Dosage regimen for estrogen receptor degraders

Abstract

The present specification provides a daily dose of Compound A TIFF2025530742000058.tif78134, or a pharmaceutically acceptable salt thereof in combination with a CDK4 / 6 inhibitor to a subject.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to and the benefit of 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, each of which is incorporated by reference in its entirety. [Background technology]

[0002] Certain bifunctional compounds target specific cellular proteins for degradation via the ubiquitin-proteasome system.Examples of such proteolytic targeting chimeric compounds (i.e., "PROTAC® proteolytic agents") that target estrogen receptor (ER) for ubiquitination and subsequent degradation are disclosed in International Publication No. WO2018 / 102725, which is incorporated herein by reference in its entirety.Such bifunctional molecules exhibit a range of pharmacological activities consistent with the degradation of ER, including but not limited to 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] Bifunctional molecules of particular interest include bepdegestrant (i.e., (S)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione or (3S)-3-[1,3-dihydro-1-oxo-5-[4-[[1-[4-[(1R,2S)-1,2,3,4-tetrahydro-6-hydroxy-2-phenyl-1-naphthalenylphenyl]-4-piperidinyl]methyl]-1-piperazinyl]-2H-isoindol-2-yl]-2,6-piperidinedione (referred to herein as "Compound A" or "Cpd A"), Cpd 45 H 49 It has the molecular formula of N5O4 and the following structure: [ka] .

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

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

[0006] The present disclosure provides, in part, dosing regimens for administering Compound A or a pharmaceutically acceptable salt thereof to a subject in combination therapy for treating cancer. This Summary is provided to introduce selected concepts in a simplified form that are further described below in the Detailed Description. This Summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used solely as an aid in determining the scope of the claimed subject matter.

[0007] As used herein, a daily dose of Compound A having the following structure: [ka] or a pharmaceutically acceptable salt thereof in combination with a CDK4 / 6 inhibitor to a subject, wherein the daily dose of Compound A is about 100 mg or about 200 mg.

[0008] As used herein, a daily dose of Compound A having the following structure: [ka] In one embodiment, a method of treating cancer is provided, comprising administering to a subject a compound selected from the group consisting of benzodiazepines, ... and benzocaine in combination with a CDK4 / 6 inhibitor.

[0009] In embodiments, the daily dose of Compound A is about 200 mg. In embodiments, the daily dose of Compound A is about 100 mg.

[0010] In several embodiments, the CDK4 / 6 inhibitor is dalpiciclib, trilaciclib, lerociclib, AT7519M, dinaciclib, ribociclib, abemaciclib, palbociclib, or a pharmaceutically acceptable salt thereof. In several embodiments, the CDK4 / 6 inhibitor is abemaciclib, ribociclib, or palbociclib, or a pharmaceutically acceptable salt thereof. In several embodiments, the CDK4 / 6 inhibitor is abemaciclib, or a pharmaceutically acceptable salt thereof. In several embodiments, the CDK4 / 6 inhibitor is ribociclib, or a pharmaceutically acceptable salt thereof. In several embodiments, 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 in combination with a CDK4 / 6 inhibitor every day for a 28-day cycle. In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, may be administered in combination with a CDK4 / 6 inhibitor every day for a 28-day cycle. In certain embodiments, the CDK4 / 6 inhibitor is palbociclib, or a pharmaceutically acceptable salt thereof. For example, palbociclib may be administered orally at 125 mg / day once daily for 21 days, followed by 7 days off treatment for each 28-day cycle.

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

[0013] In embodiments, a daily dose of Compound A is administered orally to a subject.

[0014] In embodiments, the subject is in a fed state.

[0015] In embodiments, the cancer is breast cancer, lung cancer, colon cancer, brain cancer, head and neck cancer, prostate cancer, gastric cancer, pancreatic cancer, ovarian cancer, testicular cancer, melanoma, endocrine cancer, uterine cancer, testicular cancer, or bladder cancer.

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

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

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

[0019] In embodiments, the subject is a human.

[0020] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed. [Brief explanation of the drawings]

[0021] [Figure 1-1] 1A-1H are graphs showing quantification of MCF7 and T47D live cell imaging proliferation assays. [Figure 1-2] Figures 1A and 1C show the relative cell proliferation kinetics over 120 hours by live cell imaging of MCF7 and T47D cells treated with Compound A (10 nM) or fulvestrant (1 nM) alone or in combination with abemaciclib (40 nM) at their respective approximate GI concentrations. Each plot represents three independent experiments. [Figure 1-3] Figures 1E and 1G show the relative cell proliferation kinetics over 120 hours by live cell imaging of MCF7 and T47D cells treated with Compound A (10 nM) and / or ribociclib (40 nM) at their respective approximate GI concentrations. Each plot is representative of three independent experiments, except for the T47D fulvestrant group in Figures 1A and 1C, which are the results of two independent experiments. [Figure 1-4]Figures 1B, 1D, 1F, and 1H show the difference in relative MCF7 and T47D cell proliferation compared to vehicle control at 120 hours of treatment. Graphs show the average of three independent experiments, except for the T47D fulvestrant group in Figures 1B and 1D, which is the result 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 ANOVA test). [Figure 2-1] Figures 2A-2L are graphs showing the viability and synergy analysis of MCF7 cells on day 5 administered Compound A in combination with abemaciclib or ribociclib in an 8 x 8 block matrix. Figures 2A, 2B, 2G, and 2H show the single-agent curves for Compound A, abemaciclib, Compound A, and ribociclib, respectively. [Figure 2-2] FIG. 2C shows the dose-response shift of Compound A with the addition of abemaciclib. [Figure 2-3] BLISS (2D and 2J), Loewe (2E and 2K), and best single agent (2F and 2L) model outputs are shown (representative of three independent experiments). [Figure 2-4] Figures 2A, 2B, 2G, and 2H show the single-agent curves for Compound A, abemaciclib, Compound A, and ribociclib, respectively. [Figure 2-5] BLISS (2D and 2J), Loewe (2E and 2K), and best single agent (2F and 2L) model outputs are shown (representative of three independent experiments). [Figure 2-6] Figure 2I shows the dose-response shift of Compound A with the addition of ribociclib. Drug synergy was assessed using Combenefit software. [Figure 3-1] Figures 3A and 3B are graphs showing in vivo efficacy testing of compound A in combination with the CDK4 / 6 inhibitors abemaciclib (Figure 3A) and ribociclib (Figure 3B) using an MCF7 orthotopic xenograft model. Mean tumor volumes ± SEM are reported. The 1-day drug holiday period is indicated by the small black arrow. [Figure 3-2] Figures 3A and 3B are graphs showing in vivo efficacy testing of Compound A in combination with the CDK4 / 6 inhibitors abemaciclib (Figure 3A) and ribociclib (Figure 3B) using an MCF7 orthotopic xenograft model. [Figure 4-1] Figure 4A is a graph showing the body weight (±SEM) of MCF7 orthotopic xenograft efficacy using Compound A in combination with the CDK4 / 6 inhibitor abemaciclib. The compounds were administered as single agents or in combination, 10 mice per group. [Figure 4-2] Figure 4B is a graph showing the body weight (±SEM) of MCF7 orthotopic xenograft efficacy using Compound A in combination with the CDK4 / 6 inhibitor ribociclib. The compounds were administered as single agents or in combination, 10 mice per group. [Figure 5] Figure 5 is a graph showing tumor growth inhibition by Compound A (30 mg / kg, orally [oral administration; PO], once daily [QD] x 28) or fulvestrant (200 mg / kg, subcutaneously, twice weekly for 2 weeks, followed by once weekly for 2 weeks) as single agents or in combination with the CDK4 / 6 inhibitor palbociclib ("Palbo"; 60 mg / kg, PO; QD x 28). Female severe combined immunodeficient mice on a non-obese background (NOD / scid) were implanted with MCF7 cells, and compound administration began when tumors reached 200 mm3. Tumor volume was assessed twice weekly for 28 days. At the end of the study, single-agent Compound A and fulvestrant inhibited tumor growth by 105% and 46%, respectively. When combined with palbociclib, growth inhibition with Compound A or fulvestrant was 131% and 108%, respectively. Data are expressed as mean ± standard error of the mean (SEM) DETAILED DESCRIPTION OF THE INVENTION

[0022] The present invention may be understood more readily by reference to the following detailed description of embodiments of the invention and examples contained herein. It is also understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting of the invention.

[0023] bepdegestrant (i.e., (S)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione or (3S)-3-[1,3-dihydro-1-oxo-5-[4-[[1-[4-[(1R,2S)-1,2,3,4-tetrahydro-6-hydroxy-2-phenyl-1-naphthalenylphenyl]-4-piperidinyl]methyl]-1-piperazinyl]-2H-isoindol-2-yl]-2,6-piperidinedione (also referred to herein as Compound A)): [ka] is being developed as a PROTAC® protein degrader targeting the estrogen receptor (ER) for the potential treatment of breast cancer and has been shown to be a useful regulator of target protein ubiquitination and degradation via the ubiquitin-proteasome pathway.

[0024] Compound A and its pharmaceutically acceptable salts are disclosed in International Publication No. 2018 / 102725 and U.S. Patent Nos. 10,647,698, 10,899,742 and 11,104,666, International Publication No. 2021 / 041348, U.S. Patent No. 17 / 472,847, U.S. Patent No. 17 / 548,842, and U.S. Patent No. 17 / 873,748. The contents of each of the foregoing references are incorporated herein by reference in their entirety.

