Dosing regimen of estrogen receptor degrading agent

Abstract

Disclosed herein are methods for treating cancer comprising administering to a subject a daily dose of Compound A, or a pharmaceutically acceptable salt thereof, in combination with a CDK4 / 6 inhibitor. # imgabs0 #

Description

[0001] Cross-reference to related applications

[0002] This application claims priority to and the benefit of U.S. Application No. 63 / 402,651, filed on August 31, 2022, U.S. Application No. 63 / 443,892, filed on February 7, 2023, U.S. Application No. 63 / 454,485, filed on March 24, 2023, U.S. Application No. 63 / 454,422, filed on March 24, 2023, and U.S. Application No. 63 / 508,503, filed on June 15, 2023, the entire contents of each of which are incorporated herein by reference. Background Art

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

[0004] Of particular interest is the bifunctional molecule vepdegestrant (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-naphthylphenyl]-4-piperidinyl]methyl]-1-piperazinyl]-2H-isoindol-2-yl]-2,6-piperidinedione (referred to herein as "Compound A" or "Cpd A")) having C 45 H 49 N 5 O 4 The molecular formula and the following structure:

[0005]

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

[0007] An appropriate dosing regimen for Compound A as an oral therapy for treating cancer (eg, breast cancer) is needed to improve its benefits including safety and efficacy and convenience to patients while minimizing adverse events and risks to patients. Summary of the invention

[0008] The present disclosure provides, in part, a dosing regimen for administering compound A or a pharmaceutically acceptable salt thereof to a subject for treating cancer in combination therapy. The present disclosure is provided to introduce a series of concepts further described in the following specific embodiments in a simplified form. The present disclosure is not intended to identify the key features or essential features of the claimed subject matter, nor is it intended to be used alone as an aid in determining the scope of the claimed subject matter.

[0009] Provided herein are methods for treating cancer, the methods comprising administering to a subject a daily dose of Compound A having the following structure:

[0010]

[0011] or a pharmaceutically acceptable salt thereof, in combination with a CDK4 / 6 inhibitor, wherein the daily dose of Compound A is about 100 mg or about 200 mg.

[0012] Provided herein are methods for treating cancer, the methods comprising administering to a subject a daily dose of Compound A having the following structure:

[0013]

[0014] Combination with CDK4 / 6 inhibitors.

[0015] In an embodiment, the daily dose of Compound A is about 200 mg. In an embodiment, the daily dose of Compound A is about 100 mg.

[0016] In an embodiment, the CDK4 / 6 inhibitor is dalpiciclib, trilaciclib, lerociclib, AT7519M, dinaciclib, ribociclib, abemaciclib or palbociclib or a pharmaceutically acceptable salt thereof. In an embodiment, the CDK4 / 6 inhibitor is abemaciclib, ribociclib or palbociclib or a pharmaceutically acceptable salt thereof. In an embodiment, the CDK4 / 6 inhibitor is abemaciclib or a pharmaceutically acceptable salt thereof. In an embodiment, the CDK4 / 6 inhibitor is abemaciclib or a pharmaceutically acceptable salt thereof. In an embodiment, the CDK4 / 6 inhibitor is ribociclib or a pharmaceutically acceptable salt thereof. In an embodiment, the CDK4 / 6 inhibitor is ribociclib or a pharmaceutically acceptable salt thereof. In an embodiment, the CDK4 / 6 inhibitor is palbociclib or a pharmaceutically acceptable salt thereof.

[0017] In an embodiment, Compound A or a pharmaceutically acceptable salt thereof can be administered daily in a 28-day cycle in combination with a CDK4 / 6 inhibitor. In an embodiment, Compound A can be administered daily in a 28-day cycle in combination with a CDK4 / 6 inhibitor. In certain embodiments, the CDK4 / 6 inhibitor is Palbociclib or a pharmaceutically acceptable salt thereof. For example, Palbociclib can be orally administered once a day at 125 mg / day for 21 days in each 28-day cycle, followed by an intermittent treatment for 7 days.

[0018] In the Examples, the daily dose of Compound A is administered once a day (QD).

[0019] In embodiments, the daily dose of Compound A is administered orally to the subject.

[0020] In embodiments, the subject is in a fed state.

[0021] In embodiments, the cancer is breast cancer, lung cancer, colon cancer, brain cancer, head and neck cancer, prostate cancer, gastric cancer, pancreatic cancer, ovarian cancer, melanoma, endocrine cancer, uterine cancer, testicular cancer, or bladder cancer.

[0022] In embodiments, the cancer is breast cancer, lung cancer, prostate cancer, pancreatic cancer, or ovarian cancer.

[0023] In embodiments, the cancer is breast cancer, lung cancer, or prostate cancer.

[0024] In an embodiment, the cancer is breast cancer. For example, the breast cancer can be metastatic or locally advanced. Alternatively, the breast cancer can be estrogen receptor positive (ER+) breast cancer (e.g., human epidermal growth factor receptor 2 negative (HER2-)).

[0025] In embodiments, the subject is a human.

[0026] 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 DESCRIPTION OF THE DRAWINGS

[0027] Figures 1A-1H is a graph showing quantification of MCF7 and T47D live cell imaging proliferation assays. Figure 1A and 1C shows that by using their respective approximate GI 50 Relative cell growth kinetics over 120 hours obtained by live cell imaging of MCF7 and T47D cells dosed with Compound A (10 nM) or fulvestrant (1 nM) alone or in combination with abemaciclib (40 nM) at 240 μg / mL. Each graph represents three independent experiments. Figure 1E and 1G shows that by using their respective approximate GI 50 Relative cell growth kinetics over 120 h obtained by live cell imaging of MCF7 and T47D cells treated with Compound A (10 nM) and / or Ribociclib (40 nM) at different concentrations. Each graph represents three independent experiments, except Figure 1A and 1C Except for the T47D fulvestrant group in , the T47D fulvestrant group was the result of 2 independent experiments. Figure 1B , 1D , 1F and 1H show the difference in relative MCF7 and T47D cell growth at 120 hours of treatment compared to vehicle control. The graphs show the average of three independent experiments, except Figure 1B and Figure 1D Except for the T47D Fulvestrant group in , the T47D Fulvestrant group is the result of 2 independent experiments. Error bars = standard error of the mean (SEM). *p<0.025, **p≤0.008, ***p≤0.0006, ****p<0.0001, ns=not significant (one-way ANOVA test).

[0028] Figure 2A-2L is a graph showing the viability and synergy analysis of MCF7 cells on day 5 of dosing with the combination of Compound A with abemaciclib or ribociclib in an 8x8 block matrix. Figure 2A , 2B , 2G, and 2H show the single-agent curves for Compound A, abemaciclib, Compound A, and ribociclib, respectively. Figure 2C Shown is the change in Compound A dose response with the addition of abemaciclib. Fig.2IThe dose response change of Compound A with the addition of Ribociclib is shown. Drug synergy was evaluated using Combefit software. BLISS (2D and 2J), Loewe (2E and 2K) and highest single agent (2F and 2L) model outputs are shown (representative of three independent experiments).

