration. These compounds can be formulated with pharmaceutically acceptable excipients known in the art and administered in a variety of dosage forms known in the art. 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 further dispensing into individual doses.

[0100] In embodiments, palbociclib or its pharmaceutically acceptable salts are administered at a daily dose of about 125 mg, about 100 mg, about 75 mg, about 50 mg, or about 25 mg once daily. In embodiments, palbociclib or its pharmaceutically acceptable salts are administered at a daily dose of about 125 mg once daily. For example, palbociclib or its pharmaceutically acceptable salts are administered at a dose of about 100 mg, about 75 mg, or about 50 mg once daily. In one embodiment, palbociclib or its pharmaceutically acceptable salts are administered at a dose of about 100 mg once daily. In one embodiment, palbociclib or its pharmaceutically acceptable salts are administered at a dose of about 75 mg once daily. In one embodiment, palbociclib or its pharmaceutically acceptable salts are administered at a dose of about 50 mg once daily. The dosages provided in this article refer to the dosage of palbociclib in its free base form, or calculated as the free base equivalent of the palbociclib salt administered. For example, the dosage or amount of palbociclib, such as 100 mg, 75 mg, or 50 mg, refers to the free base equivalent.

[0101] In embodiments, abexicillin or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 400 mg (e.g., about 200 mg twice daily), about 300 mg (e.g., about 150 mg twice daily), about 200 mg (e.g., about 100 mg twice daily), or about 100 mg (e.g., about 50 mg twice daily). In embodiments, abexicillin or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 300 mg (e.g., about 150 mg twice daily), about 200 mg (e.g., about 100 mg twice daily), or about 100 mg (e.g., about 50 mg twice daily). In embodiments, abexicillin or a pharmaceutically acceptable salt thereof is administered at a daily dose of 300 mg (e.g., about 150 mg twice daily). In one embodiment, abexicillin or a pharmaceutically acceptable salt thereof is administered at a dose of about 200 mg (e.g., about 100 mg twice daily). In the embodiments, abexicillin or a pharmaceutically acceptable salt thereof is administered at a dose of about 50 mg twice daily, i.e., about 100 mg (e.g., about 50 mg twice daily). The doses provided herein refer to the dose of abexicillin in its free base form, or are calculated as the free base equivalent of the abexicillin salt administered. For example, a dose or amount of abexicillin, such as 200 mg, 150 mg, 100 mg, or 50 mg, refers to the free base equivalent.

[0102] In embodiments, reboxil or its pharmaceutically acceptable salts are administered at a daily dose of about 600 mg, about 400 mg, about 200 mg, or about 50 mg once daily. In embodiments, reboxil or its pharmaceutically acceptable salts are administered at a daily dose of about 600 mg once daily. In one embodiment, reboxil or its pharmaceutically acceptable salts are administered at a dose of about 400 mg once daily. In another embodiment, reboxil or its pharmaceutically acceptable salts are administered at a dose of about 200 mg once daily. The doses provided herein refer to the dose of reboxil in its free base form, or are calculated as the free base equivalent of the reboxil salt administered. For example, a dose or amount of reboxil, such as 600 mg, 400 mg, or 200 mg, refers to a free base equivalent.

[0103] Repeating the dosing or administration regimen may be performed as needed to achieve the desired reduction or attenuation of cancer cells. As used herein, "continuous dosing duration" refers to a dosing or administration regimen without dose interruption, such as without a treatment stop date. Repeating a 28-day treatment cycle without dose interruption between treatment cycles is an example of continuous dosing duration. In embodiments, the compounds in the combinations of the present invention may be administered during continuous dosing duration. In embodiments, the compounds in the combinations disclosed herein may be administered simultaneously during continuous dosing duration.

[0104] In the embodiments, compound A is administered once daily to constitute a complete 28-day cycle. During treatment according to the method and use of this disclosure, the 28-day treatment cycle is continuously repeated.

[0105] The standard recommended dosing regimen for palbociclib or its pharmaceutically acceptable salts, including the standard dosing schedule, is once daily for 21 consecutive days, followed by a 7-day break to constitute a complete 28-day cycle. This 28-day cycle is repeated during treatment with the combination therapy of the present invention.

[0106] The standard clinical dosing regimen for palbociclib or its pharmaceutically acceptable salts is to administer 125 mg once daily for 21 consecutive days, followed by a 7-day break to constitute a complete 28-day cycle. This 28-day cycle is repeated during combination therapy with the present invention.

[0107] The standard clinical dosing regimen for reboxil or its pharmaceutically acceptable salts is 600 mg once daily for 21 consecutive days, followed by a 7-day break to constitute a complete 28-day cycle. This 28-day cycle is repeated during combination therapy with the present invention.

[0108] This invention also relates to kits comprising therapeutic agents of the present invention and written instructions relating to the administration of such therapeutic agents. In embodiments, the written instructions detail and define the administration pattern of the therapeutic agents, such as administering the therapeutic agents of this disclosure simultaneously or sequentially. In embodiments, the written instructions detail and define the administration pattern of the therapeutic agents, such as specifying the number of days for administering each therapeutic agent during a 28-day treatment cycle. Treatment

[0109] In the embodiments, this document provides a method for treating cancer in an individual, comprising administering to the individual an effective amount of a combination of compound A as described herein and a certain amount of a CDK4 / 6 inhibitor.

[0110] Unless otherwise indicated, as used herein, the term "combination" means 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 routes of administration and according to the same or different time schedules of administration.

[0111] As used in this article, the term "locally advanced" in cancer may or may not be treated with a curative intent. For example, locally advanced breast cancer (LABC) is defined by the US National Comprehensive Cancer Network as a small group of breast cancers characterized by: the most advanced stage of tumor without distant metastasis, wherein the tumor is larger than 5 cm in size and accompanied by local lymph node enlargement; a tumor of any size (including ulcers or satellite nodules) extending directly to the chest wall or skin or both, regardless of the presence or absence of local lymph node enlargement; and the presence of local lymph node enlargement (clinically fixed or entangled axillary lymph nodes, or any of the following: 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.)

[0112] As used in this article, the term "metastatic" in cancer cannot be treated with a 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 bone, liver, lungs, or brain. (www.cancer.org / cancer / breast-cancer.)

[0113] Those skilled in this technique will be able to identify and diagnose locally advanced and metastatic cancers in patients or individuals.

[0114] For convenience, certain well-known abbreviations may be used in this article, 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).

[0115] In the embodiments, cancer is selected from lung cancer, mesothelioma, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, melanoma of the skin or eye, uterine cancer, ovarian cancer, rectal cancer, anal cancer, stomach cancer, liver cancer, colon cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small bowel cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, hematologic malignancies, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) sarcoma, primary CNS lymphoma, spinal axis tumor, glioblastoma, brainstem glioma, pituitary adenoma, head and neck cancer, and a combination of two or more of the aforementioned cancers.

[0116] This document also discloses methods for treating cancer in an individual. In embodiments, these methods involve treating cancer in an individual by administering to the individual an amount of the compound described herein that is effective in treating the cancer.

[0117] In the 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.

[0118] In the embodiments, the cancer is breast cancer, lung cancer, prostate cancer, pancreatic cancer, or ovarian cancer.

[0119] In the embodiments, the cancer is breast cancer, lung cancer, or prostate cancer.

[0120] In this embodiment, the cancer is breast cancer.

[0121] In this embodiment, the breast cancer is metastatic breast cancer.

[0122] In this embodiment, the breast cancer is locally advanced breast cancer.

[0123] In this embodiment, the breast cancer is HR+ breast cancer.

[0124] In the embodiments, the HR+ breast cancer is PR+ and / or ER+ breast cancer.