[0025] Cyclin-dependent kinases (CDKs) and related serine / threonine protein kinases are important cellular enzymes that perform essential functions in the control of eukaryotic cell division and proliferation. The CDK catalytic units are activated by regulatory subunits known as cyclins. At least 16 mammalian cyclins have been identified (Johnson DG, Walker CL. Cyclins and Cell Cycle Checkpoints. Annu. Rev. Pharmacol. Toxicol. (1999) 39:295-312). Cyclin B / CDK1, cyclin A / CDK2, cyclin E / CDK2, cyclin D / CDK4, cyclin D / CDK6, and possibly other heterodynes are important regulators of cell cycle progression. Additional functions of cyclin / CDK heterodynes include regulation of transcription, DNA repair, differentiation, and apoptosis (Morgan DO, Cyclin-dependent kinases: engines, clocks, and microprocessors. Annu. Rev. Cell. Dev. Biol. (1997) 13:261-291).

[0026] CDK inhibitors have been demonstrated to be useful in the treatment of cancer. Increased activity or abnormal temporal activation of cyclin-dependent kinases has been shown to lead to the development of human tumors, which are generally associated with alterations in either 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).

[0027] CDK4 and CDK6 are key regulators of cell cycle progression at the G1-S checkpoint, which is mediated by D-type cyclins and e.g., p16 INK4a It is regulated by endogenous CDK inhibitors such as INK4 (CDKN2A). Dysregulation of the cyclin D-CDK4 / 6-INK4-retinoblastoma (Rb) pathway has been reported to be associated with the development of endocrine therapy resistance.

[0028] Clinical trials of the CDK4 / 6 inhibitors, palbociclib, ribociclib, and abemaciclib, are ongoing as single agents or in combination with other therapeutic agents in breast cancer and other cancers. The use of CDK4 / 6 inhibitors in combination with endocrine therapy has shown significant efficacy in the treatment of hormone receptor (HR)-positive, human epidermal growth factor 2 (HER2)-negative advanced or metastatic breast cancer, and CDK4 / 6 inhibitors, including palbociclib, ribociclib, and abemaciclib, have been approved for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer in the first- or second-line setting in combination with endocrine therapy. Palbociclib, ribociclib, and abemaciclib are approved in combination with aromatase inhibitors, such as letrozole, in combination with fulvestrant in the first-line setting and in second- or later-line treatment in certain patients. (O'Leary et al. Treating cancer with selective CDK4 / 6 inhibitors. Nature Reviews (2016) 13:417-30).

[0029] Palbociclib, or 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (also referred to as "PD-0332991"), is a potent and selective inhibitor of CDK4 and CDK6 and has the following structure: [ka]

[0030] Palbociclib is described in WHO Drug Information, Vol. 27, No. 2, page 172 (2013). Palbociclib and its pharmaceutically acceptable salts are disclosed in International Publication No. 2003 / 062236, U.S. Patent Nos. 6,936,612, 7,456,168, and RE47,739, International Publication No. 2005 / 005426, U.S. Patent Nos. 7,345,171 and 7,863,278, International Publication No. 2008 / 032157, U.S. Patent No. 7,781,583, and International Publication No. 2014 / 128588. The contents of each of the foregoing references are incorporated herein by reference in their entirety.

[0031] Abemaciclib, N-(5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-amine (sold, for example, under the brand name Verzenio® (and others)), is a selective inhibitor of CDK4 and CDK6 having the following structure: [ka] .

[0032] Abemaciclib and pharmaceutically acceptable salts thereof are disclosed in International Publication No. WO2010 / 075074 and U.S. Patent No. 7,855,211. The contents of each of the foregoing references are incorporated herein by reference in their entirety.

[0033] Ribociclib, 7-cyclopentyl-N,N-dimethyl-2-[(5-piperazin-1-ylpyridin-2-yl)amino]pyrrolo[2,3-d]pyrimidine-6-carboxamide (sold, for example, under the brand names Kisqali® and Kryxana®), is an inhibitor of cyclin D1 / CDK4 and CDK6 having the following structure: [ka]

[0034] Ribociclib and its pharmaceutically acceptable salts are described in International Publication Nos. WO2007140222, WO2010 / 020675, WO2012 / 064805, and WO2016 / 166703, and in U.S. Patent Nos. 8,324,225, 8,415,355, 8,685,980, 8,962,630, 9,193,732, 9,416,136, 9,868,739, and 10,799,506. The contents of each of the foregoing references are incorporated herein by reference in their entirety.

[0035] CDK4 / 6 inhibitors have shown significant clinical efficacy in ER-positive metastatic breast cancer, but, like other kinases, their efficacy can be limited over time by the development of primary or acquired resistance.The selective CDK4 / 6 inhibitor palbociclib has proven clinically effective in breast cancer (DeMichele A, Clark AS, Tan KS, et al. CDK4 / 6 inhibitor palbociclib (PD-0332991) in Rb+ advanced breast cancer: phase II activity, safety, and predictive biomarker assessment. Clin Cancer Res 2015; 21(5):995-1001, Finn RS, Martin M, Rugo HS, et al. Palbociclib and Letrozole in Advanced Breast Cancer. New Engl J Med 2016; 375(20):1925-36, Cristofanilli M, Turner NC, Bondarenko I, et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy). (PALOMA-3: final analysis of the multicenter, double-blind, phase 3 randomized controlled trial. Lancet Oncol 2016; 17(4):425-39), however, acquired resistance to palbociclib can develop after 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).

[0036] definition Unless otherwise defined, all technical and scientific terms used in connection with the present invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0037] The invention described herein may suitably be practiced in the absence of any element not specifically disclosed herein.

[0038] As used herein, the singular forms "a," "an," and "the" include plural references unless otherwise indicated. For example, "a" (one) substituent includes one or more substituents.

[0039] As used herein, when used to modify a numerically defined parameter (e.g., a dose of Compound A), the term "about" means that the parameter may vary by 10% below or above the numerical value stated for that parameter. For example, a dose of about 5 mg means 5 mg ± 10%, i.e., may vary from 4.5 mg to 5.5 mg.

[0040] As used herein, terms including, but not limited to, "reagent," "composition," "compound," "agent," and "therapeutic agent" may be used interchangeably to refer to compounds included in the methods and uses of the present disclosure.

[0041] As used herein, the terms "subject," "participant," and "patient" are used interchangeably to refer to any animal, including mammals. Mammals according to the present disclosure include dogs, cats, cows, goats, horses, sheep, pigs, rodents, lagomorphs, primates, humans, and the like, including mammals in utero. In embodiments, humans are preferred subjects. Human subjects can be of any gender and at any stage of development.

[0042] Bepdegestrant (i.e., (S)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione or (3S)-3-[1,3-dihydro-1-oxo-5-[4-[[1-[4-[(1R,2S)-1,2,3,4-tetrahydro-6-hydroxy-2-phenyl-1-naphthalenylphenyl]-4-piperidinyl]methyl]-1-piperazinyl]-2H-isoindol-2-yl]-2,6-piperidinedione (also referred to herein as “Compound A”) is a compound having the following structure: [ka]

[0043] Compound A is a Biopharmaceutical Classification System Class IV compound (poorly soluble / poorly permeable). Compound A can be interconverted with its epimer, Compound B: [ka]

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

[0045] 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 wide range of CDKs, and selective CDK inhibitors that target specific CDKs.

[0046] Examples of CDK4 / 6 inhibitors include, but are not limited to, abemaciclib, ribociclib, and palbociclib.Further examples of CDK4 / 6 inhibitors include relociclib (also known as G1T38) and trilaciclib (also known as GTI128).

[0047] In some embodiments, the CDK4 / 6 inhibitor of the present invention comprises palbociclib. Unless otherwise indicated herein, palbociclib (also referred to herein as palvo) is 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one: [ka] or a pharmaceutically acceptable salt thereof.

[0048] Alternatively, in embodiments, the CDK4 / 6 inhibitor is abemaciclib or ribociclib. Unless otherwise indicated, abemaciclib is N-(5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-amine: [ka] and ribociclib refers to 7-cyclopentyl-N,N-dimethyl-2-[(5-piperazin-1-ylpyridin-2-yl)amino]pyrrolo[2,3-d]pyrimidine-6-carboxamide. [ka]

[0049] Other embodiments relate to pharmaceutically acceptable salts of the compounds described herein. Pharmaceutically acceptable salts of the compounds described herein include acid addition and base addition salts thereof.

[0050] 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, acetate, citrate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, bitartrate, borate, camsylate, citrate, cyclamate, edisylate, esylate, ethanesulfonate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybenzate, hydrochloride / chloride, bromide, etc. These salts include hydrochloride / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methanesulfonate, methylsulfate, napsylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, p-toluenesulfonate, tosylate, trifluoroacetate, and xinafoate.

[0051] Another embodiment relates to the base addition salts of the compounds described herein.Suitable base addition salts are formed from bases that form non-toxic salts.Non-limiting examples of suitable base salts include aluminum salt, arginine salt, benzathine salt, calcium salt, choline salt, diethylamine salt, diolamine salt, glycine salt, lysine salt, magnesium salt, meglumine salt, olamine salt, potassium salt, sodium salt, tromethamine salt and zinc salt.