[0029] Figure 3A and 3B The results show that compound A and the CDK4 / 6 inhibitor abemaciclib ( Figure 3A ) and Ribociclib ( Figure 3B ) in vivo efficacy study of the combination of . Mean tumor volumes ± SEM are reported. Single-day dosing breaks are indicated by small black arrows.

[0030] Figure 4A Graph showing body weight (± SEM) of MCF7 orthotopic xenograft efficacy with the combination of Compound A and the CDK4 / 6 inhibitor abemaciclib. Compounds were administered as single agents or in combination, 10 mice / group.

[0031] Figure 4B Graph showing body weight (± SEM) of MCF7 orthotopic xenograft efficacy with the combination of Compound A and the CDK4 / 6 inhibitor ribociclib. Compounds were administered as single agents or in combination, 10 mice / group.

[0032] Figure 5 is a graph showing the inhibition of tumor growth obtained by Compound A (30 mg / kg, orally [orally administered; PO]; once daily [QD] for 28 days) or Fulvestrant (200 mg / kg, subcutaneously; twice weekly for 2 weeks, then once weekly for 2 weeks) as single agents or in combination with the CDK4 / 6 inhibitor Palbociclib ('Palbo'; 60 mg / kg, PO; once daily for 28 days). Female severe combined immunodeficient mice in non-obese background (NOD / scid) mice were implanted with MCF7 cells, and once tumors reached 200 mm 3 The compound was administered at 1:100 of the time point. Tumor volume was assessed twice a week for 28 days. At the end of the study, single agent Compound A and Fulvestrant inhibited tumor growth by 105% and 46%, respectively. When combined with Palbociclib, the growth inhibition obtained with Compound A or Fulvestrant was 131% and 108%, respectively. Data are expressed as mean ± standard error of the mean (SEM). DETAILED DESCRIPTION

[0033] The present invention may be more readily understood by reference to the following detailed description of embodiments of the invention and the examples included herein.It should be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0034] vepdegestant (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-naphthylphenyl]-4-piperidinyl]methyl]-1-piperazinyl]-2H-isoindol-2-yl]-2,6-piperidinedione (also referred to herein as "Compound A")):

[0035]

[0036] A is being developed as a potential treatment for breast cancer targeting the estrogen receptor (ER). Protein degraders and have been shown to be useful modulators of targeted protein ubiquitination and degradation via the ubiquitin-proteasome pathway.

[0037] Compound A and pharmaceutically acceptable salts thereof are disclosed in International Publication No. WO 2018 / 102725 and U.S. Pat. Nos. 10,647,698, 10,899,742 and 11,104,666; International Publication No. WO 2021 / 041348; U.S. Serial No. 17 / 472,847; U.S. Serial No. 17 / 548,842; and U.S. Serial No. 17 / 873,748. The contents of each of the foregoing references are incorporated herein by reference in their entirety.

[0038] Cyclin-dependent kinases (CDKs) and related serine / threonine protein kinases are important cellular enzymes that play basic functions in regulating eukaryotic cell division and proliferation. The CDK catalytic unit is activated by a regulatory subunit called a cyclin. At least sixteen mammalian cyclins have been identified (Johnson DG, Walker CL. Cyclin and cell cycle checkpoints. "Annual Book of Pharmacology and Toxicology (Annu. Rev. Pharmacol. Toxicol.)" (1999) 39: 295-312). Cyclin B / CDK1, cyclin A / CDK2, cyclin E / CDK2, cyclin D / CDK4, cyclin D / CDK6 and possible other isorotatory proteins are important regulatory factors for cell cycle progression. Other functions of cyclin / CDK isochromats 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).

[0039] CDK inhibitors have been shown to be useful in treating cancer. Increased activity or transient abnormal activation of cyclin-dependent kinases has been shown to contribute to the development of human tumors, and human tumor development is often associated with changes in the CDK protein itself or its regulators (Cordon-Cardo C. Mutations of cell cycle regulators: biological and clinical implications for human neoplasia. Am. J. Pathol. (1995) 147: 545-560; Karp JE, Broder S. Molecular foundations of cancer: new targets for intervention. Nat. Med. (1995) 1: 309-320; Hall M, Peters G. Genetic alterations of cyclins, cyclin-dependent kinases, and Cdk inhibitors in human cancer. Adv. Cancer Res. Res.) (1996) 68: 67-108).

[0040] CDK4 and CDK6 are important regulators of cell cycle progression at the G1-S checkpoint, which is activated by D-type cyclins and endogenous CDK inhibitors such as p16 INK4a (CDKN2A) control. Dysregulation of the cyclin D-CDK4 / 6–INK4-retinoblastoma (Rb) pathway has been reported to be associated with the development of resistance to endocrine therapy.

[0041] Clinical trials of CDK4 / 6 inhibitors palbociclib, ribociclib and abemaciclib are being conducted to be used as a single agent or in combination with other therapeutic agents for the treatment of breast cancer and other cancers. The use of CDK4 / 6 inhibitors in combination with endocrine therapy has been shown to have 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 combination with endocrine therapy in the first-line or second-line setting. Palbociclib, ribociclib and abemaciclib have been approved for combination with aromatase inhibitors (such as letrozole) in the first-line setting in certain patients, and in combination with fulvestrant in the second-line therapy or later therapy, to treat hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2) negative advanced or metastatic breast cancer. (O'Leary et al. Treating cancer with selective CDK4 / 6 inhibitors. Nature Reviews (2016) 13:417-30).

[0042] 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 known as "PD-0332991") is a potent and selective inhibitor of CDK4 and CDK6 with the following structure:

[0043]

[0044] Palbociclib is described in WHO Drug Information, Vol. 27, No. 2, p. 172 (2013). Palbociclib and its pharmaceutically acceptable salts are disclosed in International Publication No. WO 2003 / 062236 and U.S. Pat. Nos. 6,936,612, 7,456,168 and RE47,739; International Publication No. WO 2005 / 005426 and U.S. Pat. Nos. 7,345,171 and 7,863,278; International Publication No. WO 2008 / 032157 and U.S. Pat. No. 7,781,583; and International Publication No. WO 2014 / 128588. The contents of each of the foregoing references are incorporated herein by reference in their entirety.

[0045] 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 (e.g., sold under the brand name (and others) are sold as selective inhibitors of CDK4 and CDK6 with the following structure:

[0046]

[0047] Abemaciclib and its pharmaceutically acceptable salts are disclosed in International Publication No. WO2010 / 075074 and U.S. Patent No. 7,855,211. The contents of each of the foregoing references are incorporated herein by reference in their entirety.

[0048] Ribociclib, 7-cyclopentyl-N,N-dimethyl-2-[(5-piperazin-1-ylpyridin-2-yl)amino]pyrrolo[2,3-d]pyrimidine-6-carboxamide (e.g., sold under the brand name and Sold) is an inhibitor of cyclin D1 / CDK4 and CDK6 with the following structure:

[0049]

[0050] Ribociclib and its pharmaceutically acceptable salts are disclosed in International Publication Nos. WO2007140222, WO2010 / 020675, WO2012 / 064805 and WO2016 / 166703 and U.S. Pat. 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.