[0125] In this embodiment, the breast cancer is PR+ breast cancer.

[0126] In this embodiment, the breast cancer is ER+ breast cancer.

[0127] In this embodiment, the breast cancer is ER+HER2- breast cancer.

[0128] In this embodiment, the breast cancer is ER+HER2+ breast cancer.

[0129] In this embodiment, the breast cancer is locally advanced or metastatic ER+ breast cancer.

[0130] In this embodiment, the breast cancer is locally advanced or metastatic ER+HER2- breast cancer.

[0131] In this embodiment, the breast cancer is locally advanced or metastatic ER+HER2+ breast cancer.

[0132] In this embodiment, the breast cancer is a metastatic ER+HER2- breast cancer.

[0133] In this embodiment, the breast cancer is a metastatic ER+HER2- breast cancer, which is also locally advanced.

[0134] In this embodiment, the lung cancer is non-small cell lung cancer.

[0135] In the embodiments, the lung cancer is locally advanced or metastatic non-small cell lung cancer.

[0136] In this embodiment, the prostate cancer is CRPC.

[0137] In this embodiment, the prostate cancer is locally advanced or metastatic CRPC.

[0138] This document also discloses a method for treating a solid tumor in an individual. In embodiments, this document discloses a method for treating a solid tumor in an individual, comprising administering to the individual an amount of the compound described herein that is effective in treating the solid tumor.

[0139] In the 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.

[0140] In the embodiments, the solid tumor is breast cancer, lung cancer, prostate cancer, pancreatic cancer, or ovarian cancer.

[0141] In the embodiments, the solid tumor is breast cancer, lung cancer, or prostate cancer.

[0142] In this embodiment, the solid tumor is breast cancer. For example, in some embodiments, the breast cancer is HR+ breast cancer. In other embodiments, the HR+ breast cancer is PR+ and / or ER+ breast cancer.

[0143] In this embodiment, the solid tumor is breast cancer. For example, in some embodiments, the breast cancer is ER+HER2- breast cancer.

[0144] In this embodiment, the solid tumor is breast cancer. For example, in some embodiments, the breast cancer is ER+HER2+ breast cancer.

[0145] In this embodiment, the solid tumor is breast cancer. For example, in some embodiments, the breast cancer is locally advanced or metastatic ER+ HER2- breast cancer.

[0146] In this embodiment, the solid tumor is breast cancer. For example, in some embodiments, the breast cancer is locally advanced or metastatic ER+ HER2+ breast cancer.

[0147] In this embodiment, the solid tumor is lung cancer. For example, in some embodiments, the lung cancer is non-small cell lung cancer.

[0148] In this embodiment, the solid tumor is lung cancer. For example, in some embodiments, the lung cancer is locally advanced or metastatic non-small cell lung cancer.

[0149] In this embodiment, the solid tumor is prostate cancer. For example, in some embodiments, the prostate cancer is CRPC.

[0150] In this embodiment, the solid tumor is prostate cancer. For example, in some embodiments, the prostate cancer is locally advanced or metastatic castration-resistant prostate cancer.

[0151] This document also discloses a method for treating hematologic malignancies in an individual. In an embodiment, the method involves treating a hematologic malignancy in an individual by administering to the individual an amount of the compound described herein that is effective in treating the hematologic malignancy.

[0152] In the embodiments, hematologic malignancies are leukemia, lymphoma, or multiple myeloma.

[0153] In the embodiments, the hematologic malignancy is leukemia or lymphoma.

[0154] This article also reveals methods for treating cancer in individuals with locally advanced or metastatic ER+ HER2- breast cancer, CRPC, or NSCLC whose disease has progressed after or who are intolerant to standard therapy.

[0155] This article also reveals methods for treating cancer in individuals with locally advanced or metastatic ER+ HER2- breast cancer, CRPC, or NSCLC whose disease has progressed after or who are intolerant to standard therapy.

[0156] This article also discloses a method for treating cancer in individuals with locally advanced or metastatic 2L+ ER+ HER2 breast cancer who have previously received hormone / endocrine therapy and chemotherapy in a locally advanced / metastatic setting. In an example, the method involves administering a combination of compound A and a CDK4 / 6 inhibitor to the individual.

[0157] This article also discloses a method for treating cancer in individuals with locally advanced or metastatic 2L+ ER+ HER2 breast cancer who have previously received treatment with a CDK4 / 6 inhibitor. In an example, the method involves administering a combination of compound A and a CDK4 / 6 inhibitor to the individual.

[0158] This article also reveals the treatment combination, which includes: (i) Compound A: (Compound A), or a pharmaceutically acceptable salt thereof; and (ii) CDK4 / 6 inhibitors; These treatment combinations are used simultaneously, independently, or sequentially in methods of treating cancer; wherein the method comprises administering a daily dose of compound A or a medically acceptable salt thereof.

[0159] This article also reveals the treatment combination, which includes: (i) Compound A: (Compound A); and (ii) CDK4 / 6 inhibitors; These treatment combinations are used simultaneously, independently, or sequentially in methods of treating cancer; wherein the method includes administering a daily dose of compound A.

[0160] This article also reveals compound A: (Compound A), or a pharmaceutically acceptable salt thereof, is used 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.

[0161] This article also reveals compound A: (Compound A), which is a method for treating cancer, wherein the method comprises administering Compound A, and wherein the method further comprises administering a CDK4 / 6 inhibitor.

[0162] This article also discloses a CDK4 / 6 inhibitor in a method for treating cancer, wherein the method further includes administering compound A or a pharmaceutically acceptable salt thereof.

[0163] This article also discloses a CDK4 / 6 inhibitor in a method for treating cancer, wherein the method further includes administering compound A.

[0164] In one embodiment, the method comprises administering approximately 200 mg of compound A daily or an equivalent amount of its pharmaceutically acceptable salt. In another embodiment, the method comprises administering approximately 200 mg of compound A daily. In yet another embodiment, the method comprises administering approximately 100 mg of compound A daily. Example

[0165] To better understand the present invention, the following examples are provided. These examples are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way.

[0166] The abbreviations used in this article include: ● AUC0-8 = Area under the plasma concentration-time curve from zero to 8 hours; ● AUC0-12 = Area under the plasma concentration-time curve from 0 to 12 hours; ● AUCτ = 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 reaction ● CBR = Clinical Benefit Rate; ● Cmax = Maximum plasma concentration; ● DDI = Drug-Drug Interaction; ● ER = estrogen receptor; ● GCV = Geometric coefficient of variation; ● HER2 = Human Epidermal Growth Factor Receptor 2; ● FIH = First time used in humans; ● IR = Immediate Release; ● mBC = metastatic breast cancer; ● MTD = Maximum Tolerated Dose; ● ORR = Overall Reaction Rate; ● PPI = Proton Pump Inhibitor; ● PR = Partial Response ● rBA = Relative Bioavailability; ● RP2D = Recommended Phase 2 dose; ● QD = Once daily; ● SA = Single drug; ● SD = Stable disease; and ● TRAE = Treatment-related adverse events. Clinical trials of compound A ("FIH Study" and "Clinical Pharmacology Study") First use in human studies ("FIH") []

[0167] The ongoing Phase 1 / 2, open-label, dose-escalation, and cohort-extension study is investigating compound A 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 previously received hormonal and chemotherapy in a locally advanced / metastatic setting. An overview of the FIH study is provided below. [surface] [1] in.

[0168] The FIH study will evaluate the safety and tolerability of compound A in combination with palbociclib in patients with locally advanced or mBC, and will determine its MTD and / or RP2D. The study will also assess the clinical activity of compound A in combination with palbociclib at its RP2D level. Further evaluations will include single-dose and multiple-dose pharmacokinetics and biochemical activity.