[0052] The compounds described herein that are basic in nature can form a wide variety of salts with various inorganic and organic acids.The acids used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned compounds useful in this embodiment are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoic acid) salts). Compounds described herein that include a basic moiety, such as an amino group, may form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above.

[0053] Chemical bases that can be used as reagents to prepare pharmaceutically acceptable base salts of compounds described herein that are acidic in nature are those that form non-toxic base salts with such compounds. These non-toxic base salts include, but are not limited to, base salts derived from pharmacologically acceptable cations such as alkali metal cations (e.g., potassium and sodium), and alkaline earth metal cations (e.g., calcium and magnesium), ammonium, or water-soluble amine addition salts such as N-methylglucamine (meglumine), and lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines.

[0054] Hemisalts of acids and bases may also be formed, for example, hemisulfate and hemicalcium salts.

[0055] For suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002). Methods for making pharmaceutically acceptable salts of the compounds described herein are known to those skilled in the art.

[0056] Dosage regimen In combination with a CDK4 / 6 inhibitor, [ka] or a pharmaceutically acceptable salt thereof.

[0057] Also, in combination with a CDK4 / 6 inhibitor, the compound of the following structure: [ka] Also provided herein are methods for treating cancer, comprising administering to a subject a daily dose of Compound A having the formula:

[0058] In some embodiments, the structure : [ka] or a pharmaceutically acceptable salt thereof is administered once daily (QD).

[0059] In some embodiments, a daily dose of Compound A having the following structure: [ka] or a pharmaceutically acceptable salt thereof is orally administered to the subject.

[0060] In embodiments, the subject is in a fed state.

[0061] In some embodiments, compound A: [ka] The daily dose of the compound, or a pharmaceutically acceptable salt thereof, is about 200 mg, or the equivalent amount of a pharmaceutically acceptable salt thereof.

[0062] In some embodiments, compound A: [ka] The daily dose of 200 mg, or the equivalent amount of a pharmaceutically acceptable salt thereof, is 200 mg, or the equivalent amount of a pharmaceutically acceptable salt thereof.

[0063] In some embodiments, Compound A [ka] The daily dose is about 200 mg.

[0064] In some embodiments, Compound A [ka] The daily dose is 200 mg.

[0065] In some embodiments, Compound A [ka] The daily dose of , or a pharmaceutically acceptable salt thereof, is the equivalent of about 100 mg or a pharmaceutically acceptable salt thereof.

[0066] In some embodiments, Compound A [ka] or a pharmaceutically acceptable salt thereof, the daily dose is the equivalent of 100 mg or a pharmaceutically acceptable salt thereof.

[0067] In some embodiments, Compound A [ka] The daily dose is about 100 mg.

[0068] In some embodiments, Compound A [ka] The daily dose is 100 mg.

[0069] In some embodiments, compound A: [ka] is administered as the free base.

[0070] In some embodiments, the CDK4 / 6 inhibitor is darpiciclib, trilaciclib, relociclib, AT7519M, dinaciclib, ribociclib, abemaciclib, palbociclib, or a pharmaceutically acceptable salt thereof. In some embodiments, the CDK4 / 6 inhibitor is darpiciclib, trilaciclib, relociclib, AT7519M, dinaciclib, ribociclib, abemaciclib, or palbociclib.

[0071] In some embodiments, the CDK4 / 6 inhibitor is abemaciclib, ribociclib, or palbociclib, or a pharmaceutically acceptable salt thereof. In some embodiments, the CDK4 / 6 inhibitor is abemaciclib, ribociclib, or palbociclib.

[0072] In embodiments, the CDK4 / 6 inhibitor is abemaciclib, or a pharmaceutically acceptable salt thereof. In embodiments, the CDK4 / 6 inhibitor is abemaciclib.

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

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

[0075] In some embodiments, Compound A is administered daily in a 28-day cycle. In certain embodiments, palbociclib or a pharmaceutically acceptable salt thereof is administered orally at 125 mg / day once daily for 21 days, followed by 7 days of treatment rest for each 28-day cycle.

[0076] In embodiments, the cancer is breast cancer, lung cancer, colon cancer, brain cancer, head and neck cancer, prostate cancer, gastric cancer, pancreatic cancer, ovarian cancer, testicular cancer, melanoma, endocrine cancer, uterine cancer, testicular cancer, or bladder cancer.

[0077] In embodiments, the cancer is breast cancer, lung cancer, prostate cancer, pancreatic cancer, or ovarian cancer.

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

[0079] In embodiments, the cancer is breast cancer.

[0080] In embodiments, the breast cancer is metastatic or locally advanced.

[0081] In embodiments, the breast cancer is estrogen receptor positive (ER+) breast cancer.

[0082] In embodiments, the estrogen receptor positive (ER+) breast cancer is human epidermal growth factor receptor 2 negative (HER2-).

[0083] In embodiments, the subject is a human.

[0084] Also provided herein is a compound A for use according to any one of the above embodiments: [ka] or a pharmaceutically acceptable salt thereof is disclosed.

[0085] Also provided herein is a compound A for use according to any one of the above embodiments: [ka] or a pharmaceutically acceptable salt thereof is disclosed.

[0086] Also provided herein is a method for the manufacture of a medicament according to any one of the above embodiments, comprising administering to a patient a compound A: [ka] or a pharmaceutically acceptable salt thereof is disclosed.

[0087] Also provided herein is a method for the manufacture of a medicament according to any one of the above embodiments, comprising administering to a patient a compound A: [ka] or a pharmaceutically acceptable salt thereof is disclosed.

[0088] Each of the embodiments described herein may be combined with any other embodiment described herein that is not inconsistent with the embodiment with which it is combined.

[0089] Dosage and Administration The term "treat" cancer or a cancer-related disease, as used herein, refers to administering a combination therapy according to the present disclosure to a subject to achieve at least one positive therapeutic effect in a participant or patient with cancer, or in the case of a cancer diagnosis, such as a reduction in the number of cancer cells, a reduction in tumor size, a decrease in the rate of cancer cell invasion into peripheral organs, or a decrease in the rate of tumor metastasis or tumor growth, or to reverse, alleviate, or inhibit the disease or condition to which such term applies, or one or more symptoms of such disease or condition. As used herein, unless otherwise indicated, the term "treatment" refers to the act of treating as defined immediately above as "treating." For purposes of this disclosure, beneficial or desirable clinical results include, but are not limited to, one or more of the following: reducing (or destroying) the proliferation of neoplastic or cancerous cells, inhibiting metastasis or neoplastic cells, shrinking or reducing tumor size, cancer remission, reducing symptoms resulting from cancer, improving the quality of life of those afflicted with cancer, reducing the dose of other drugs required to treat cancer, slowing the progression of cancer, curing cancer, overcoming one or more resistance mechanisms of cancer, and / or extending the survival of cancer patients. Positive therapeutic effects in cancer can be measured in many ways (see, e.g., W.A. Weber, J. Nucl. Med. (2009) 50:1S-10S).

[0090] As used herein to describe a subject, "fed condition" or "fed state" means that the subject ingested a meal less than 4 hours prior to the time of interest, such as the time of administration of Compound A. In one embodiment, a subject in a fed state ingested a meal within any of 4, 3, 2, 1, or 0.5 hours prior to administration of a compound of the present disclosure.

[0091] An "amount" for use in treating a subject refers to an amount that, in combination with one or more other agents, provides a detectable response for any period of time (temporary, moderate, or long-term), any measurable or detectable degree in a subject, or for any period of time (e.g., hours, days, months, years, remission, or cure), a desired result, or an objective or subjective benefit. Such an amount is typically effective to measurably improve a disease, or one, several, or all adverse effects / symptoms, consequences, or complications of a disease, although reducing or inhibiting the progression or worsening of the disease, or providing a stable (i.e., non-worsening) state of the disease, is considered a satisfactory outcome. The term "therapeutically effective amount" also refers to an amount of an agent, in combination with one or more other agents, that is effective to produce a desired therapeutic effect when administered to a subject, for example, to stop the growth of or cause the shrinkage of a cancerous tumor. With respect to the treatment of cancer, a therapeutically effective amount refers to an amount that has the effect of (1) reducing tumor size, (2) inhibiting (i.e., slowing to some extent, preferably stopping) the development of tumor metastasis, (3) inhibiting (i.e., slowing to some extent, preferably stopping) tumor growth or tumor invasiveness to some extent, and / or (4) alleviating to some extent (or preferably eliminating) one or more signs or symptoms associated with cancer. The therapeutic or pharmacological effectiveness of doses and administration regimens may also be characterized as the ability to induce, enhance, maintain, or prolong disease control and / or overall survival in patients with these particular tumors, which may be measured as the extension of the time before disease progression.

[0092] As used herein, "amelioration" refers to any decrease in the degree, severity, frequency, and / or likelihood of a symptom or clinical sign characteristic of a particular disease. "Symptom" refers to any subjective evidence of a disease or condition in a subject.

[0093] An embodiment of the present invention provides a dose, dosage, and administration regimen comprising administering to a subject an amount, or an effective amount, of Compound A, or a pharmaceutically acceptable salt thereof. The amount, or therapeutically effective amount, can be a daily dose of about 200 mg. In another embodiment, the daily dose is 200 mg.

[0094] In embodiments, the daily dose of Compound A, or a pharmaceutically acceptable salt thereof, is administered once daily (QD).

[0095] The compounds disclosed herein can be administered orally, which may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed, whereby the compound enters the blood stream directly from the mouth.