[0051] Although CDK4 / 6 inhibitors have shown significant clinical efficacy in ER-positive metastatic breast cancer, like other kinases, their effects may be limited over time by the development of primary or acquired resistance. The selective CDK4 / 6 inhibitor palbociclib has been shown to be clinically effective in breast cancer (DeMichele A, Clark AS, Tan KS et al. CDK4 / 6 inhibitor palbociclib (PD-0332991) in Rb+ advanced breast cancer: phase II activity, safety, and predictive biomarker assessment. Clin Cancer Res 2015; 21(5):995-1001; Finn RS, Martin M, Rugo HS et al. Palbociclib and Letrozole in Advanced Breast Cancer. New Engl J Med 2016; 375(20):1925-36; Cristofanilli et al. Palbociclib and Letrozole in Advanced Breast Cancer. New Engl J Med 2016; 375(20):1925-36; Cristofanilli et al. M, Turner NC, Bondarenko I, et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol 2016; 17(4): 425-39. However, acquired resistance to palbociclib may develop after the initial clinical benefit (Knudsen Erik S.,Witkiewicz Agnieszka K.,The Strange Case of CDK4 / 6 Inhibitors:Mechanisms,Resistance,and Combination Strategies. Trends Cancer (2017) 3(1):39-55). .

[0052] definition

[0053] Unless otherwise defined herein, scientific and technical terms used in connection with the present invention have the meanings that are commonly understood by one of ordinary skill in the art.

[0054] The invention described herein may suitably be practiced in the absence of any element or elements not specifically disclosed herein.

[0055] As used herein, the singular forms "a," "an," and "the" include plural referents unless otherwise indicated. For example, "a" or "an" substituent includes one or more substituents.

[0056] As used herein, the term "about" when used to modify a numerically defined parameter (e.g., the dose of Compound A) means that the parameter can vary by up to 10% below or above the stated value of the parameter. For example, a dose of about 5 mg means 5 mg ± 10%, i.e., it can vary from 4.5 mg to 5.5 mg.

[0057] As used herein, terms including but not limited to "agent," "composition," "compound," "drug," and "therapeutic agent" may be used interchangeably to refer to compounds included in the methods and uses of the present disclosure.

[0058] 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 canines, felines, bovines, goats, equines, sheep, porcines, rodents, lagomorphs, primates, humans, etc., and encompass mammals in utero. In embodiments, humans are suitable subjects. Human subjects can be of any gender and at any stage of development.

[0059] Vepdegestant (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-naphthylphenyl]-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:

[0060]

[0061] Compound A is a Class IV compound of the Biopharmaceutical Classification System (low solubility / low permeability). Compound A can be interconverted with its diastereomer Compound B:

[0062]

[0063] Without wishing to be bound by theory, preclinical data suggest that exposure of Compound B is limited compared to Compound A (<26%). There is evidence that Compound B does not degrade ER; however, Compound B exhibits similar ER-dependent transcriptional antagonism compared to Compound A.

[0064] Cyclin-dependent kinases (CDKs) and related serine / threonine kinases are important cellular enzymes that play essential functions in regulating cell division and proliferation. CDK inhibitors include pan-CDK inhibitors that target a broad spectrum of CDKs or selective CDK inhibitors that target one or more specific CDKs.

[0065] Examples of CDK4 / 6 inhibitors include, but are not limited to, abemaciclib, ribociclib, and palbociclib. Additional examples of CDK4 / 6 inhibitors include leloxilib (also known as G1T38) and trexacil (also known as GTI128).

[0066] In an embodiment, the CDK4 / 6 inhibitors of the present invention include palbociclib. Unless otherwise indicated herein, palbociclib (also referred to herein as "palbo" or "Palbo") refers to 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazine-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one:

[0067]

[0068] or a pharmaceutically acceptable salt thereof.

[0069] Alternatively, in an embodiment, the CDK4 / 6 inhibitor is abemaciclib or ribociclib. Unless otherwise indicated, abemaciclib refers to 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:

[0070]

[0071] And Ribociclib refers to 7-cyclopentyl-N,N-dimethyl-2-[(5-piperazin-1-ylpyridin-2-yl)amino]pyrrolo[2,3-d]pyrimidine-6-carboxamide:

[0072]

[0073] Other embodiments relate to pharmaceutically acceptable salts of the compounds described herein. Pharmaceutically acceptable salts of the compounds described herein include acid addition salts and base addition salts thereof.

[0074] Other embodiments also relate to pharmaceutically acceptable acid addition salts of the compounds described herein. Suitable acid addition salts are formed from acids that form non-toxic salts. Non-limiting examples of suitable acid addition salts, i.e., salts containing pharmacologically acceptable anions, include, but are not limited to, acetates, acid citrates, adipates, aspartates, benzoates, benzenesulfonates, bicarbonates / carbonates, bisulfates / sulfates, bitartrates, borates, camphorsulfonates, citrates, cyclamates, edisylate, ethanesulfonates, ethanesulfonates, formates, fumarates, glucoheptonates, gluconates, glucuronates, hexafluorophosphates, hyphenates, Hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthoate, 2-naphthalenesulfonate, nicotinate, nitrate, lactate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, p-toluenesulfonate, toluenesulfonate, trifluoroacetate, and xinafoate.

[0075] Additional embodiments relate to base addition salts of the compounds described herein. Suitable base addition salts are formed from bases that form non-toxic salts. Non-limiting examples of suitable base salts include aluminum, arginine, benzathine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine, and zinc salts.

[0076] The compounds described herein that are basic in nature can form a variety of salts with various inorganic and organic acids. Acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds described herein are acids that form non-toxic acid addition salts, for example, salts containing pharmacologically acceptable anions such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)] salts. In addition to the acids listed above, the compounds described herein that include a basic moiety (eg, an amino group) can form pharmaceutically acceptable salts with various amino acids.

[0077] Chemical bases that can be used as reagents for preparing pharmaceutically acceptable base salts of the compounds described herein that are acidic in nature are chemical bases that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to, base salts derived from such pharmacologically acceptable cations, such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-soluble amine addition salts, such as N-methylglucamine-(meglumine), and other base salts of lower alkylammonium and pharmaceutically acceptable organic amines.

[0078] Hemisalts of acids and bases can also be formed, for example, hemisulphate and hemicalcium salts.

[0079] For a review of suitable salts, see Stahl and Wermuth, Pharmaceutical Salts: Properties, Selection, and Use (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds described herein are known to those skilled in the art.

[0080] Dosage regimen

[0081] Provided herein are methods for treating cancer, the methods comprising administering to a subject a daily dose of Compound A having the following structure: or a pharmaceutically acceptable salt thereof, in combination with a CDK4 / 6 inhibitor.