[0169] Study Design: Part C of the FIH study is Phase 1b of the evaluation of the combination of compound A and palbociclib. Investment method

[0170] Over a 28-day period, the combination of compound A and palbociclib (Part C) was administered orally at the doses shown in Table 1. Compound A was supplied in immediate-release tablets at strengths of 10 mg, 50 mg, and 100 mg. The tablet excipients were inert pharmacopoeia components commonly used in oral formulations, including lactose monohydrate and sodium stearate fumarate.

[0171] According to the product label and local prescribing information, palbociclib was administered orally at 125 mg once daily for 21 days in each 28-day cycle, followed by a 7-day break.

[0172] As of the data cutoff date of June 6, 2022, 176 patients had been treated in the FIH study (Part C, n=27) and preliminary evidence of clinical activity had been observed. [surface] [1. C] [part] [FIH] [Overview of the Research] [] Research Title Research Design research group Evaluation of Compound A treatment group This is a phase 1 / 2, open-label, dose-escalation, and cohort-extension clinical 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. These patients had previously received hormonal and chemotherapy in a locally advanced / metastatic setting. FIH, open-label, continuous group, dose escalation 3+3 and cohort expansion consist of the following: Part C—a combination of Phase 1b compound A and palbociclib. Patients with histologically or cytologically confirmed ER+ / HER2- metastatic, recurrent, or locally advanced unresectable breast cancer for whom standard curative therapy is no longer effective or available. Age: ≥18 years old Part C—Phase 1b and the combination with Papacicli: ● 180 mga, 200 mg, 400 mg or 500 mg QD compound A + palbociclib: Administer 125 mg orally once daily for 21 days, followed by a 7-day treatment-free period. Patients initially enrolled in this cohort received a 180 mg QD, but based on the availability of 100 mg tablets, the dose was rounded up to a 200 mg QD. Clinical pharmacology studies

[0173] An ongoing Phase 1 clinical pharmacology study is investigating compound A to evaluate the effects of food or a PPI (esomeprazole) on the single-dose pharmacokinetic (PK) and safety of compound A in healthy postmenopausal female volunteers ("Participants"). An overview of the clinical pharmacology study is provided below. [surface] [2] in.

[0174] Study Design: The clinical pharmacology study consisted of three independent cohorts: 1) an open-label, randomized, two-stage crossover eating / fasting cohort for determining the effects of food; 2) an open-label, two-stage, fixed-sequence PPI cohort for evaluating interactions with esomeprazole; and 3) an open-label, randomized, two-stage crossover rBA cohort for evaluating the two tablet formulations.

[0175] As of the data cutoff date of June 16, 2022, 47 participants had been treated in three clinical pharmacology study cohorts (14 participants in the eating / fasting cohort, 17 participants in the PPI cohort, and 16 participants in the rBA cohort). Each participant received two doses of compound A at 200 mg each, one dose in each phase, with the compound A treatment separated by a clearance period of at least 14 days.

[0176] The 200 mg dose of compound A was well tolerated in the participants, and no grade 2 or higher TRAEs were reported. [surface] [2.] [Overview of Clinical Pharmacology Research] [] Research Title Research Design research group Evaluation of Compound A treatment group This is a phase 1, multi-part, open-label study conducted in healthy postmenopausal female volunteers to evaluate the effects of a single dose of food or a proton pump inhibitor (esomeprazole) on the pharmacokinetics and safety of compound A, and to assess the relative bioavailability of different tablet formulations. Open-label studies with 3 independent components: Fasting / Eating: Two-phase, cross-feeding / fasting cohorts were used to determine the effects of food. PPI: A two-stage, fixed-sequence PPI cohort was used to evaluate the interaction with esomeprazole. rBA: Randomized grouping, two-stage, crossover rBA cohorts were used to evaluate two 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. Feeding / Fasting Cohort: Compound A was administered on days 1 and 15. ● Fasting period: Continue fasting for at least 4 hours after administration. ● Feeding phase: Administer compound A 30 minutes after starting the high-fat meal, followed by fasting for at least 4 hours after the administration of compound A. PPI queue: ● Single-dose phase: Compound A was administered on day 1 and day 19 while the patient was eating. ● Continuous dosing phase: For 5 days from day 15 to day 19, take esomeprazole delayed-release capsules (40 mg QD) at least 1 hour before meals. On day 19, administer compound Ad at least 90 minutes after taking esomeprazole, with food. rBA queue: On days 1 and 15, compound A was administered at a loading of 200 mg with a 20% (reference) or 42% (test) dose while the patient was eating. c. The study drug was administered 30 minutes after the start of a moderate-fat meal, followed by fasting for at least 4 hours after the administration of compound A. [Example] [1] Pharmacokinetics in breast cancer patients [(PK)(FIH)] [Research] [)] [] []

[0177] Preliminary PK data from Part C of the FIH study (compound A administered in combination with palbociclib) were obtained from dose levels ranging from 180 mg to 500 mg QD. Preliminary results indicated a dose-dependent increase in Cmax and AUCτ when up to 500 mg QD of compound A, compound B, and the sum of compound A and compound B were administered on days 1 and 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 from Part C on day 15 of cycle 1 with relevant PK data observed in previously completed studies administering palbociclib or compound A as monotherapy. The PK data from Part C indicated that palbociclib had no effect on compound A exposure, as evidenced by the similarity of Cmax and AUCτ of compound A in patients receiving both compound A and palbociclib to those in patients receiving compound A monotherapy. On the other hand, after administration of a combination of 125 mg QD palbociclib and 500 mg QD compound A on day 15 of cycle 1, the preliminary Cmax and AUCτ of palbociclib were approximately 18% to 25% and 34%, respectively, higher than the equivalent values ​​observed in studies PALOMA-1 and PALOMA-2 when palbociclib was administered with 125 mg QD (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. March 2018;29(3):271-280). Further evaluation of the DDI potential between palbociclib and compound A is underway. Example 2: Pharmacokinetics (PK) in healthy volunteers (clinical pharmacology study)

[0178] In a clinical pharmacology study, preliminary pharmacokinetic parameters were calculated for all three cohorts following a single 200 mg dose of compound A. The median Tmax for each cohort ranged from 6.0 to 8.0 hours. The geometric mean T1 / 2 following a single 200 mg dose was approximately 40 hours under feeding conditions.

[0179] Statistical analysis showed that, compared to fasting, food intake significantly increased the Cmax and AUCinf of compound A by 3 to 2 times. Therefore, patients should be instructed to take compound A with food. When administered with or without a PPI, the AUC value of compound A was similar, but the PPI reduced the median Cmax of compound A by approximately 18%, which was not considered clinically significant. This indicates that when administered with a moderate-fat meal, the PPI has no effect on the exposure to compound A. Example 3: Safety in healthy volunteers (clinical pharmacology study)

[0180] Adverse events (AEs) are coded according to the Medical Dictionary for Regulatory Activities (MedDRA) version 24.1, based on the system organ type and preferred terminology. The severity of adverse events is graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.

[0181] Treatment-induced adverse events (TEAEs) are AEs that occur within 30 days after the first administration of compound A and the last administration of compound A, regardless of the investigational drug attribution or grade.

[0182] Treatment-related adverse events (TRAEs) are AEs assessed by the investigator as "probably related", "very likely related", or "related" to compound A. Treatment-associated adverse events (TEAEs)

[0183] Regardless of the attribution and grade of the investigational drug, TEAEs were observed in 15 of the 47 participants treated with 200 mg of compound A in ongoing clinical pharmacology studies (all cohorts).