[0096] In embodiments, the daily dose of Compound A, or a pharmaceutically acceptable salt thereof, is administered orally.

[0097] Compound A or a pharmaceutically acceptable salt thereof may be present in a pharmaceutical composition, which includes a pharmaceutically acceptable excipient. A "pharmaceutically acceptable excipient" refers to a component that may be included in the compositions described herein, which is physiologically suitable for pharmaceutical use and does not cause any significant adverse effects or therapeutic effects in the subject. The term "excipient" is used herein to describe any component other than the compound of the present invention. The selection of an excipient largely depends on factors such as the mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

[0098] The compound of the method, use or combination of the present invention can be formulated before administration.Preferably, the formulation is adapted to a specific mode of administration.These compounds can be formulated with pharmaceutically acceptable excipients known in the art and administered in a variety of dosage forms known in the art.The dosage unit form or pharmaceutical composition suitable for oral administration includes, but is not limited to, tablets, capsules, such as gelatin capsules, pills, powders, granules, aqueous solutions and non-aqueous oral solutions and suspensions, which are packaged in a container suitable for subdivision into individual doses.

[0099] In some embodiments, palbociclib or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 125 mg once daily, about 100 mg once daily, about 75 mg once daily, about 50 mg once daily, or about 25 mg once daily. In some embodiments, palbociclib or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 125 mg once daily. For example, palbociclib or a pharmaceutically acceptable salt thereof is administered at a dose of about 100 mg once daily, about 75 mg once daily, or about 50 mg once daily. In one embodiment, palbociclib or a pharmaceutically acceptable salt thereof is administered at a dose of about 100 mg once daily. In some embodiments, palbociclib or a pharmaceutically acceptable salt thereof is administered at a dose of about 75 mg once daily. In some embodiments, palbociclib or its pharmaceutically acceptable salt is administered at a dose of about 50 mg once a day.The dosage provided herein refers to the dosage of palbociclib free base form or is calculated as the free base equivalent of the administered palbociclib salt form.For example, the dosage or amount of palbociclib, such as 100 mg, 75 mg, or 50 mg, refers to the free base equivalent.

[0100] In several embodiments, abemaciclib or a pharmaceutically acceptable salt thereof is administered in a daily amount 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 several embodiments, abemaciclib or a pharmaceutically acceptable salt thereof is administered in a daily amount 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 several embodiments, abemaciclib or a pharmaceutically acceptable salt thereof is administered in a daily amount of 300 mg (e.g., about 150 mg twice daily). In one embodiment, abemaciclib or a pharmaceutically acceptable salt thereof is administered at a dose of about 200 mg (e.g., about 100 mg twice daily). In an embodiment, abemaciclib or a pharmaceutically acceptable salt thereof is administered at a dose of about 50 mg twice daily, or at a dose of about 100 mg (e.g., about 50 mg twice daily). The dosage amounts provided herein refer to the dose of the free base form of abemaciclib or are calculated as the free base equivalent of the administered abemaciclib salt form. For example, dosage amounts or amounts of abemaciclib such as 200 mg, 150 mg, 100 mg, or 50 mg refer to the free base equivalent.

[0101] In some embodiments, ribociclib or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 600 mg once daily, about 400 mg once daily, about 200 mg once daily, or about 50 mg once daily. In some embodiments, ribociclib or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 600 mg once daily. In one embodiment, ribociclib or a pharmaceutically acceptable salt thereof is administered at a dose of about 400 mg once daily. In some embodiments, ribociclib or a pharmaceutically acceptable salt thereof is administered at a dose of about 200 mg once daily. The dosage amounts provided herein refer to the dose of the free base form of ribociclib or are calculated as the free base equivalent of the administered ribociclib salt form. For example, dosages or amounts of ribociclib such as 600 mg, 400 mg, 200 mg, etc. refer to the free base equivalent.

[0102] Repeated administration or administration schedules may be performed as necessary to achieve the desired reduction or decrease in cancer cells. As used herein, a "continuous administration schedule" refers to an administration or administration schedule without dose interruptions, e.g., without treatment breaks. Repeated 28-day treatment cycles without dose interruptions between treatment cycles is an example of a continuous administration schedule. In some embodiments, the compounds of the combination of the present invention can be administered in a continuous administration schedule. In some embodiments, the compounds of the combination disclosed herein can be administered simultaneously in a continuous administration schedule.

[0103] In some embodiments, Compound A is administered once daily, comprising a complete 28-day cycle. Repeated 28-day treatment cycles continue during treatment according to the methods and uses of the present disclosure.

[0104] A standard recommended dosing regimen, including the standard dosing schedule for palbociclib or a pharmaceutically acceptable salt thereof, is once daily for 21 consecutive days, followed by 7 days off treatment, comprising a complete 28-day cycle, with repetition of the 28-day cycle continuing during treatment with the combination of the present invention.

[0105] The standard clinical dosing regimen for palbociclib or a pharmaceutically acceptable salt thereof comprises 125 mg administered once daily for 21 consecutive days, followed by 7 days off treatment, for a complete 28-day cycle, with repetition of the 28-day cycle continuing during treatment with the combination of the present invention.

[0106] The standard clinical dosing regimen for ribociclib or a pharmaceutically acceptable salt thereof involves 600 mg administered once daily for 21 consecutive days, followed by 7 days off treatment, for a complete 28-day cycle, with repeated 28-day cycles continuing during treatment with the combination of the present invention.

[0107] Also disclosed herein is a kit comprising a combination of therapeutic agents of the present disclosure and written instructions for administering the therapeutic agents. In some embodiments, the written instructions detail and qualify the mode of administration of the therapeutic agents, for example, for simultaneous or sequential administration of the therapeutic agents of the present disclosure. In some embodiments, the written instructions detail and qualify the mode of administration of the therapeutic agents, for example, by specifying the administration date of each of the therapeutic agents during a 28-day treatment cycle.

[0108] Treatment methods In embodiments, provided herein is a method for treating cancer in a subject, comprising administering to the subject an effective amount of Compound A described herein in combination with an amount of a CDK4 / 6 inhibitor.

[0109] As used herein, unless otherwise indicated, the term "combination" refers to the use of Compound A with 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 dosing schedules.

[0110] As used herein, the term "locally advanced" when referring to cancer may or may not be treated with curative intent. For example, locally advanced breast cancer (LABC) is defined by the National Comprehensive Cancer Network as a subset of breast cancer characterized by the absence of distant metastasis and the most advanced breast tumors, tumors greater than 5 cm in size with regional lymphadenopathy, tumors of any size with direct extension to the chest wall or skin, or both (including ulcers or satellite nodules), regardless of regional lymphadenopathy, and the presence of regional lymphadenopathy (either clinically fixed or matted axillary lymph nodes, or infraclavicular, supraclavicular, or internal mammary lymphadenopathy), 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.)

[0111] As used herein, the term "metastatic" as it relates to cancer cannot be treated with curative intent. Metastatic breast cancer, or metastasis, refers to breast cancer that has spread beyond the breast and nearby lymph nodes to other parts of the body, such as the bone, liver, lungs, or brain (https: / / www.cancer.org / cancer / breast-cancer.).

[0112] One skilled in the art will be able to recognize and diagnose locally advanced and metastatic cancer in a patient or subject.

[0113] For convenience, certain well-known abbreviations may be used herein, including castration-resistant prostate cancer (CRPC), estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-), hormone receptor (HR), human epidermal growth factor receptor 2 positive (HER2+), non-small cell lung cancer (NSCLC), and progesterone receptor (PR).

[0114] In embodiments, the cancer is lung cancer, mesothelioma, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, liver cancer, colon cancer, breast cancer, uterine cancer, malignant tumors of the fallopian tubes, malignant tumors of the endometrium, malignant tumors of the cervix, malignant tumors of the vagina, cancer of the vulva, Hodgkin's disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland cancer of the bladder, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, hematologic malignancies, chronic or acute leukemia, lymphocytic lymphoma, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, malignant tumors of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumors, glioblastoma, brain stem glioma, pituitary adenoma, head and neck cancer, and combinations of two or more of the foregoing cancers.

[0115] Also disclosed herein are methods of treating cancer in a subject. In embodiments, the methods include treating cancer in a subject, comprising administering to the subject an amount of a compound described herein effective to treat the cancer.

[0116] In embodiments, the cancer is breast cancer, lung cancer, colon cancer, brain cancer, head and neck cancer, prostate cancer, gastric cancer, pancreatic cancer, ovarian cancer, testicular cancer, melanoma, endocrine cancer, uterine cancer, testicular cancer, or bladder cancer.

[0117] In embodiments, the cancer is breast cancer, lung cancer, prostate cancer, pancreatic cancer, or ovarian cancer.

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

[0119] In embodiments, the cancer is breast cancer.

[0120] In embodiments, the breast cancer is metastatic breast cancer.

[0121] In embodiments, the breast cancer is locally advanced breast cancer.

[0122] In embodiments, the breast cancer is HR+ breast cancer.

[0123] In embodiments, the HR+ breast cancer is PR+ and / or ER+ breast cancer.

[0124] In embodiments, the breast cancer is PR+ breast cancer.

[0125] In embodiments, the breast cancer is ER+ breast cancer.

[0126] In embodiments, the breast cancer is ER+ HER2- breast cancer.

[0127] In embodiments, the breast cancer is ER+ HER2+ breast cancer.