[0082] Also provided herein is a method for treating cancer, the method comprising administering to a subject a daily dose of Compound A having the following structure: Combination with CDK4 / 6 inhibitors.

[0083] In an embodiment, the daily dose is a compound A having the following structure: or a pharmaceutically acceptable salt thereof is administered once a day (QD).

[0084] In an embodiment, the daily dose is a compound A having the following structure:

[0085] or a pharmaceutically acceptable salt thereof is orally administered to the subject.

[0086] In embodiments, the subject is in a fed state.

[0087] In an embodiment, the daily dose of Compound A is:

[0088] or a pharmaceutically acceptable salt thereof is about 200 mg or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0089] In an embodiment, the daily dose of Compound A is:

[0090] or a pharmaceutically acceptable salt thereof is 200 mg or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0091] In an embodiment, the daily dose of Compound A is:

[0092] It is about 200mg.

[0093] In an embodiment, the daily dose of Compound A is:

[0094] It is 200mg.

[0095] In an embodiment, the daily dose of Compound A is:

[0096] or a pharmaceutically acceptable salt thereof is about 100 mg or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0097] In an embodiment, the daily dose of Compound A is:

[0098] or a pharmaceutically acceptable salt thereof is 100 mg or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0099] In an embodiment, the daily dose of Compound A is:

[0100] It is about 100mg.

[0101] In an embodiment, the daily dose of Compound A is:

[0102] It is 100mg.

[0103] In an embodiment, compound A:

[0104] Administered as the free base.

[0105] In an embodiment, the CDK4 / 6 inhibitor is dalcili, trelacili, leloxilib, AT7519M, dinasiku, ribociclib, abexilib or palbociclib or a pharmaceutically acceptable salt thereof. In an embodiment, the CDK4 / 6 inhibitor is dalcili, trelacili, leloxilib, AT7519M, dinasiku, ribociclib, abexilib or palbociclib.

[0106] In an embodiment, the CDK4 / 6 inhibitor is abemaciclib, ribociclib or palbociclib or a pharmaceutically acceptable salt thereof. In an embodiment, the CDK4 / 6 inhibitor is abemaciclib, ribociclib or palbociclib.

[0107] In an embodiment, the CDK4 / 6 inhibitor is abemaciclib or a pharmaceutically acceptable salt thereof. In an embodiment, the CDK4 / 6 inhibitor is abemaciclib.

[0108] In an embodiment, the CDK4 / 6 inhibitor is ribociclib or a pharmaceutically acceptable salt thereof. In an embodiment, the CDK4 / 6 inhibitor is ribociclib.

[0109] In an embodiment, the CDK4 / 6 inhibitor is palbociclib or a pharmaceutically acceptable salt thereof. In an embodiment, the CDK4 / 6 inhibitor is palbociclib.

[0110] In an embodiment, Compound A is administered daily in a 28-day cycle. In certain embodiments, palbociclib or a pharmaceutically acceptable salt thereof is orally administered once daily at 125 mg / day for 21 days in each 28-day cycle, followed by a 7-day break in treatment.

[0111] In embodiments, the cancer is breast cancer, lung cancer, colon cancer, brain cancer, head and neck cancer, prostate cancer, gastric cancer, pancreatic cancer, ovarian cancer, melanoma, endocrine cancer, uterine cancer, testicular cancer, or bladder cancer.

[0112] In embodiments, the cancer is breast cancer, lung cancer, prostate cancer, pancreatic cancer, or ovarian cancer.

[0113] In embodiments, the cancer is breast cancer, lung cancer, or prostate cancer.

[0114] In embodiments, the cancer is breast cancer.

[0115] In embodiments, the breast cancer is metastatic or locally advanced.

[0116] In embodiments, the breast cancer is estrogen receptor positive (ER+) breast cancer.

[0117] In embodiments, the estrogen receptor positive (ER+) breast cancer is human epidermal growth factor receptor 2 negative (HER2-).

[0118] In embodiments, the subject is a human.

[0119] Also disclosed herein is Compound A:

[0120] or a pharmaceutically acceptable salt thereof, for use according to any one of the preceding embodiments.

[0121] It is also disclosed herein that compound A is:

[0122] or a pharmaceutically acceptable salt thereof, for use according to any one of the preceding embodiments.

[0123] Also disclosed herein is compound A:

[0124] Or use of a pharmaceutically acceptable salt thereof for preparing a medicament according to any one of the aforementioned embodiments.

[0125] Also disclosed herein is compound A:

[0126] Or use of a pharmaceutically acceptable salt thereof for preparing a medicament according to any one of the aforementioned embodiments.

[0127] Each embodiment described herein may be combined with any one or more other embodiments described herein without being inconsistent with the one or more embodiments with which it is combined.

[0128] Administration and dosing

[0129] As used herein, the terms "treat" and "treating" cancer or a cancer-related disease mean administering a combination therapy according to the present disclosure to a subject, participant, or patient who has cancer or is diagnosed with cancer, to achieve at least one positive therapeutic effect, such as a decrease in the number of cancer cells, a decrease in tumor size, a decrease in the rate of cancer cell infiltration into peripheral organs, or a decrease in the rate of tumor metastasis or tumor growth, reversal, improvement, inhibition of progression of the disorder or condition to which such terms apply, or prevention of the disorder or condition or one or more symptoms of such disorder or condition. As used herein, unless otherwise indicated, the terms "treat" and "therapy" refer to the therapeutic behavior defined immediately above as "treatment". For the purposes of this disclosure, beneficial or desired clinical results include, but are not limited to, one or more of the following: reducing the proliferation of tumor cells or cancer cells (or destroying tumor cells or cancer cells); inhibiting metastasis or tumor cells; shrinking or reducing the size of tumors; cancer remission; reducing symptoms caused by cancer; increasing the quality of life of people with cancer; reducing the dose of other drugs required to treat cancer; delaying the progression of cancer; curing cancer; overcoming one or more resistance mechanisms of cancer; and / or prolonging the survival of patients with cancer. The positive effects of cancer treatment can be measured in a variety of ways (see, eg, WA Weber, J. Nucl. Med. (2009) 50: 1S-10S).

[0130] As used to describe a subject herein, "fed condition" or "fed state" refers to a subject that has eaten less than 4 hours prior to a target time point (e.g., the time of administration of Compound A). In embodiments, a subject in a fed state eats within any one of 4 hours, 3 hours, 2 hours, 1 hour, or 0.5 hours prior to administration of Compound A.