[0184] Fasting / feeding cohort (n=14): The most common TEAE (whether or not attributable to the study drug) observed in ≥10% of participants was ligament sprain (2 participants, 14.3%). All other TEAEs were reported in <10% of participants.

[0185] All participants who reported TEAEs in the fasting / feeding cohort experienced either Level 1 (21.4%) or Level 2 (14.3%) TEAEs. No participants reported Level 3 or higher TEAEs.

[0186] There were no clinically significant differences in reported TEAEs among participants treated with compound A under both fasting and feeding conditions.

[0187] PPI cohort (n=17): The most common TEAEs (whether or not attributed to the study drug) observed in ≥10% of participants were headache (5 participants, 29.4%) and COVID-19 (2 participants, 11.8%).

[0188] All participants who reported TEAEs in the PPI cohort experienced either Level 1 (47.1%) or Level 2 (5.9%) TEAEs. No participants reported Level 3 or higher TEAEs.

[0189] There was no clinically significant difference in reported TEAEs between participants treated with compound A and PPIs and participants treated with compound A but not PPIs.

[0190] rBA cohort (n=16): Only 1 participant (6.3%) reported TEAE (vertigo, grade 1). There was no clinically significant difference in reported TEAEs between participants treated with 20% drug loading and those treated with 42% drug loading. Treatment-related adverse events (TRAE)

[0191] Of the 47 participants, 3 experienced at least one TEAE (regardless of severity) that was considered to be possibly related to compound A.

[0192] Fasting / eating cohort (n=14): 1 participant (7.1%) reported TRAE urinary frequency.

[0193] PPI cohort (n=17): 2 participants (11.8%) reported at least one TRAE. The reported TRAEs included nausea, headache, and itching (1 participant each [5.9%]).

[0194] rBA queue (n=16): No participants reported TRAE. Serious adverse events (SAEs), serious adverse drug reactions (SARs), and death

[0195] No SAEs, SARs, or deaths were reported in clinical pharmacology studies (all cohorts). Treatment-associated adverse events (TEAEs) that led to the discontinuation of the study

[0196] A healthy participant reported a TEAE that led to the discontinuation of the clinical pharmacology study. This participant was in the PPI cohort, treated with 200 mg of compound A without PPI treatment, and was unable to receive a second dose of compound A and PPI due to COVID. Example 4: Safety and efficacy in breast cancer patients (FIH study) [I.] [Safety in breast cancer patients] [(FIH)] [Research] [)] [] []

[0197] The TEAE and TRAE data in the clinical trial database use MedDRA version 22.0, coded for system organ classification and preferred terminology, while the SAE data in the centralized safety database uses MedDRA version 25.0. The severity of adverse events is based on the NCI CTCAE classification version 5.0.

[0198] TEAE refers to adverse events that occur after the first administration of compound A and within 30 days after the last administration of compound A, regardless of the investigational drug attribution or grade.

[0199] TRAEs are AEs that researchers assess as "possibly related", "very likely related", or "related" to compound A.

[0200] Preliminary safety data from the FIH study are presented below. Part C continues registration. [Summary of Adverse Events] [] []

[0201] Based on the data cutoff date of June 6, 2022, regardless of the attribution and grade of the study drug, TEAEs were observed in 157 out of a total of 176 patients treated with compound A in the ongoing FIH study (all parts). Compound A Combination Therapy—Part C

[0202] Preliminary safety data evaluating patients treated with the combination of compound A and palbociclib showed TEAEs consistent with those observed after treatment with compound A or palbociclib alone (Pfizer. IBRANCE® (palbociclib). US FDA Package Insert. Capsules, for oral use: Full Prescribing Information. New York, NY: Pfizer Laboratories; Revision: 04 / 2019). Available at: (www.accessdata.fda.gov / drugsatfda_docs / label / 2019 / 207103s008lbl.pdf).

[0203] Based on the data cutoff date of June 6, 2022, 24 out of 27 patients (88.9%) reported at least one TEAE in Part C.

[0204] The most common TEAEs (regardless of whether they were attributable to the study drug) observed in ≥20% of patients included neutropenia (51.9%), fatigue (44.4%), neutropenia (37.0%), thrombocytopenia (33.3%), anemia (29.6%), nausea (25.9%), cough (22.2%), diarrhea (22.2%), and leukopenia (22.2%). Compound A Combination Therapy—Part C—Combination of Compound A and Palbociclib:

[0205] Based on the data cutoff date of June 6, 2022, 5 out of 27 patients reported a total of 7 SAEs. All SAEs reported in Part C were assessed by the investigators as unrelated to compound A. One case of grade 3 bacteremia SAE was assessed by the investigators as possibly related to palbociclib treatment. [II.] [Efficacy in breast cancer patients] [(FIH)] [Research] [)] [] []

[0206] For Part C, we will continue to collect efficacy data. in conclusion

[0207] Without being bound by theory, based on the aforementioned examples, a daily dose of 200 mg of compound A in combination with a CDK4 / 6 inhibitor may be beneficial. Example 5: TACTIVE-U: A phase 1b / 2 comprehensive study of compound A as a proteolytically targeted chimeric (PROTAC) estrogen receptor (ER) degrader in ER+ advanced or metastatic breast cancer in combination with other anticancer therapies.

[0208] Patients eligible for Subsidiaries A and B were ≥18 years of age, had histologically or cytologically confirmed ER+ / HER2- advanced or metastatic breast cancer unsuitable for surgical resection, with ≥1 measurable lesion, and had received ≤2 lines of prior therapy for advanced or metastatic disease, including 1 line of any CDK4 / 6 inhibitor-based regimen. In Subsidiary A, patients received compound A orally once daily (QD) and abexicillin orally twice daily (BID). In Subsidiary B, patients received compound A orally once daily (QD) and reboxil orally once daily (QD); compound A was administered continuously, while reboxil was administered for 21 days, followed by a 7-day treatment break. For both subsidiaries, the primary endpoint for the Phase 1b portion was dose-limiting toxicity, used to determine the recommended Phase 2 dose of compound A in combination with abexicillin or reboxil. Secondary endpoints for Phase 1b include 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 concentration of the study drug; sub-study B will measure the AUCτ and Cmax of compound A+ / - reboxilide. Phase 2 will further evaluate 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 concentration of the study drug, and changes in circulating tumor DNA.

[0209] As of the data cutoff date of June 6, 2023, four patients in sub-study A received 200 mg QD compound A and 150 mg BID abecilibi, and two patients in sub-study B received 100 mg QD compound A and 600 mg QD reboxilibi. Example 6: Enhanced efficacy of compound A combined with a CDK4 / 6 inhibitor in an ER+ breast cancer model. [method] [] Live cell imaging proliferation analysis

[0210] MCF7 or T47D cells were seeded in 6-well plates and treated with a specified concentration of compound. The plates were then placed in an 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, thereby quantifying cell surface area coverage as confluence values. Relative growth was calculated at all time points under all growth conditions relative to the confluence values ​​observed at 120 hours in the control. [picture] [1A] [and] [1C]). GraphPad Prism (GraphPad Software) was used for plotting and statistical analysis.