[0128] In embodiments, the breast cancer is locally advanced or metastatic ER+ breast cancer.

[0129] In embodiments, the breast cancer is locally advanced or metastatic ER+ HER2- breast cancer.

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

[0131] In embodiments, the breast cancer is metastatic ER+ HER2- breast cancer.

[0132] In embodiments, the breast cancer is metastatic ER+ HER2- breast cancer that is also locally advanced.

[0133] In embodiments, the lung cancer is non-small cell lung cancer.

[0134] In embodiments, the lung cancer is locally advanced or metastatic non-small cell lung cancer.

[0135] In embodiments, the prostate cancer is CRPC.

[0136] In embodiments, the prostate cancer is metastatic or locally advanced CRPC.

[0137] Also disclosed herein are methods of treating a solid tumor in a subject. In embodiments, disclosed herein are methods of treating a solid tumor in a subject, the methods comprising administering to the subject an amount of a compound described herein effective to treat the solid tumor.

[0138] In embodiments, the solid tumor is breast cancer, lung cancer, colon cancer, brain cancer, head and neck cancer, prostate cancer, gastric cancer, pancreatic cancer, ovarian cancer, melanoma, endocrine cancer, uterine cancer, testicular cancer, or bladder cancer.

[0139] In embodiments, the solid tumor is breast cancer, lung cancer, prostate cancer, pancreatic cancer, or ovarian cancer.

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

[0141] In some embodiments, the solid tumor is breast cancer. For example, in certain embodiments, the breast cancer is HR+ breast cancer. In other embodiments, the HR+ breast cancer is PR+ and / or ER+ breast cancer.

[0142] In some embodiments, the solid tumor is breast cancer. For example, in certain embodiments, the breast cancer is ER+ HER2- breast cancer.

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

[0144] In some embodiments, the solid tumor is breast cancer. For example, in certain embodiments, the breast cancer is locally advanced or metastatic ER+ HER2- breast cancer.

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

[0146] In some embodiments, the solid tumor is lung cancer, e.g., in certain embodiments, the lung cancer is non-small cell lung cancer.

[0147] In some embodiments, the solid tumor is lung cancer. For example, in certain embodiments, the lung cancer is locally advanced or metastatic non-small cell lung cancer.

[0148] In some embodiments, the solid tumor is prostate cancer, e.g., in certain embodiments, the prostate cancer is CRPC.

[0149] In embodiments, the solid tumor is prostate cancer. For example, in certain embodiments, the prostate cancer is locally advanced or metastatic castration-resistant prostate cancer.

[0150] Also disclosed herein are methods of treating a hematological tumor in a subject. In certain embodiments, the method comprises treating a hematological tumor in a subject, comprising administering to the subject an amount of a compound described herein effective to treat the hematological tumor.

[0151] In embodiments, the hematological tumor is leukemia, lymphoma, or multiple myeloma.

[0152] In embodiments, the hematological tumor is a leukemia or lymphoma.

[0153] Also disclosed herein are methods of treating cancer in a subject with locally advanced or metastatic ER+ HER2- breast cancer, CRPC, or NSCLC whose disease is progressing on standard treatment or whose disease is intolerant to standard treatment.

[0154] Also disclosed herein are methods of treating cancer in a subject with locally advanced or metastatic ER+ HER2- breast cancer, CRPC, or NSCLC whose disease is progressing on standard treatment or whose disease is intolerant to standard treatment.

[0155] Also disclosed herein is a method for treating cancer in a subject with locally advanced or metastatic 2L+ ER+ HER2 breast cancer who has received prior hormonal / endocrine therapy and chemotherapy in the locally advanced / metastatic setting. In embodiments, the method comprises administering Compound A to the subject in combination with a CDK4 / 6 inhibitor.

[0156] Also disclosed herein are methods for treating cancer in a subject with locally advanced or metastatic 2L+ ER+ HER2 breast cancer who has received prior treatment with a CDK4 / 6 inhibitor. In embodiments, the method comprises administering Compound A to the subject in combination with a CDK4 / 6 inhibitor.

[0157] Further, in this specification, (i) Compound A: [ka] or a pharmaceutically acceptable salt thereof, and (ii) CDK4 / 6 inhibitors, Therapeutic combinations for simultaneous, separate, or sequential use in methods of treating cancer are disclosed, the methods comprising administering a daily dose of Compound A, or a pharmaceutically acceptable salt thereof.

[0158] Further, in this specification, (i) Compound A: [ka] , and (ii) CDK4 / 6 inhibitors, The present invention discloses a therapeutic combination for simultaneous, separate, or sequential use in a method of treating cancer, comprising administering a daily dose of Compound A.

[0159] Also described herein is Compound A: [ka] or a pharmaceutically acceptable salt thereof, wherein the method comprises administering Compound A or a pharmaceutically acceptable salt thereof, and the method further comprises administering a CDK4 / 6 inhibitor.

[0160] Also provided herein is a compound A for use in a method of treating cancer: [ka] is disclosed, wherein the method comprises administering Compound A, and the method further comprises administering a CDK4 / 6 inhibitor.

[0161] Also disclosed herein are CDK4 / 6 inhibitors for use in a method for treating cancer, the method further comprising administering Compound A, or a pharmaceutically acceptable salt thereof.

[0162] Also disclosed herein is a CDK4 / 6 inhibitor for use in a method of treating cancer, the method further comprising administering Compound A.

[0163] In some embodiments, the method comprises administering a daily dose of about 200 mg of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering a daily dose of about 200 mg of Compound A. In some embodiments, the method comprises administering a daily dose of about 100 mg of Compound A. [Example]

[0164] In order that this invention may be better understood, the following examples are set forth. These examples are for illustrative purposes only and are not to be construed as limiting the scope of the invention in any way.

[0165] Abbreviations used herein include the following: TIFF2025530742000035.tif145170

[0166] Compound A Clinical Trial (FIH Trial and Clinical Pharmacology Trial) First-in-Human ("FIH") Study Compound A is being investigated in an ongoing Phase 1 / 2, open-label, dose-escalation and cohort expansion study to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of 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 therapy and chemotherapy in the locally advanced / metastatic setting. A summary of the FIH study is shown below in Table 1.

[0167] The FIH study will evaluate the safety and tolerability of Compound A in combination with palbociclib in patients with locally advanced or mBC and determine the MTD and / or RP2D. The study will also evaluate the clinical activity of Compound A at RP2Ds in combination with palbociclib. Additional evaluations will include single- and multiple-dose pharmacokinetics and biochemical activity.

[0168] Study Design: Part C of the FIH study is a Phase Ib study evaluating the combination of Compound A and palbociclib.

[0169] Method of administration Compound A was administered orally in combination with palbociclib (Part C) in 28-day cycles at the doses shown in Table 1. Compound A was supplied as immediate-release tablets in strengths of 10 mg, 50 mg, and 100 mg. Tablet excipients were inactive compendial ingredients commonly used in oral formulations, including lactose monohydrate and sodium stearyl fumarate.

[0170] Palbociclib was administered orally at 125 mg / day once daily for 21 days, followed by a 7-day treatment break for each 28-day cycle, according to the product label and local prescribing information.

[0171] As of the data cutoff date of June 6, 2022, 176 patients have been treated in the FIH trial (Part C, n=27), and preliminary evidence of clinical activity has been observed.

[0172] [Table 1]

[0173] Clinical pharmacology studies Compound A is being investigated in an ongoing Phase I clinical pharmacology study to evaluate the effect of food or a PPI (esomeprazole) on the single-dose PK and safety of Compound A in healthy postmenopausal female volunteers (participants). A summary of the clinical pharmacology study is shown below in Table 2.

[0174] Study Design: The clinical pharmacology study consisted of three independent cohorts: 1) an open-label, randomized, two-period, crossover fed / fasted cohort to determine food effects; 2) an open-label, two-period, fixed-sequence PPI cohort to evaluate interactions with esomeprazole; and 3) an open-label, randomized, two-period, crossover rBA cohort to evaluate two tablet formulations.

[0175] As of the data cutoff date of June 16, 2022, 47 participants are currently being treated in the three cohorts of the clinical pharmacology study (14 participants in the fed / fasted cohort, 17 participants in the PPI cohort, and 16 participants in the rBA cohort). Each participant received two doses of 200 mg Compound A in each of two periods, with Compound A treatments separated by at least a 14-day washout period.

[0176] The 200 mg dose of Compound A was well tolerated in participants, with no grade 2 or higher TRAEs reported.