[0131] "Amount" for use and for treating a subject refers to an amount that provides a detectable response, desired outcome, or objective or subjective benefit to a subject in any duration (short, medium, or long term) in any measurable or detectable degree or in any duration (e.g., relief or cure in hours, days, months, years) in a single or multiple doses in combination with one or more other agents. Such amounts are generally effective to improve the disease or one, multiple, or all adverse effects / symptoms, consequences, or complications of the disease to a measurable degree, but reducing or inhibiting the progression or worsening of the disease, or providing a stable (i.e., non-worsening) state of the disease is considered a satisfactory result. The term "therapeutically effective amount" also means an amount of a pharmaceutical agent in combination with one or more other agents that, when administered to a subject, is effective to produce a desired therapeutic effect, such as preventing the growth of a cancerous tumor or shrinking a cancerous tumor. With reference to the treatment of cancer, a therapeutically effective amount refers to an amount that has the following effects: (1) reduces the size of a tumor, (2) inhibits (i.e., slows to some extent, preferably stops) the appearance of tumor metastases, (3) inhibits (i.e., slows to some extent, preferably stops) tumor growth or tumor invasiveness, and / or (4) alleviates (or preferably eliminates) to some extent one or more signs or symptoms associated with cancer. The therapeutic or pharmacological effectiveness of the dose and administration regimen can also be characterized as the ability to induce, enhance, maintain or prolong disease control and / or overall survival in patients with these specific tumors, which can be measured as a prolongation of the time before disease progression.

[0132] As used herein, "improvement" refers to any reduction in the extent, severity, frequency, and / or likelihood of symptoms or clinical signs characteristic of a particular disease. "Symptom" refers to any subjective evidence of a disease or condition in a subject.

[0133] Embodiments of the present invention provide a dosage, dosage and administration regimen, which comprises administering to a subject a certain amount or effective amount of Compound A or a pharmaceutically acceptable salt thereof. The amount or the therapeutically effective amount can be a daily dose of about 200 mg. In another embodiment, the daily dose is 200 mg.

[0134] In embodiments, the daily dose of Compound A or a pharmaceutically acceptable salt thereof is administered once a day (QD).

[0135] The compounds disclosed herein can be administered orally. Oral administration can involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration can be employed, whereby the compound enters the bloodstream directly from the mouth.

[0136] In embodiments, the daily dose of Compound A or a pharmaceutically acceptable salt thereof is administered orally.

[0137] Compound A or a pharmaceutically acceptable salt thereof may be present in a pharmaceutical composition comprising a pharmaceutically acceptable excipient. A "pharmaceutically acceptable excipient" refers to a component that can be included in the composition described herein, is physiologically suitable for pharmaceutical use, and does not produce significant adverse effects or therapeutic effects on the subject. The term "excipient" is used herein to describe any ingredient other than one or more compounds of the present invention. The choice of excipient will depend to a large extent on factors such as the mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

[0138] The compounds of the methods, uses or combinations of the present invention can be formulated prior to administration. The formulations are preferably suitable for specific modes of administration. These compounds can be formulated with pharmaceutically acceptable excipients as known in the art and administered in a variety of dosage forms as known in the art. Dosage unit forms or pharmaceutical compositions suitable for oral administration include, but are not limited to, tablets, capsules (such as gelatin capsules), pills, powders, granules, aqueous and non-aqueous oral solutions and suspensions, packaged in containers suitable for subdividing into individual doses.

[0139] In an embodiment, palbociclib or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 125 mg once a day, about 100 mg once a day, about 75 mg once a day, about 50 mg per day, or about 25 mg per day. In an embodiment, palbociclib or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 125 mg once a day. For example, palbociclib or a pharmaceutically acceptable salt thereof is administered at a dose of about 100 mg once a day, about 75 mg once a day, or about 50 mg once a day. In one embodiment, palbociclib or a pharmaceutically acceptable salt thereof is administered at a dose of about 100 mg once a day. In an embodiment, palbociclib or a pharmaceutically acceptable salt thereof is administered at a dose of about 75 mg once a day. In an embodiment, palbociclib or a pharmaceutically acceptable salt thereof is administered at a dose of about 50 mg once a day. The doses provided herein refer to the dose of the free base form of palbociclib, or are calculated as the free base equivalent of the palbociclib salt form administered. For example, a dose or amount of palbociclib, such as 100 mg, 75 mg or 50 mg, refers to the free base equivalent.

[0140] In an embodiment, abemaciclib or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 400 mg (e.g., about 200 mg twice a day), about 300 mg (e.g., about 150 mg twice a day), about 200 mg (e.g., about 100 mg twice a day) or about 100 mg (e.g., about 50 mg twice a day). In an embodiment, abemaciclib or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 300 mg (e.g., about 150 mg twice a day), about 200 mg (e.g., about 100 mg twice a day) or about 100 mg (e.g., about 50 mg twice a day). In an embodiment, abemaciclib or a pharmaceutically acceptable salt thereof is administered at a daily dose of 300 mg (e.g., about 150 mg twice a day). In one embodiment, abemaciclib or a pharmaceutically acceptable salt thereof is administered at a dose of about 200 mg (e.g., about 100 mg twice a day). In an embodiment, abemaciclib or a pharmaceutically acceptable salt thereof is administered at a dose of about 50 mg, about 100 mg twice a day (e.g., about 50 mg twice a day). The dosage provided herein refers to the dosage of the free base form of abemaciclib, or is calculated as the free base equivalent of the administered abemaciclib salt form. For example, the dosage or amount of abemaciclib, such as 200 mg, 150 mg, 100 mg or 50 mg, refers to the free base equivalent.

[0141] In an embodiment, ribociclib or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 600 mg once a day, about 400 mg once a day, about 200 mg once a day, or about 50 mg once a day. In an embodiment, ribociclib or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 600 mg once a day. In one embodiment, ribociclib or a pharmaceutically acceptable salt thereof is administered at a dose of about 400 mg once a day. In an embodiment, ribociclib or a pharmaceutically acceptable salt thereof is administered at a dose of about 200 mg once a day. The dosages provided herein refer to the dosage of the free base form of ribociclib, or are calculated as the free base equivalent of the administered ribociclib salt form. For example, the dosage or amount of ribociclib, such as 600 mg, 400 mg, 200 mg, refers to the free base equivalent.

[0142] The administration or dosing regimen may be repeated as needed to achieve the desired reduction or decrease in cancer cells. As used herein, a "continuous dosing schedule" is an administration or dosing regimen that does not interrupt the dosage, e.g., the days of treatment without interruptions. Repetition of a 28-day treatment cycle without dose interruptions between treatment cycles is an example of a continuous dosing schedule. In embodiments, the compounds of the combination of the present invention may be administered in a continuous dosing schedule. In embodiments, the compounds of the combination disclosed herein may be administered simultaneously in a continuous dosing schedule.

[0143] In an embodiment, Compound A is administered once daily to comprise a complete cycle of 28 days. According to the methods and uses of the present disclosure, the 28-day treatment cycle is continuously repeated during the treatment period.

[0144] The standard recommended dosing regimen for palbociclib or its pharmaceutically acceptable salt, including the standard dosing schedule, is once daily administration for 21 consecutive days, followed by 7 days of discontinuation of treatment to comprise a complete cycle of 28 days. The 28-day cycle continues to be repeated during treatment with the combination of the present invention.