[0211] In MCF7 and T47D cells treated for 5 days with compound A or fulvestrant at concentrations close to their respective GI50, either as a single agent or in combination with abexilide, the mean reductions in MCF7 cell growth induced by compound A, abexilide, and the combination were 41%, 49%, and 65%, respectively, compared to control cells (Figs. 1A-1B). For fulvestrant and fulvestrant + abexilide, the mean reductions in MCF7 cell growth were 48% and 68%, respectively. The mean reductions in T47D cell growth induced by compound A, abexilide, and the combination were 42%, 32%, and 63%, respectively, with the mean reductions induced by fulvestrant and fulvestrant + abexilide being 16% and 50%, respectively (Figs. 1C-1D). Similar results were obtained with single-agent or combination treatment with compound A and reboxil. After 5 days of treatment at concentrations close to their respective GI50 levels, the mean reductions in MCF7 cell growth induced by compound A, reboxil, and their combinations were 41%, 44%, and 63%, respectively, compared to control cells (Fig. 1E-1F); the mean changes in T47D cell growth induced by compound A, reboxil, and their combinations were 41%, 32%, and 61%, respectively (Fig. 1G-1H). When compared to either single agent alone, the combination of compound A with abecil or reboxil demonstrated a significantly stronger inhibitory effect on the growth of both MCF7 and T47D cells. These results, when combined with abecil or reboxil, were similar to those observed with fulvestrant.

[0212] When compared with the activity of single-agent compound A (105% TGI) in this model ( [picture] [5]), the combination of compound A and palbociclib caused tumor regression (131% TGI). In contrast, subcutaneous administration of fulvestrant as a single agent caused only a moderate TGI (46% TGI), while the combination of fulvestrant and palbociclib caused enhanced tumor growth inhibition (108% TGI), but not to the level achieved by compound A and palbociclib alone. 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.

[0213] The in vivo effects of combination compound A or fulvestrant with abexicillin were also evaluated in mice with MCF7 tumors. As single agents, compound A and abexicillin treatment induced 88% and 50% TGI, respectively, while the combination caused higher growth inhibition (111% TGI) than either single agent alone. [picture] [3A]). Fulvestrant exhibits a moderate TGI (42%) as a single agent and an enhanced TGI (77%) when combined with abexicillin. However, the TGI observed with the combination of fulvestrant and abexicillin did not reach the level observed with the combination of compound A and abexicillin.

[0214] Treatment of mice with MCF7 tumors with compound A as a single agent and reboxil as a single agent resulted in a TGI of 87% and 58%, respectively, while the combination resulted in a higher TGI (124%) than either single agent alone. [picture] [3B]). Fulvestrant as a single agent showed a moderate TGI (31%) and an enhanced TGI (76%) when combined with reboxil, but it did not reach the level achieved by combining compound A with reboxil, similar to the observations of combining fulvestrant with abecitabine.

[0215] In summary, these results demonstrate that in the BC tumor model, compound A exhibits antitumor activity as a single agent and shows higher antitumor activity when combined with the CDK4 / 6 inhibitors abexilide and reboxil, demonstrating a higher antitumor effect than that observed when fulvestrant is combined with any of these CDK4 / 6 inhibitors. Dose-response matrix analysis

[0216] Cells were seeded at a density of 2 × 10³ cells per well in 200 μl of culture medium and incubated overnight at 37°C. The concentration curves for compound A and abexicillin are eight-point curves starting at 100 nM and ranging from 100 nM to 0.046 nM. [picture] [2A] [、] [2C] and [B]). The reboxil concentration curve is an 8-point concentration curve in the range of 3000 nM to 1.37 nM, starting from 3000 nM. [picture] [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 abecitabine or reboxil with compound A showed enhanced cell growth inhibition compared to monotherapy and elicited synergistic effects in Bliss, Leucocytosis, and HSA models, except in the Bliss model of T47D cells. [MCF7] [Xenotransplantation Model]

[0217] In short, MCF7 cells were orally implanted into the mammary fat pads of female NOD / SCID mice. Two to three days prior to MCF7 cell implantation, a 0.72 mg 90-day timed-release 17β-estradiol pellet was implanted (Innovative Research of America). For the combination arm, compound A was administered first, followed by the combination drug one hour later. Mice treated with compound A and / or the combination drug were administered orally once daily. Mice treated with fulvestrant were administered subcutaneously twice weekly for two weeks, followed by once weekly for two weeks.

[0218] More specifically, using the MCF7 orthotopic xenograft model, the synergistic effect between compound A and abecicilline and reboxil was tracked in vivo. Eight- to ten-week-old female NOD / SCID mice were surgically implanted subcutaneously with a 90-day timed-release 17β-estradiol pellet. One to two days later, 5 × 10⁶ cells / 200 µL of MCF7 cells were injected into one mammary fat pad of each mouse. The cell line was prepared at 25 × 10⁶ cells / mL in 50 / 50 phenol red-free RPMI-1640 medium / Corning Matrigel membrane matrix mixture. Administration was initiated after the tumor reached an average of 200 mm³. In the case of oral administration, compound A (30 mg / kg) was administered first, followed by abecicilline (30 mg / kg) and reboxil (75 mg / kg) 30–60 minutes later. The study also evaluated fulvestrant as a single agent (200 mg / kg, subcutaneously; twice weekly for 2 weeks, followed by once weekly for 2 weeks) and its combination with abecicilline and reboxil. Ten mice / arm were administered the designated drugs as single agents or in combination. Compound A, along with abecicilline and reboxil, were administered once daily at a dose of 5 ml / kg for 28 days (qdx28). The mediator for compound A was 2% Tween 80 / PEG400. The mediator for abecicilline was 1% hydroxymethylcellulose (HEC) in 20 mM HCl pH2. The mediator for reboxil was 0.5% methylcellulose. The mediator for fulvestrant was 10% w / v ethanol, 10% w / v benzyl alcohol, and 15% w / v methyl benzoate, prepared with castor oil to form 100% w / v. If any weight loss approached 10% (days 11, 12, 19, and 20 of the reboxil study), a one-day dosing break was implemented for all arms. During the one-day dosing break, weight was well maintained. [picture] [4A] and [4B]). In the efficacy study, tumor volume was measured twice weekly and calculated using (width 2 × length) / 2, with all measurements in millimeters (mm) and tumor volume in mm³. Body weight was recorded twice weekly. At the end of the study, mice were euthanized 18 hours after the last administration, and the collected tissue was rapidly frozen on dry ice. Tumor growth inhibition rate (TGI) was calculated as follows, with tumor volume in mm³: TGI (%) = [1- (Tumor volume on day X, compound) - (Tumor volume on day 0, compound) ] × 100 (Tumor volume on day X, mediator) - (Tumor volume on day 0, mediator)

[0219] At the end of the abeciclib study, compound A alone and abeciclib inhibited tumor growth by 88% and 50%, respectively. The combination of compound A and abeciclib resulted in a growth inhibition rate of 111%. Fulvestrant, as a single agent, inhibited tumor growth by 42% and, when combined with abeciclib, inhibited tumor growth by 77%.

[0220] At the end of the reboxil study, compound A alone and reboxil alone inhibited tumor growth by 87% and 58%, respectively. The combination of compound A and reboxil resulted in a growth inhibition rate of 124%. Fulvestrant alone inhibited tumor growth by 31% and in combination with reboxil by 76%.

[0221] The data is presented as mean ± standard error of mean. [in conclusion] [] []

[0222] In vitro studies have revealed evidence of synergistic interactions between compound A and CDK4 / 6 inhibitors abecilibi and reboxil. [picture] [1] and [2] Evidence shows that the combination of compound A with CDK4 / 6 inhibitors (i.e., abecilibi and reboxil) exhibits enhanced efficacy and in vitro synergistic effects.

[0223] Compared to single agents, the combination of compound A with CDK4 / 6 inhibitors abecilibi and reboxil resulted in enhanced tumor regression in MCF7 xenografts.

[0224] Compound A, when combined with abexicillin or reboxil, exhibits greater antitumor activity than that observed when fulvestrant is combined with these agents.