[0177] [Table 2]

[0178] Example 1: Pharmacokinetics (PK) in breast cancer patients (FIH study) Preliminary PK data from Part C of the FIH study (Compound A administered with palbociclib) were available from dose levels ranging from 180 to 500 mg QD. Preliminary results showed that C1, C2, and C3 for Compound A, Compound B, and the combined C1 and C2 for Compound A + Compound B were significantly increased on both Days 1 and 15 of Cycle 1. max and AUC tau The potential for clinical DDIs between Compound A and palbociclib was assessed by comparing the palbociclib and Compound A (C max and AUC tau ) plasma PK exposure parameters were assessed by comparing them with relevant PK data observed in previously completed studies in which palbociclib or Compound A were administered as single agents. PK data from Part C demonstrated similar C and D of Compound A in patients receiving palbociclib compared with patients receiving Compound A monotherapy. max and AUC tauThe lack of effect of palbociclib on Compound A exposure was suggested as evidenced by the preliminary C of palbociclib on Day 15 of Cycle 1 after 125 mg QD palbociclib in combination with 500 mg QD Compound A. max and AUC tau were approximately 18% to 25% and 34% higher than those observed in studies PALOMA-1 and PALOMA-2, respectively, when palbociclib was administered at 125 mg QD (see Pfizer. IBRANCE® (palbociclib). Product Monograph Including Patient Medication Information. Kirkland, Quebec: Pfizer Canada ULC; Revised: 15 July 2021. Available at: www.pfizer.ca / sites / default / files / 202107 / Ibrance_PM_EN_243405_15-Jul-2021.pdf; Durairaj C, Ruiz-Garcia A, Gauthier ER, et al. Palbociclib has no clinically relevant effect on the QTc interval in patients with advanced breast cancer. Anticancer Drugs. 2018 Mar;29(3):271280). Further evaluation of the potential for DDI between palbociclib and Compound A is ongoing.

[0179] Example 2: Pharmacokinetics (PK) in healthy volunteers (clinical pharmacology study) In the clinical pharmacology study, preliminary PK parameters were calculated following a single dose of 200 mg of Compound A from all three cohorts. max Median values ​​ranged from 6.0 to 8.0 hours across the cohort. Geometric mean T after a single 200 mg dose 1 / 2 was approximately 40 hours under fed conditions.

[0180] Statistical analysis showed that food intake significantly increased the risk of developing cerebrospinal fluid (C1) in the fasted condition compared to the fasted condition. max and AUC inf The results showed that Compound A significantly increased serotonin levels by 3- and 2-fold, respectively. Therefore, patients should be instructed to take Compound A with food. Compound A AUC values ​​were similar when administered with or without a PPI, but PPI significantly increased Compound A median C max by approximately 18%, which is not considered clinically significant, indicating no effect of PPIs on Compound A exposure when administered with a moderate fat meal.

[0181] Example 3: Safety in healthy volunteers (clinical pharmacology study) Adverse events (AEs) were coded into system organ class and preferred terminology according to the Medical Dictionary for Regulatory Activities (MedDRA), version 24.1. The severity of AEs was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.0.

[0182] Treatment-emergent adverse events (TEAEs) were AEs occurring after the first dose of Compound A and within 30 days of the last dose of Compound A, regardless of study drug attribution or grade.

[0183] Treatment-related adverse events (TRAEs) are AEs assessed by the investigator as "possibly related," "probably related," or "related" to Compound A.

[0184] Treatment-emergent adverse events (TEAEs) Regardless of study drug attribution and grade, TEAEs were observed in 15 of 47 patients treated with 200 mg Compound A in the ongoing clinical pharmacology study (all cohorts). Fasting / Fed Cohort (n=14): The most common TEAE observed in ≥10% of participants (regardless of attribution to study drug) was ligament sprain (2 participants, 14.3%). All other TEAEs were reported in <10% of participants.

[0185] All participants in the fasted / fed cohort who reported TEAEs experienced grade 1 (21.4%) or grade 2 (14.3%) TEAEs. No participants reported grade 3 or higher TEAEs.

[0186] There were no clinically significant differences in reported TEAEs between Compound A-treated participants in fasted and fed conditions.

[0187] PPI cohort (n=17): The most common TEAEs observed in ≥10% of participants (regardless of attribution to study drug) were headache (5 participants, 29.4%) and COVID-19 (2 participants, 11.8%).

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

[0189] There were no clinically significant differences in TEAEs reported between participants treated with Compound A with a PPI and those treated with Compound A without a PPI. rBA cohort (n=16): Only one participant (6.3%) reported a TEAE (dizziness, grade 1).

[0190] There were no clinically significant differences in reported TEAEs between participants treated with a 20% drug load and those treated with a 42% drug load.

[0191] Treatment-related adverse events (TRAEs) A total of 3 of 47 participants had at least one TEAE considered potentially related to Compound A (regardless of severity grade).

[0192] Fasting / Fed Cohort (n=14): One participant (7.1%) reported a TRAE of frequent urination.

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

[0194] rBA cohort (n=16): No participants reported TRAEs.

[0195] Serious Adverse Events (SAEs), Serious Adverse Reactions (SARs) and Deaths No SAEs, SARs, or deaths were reported in the clinical pharmacology study (all cohorts).

[0196] Treatment-emergent adverse events (TEAEs) leading to discontinuation One healthy participant reported a TEAE leading to discontinuation of the clinical pharmacology study. This participant was in the PPI cohort, was treated with 200 mg of Compound A, and was not on a PPI. However, due to COVID-19, Compound A could not be administered with a PPI for the second time.

[0197] Example 4: Safety and Efficacy in Breast Cancer Patients (FIH Study) Safety in breast cancer patients (FIH study) TEAEs and TRAEs from the clinical trial database were coded to system organ classes and preferred terms using MedDRA version 22.0, and SAEs from the centralized safety database were coded using MedDRA version 25.0. The severity of adverse events was graded according to the NCI CTCAE version 5.0.

[0198] A TEAE is an AE occurring after the first dose of Compound A and within 30 days of the last Compound A dose, regardless of study drug attribution or grade.

[0199] TRAEs are AEs assessed by the investigator as "possibly related," "probably related," or "related" to Compound A.

[0200] Preliminary safety data from the FIH study are shown below. Part C continues enrollment.

[0201] Summary of adverse events Based on a data cutoff of June 6, 2022, TEAEs, regardless of study drug attribution and grade, were observed in 157 of a total of 176 patients treated with Compound A in the ongoing FIH study (all parts).

[0202] Compound A Combination Therapy - Part C Evaluation of preliminary safety data from patients treated with the combination of Compound A and palbociclib indicates TEAEs consistent with those observed after treatment with Compound A and palbociclib alone (Pfizer. IBRANCE® (palbociclib). US FDA Package Insert. Capsules, for oral use: Full Prescribing Information. New York, NY: Pfizer Laboratories; Revised: 04 / 2019. Available at: www.accessdata.fda.gov / drugsatfda_docs / label / 2019 / 207103s008lbl.pdf).

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

[0204] The most common TEAEs observed in ≥20% of patients (regardless of attribution to study drug) included neutropenia (51.9%), fatigue (44.4%), neutropenia (37.0%), platelet count decreased (33.3%), anemia (29.6%), nausea (25.9%), cough (22.2%), diarrhea (22.2%), and leukopenia (22.2%).

[0205] Compound A Combination Therapy - Part C - Compound A in Combination with Palbociclib :

[0206] Based on the data cutoff of June 6, 2022, 5 of 27 patients reported a total of 7 SAEs. All SAEs reported in Part C were assessed by the investigator as not related to Compound A. One SAE of grade 3 bacteremia was assessed by the investigator as possibly related to palbociclib treatment.

[0207] Efficacy in breast cancer patients (FIH study) Efficacy data collection is ongoing for Part C. conclusion Without wishing to be bound by theory, based on the foregoing examples, a daily dose of 200 mg may be beneficial for Compound A in combination with administration of a CDK4 / 6 inhibitor.

[0208] Example 5: TACTIVE-U: A Phase 1b / 2 Umbrella Study of Compound A, a Proteolysis Targeted Chimeric (PROTAC) Estrogen Receptor (ER) Degrader, in Combination with Other Anticancer Treatments in ER+ Advanced or Metastatic Breast Cancer Patients eligible for substudies A and B were aged 18 years or older, had histologically or cytologically confirmed ER+ / HER2- advanced or metastatic breast cancer not amenable to surgical resection with one or more measurable lesions, and had received no more than two lines of prior therapy for advanced or metastatic disease, including one line of any CDK4 / 6 inhibitor-based regimen. In substudy A, patients received oral compound A once daily (QD) in a dose-escalation / de-escalation approach, and oral abemaciclib twice daily (BID) continuously. In substudy B, patients received oral compound A QD and oral ribociclib QD in a dose-escalation / de-escalation approach. Compound A was administered continuously, and ribociclib was administered for 21 days, followed by a 7-day treatment break. For both substudies, the primary endpoint of the Phase 1b portion is dose-limiting toxicity to determine the recommended Phase 2 dose of Compound A in combination with abemaciclib or ribociclib. Secondary endpoints of Phase 1b are progression-free survival (PFS), antitumor activity (overall response rate [ORR], clinical benefit rate [CBR], and duration of response [DOR]), safety (type, frequency, and severity of adverse events and laboratory abnormalities), and plasma concentrations of the investigational drug. AUC of Compound A + / - ribociclib tau and C max will be determined in substudy B. Phase II will further evaluate the antitumor activity of the combination, with the primary endpoint being ORR and secondary endpoints including overall survival, PFS, antitumor activity (CBR and DOR), safety, plasma concentrations of the investigational drug, and changes in circulating tumor DNA.

[0209] As of the data cutoff date of June 6, 2023, four patients received Compound A 200 mg QD and abemaciclib 150 mg BID in substudy A, and two patients received Compound A 100 mg QD and ribociclib 600 mg QD in substudy B.

[0210] Example 6: Enhanced efficacy of Compound A in combination with a CDK4 / 6 inhibitor in an ER+ breast cancer model

[0211] method Live cell imaging proliferation assay MCF7 or T47D cells were seeded in 6-well plates and treated with the indicated concentrations of compounds. 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 (120 hours). Data were analyzed using Incucyte® software v2020C, which quantifies the extent of cell surface area as confluence. Relative proliferation was calculated for all growth conditions and time points relative to the confluence value observed for the control at 120 hours (Figures 1A and 1C). Graphical and statistical analysis was performed using Graphpad Prism (GraphPad Software).