[0145] The standard clinical dosing regimen for palbociclib or its pharmaceutically acceptable salt is to administer 125 mg once daily for 21 consecutive days, followed by 7 days of intermittent treatment to comprise a complete cycle of 28 days. The 28-day cycle continues to be repeated during treatment with the combination of the present invention.

[0146] The standard clinical dosing regimen for ribociclib or its pharmaceutically acceptable salt is 600 mg once daily for 21 consecutive days, followed by 7 days of intermittent treatment to comprise a complete cycle of 28 days. The 28-day cycle continues to be repeated during treatment with the combination of the present invention.

[0147] Also disclosed herein are kits comprising a therapeutic agent of the combination of the present disclosure and written instructions for administering the therapeutic agent. In an embodiment, the written instructions describe and define the mode of administration of the therapeutic agent in detail, e.g., for simultaneous or sequential administration of the therapeutic agents of the present disclosure. In an embodiment, the written instructions describe and define the mode of administration of the therapeutic agent in detail, e.g., by specifying the days of administration of each therapeutic agent during a 28-day treatment cycle.

[0148] Treatment

[0149] In an embodiment, provided herein is a method for treating cancer in a subject, the method comprising administering to the subject an effective amount of Compound A as described herein in combination with an amount of a CDK4 / 6 inhibitor.

[0150] As used herein, unless otherwise indicated, the term "combination" refers to the use of Compound A and one or more therapeutic agents, wherein Compound A and the one or more therapeutic agents are administered intermittently, simultaneously or sequentially according to the same or different administration routes and according to the same or different dosage schedules.

[0151] As used herein, the term "locally advanced" may or may not be treated with curative intent as it relates to cancer. For example, locally advanced breast cancer (LABC) is defined by the US National Comprehensive Cancer Network as a subset of breast cancer characterized by: the most advanced breast tumor in the absence of distant metastases, wherein the size of the tumor is greater than 5 cm, with regional lymphadenopathy; tumors of any size extending directly to the chest wall or skin or both (including ulcers or satellite nodules), regardless of whether there is regional lymphadenopathy; the presence of regional lymphadenopathy (clinically fixed or tangled axillary lymph nodes, or any of subclavian, supraclavicular, or internal mammary lymphadenopathy), regardless of the 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.).

[0152] As used herein, the term "metastatic" refers to cancer that cannot be treated with curative intent. For example, metastatic breast cancer refers to breast cancer that has spread beyond the breast and nearby lymph nodes to other parts of the body, such as the bones, liver, lungs, and brain. (www.cancer.org / cancer / breast-cancer).

[0153] One skilled in the art will be able to identify and diagnose locally advanced and metastatic cancer in a patient or subject.

[0154] 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).

[0155] In embodiments, the cancer is selected from the group consisting of 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, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, hematological malignancies, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney cancer or ureter cancer, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) tumors, primary CNS lymphomas, spinal axis tumors, glioblastomas, brain stem gliomas, pituitary adenomas, head and neck cancers, and combinations of two or more of the foregoing cancers.

[0156] Also disclosed herein are methods of treating cancer in a subject. In embodiments, the method comprises treating cancer in a subject, the method comprising administering to the subject an amount of a compound described herein effective to treat the cancer.

[0157] In embodiments, the cancer is breast cancer, lung cancer, colon cancer, brain cancer, head and neck cancer, prostate cancer, gastric cancer, pancreatic cancer, ovarian cancer, melanoma, endocrine cancer, uterine cancer, testicular cancer, or bladder cancer.

[0158] In embodiments, the cancer is breast cancer, lung cancer, prostate cancer, pancreatic cancer, or ovarian cancer.

[0159] In embodiments, the cancer is breast cancer, lung cancer, or prostate cancer.

[0160] In embodiments, the cancer is breast cancer.

[0161] In embodiments, the breast cancer is metastatic breast cancer.

[0162] In embodiments, the breast cancer is locally advanced breast cancer.

[0163] In embodiments, the breast cancer is HR+ breast cancer.

[0164] In embodiments, the HR+ breast cancer is PR+ and / or ER+ breast cancer.

[0165] In embodiments, the breast cancer is PR+ breast cancer.

[0166] In embodiments, the breast cancer is ER+ breast cancer.

[0167] In embodiments, the breast cancer is ER+HER2- breast cancer.

[0168] In embodiments, the breast cancer is ER+HER2+ breast cancer.

[0169] In embodiments, the breast cancer is locally advanced or metastatic ER+ breast cancer.

[0170] In embodiments, the breast cancer is locally advanced or metastatic ER+HER2- breast cancer.

[0171] In embodiments, the breast cancer is locally advanced or metastatic ER+HER2+ breast cancer.

[0172] In embodiments, the breast cancer is metastatic ER+, HER2- breast cancer.

[0173] In embodiments, the breast cancer is metastatic ER+, HER2- breast cancer, which is also locally advanced.

[0174] In embodiments, the lung cancer is non-small cell lung cancer.

[0175] In embodiments, the lung cancer is locally advanced or metastatic non-small cell lung cancer.

[0176] In embodiments, the prostate cancer is CRPC.

[0177] In embodiments, the prostate cancer is locally advanced or metastatic CRPC.

[0178] Also disclosed herein are methods of treating a solid tumor in a subject. In an embodiment, disclosed herein are methods of treating a solid tumor in a subject, the method comprising administering to the subject an amount of a compound described herein effective to treat the solid tumor.

[0179] 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.

[0180] In embodiments, the solid tumor is breast cancer, lung cancer, prostate cancer, pancreatic cancer or ovarian cancer.

[0181] In embodiments, the solid tumor is breast cancer, lung cancer or prostate cancer.

[0182] In 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 ER+ breast cancer.

[0183] In embodiments, the solid tumor is breast cancer. For example, in certain embodiments, the breast cancer is ER+HER2- breast cancer.

[0184] In embodiments, the solid tumor is breast cancer. For example, in certain embodiments, the breast cancer is ER+HER2+ breast cancer.

[0185] In embodiments, the solid tumor is breast cancer. For example, in certain embodiments, the breast cancer is locally advanced or metastatic ER+HER2- breast cancer.

[0186] In embodiments, the solid tumor is breast cancer. For example, in certain embodiments, the breast cancer is locally advanced or metastatic ER+HER2+ breast cancer.

[0187] In embodiments, the solid tumor is lung cancer. For example, in certain embodiments, the lung cancer is non-small cell lung cancer.

[0188] In embodiments, the solid tumor is lung cancer. For example, in certain embodiments, the lung cancer is locally advanced or metastatic non-small cell lung cancer.

[0189] In embodiments, the solid tumor is prostate cancer. For example, in certain embodiments, the prostate cancer is CRPC.

[0190] 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.

[0191] Also disclosed herein are methods of treating a blood tumor in a subject. In certain embodiments, the method comprises treating a blood tumor in a subject, the method comprising administering to the subject an amount of a compound described herein effective to treat the blood tumor.

[0192] In embodiments, the hematological tumor is leukemia, lymphoma or multiple myeloma.

[0193] In embodiments, said hematological tumor is a leukemia or a lymphoma.