[0225] In summary, this data highlights the potential efficacy of compound A as a combination of clinically relevant targeted agents for the treatment of early and late ER+ disease. Example 6: A study of compound 1 in individuals with ER+ / HER2- advanced breast cancer in China. [, , ] Brief Overview

[0226] The purpose of this clinical trial is to study the pharmacokinetics, safety, and tolerability of compound 1 as a potential treatment for advanced estrogen receptor-positive and human epidermal growth factor receptor 2-negative breast cancer.

[0227] This study seeks participants who: —have ER+ / HER2- advanced breast cancer — Received at least one line of endocrine therapy, and may or may not receive a CDK4 / 6 inhibitor. —Receive up to two prior chemotherapy regimens in late-stage settings.

[0228] All participants in this study will receive compound A.

[0229] Compound A will be administered orally once daily at home.

[0230] The experiences of individuals who received the investigational drug will be examined. This will help determine whether the investigational drug is safe and effective.

[0231] Participants will remain in this study until their cancer becomes unresponsive. During this period, they will visit the study clinic approximately every four weeks.

[0232] All participants will stay at the research clinic for 10 days and 9 nights. Research type: Interventional Research phases: Phase 1 Research arm: A research arm Blindness: No blindness Number of registrants: 9 intervention [Arm Title] [type] [describe] Rosuvastatin, which utilizes / does not utilize compound A experimental [Intervention Name] [type] [Related Arm] [describe] [Other names] Compound A drug Compound A For the study of monotherapy as defined in ARV-471-mBC-101, compound A was administered orally once daily with food (e.g., a light meal of about 400 to 600 calories, including a mixture of fats, carbohydrates and proteins) for a continuous 28-day cycle. Results Measurement [Result Measurement] [Time Range] [describe] Single-dose Cmax (maximum plasma concentration) 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours after administration, up to day 71. Maximum plasma concentration Single-dose AUCτ 0, 1, 2, 3, 4, 6, 8, and 12 hours after administration, up to 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 doses of Cmax 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours after administration The observed maximum plasma concentration (Cmax) Multiple doses of AUCτ 0, 1, 2, 3, 4, 6, 8, and 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 measurement [Result Measurement] [Time Range] [describe] Objective response rate—the percentage of participants who have an objective response. Baseline until 24 weeks The percentage of participants with an objective response assessed based on the Response Evaluation Criteria in Solid Tumors (RECIST). A confirmed response is defined as a response maintained for at least 4 weeks after the initial recording in a repeat imaging study. According to RECIST v1.1: CR is defined as the complete disappearance of all target and non-target lesions, excluding nodular lesions. All target and non-target nodules must shrink to normal size (short axis <10 mm). No new lesions are present. PR is defined as a reduction of ≥30% in the percentage of participants with an objective response assessed based on either a complete response (CR) or a partial response (PR) according to RECIST criteria for evaluation of response to solid tumors. Percentage of participants who experienced clinical benefit Baseline until 24 weeks The percentage of participants confirmed by RECIST to have a complete response (CR), partial response (PR), or stable disease (SD) within at least 24 weeks of the study. According to RECIST v1.1: CR is defined as the complete disappearance of all target lesions and non-target lesions, excluding nodular disease. All target and non-target nodules must shrink to normal (short axis <10 mm). No new lesions. PR is defined as a reduction of ≥30% in the sum of the diameters of all target lesions compared to baseline. The short axis is used in the sum of the target nodules, while the longest diameter is used in the sum of all other target lesions. No significant progression of non-target diseases. No new lesions. SD is defined as not meeting CR, PR, or disease progression (PD). Objective Response Duration (DOR) From the date of the first recorded response (CR or PR) to the date of the first recorded progression or death DOR: The time from the date of first recorded response (CR or PR) to the date of first recorded progression or death due to 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 decrease to <10 mm; for non-TL, tumor marker levels return to normal; b) PR: A >=30% reduction in the sum of diameters (dia) of all TLs relative to baseline; c) PD: A >=20% increase in the sum of diameters of all measured target lesions, with an absolute increase of >=5 mm relative to the minimum sum of diameters of all target lesions recorded at or after baseline. Significant progression of existing non-target lesions. At least one new lesion appears. If a participant with CR or PR does not have PD or death due to underlying cancer, the participant is reviewed on the last appropriate tumor assessment date. Presence (ratio) or absence of blood biomarkers Baseline until end of treatment Biomarkers for identifying complete response and progression (if it occurs) (ESR1 mutation) The number of participants with noteworthy electrocardiogram (ECG) values From baseline until 28 days after the last administration of the study drug The criteria for noteworthy ECG values ​​are as follows: a new (post-baseline) QT interval (in milliseconds [msec]) exceeding 450, 480, or 500, or an increase of >30 relative to baseline. The following are considered abnormal conditions: A new (post-baseline) QT interval (QTcF) corrected by the Fredericia formula in msec > 450, 480, or 500, with an increase of > 30 or > 60 relative to baseline; a new (post-baseline) QT interval (QTcB) corrected by Bazett's formula in msec > 450, 480, or 500, with an increase of > 30 or > 60 relative to baseline; and a new (post-baseline) heart rate in bpm < 60 and > 100. Number of participants with laboratory abnormalities Baseline (Day 1) until 28 days after the last administration of the study drug Hemoglobin (HGB), hematocrit, erythrocytes (ery.), HDL cholesterol (chl.) <0.8*lower limit of normal (LLN); reticulocytes (ret.), ret. / ery. (%) <0.5*LLN, >1.5*upper limit of normal (ULN); mean corpuscular volume (EMC), EMC HGB, EMC HGB The number of participants whose vital signs showed clinically significant changes relative to baseline Baseline until 28 days after the last administration of the study drug Vital signs (temperature, respiratory rate, pulse, systolic blood pressure, and diastolic blood pressure) were obtained from participants in a seated position after they had been sitting calmly for at least 5 minutes. The clinical significance of vital signs was determined at the discretion of the investigator. The number of participants with adverse events categorized by type, frequency, severity (according to NCI CTCAE classification version 5.0), timing, severity, and relationship to the study treatment. Baseline until 28 days after the last administration of the study drug The count of participants who experienced treatment-induced adverse events (TEAEs) is as follows: TEAEs are defined as new occurrences or worsening after the first dose. The relevance to the [investigation drug] is assessed by the investigator. Participants who experience multiple AEs within a category are counted once within that category. An adverse event (AE) is any adverse medical event in a participant receiving the investigation drug, regardless of the likelihood of causation. According to CTCAE 4, Grade 1 = Mild AE; Grade 2 = Moderate AE; Grade 3 = Severe AE; Grade 4 = Life-threatening or disabling AE; Grade 5 = Death related to an AE. Single dose Tmax 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours after administration When did Cmax appear? Single dose AUClast Until the last quantifiable concentration Area under the concentration-time curve from time zero to the last quantifiable concentration (Clast) Single dose MRCmax Until the 71st day 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 Area under the concentration-time curve extrapolated from time zero to infinity Single-dose CL / F Week X Drug clearance is a measure of the rate at which a drug is metabolized or eliminated through normal biological processes. The clearance obtained after oral administration (apparent oral clearance) is affected by the fraction of the absorbed dose. Clearance is estimated using population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which an active pharmaceutical ingredient is removed from the bloodstream. Single dose Vz / F 0 (before administration), 1, 2, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96 and 144 hours after administration Apparent volume distribution Single dose t½ 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours after administration terminal half-life Multiple doses of Tmax 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours after administration Time to reach maximum observed plasma concentration Multiple doses of Tmax 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours after administration When did Cmax appear? Multiple doses MRCmax Until the 71st day Cmax ratio of compound 2 to compound 1 Rac Until the 71st day Cumulative ratio based on AUC (observations) t½eff Until the 71st day Effective half-life (t½eff) based on cumulative ratio Multiple doses of CL / F Until the 71st day Drug clearance is a measure of the rate at which a drug is metabolized or eliminated through normal biological processes. The clearance obtained after oral administration (apparent oral clearance) is affected by the fraction of the absorbed dose. Clearance is estimated using population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which an active pharmaceutical ingredient is removed from the bloodstream. Multiple doses t½ 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours after administration terminal half-life qualifications age all Age restrictions Minimum age: 18 years old Maximum age: N / A Accepting healthy volunteers no Qualification Standards Inclusion criteria: —Histological or cytological diagnosis of breast cancer and evidence of ER+ / HER2- locally advanced or metastatic disease, unsuitable for curative surgical resection or radiation therapy. —SOC receiving at least one line of endocrine therapy and receiving or not receiving CDK4 / 6 inhibitors for locally advanced or metastatic disease. —At most two prior chemotherapy regimens are permitted for use in advanced or metastatic disease settings. Exclusion criteria: —Known active, uncontrolled or symptomatic CNS metastases, carcinomatous meningitis or leptomeningeal disease indicated by clinical symptoms, cerebral edema, and / or progressive growth. Participants with a history of CNS metastases or spinal cord compression were eligible if they had received definite treatment (e.g., radiotherapy, stereotactic surgery) prior to their first administration of the study drug and had been clinically stable for at least 28 days after discontinuation of enzyme-inducing anticonvulsants and steroids (including patients with residual CNS symptoms / deficiencies). —Having experienced any of the following in the past 6 months: myocardial infarction, severe / unstable angina, coronary artery bypass graft, symptomatic congestive heart failure (New York Heart Association Class III or IV), cerebrovascular accident, transient ischemic attack, or other clinically significant episode of symptomatic pulmonary embolism or thromboembolic disease, congenital long QT syndrome, polymorphic ventricular tachycardia, severe conduction system abnormalities (e.g., bifascicular block defined as right bundle branch and left anterior or left posterior half block, third-degree AV block), clinically significant arrhythmia, left anterior half block (bifascicular block), persistent cardiac arrhythmia of NCI CTCAE ≥2, or atrial fibrillation of any grade. Example 6: TEAE (Traditional Therapeutic Effect) occurring during treatment [, , ]