[0212] Compound A or fulvestrant as single agents, or for 5 days, their respective GI 50 In MCF7 and T47D cells treated in combination with abemaciclib at concentrations approaching GI, the mean reduction in MCF7 cell proliferation for Compound A, abemaciclib, and the combination was 41%, 49%, and 65%, respectively, compared to control cells (Figures 1A-1B). For fulvestrant and the combination of fulvestrant and abemaciclib, the mean reduction in MCF7 cell proliferation was 48% and 68%, respectively. For Compound A, abemaciclib, and the combination, the mean reduction in T47D cell proliferation was 42%, 32%, and 63%, respectively, and for fulvestrant and fulvestrant + abemaciclib, the mean reduction was 16% and 50%, respectively (Figures 1C-1D). Treatment with either the single agent or the combination of Compound A and ribociclib yielded similar results. The respective GI 50After 5 days of treatment at concentrations approaching fulvestrant, the mean reduction in MCF7 cell proliferation for compound A, ribociclib, and the combination was 41%, 44%, and 63%, respectively, compared to control cells (Figures 1E-1F), and the mean change in T47D cell proliferation for compound A, ribociclib, and the combination was 41%, 32%, and 61%, respectively (Figures 1G-1H). The combination of compound A with either abemaciclib or ribociclib demonstrated significantly greater inhibition of proliferation of both MCF7 and T47D cells compared to either single agent alone. These results were similar to those observed with fulvestrant when combined with either abemaciclib or ribociclib.

[0213] The combination of Compound (Ic) and palbociclib resulted in significant tumor regression (131% TGI) compared to single-agent Compound A activity (105% TGI) in this model (Figure 5). In contrast, single-agent fulvestrant administered subcutaneously resulted in only modest tumor growth inhibition (46% TGI), while the combination of fulvestrant and palbociclib resulted in improved tumor growth inhibition (108% TGI), but not near the level achieved with Compound A and palbociclib. Similar results were observed in a tamoxifen-resistant xenograft model, where the combination of Compound A and palbociclib caused greater TGI compared to either single agent alone.

[0214] The in vivo effects of combining Compound A or fulvestrant with abemaciclib were also evaluated in MCF7 tumor-bearing mice. As single agents, Compound A and abemaciclib treatment resulted in 88% and 50% TGI, respectively, but the combination resulted in greater growth inhibition (111% TGI) than either single agent alone (Figure 3A). Fulvestrant as a single agent showed moderate TGI (42%) and enhanced TGI (77%) when combined with abemaciclib. However, the TGI observed with the combination of fulvestrant and abemaciclib did not reach the level observed with the combination of Compound A and abemaciclib.

[0215] Treatment of MCF7 tumor-bearing mice with Compound A and ribociclib as single agents resulted in 87% and 58% TGI, respectively, whereas the combination resulted in a greater TGI (124%) than either single agent alone (Figure 3B). As a single agent, fulvestrant showed moderate TGI (31%) and enhanced TGI (76%) in combination with ribociclib, but did not reach the levels achieved with the combination of Compound A and ribociclib, similar to observations with the combination of fulvestrant and abemaciclib.

[0216] Taken together, these results demonstrate that compound A exhibits antitumor activity as a single agent, exhibits higher antitumor activity in combination with the CDK4 / 6 inhibitors abemaciclib and ribociclib, and exhibits greater antitumor efficacy than that observed with the combination of fulvestrant with either of these CDK4 / 6 inhibitors in BC tumor models.

[0217] Dose-response matrix assay Cells were plated at 2 x 10 in 200 μl of medium per well in a 96-well plate. 3Cells were seeded and incubated overnight at 37°C. Compound A and abemaciclib concentration curves were run starting at 100 nM for an 8-point concentration curve ranging from 100 nM to 0.046 nM (Figure 2A, 2C, and 2B). Ribociclib concentration curves were run starting at 3000 nM for an 8-point concentration curve ranging from 3000 nM to 1.37 nM (Figure 2B). Cell viability was measured on day 5 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). Combination of Compound A with either abemaciclib or ribociclib demonstrated enhanced cell growth inhibition compared to single-agent treatment and resulted in synergistic effects by the Bliss, Loewe, and HSA models, except for the Bliss model for T47D cells.

[0218] MCF7 xenograft model Briefly, MCF7 cells were orthotopically implanted into the mammary fat pads of NOD / SCID female mice. A 90-day pellet containing 0.72 mg of 17β-estradiol (Innovative Research of America) was implanted 2–3 days prior to MCF7 cell implantation. For the combination group, Compound A was administered first, followed by the combination partner 1 hour later. Compound A and / or combination partner-treated mice were orally administered once daily. Fulvestrant-treated mice were subcutaneously administered twice weekly for 2 weeks, followed by subcutaneous administration once weekly for 2 weeks.

[0219] More specifically, we used an MCF7 orthotopic xenograft model to investigate the synergy between Compound A and abemaciclib and ribociclib in vivo. Female NOD / SCID mice aged 8–10 weeks were subcutaneously implanted with 0.36 mg 90-day release 17β-estradiol pellets. One to two days later, each mouse received 5 × 10 6 MCF7 cells were injected into one mammary fat pad at 25 × 10 / 200 μL in a 50 / 50 RPMI-1640 phenol red-free medium / Corning Matrigel Membrane Matrix mixture. 6 The tumors were prepared at 200 mm 3 Dosing began when the stool reached a saturation point. When administering oral combinations, compound A (30 mg / kg) was administered first, followed by abemaciclib (30 mg / kg) and ribociclib (75 mg / kg) 30–60 minutes later. Fulvestrant (200 mg / kg, subcutaneous, twice weekly for 2 weeks, followed by once weekly for 2 weeks) was also evaluated as a single agent and in combination with abemaciclib and ribociclib. The indicated agents were administered as single agents or in combination to 10 mice per group. Compound A, abemaciclib, and ribociclib were administered once daily for 28 days (qdx28) at a volume of 5 ml / kg. The vehicle for compound A was 2% Tween 80 / PEG400. The vehicle for abemaciclib was 1% hydroxymethylcellulose (HEC) in 20 mM HCl pH 2. The vehicle for ribociclib was 0.5% methylcellulose. The vehicle for fulvestrant was 10% w / v ethanol, 10% w / v benzyl alcohol, and 15% w / v benzyl benzoate, made up to 100% w / v in castor oil. A 1-day washout period was implemented for all groups when body weight loss approached 10% (days 11, 12, 19, and 20 of the ribociclib study). Body weight was well maintained during the 1-day washout period (Figures 4A and 4B). Tumor volume was measured twice weekly throughout the efficacy study (width). 2 × length) / 2, where all measurements are in millimeters (mm) and tumor volume is mm 3Body weights were recorded twice weekly. At the end of the study, mice were euthanized 18 hours after the last dose, and the collected tissues were snap-frozen on dry ice. Tumor growth inhibition (TGI) was calculated as follows, with tumor volume in mm 3 is.

[0220] [Table 3]

[0221] At the end of the abemaciclib study, single-agent Compound A and abemaciclib inhibited tumor growth by 88% and 50%, respectively. Growth inhibition for Compound A in combination with abemaciclib was 111%. Fulvestrant inhibited tumor growth by 42% as a single agent and by 77% when combined with abemaciclib.

[0222] At the end of the ribociclib study, single-agent Compound A and ribociclib inhibited tumor growth by 87% and 58%, respectively. Growth inhibition for Compound A in combination with ribociclib was 124%. Fulvestrant inhibited tumor growth by 31% as a single agent and by 76% when combined with ribociclib.

[0223] Data are expressed as mean ± standard error of the mean.

[0224] findings In vitro studies revealed evidence of synergistic interactions between Compound A and the CDK4 / 6 inhibitors abemaciclib and ribociclib. Figures 1 and 2 show that Compound A in combination with CDK4 / 6 inhibitors (i.e., abemaciclib and ribociclib) exhibits enhanced efficacy and evidence of synergy in vitro.

[0225] Compound A in combination with the CDK4 / 6 inhibitors abemaciclib and ribociclib resulted in enhanced tumor regression in MCF7 xenografts compared with either agent alone.

[0226] Compound A had greater antitumor activity in combination with abemaciclib or ribociclib than that observed with fulvestrant in combination with these agents. Collectively, these data highlight the potential utility of Compound A as a clinically relevant targeted agent combination partner for the treatment of early and late stage ER+ disease.

[0227] Example 6: Study to learn about Compound 1 in patients with ER+ / HER2- advanced breast cancer in China

[0228] A brief summary The objective of this clinical trial is to learn about the pharmacokinetics, safety, and tolerability of compound 1 for the potential treatment of advanced estrogen receptor-positive and human epidermal growth factor receptor 2-negative breast cancer.

[0229] The trial is recruiting participants with ER+ / HER2- advanced breast cancer - Received at least one line of endocrine therapy with or without a CDK4 / 6 inhibitor - Received up to two prior regimens of chemotherapy for the advanced setting.

[0230] All participants in this study will receive Compound A.

[0231] Compound A will be administered orally once daily at home.

[0232] The experiences of people receiving the investigational drug are reviewed to help determine whether the drug is safe and effective.