[0194] 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 has progressed on or is intolerant to standard therapy.

[0195] 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 has progressed on or is intolerant to standard therapy.

[0196] Also disclosed herein are methods of treating cancer in a subject with locally advanced or metastatic 2L+ER+HER2 breast cancer who has received prior hormone / endocrine therapy and chemotherapy in the locally advanced / metastatic setting. In an embodiment, the method comprises administering to the subject a combination of Compound A and a CDK4 / 6 inhibitor.

[0197] Also disclosed herein are methods of 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 an embodiment, the method comprises administering to the subject a combination of Compound A and a CDK4 / 6 inhibitor.

[0198] Also disclosed herein are therapeutic combinations comprising:

[0199] (i) Compound A:

[0200] (Compound A) or a pharmaceutically acceptable salt thereof; and

[0201] (ii) CDK4 / 6 inhibitors;

[0202] A method for simultaneous, separate or sequential use in the treatment of cancer; wherein the method comprises administering a daily dose of Compound A or a pharmaceutically acceptable salt thereof.

[0203] Also disclosed herein are therapeutic combinations comprising:

[0204] (i) Compound A:

[0205] (Compound A); and

[0206] (ii) CDK4 / 6 inhibitors;

[0207] A method for simultaneous, separate or sequential use in the treatment of cancer; wherein the method comprises administering a daily dose of Compound A.

[0208] Also disclosed herein is compound A:

[0209] (Compound A) or a pharmaceutically acceptable salt thereof, for use in a method for treating cancer, wherein the method comprises administering Compound A or a pharmaceutically acceptable salt thereof, and wherein the method further comprises administering a CDK4 / 6 inhibitor.

[0210] Also disclosed herein is compound A:

[0211] (Compound A) for use in a method for treating cancer, wherein the method comprises administering Compound A, and wherein the method further comprises administering a CDK4 / 6 inhibitor.

[0212] Also disclosed herein is a CDK4 / 6 inhibitor for use in a method for treating cancer, wherein the method further comprises administering Compound A or a pharmaceutically acceptable salt thereof.

[0213] Also disclosed herein is a CDK4 / 6 inhibitor for use in a method for treating cancer, wherein the method further comprises administering compound A.

[0214] In embodiments, the method comprises administering a daily dose of about 200 mg of Compound A or an equivalent amount of a pharmaceutically acceptable salt thereof. In embodiments, the method comprises administering a daily dose of about 200 mg of Compound A. In embodiments, the method comprises administering a daily dose of about 100 mg of Compound A.

[0215] Examples

[0216] In order to better understand the present invention, the following examples are described. These examples are for illustrative purposes only and should not be construed as limiting the scope of the present invention in any way.

[0217] Abbreviations used in this article include:

[0218] AUC 0-8 = area under the plasma concentration-time curve from zero to 8 hours;

[0219] AUC 0-12 = area under the plasma concentration-time curve from 0 to 12 hours;

[0220] AUC tau = area under the plasma concentration-time curve during the dosing interval, where tau = 24 hours for once-daily dosing and 12 hours for twice-daily dosing;

[0221] BID = twice daily.

[0222] ●BMI=body mass index;

[0223] CI = confidence interval.

[0224] CR = Complete Response

[0225] CBR = clinical benefit rate.

[0226] ●C max =maximum plasma concentration;

[0227] DDI = drug-drug interaction.

[0228] ER = estrogen receptor.

[0229] GCV = geometric coefficient of variation;

[0230] HER2 = human epidermal growth factor receptor 2.

[0231] FIH = first-in-human;

[0232] IR = immediate release.

[0233] mBC = metastatic breast cancer.

[0234] MTD = maximum tolerated dose.

[0235] ORR = overall response rate.

[0236] PPI = proton pump inhibitor.

[0237] PR = partial response

[0238] rBA = relative bioavailability;

[0239] RP2D = recommended phase 2 dose;

[0240] QD = once daily.

[0241] SA = single agent;

[0242] SD = stable disease; and

[0243] TRAE = treatment-related adverse event.

[0244] Compound A clinical trials ("FIH studies" and "clinical pharmacology studies")

[0245] First-in-Human ("FIH") Studies

[0246] Compound A is being studied in an ongoing Phase 1 / 2, open-label, dose-escalation and cohort expansion study to evaluate Compound A versus palbociclib The safety, tolerability, pharmacokinetics and anti-tumor activity of the combination of 100mg / ml in patients with estrogen receptor positive / human epidermal growth factor receptor 2 negative (ER+ / HER2-) locally advanced or metastatic breast cancer who have received previous hormone therapy and chemotherapy in the locally advanced / metastatic setting. An overview of the FIH study is provided in Table 1 below.

[0247] The FIH study will evaluate the safety and tolerability of the combination of Compound A and Palbociclib in patients with locally advanced or mBC and determine the MTD and / or RP2D of the combination. The study will also evaluate the clinical activity of the combination of Compound A and Palbociclib at the RP2D. Additional evaluations will include single-dose and multiple-dose pharmacokinetics and biochemical activity.

[0248] Study Design: Part C of the FIH study is a Phase 1b evaluating the combination of Compound A and palbociclib.

[0249] Application method

[0250] Compound A in combination with palbociclib (Part C) was orally administered in a 28-day cycle at the doses shown in Table 1. Compound A was provided as 10 mg, 50 mg, and 100 mg strength immediate release tablets. Tablet excipients were inert, commonly prescribed components in oral formulations, including lactose monohydrate and sodium stearyl fumarate.

[0251] According to the product label and in accordance with its local prescribing information, palbociclib was administered orally at 125 mg / day once daily for 21 days in each 28-day cycle, followed by a 7-day break in treatment.

[0252] As of the data cutoff date of June 6, 2022, 176 patients have been treated in the FIH study (Part C, n=27), and preliminary evidence of clinical activity has been observed.

[0253] Table 1: Overview of Part C FIH studies

[0254]

[0255] a Patients initially enrolled in this cohort received 180 mg once daily, but when 100 mg tablets became available, the dose was rounded to 200 mg once daily.

[0256] Clinical Pharmacology Research

[0257] Compound A is being studied in an ongoing Phase 1 clinical pharmacology study to evaluate the effects 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 provided in Table 2 below.

[0258] Study Design: The clinical pharmacology study consisted of 3 independent cohorts: 1) an open-label, randomized, 2-period, crossover fed / fasted cohort to determine food effects; 2) an open-label, 2-period, fixed-sequence PPI cohort to evaluate interactions with esomeprazole; and 3) an open-label, randomized, 2-period, crossover rBA cohort to evaluate 2 tablet formulations.

[0259] As of the data cutoff date of June 16, 2022, 47 participants have been treated in 3 cohorts of the clinical pharmacology study. (14 participants in the fed / fasted, 17 participants in the PPI, and 16 participants in the rBA cohort). Each participant received 2 doses of 200 mg of Compound A, 1 dose in each of the 2 periods, and Compound A treatment was separated by a washout period of at least 14 days.