[0233] As of June 6, 2023, a total of 46 participants (100%) who received the combination of compound A and 125 mg palbociclib reported at least one TEAE.

[0234] For all combinations of compound A doses with 125 mg palbociclib, the most common TEAEs observed in ≥20% of patients, in descending order of frequency, are as follows: neutropenia, fatigue, thrombocytopenia, anemia, constipation, nausea, leukopenia, diarrhea, and QT prolongation on ECG (Table 4). Grade 3 and Grade 4 TEAEs occurred in 23 (50%) and 19 (41.3%) participants, respectively. Neutropenia was the most common Grade 3 or Grade 4 TEAE, occurring in 47.8% (Grade 3) and 41.3% (Grade 4) of participants, respectively. [] [surface] [3.] [Based on preferred terminology and] [CTCAE] [Highest rank] [3] [Level and above] [—] [Research] [ARV-471-mbc-101(C)] [part] [)] [,] [TEAE] [≥] [5%] Dosage group Preferred AE terminology [n(%)] Any level Level 3 Level 4 Level 5 [] [occurring in any treatment] [AE] [] [46 (100.0)] [23 (50.0)] [19 (41.3)] [0] Compound A at all dose groups + 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 *Neutralization is classified according to MedDRA’s preferred terminology of neutropenia and neutropenia count. Note: An adverse event (AE) during treatment is defined as occurring on or after the date of the first study dose and within 30 days of the last study dose. Note: For each preferred term, the patient is counted only once. Note: Adverse events are coded using MedDRA version 22.0. Source: BDM TAE04C: TEAE—Full Treatment Analysis Set of All Dosage Groups Based on Preferred Terminology and Highest CTCAE Grade (Part C) and BDM TAE04RELC2: TRAE—200 mg Full Treatment Analysis Set of Compound A or Palbociclib Based on Preferred Terminology and Highest CTCAE Grade (Part C) Data cutoff date: June 6, 2023

[0235] 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%), thrombocytopenia (52.4%), anemia (42.9%), constipation (33.3%), increased alanine transaminase (23.8%), increased aspartate aminotransferase (23.8%), back pain (23.8%), dizziness (23.8%), and leukopenia (23.8%).

[0236] All patients in the 200 mg compound A and 125 mg palbociclib cohort experienced neutropenia, with 8 participants (38.1%) reporting G4 neutropenia. The median time to first occurrence of any grade of neutropenia in patients treated with the combination of 200 mg compound A and palbociclib was 14.5 days, consistent with the IBRANCE USPI. All neutropenia episodes were reversible, non-cumulative, and medically manageable, requiring / not requiring supportive care and / or dose reduction. Thirteen participants (61.9%) reported palbociclib dose reduction. [surface] [4.] [Based on preferred terminology] [(C)] [part] [)—] [Complete Treatment Analysis Collection] [(ARV-471-mBC-101)] Adverse events that occurred during treatment [≥] [10%] [AE] [Preferred Terminology] [[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) ECG QT prolongation 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 Red 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) Elevated aspartate transaminase 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) Vomit 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) Baldness 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) *Neutralization is classified according to MedDRA’s preferred terminology of neutropenia and neutropenia count. Note: An adverse event (AE) during treatment is defined as occurring on or after the date of the first study dose and within 30 days of the last study dose. Note: For each preferred term, the patient is counted only once. Note: Adverse events are coded using MedDRA version 22.0. Data cutoff date: June 6, 2023 Source: BDM TAE02C3: According to the preferred terminology (Part C)—the whole treatment analysis set, adverse events occurring in ≥10% of cases.

[0237] All 46 participants (100%) experienced at least one adverse event related to compound A or palbociclib, with neutropenia, fatigue, and thrombocytopenia being the most frequently reported adverse events (TRAEs) (Table 5).

[0238] Of the 46 participants, 39 (84.8%) reported treatment-related adverse events (TEAEs) related to compound A (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%), QT prolongation on ECG (19.6%), diarrhea (17.4%), hot flashes (15.2%), arthralgia (13%), nausea (13%), thrombocytopenia (13%), and alopecia (10.9%). Neutropenia was the most common grade 3 or grade 4 treatment-related adverse events (TRAEs) and occurred in 47.6% (grade 3) and 38.1% (grade 4) of participants, respectively.

[0239] 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%), thrombocytopenia (45.7%), anemia (34.8%), leukopenia (26.1%), constipation (17.4%), diarrhea (17.4%), and nausea (17.4%) in all patients.

[0240] Of the 46 participants, 5 (10.9%) reported death. Of these, 3 (6.5%) were found to be related to the studied disease or its complications, while the remaining 2 (4.3%) deaths were reported as being related to "other".

[0241] Four patients (8.7%) experienced TEAEs that led to the discontinuation of studies for both compound A and palbociclib: ● A patient who received a QD of 200 mg compound A + 125 mg palbociclib experienced grade 1 weight loss, which was considered by the researchers to be related to both compound A and palbociclib. ● A patient who received a 200 mg compound A + 125 mg palbociclib QD experienced a 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. ● A patient who was given a 200 mg compound A + 125 mg palbociclib QD experienced grade 1 vertigo, which was not considered to be related to compound A or palbociclib. ● A patient who received a 500 mg compound A + 125 mg palbociclib QD experienced grade 3 fatigue, which was considered by the investigators to be unrelated to compound A and related to palbociclib. The patient withdrew from the study, and the reason for discontinuation was individual withdrawal.