[0233] Participants will remain in the trial until their cancer is no longer responding. During this time, participants will visit the trial site approximately every four weeks.

[0234] All participants will stay at the clinical trial site for 10 days and 9 nights. TIFF2025530742000039.tif39170

[0235] [Table 4]

[0236] [Table 5]

[0237] [Table 6]

[0238] [Table 7-1] [Table 7-1] TIFF2025530742000045.tif253170TIFF2025530742000046.tif253170TIFF2025530742000047.tif47170

[0239] [Table 8]

[0240] Example 6: Treatment-Emergent AEs (TEAEs) As of June 6, 2023, a total of 46 participants (100%) who received Compound A in combination with palbociclib 125 mg reported at least one TEAE.

[0241] Listed in order of decreasing frequency, the most common TEAEs observed in ≥20% of patients across all Compound A doses in combination with palbociclib 125 mg were neutropenia, fatigue, decreased platelet count, anemia, constipation, nausea, decreased white blood cell count, diarrhea, and QT prolongation (Table 4). Grade 3 and 4 TEAEs occurred in 23 (50%) and 19 (41.3%) participants, respectively. Neutropenia was the most common grade 3 or 4 TEAE, occurring in 47.8% (grade 3) and 41.3% (grade 4) of participants, respectively.

[0242] [Table 9]

[0243] In patients treated with Compound A 200 mg and palbociclib 125 mg, the most common TEAEs observed in ≥20% of patients included neutropenia (100.0%), fatigue (66.7%), decreased platelet count (52.4%), anemia (42.9%), constipation (33.3%), increased alanine aminotransferase (23.8%), increased aspartate aminotransferase (23.8%), back pain (23.8%), dizziness (23.8%), and decreased leukocyte count (23.8%).

[0244] All patients experienced neutropenia in the Compound A 200 mg and palbociclib 125 mg cohort, with eight participants (38.1%) reporting Grade 4 neutropenia. The median time to the first neutropenic episode of any grade was 14.5 days in patients treated with Compound A 200 mg in combination with palbociclib, consistent with the IBRANCE USPI. All neutropenic episodes were reversible, non-cumulative, and medically manageable with or without supportive care and / or dose reduction. Palbociclib dose reductions were reported in 13 participants (61.9%).

[0245] [Table 10-1] [Table 10-2]

[0246] All 46 patients (100%) experienced at least one adverse event related to either Compound A or palbociclib, with neutropenia, fatigue, and decreased platelet count as the most frequently reported TRAEs (Table 5).

[0247] Thirty-nine of 46 (84.8%) participants reported Compound A treatment-related TEAEs (Table 6). The most common Compound A treatment-related TEAEs (all doses) observed in 10% or more patients included fatigue (47.8%), neutropenia (28.3%), constipation (21.7%), electrocardiogram QT prolongation (19.6%), diarrhea (17.4%), facial hot flashes (15.2%), arthralgia (13%), nausea (13%), decreased platelet count (13%), and alopecia (10.9%). Neutropenia was the most common grade 3 or grade 4 TRAE, occurring in 47.6% (grade 3) and 38.1% (grade 4) of participants, respectively.

[0248] The most common palbociclib treatment-related TEAEs observed in ≥10% of patients treated with all doses of Compound A and 125 mg palbociclib included neutropenia (100%), fatigue (60.9%), decreased platelet count (45.7%), anemia (34.8%), and decreased white blood cell count (26.1%) in all patients, constipation (17.4%), diarrhea (17.4%), and nausea (17.4%).

[0249] Deaths were reported in a total of five (10.9%) of the 46 participants, of which three (6.5%) were related to the disease or its complications during the study, and the remaining two (4.3%) deaths were reported as related to "other."

[0250] Four patients (8.7%) experienced TEAEs, leading to discontinuation of both Compound A and palbociclib. TIFF2025530742000052.tif68170

[0251] Four patients (8.7%) experienced TEAEs that exclusively led to discontinuation of palbociclib. TIFF2025530742000053.tif67170

[0252] [Table 11]

[0253] [Table 12-1] [Table 12-2]

[0254] equivalent Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments specifically described herein which equivalents are intended to be encompassed by the following claims.

[0255] The methods of the present disclosure have been described herein by reference to certain preferred embodiments, however, the disclosure should not be considered limited thereto, although certain variations thereof will be apparent to those skilled in the art based on the disclosure set forth herein.

[0256] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In this specification and claims, the singular forms "a," "an," and "the" also include the plural forms unless the context clearly dictates otherwise.

[0257] It will be appreciated that at least some of the descriptions of the present disclosure have been simplified to focus on elements relevant to a clear understanding of the present disclosure, but for clarity, the exclusion of other elements that would be understood by a person skilled in the art may form part of the present disclosure. However, because such elements are well known in the art and do not necessarily facilitate a better understanding of the present disclosure, descriptions of such elements are not provided herein.

[0258] Furthermore, the particular order of steps recited in a claim should not be construed as a limitation on that claim, unless the method does not depend on the particular order of steps set forth herein.

[0259] All patents, patent applications, references, and publications cited herein are incorporated by reference in their entirety as if set forth in their entirety. Such documents are not admitted to be prior art to the present disclosure.

Claims

1. Compound A, in combination with a CDK4 / 6 inhibitor, 【Chemistry 1】 A pharmaceutical composition used in a method of treating cancer, comprising a daily amount of compound A or a pharmaceutically acceptable salt thereof, wherein the daily amount of compound A is about 100 mg or 200 mg.

2. The pharmaceutical composition according to claim 1, wherein the CDK4 / 6 inhibitor is administered simultaneously or over time.

3. The pharmaceutical composition according to claim 1 or 2, wherein the daily dose of compound A or a pharmaceutically acceptable salt thereof is about 200 mg.

4. The pharmaceutical composition according to claim 1 or 2, wherein the daily dose of compound A or a pharmaceutically acceptable salt thereof is about 100 mg.

5. The pharmaceutical composition according to claim 1, wherein the daily amount of compound A or a pharmaceutically acceptable salt thereof is administered once daily (QD).

6. The pharmaceutical composition according to claim 1, wherein the daily amount of compound A or a pharmaceutically acceptable salt thereof is administered orally to the subject.

7. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is administered in an ingestion state.

8. The pharmaceutical composition according to claim 1, wherein the CDK4 / 6 inhibitor is darpiciclib, palbociclib, rerocilib, AT7519M, dinaciclib, ribociclib, abemaciclib, or a pharmaceutically acceptable salt thereof.

9. The pharmaceutical composition according to claim 8, wherein the CDK4 / 6 inhibitor is abemaciclib, ribociclib, or palbociclib, or a pharmaceutically acceptable salt thereof.

10. The pharmaceutical composition according to claim 9, wherein the CDK4 / 6 inhibitor is abemaciclib or a pharmaceutically acceptable salt thereof.

11. The pharmaceutical composition according to claim 9, wherein the CDK4 / 6 inhibitor is ribociclib or a pharmaceutically acceptable salt thereof.

12. The pharmaceutical composition according to claim 9, wherein the CDK4 / 6 inhibitor is palbociclib or a pharmaceutically acceptable salt thereof.

13. The pharmaceutical composition according to claim 10, wherein abemaciclib or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 150 mg twice daily.

14. The pharmaceutical composition according to claim 11, wherein compound A or a pharmaceutically acceptable salt thereof is administered daily in a 28-day cycle, and ribociclib or a pharmaceutically acceptable salt thereof is administered orally once daily at a daily dose of approximately 600 mg for 21 days, followed by a 7-day treatment discontinuation for each 28-day cycle.

15. The pharmaceutical composition according to 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 once daily at a dose of 125 mg / day for 21 days, followed by a 7-day discontinuation of treatment for each 28-day cycle.

16. The pharmaceutical composition according to claim 1, wherein the daily dose of compound A or a pharmaceutically acceptable salt thereof is about 200 mg, and is combined with abemaciclib or a pharmaceutically acceptable salt thereof, administered twice daily in doses of about 150 mg.

17. The pharmaceutical composition according to claim 1, wherein the daily dose of compound A or a pharmaceutically acceptable salt thereof is about 100 mg, and is combined with ribociclib or a pharmaceutically acceptable salt thereof administered in a daily dose of about 600 mg.

18. The pharmaceutical composition according to claim 1, wherein the cancer is breast cancer, lung cancer, colon cancer, brain cancer, head and neck cancer, prostate cancer, stomach cancer, pancreatic cancer, ovarian cancer, melanoma, endocrine cancer, uterine cancer, testicular cancer, or bladder cancer.

19. The pharmaceutical composition according to claim 18, wherein the cancer is breast cancer, lung cancer, prostate cancer, pancreatic cancer, or ovarian cancer.

20. The pharmaceutical composition according to claim 19, wherein the cancer is breast cancer, lung cancer, or prostate cancer.

21. The pharmaceutical composition according to claim 20, wherein the cancer is breast cancer.

22. The pharmaceutical composition according to claim 21, wherein the breast cancer is metastatic or locally advanced.

23. The pharmaceutical composition according to claim 21 or 22, wherein the breast cancer is estrogen receptor-positive (ER+) breast cancer.

24. The pharmaceutical composition according to claim 23, wherein the breast cancer is estrogen receptor positive (ER+) and human epidermal growth factor receptor 2 negative (HER2-).

25. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is for human use.

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