[0242] Four patients (8.7%) underwent TEAE, resulting in the discontinuation of palbociclib only: ● A patient who received a QD of 200 mg compound A + 125 mg palbociclib experienced grade 4 neutropenia, which researchers considered to be related to both compound A and palbociclib. ● A patient who received 200 mg of compound A + 125 mg of palbociclib QD experienced a grade 3 cerebrovascular accident, which was not considered to be related to compound A or palbociclib. ● A patient who received a QD of 500 mg compound A + 125 mg palbociclib experienced grade 4 neutropenia, which was considered by the researchers to be solely related to palbociclib. ● A patient who received a QD of 500 mg compound A + 125 mg palbociclib experienced grade 3 neutropenia, which was considered by the researchers to be solely related to palbociclib. [surface] [5.] [Based on preferred terminology] [(C)] [part] [)—] [Complete Treatment Analysis Collection] [(ARV-471-mBC-101)] [, compound] [A] [Or adverse events related to palbociclib treatment] [≥] [10%] [AE] [Preferred Terminology] [[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 compound] [A] [Or adverse events related to 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) ECG QT prolongation 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 Red 0 2 (9.5) 2 (66.7) 3 (15.0) 7 (15.2) Baldness 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) Vomit 0 3 (14.3) 0 2 (10.0) 5 (10.9) Note: Adverse events are coded using MedDRA version 22.0. Data cutoff date: June 6, 2023 Source: BDM TAE03C: According to the preferred terminology (Part C)—Full Treatment Analysis Set, compound A or palbociclib treatment-related adverse events ≥10%. [surface] [6.] [Based on preferred terminology] [(C)] [part] [)—] [Complete Treatment Analysis Collection] [(ARV-471-mBC-101)] [,] [≥] [10%] [The patient's compound] [A] [Treatment-related adverse events] [AE] [Preferred Terminology] [[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 compound] [A] [Treatment-related adverse events] 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) ECG QT prolongation 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 Red 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) Baldness 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 date: June 6, 2023 Source: BDM TAE03C1: According to the preferred terminology (Part C) - full treatment analysis set, compound A treatment-related adverse events ≥10%. Equivalent content

[0243] Those skilled in the art will recognize or be able to identify many equivalents of the specific embodiments described herein using only conventional experiments. Such equivalents are intended to be covered within the scope of the following patent applications.

[0244] The methods of this disclosure have been described herein with reference to certain preferred embodiments. However, based on the disclosure set forth herein, specific variations will become apparent to those skilled in the art, and therefore this disclosure should not be considered as limited thereto.

[0245] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Unless the context clearly indicates otherwise, the singular form also includes the plural form in the specification and claims.

[0246] It should be understood that at least some of the descriptions in this disclosure have been simplified to focus on elements relevant to a clear understanding of this disclosure, while for clarity, other elements that should be understood by one of ordinary skill in the art are excluded as part of this disclosure. However, since such elements are well known in the art and may not necessarily contribute to a better understanding of the invention, descriptions of such elements are not provided herein.

[0247] Furthermore, the specific order of steps described in the claims should not be construed as a limitation on the claim, provided that a method does not depend on a specific order of steps set forth herein.

[0248] All patents, patent applications, references, and publications cited herein are incorporated in their entirety as if they were described in full. Such references are not considered prior art to this disclosure.

Claims

1. Use of a compound A (compound A) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer, wherein: The drug is administered to an individual at a daily dose of compound A or a pharmaceutically acceptable salt thereof; the drug is administered simultaneously, independently, or sequentially with a CDK4 / 6 inhibitor; and the daily dose of compound A or a pharmaceutically acceptable salt thereof is 100 mg or 200 mg.

2. Use of a compound A (compound A) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer, wherein: The drug is administered to an individual at a daily dose of compound A or a pharmaceutically acceptable salt thereof; the drug is administered simultaneously, independently, or sequentially with a CDK4 / 6 inhibitor; the daily dose of compound A or a pharmaceutically acceptable salt thereof is 100 mg or 200 mg; and the drug is used as a second-line or subsequent line of therapy for cancer.

3. For the purposes described in claim 1 or 2, the daily dose of compound A or a pharmaceutically acceptable salt thereof is 200 mg.

4. As claimed in claim 1 or 2, wherein the daily dose of compound A or a pharmaceutically acceptable salt thereof is 100 mg.

5. As requested in paragraph 1 or 2, wherein the daily dose of compound A or its pharmaceutically acceptable salt is administered once daily (QD).

6. As requested in paragraph 1 or 2, wherein the daily dose of compound A or its medically acceptable salt is administered orally to the individual.

7. As requested in item 1 or 2, where the individual is in a feeding state.

8. As claimed in claim 1 or 2, wherein the CDK4 / 6 inhibitor is dalpiciclib, palbociclib, lerociclib, AT7519M, dinaciclib, ribociclib, or abemaciclib, or a pharmaceutically acceptable salt thereof.

9. As claimed in claim 8, wherein the CDK4 / 6 inhibitor is abecilibi, reboxil or palbociclib, or a pharmaceutically acceptable salt thereof.

10. As claimed in claim 9, wherein the CDK4 / 6 inhibitor is abexilide or a pharmaceutically acceptable salt thereof.

11. As claimed in claim 9, wherein the CDK4 / 6 inhibitor is reboxil or a pharmaceutically acceptable salt thereof.

12. As claimed in claim 9, wherein the CDK4 / 6 inhibitor is palbociclib or a pharmaceutically acceptable salt thereof.

13. As claimed in claim 10, wherein abecilib or a medically acceptable salt thereof is administered to the individual twice daily at a dose of 150 mg.

14. As claimed in claim 11, wherein compound A or a pharmaceutically acceptable salt thereof is administered daily in a 28-day cycle, and reboxil or a pharmaceutically acceptable salt thereof is administered orally once daily at a dose of 600 mg for 21 days in each 28-day cycle, followed by a 7-day cessation of treatment.

15. As claimed in claim 12, wherein compound A or a pharmaceutically acceptable salt thereof is administered daily in a 28-day cycle, and palbociclib or a pharmaceutically acceptable salt thereof is administered orally at 125 mg once daily for 21 days in each 28-day cycle, followed by a 7-day cessation of treatment.

16. As claimed in claim 10, wherein the daily dose of compound A or its pharmaceutically acceptable salt in combination with abexicillin or its pharmaceutically acceptable salt is 200 mg, and the abexicillin or its pharmaceutically acceptable salt is administered to the individual twice daily at a dose of 150 mg.

17. As claimed in claim 11, wherein the daily dose of compound A or its pharmaceutically acceptable salt in combination with reboxil or its pharmaceutically acceptable salt is 100 mg, and the reboxil or its pharmaceutically acceptable salt is administered at a daily dose of 600 mg.

18. As claimed in claim 1 or 2, 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.

19. As claimed in claim 18, wherein the cancer is breast cancer, lung cancer, prostate cancer, pancreatic cancer, or ovarian cancer.

20. As claimed in claim 19, wherein the cancer is breast cancer, lung cancer, or prostate cancer.

21. As used in claim 20, wherein the cancer is breast cancer.

22. As used in claim 21, wherein the breast cancer is metastatic or locally advanced.

23. As claimed in claim 21 or 22, wherein the breast cancer is an estrogen receptor-positive (ER+) breast cancer.

24. As claimed in claim 23, wherein the estrogen receptor-positive (ER+) breast cancer is human epidermal growth factor receptor 2 negative (HER2-).

25. As requested in item 1 or 2, in which the system is human.

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