[0260] The dose of 200 mg Compound A has been well tolerated among participants, and no grade 2 or higher TRAEs were reported.

[0261] Table 2: Overview of clinical pharmacology studies

[0262]

[0263] cStudy drug administered 30 minutes after the start of a moderate fat meal, followed by fasting for at least 4 hours after Compound A administration.

[0264] Example 1: Pharmacokinetics (PK) in patients with breast cancer (FIH study)

[0265] Preliminary PK data from Part C of the FIH study (Compound A administered with Palbociclib) are available from dose levels ranging from 180 to 500 mg once daily. Preliminary results showed that on Day 1 and Day 15 of Cycle 1, for Compound A, Compound B, and the sum of Compound A + Compound B up to 500 mg once daily, the C max and AUC tau The clinical DDI potential between Compound A and palbociclib was determined by comparing the plasma PK exposure parameters (C max and AUC tau ) and related PK data observed in previously completed studies in which palbociclib or Compound A was administered as a single agent. The PK data from Part C indicated that palbociclib had no effect on Compound A exposure, as shown by similar C values ​​of Compound A in patients receiving Compound A with palbociclib compared to patients receiving Compound A monotherapy. max and AUC tauOn the other hand, after once-daily administration of 125 mg of palbociclib in combination with 500 mg of compound A, the initial C of palbociclib on day 15 of cycle 1 was max and AUC tau The rates were approximately 18% to 25% and 34%, respectively, which are higher than those observed in studies PALOMA-1 and PALOMA-2 when 125 mg of palbociclib was administered once daily (Pfizer. (Palbociclib). Product Monograph Including Patient Medication Information. Kirkland, Quebec: Pfizer Canada ULC; Revised: July 15, 2021. Available at: www.pfizer.ca / sites / default / files / 202107 / Ibrance_PM_EN_243405_15-Jul-2021.pdf; Durairaj C, Ruiz-Garcia A, Gauthier ER, et al. Palbociclib has no clinically relevant effect on the QTc interval in patients with advanced breast cancer. Anticancer Drugs. 2018 Mar;29(3):271-280). Further evaluation of the DDI potential between palbociclib and compound A is ongoing.

[0266] Example 2: Pharmacokinetics (PK) in Healthy Volunteers (Clinical Pharmacology Study)

[0267] In the clinical pharmacology study, preliminary PK parameters were calculated following a single 200 mg dose of Compound A from all 3 cohorts. Median T across cohorts max The geometric mean T after a single 200 mg dose in the fed state was 6.0 to 8.0 hours. 1 / 2 For about 40 hours.

[0268] Statistical analysis showed that food intake increased the expression of compound AC compared with the fasting state. max and AUC inf The AUC values ​​of Compound A were similar when administered with or without PPI, but PPI increased the median C of Compound A by 3 to 2 fold.max This is a decrease of approximately 18%, which is not considered clinically relevant. This suggests that PPIs have no effect on the exposure of Compound A when administered with a moderate fat meal.

[0269] Example 3: Safety in healthy volunteers (clinical pharmacology study)

[0270] Adverse events (AEs) were coded into system organ classes and preferred terms 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.

[0271] Treatment-emergent adverse events (TEAEs) were AEs occurring after the first dose of Compound A and within 30 days of the final Compound A dose, regardless of the nature or grade of the study drug.

[0272] Treatment-related adverse events (TRAEs) were AEs assessed by the investigator as “possibly related,” “probably related,” or “related” to Compound A.

[0273] Treatment-emergent adverse events (TEAEs)

[0274] Regardless of the nature and class of study drug, TEAEs were observed in 15 of 47 participants treated with 200 mg Compound A in the ongoing clinical pharmacology study (all cohorts).

[0275] Fasting / eating group (n=14): The most common TEAE observed in ≥10% of participants (regardless of whether attributed to study drug) was ligament sprain (2 participants, 14.3%). All other TEAEs were reported in <10% of participants.

[0276] All participants reporting TEAEs in the fasting / fed cohort experienced Grade 1 (21.4%) or 2 (14.3%) TEAEs. No participant reported Grade 3 or higher TEAEs.

[0277] There were no clinically significant differences in TEAEs reported in participants treated with Compound A in the fasted and fed states.

[0278] PPI group (n=17):The most common TEAEs observed in ≥10% of participants (regardless of whether attributed to study drug) were headache (5 participants, 29.4%) and COVID-19 (2 participants, 11.8%).

[0279] All participants who reported TEAEs in the PPI cohort experienced Grade 1 (47.1%) or 2 (5.9%) TEAEs. No participant reported Grade 3 or higher TEAEs.

[0280] 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.

[0281] rBA group (n=16): Only 1 participant (6.3%) reported a TEAE (dizziness, grade 1).

[0282] There were no clinically significant differences in TEAEs reported between participants treated with 20% drug load and those treated with 42% drug load.

[0283] Treatment-related adverse events (TRAEs)

[0284] A total of 3 participants out of a total of 47 experienced at least 1 TEAE considered possibly related to Compound A (regardless of severity grade).

[0285] Fasting / eating group (n=14): One participant (7.1%) reported a TRAE of urinary frequency.

[0286] PPI group (n=17): Two participants (11.8%) reported at least 1 TRAE. Reported TRAEs included nausea, headache, and pruritus (1 participant [5.9%] each).

[0287] rBA group (n=16): No participants reported TRAEs.

[0288] Serious adverse events (SAEs), serious adverse drug reactions (SARs), and deaths

[0289] No SAEs, SARs, or deaths were reported in the clinical pharmacology studies (all cohorts).

[0290] Treatment-emergent adverse events (TEAEs) leading to discontinuation

[0291] One healthy participant reported a TEAE that led to discontinuation of the clinical pharmacology study. This participant was in the PPI cohort, was on 200 mg Compound A and was not treated with a PPI, and could not be dosed a second time with Compound A together with a PPI due to COVID.

[0292] Example 4: Safety and efficacy in patients with breast cancer (FIH study)

[0293] I. Safety in patients with breast cancer (FIH study)

[0294] TEAEs and TRAEs from the clinical research database were coded as system organ class 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 NCI CTCAE version 5.0.

[0295] A TEAE was an AE occurring after the first dose of Compound A and within 30 days of the final Compound A dose, regardless of the nature or grade of the study drug.

[0296] TRAEs were AEs assessed by the investigator as “possibly related,” “probably related,” or “related” to Compound A.

[0297] Preliminary safety data from the FIH study are shown below. Part C continues to enroll.

[0298] Overview of adverse events

[0299] Based on the data cutoff date of June 6, 2022, TEAEs were observed in 157 of a total of 176 patients treated with Compound A in the ongoing FIH study (all parts), regardless of the nature and grade of study drug.

[0300] Compound A Combination Therapy – Part C

[0301] Evaluation of preliminary safety data from patients treated with the combination of Compound A and palbociclib showed that TEAEs were consistent with those observed following treatment with Compound A and palbociclib alone (Pfizer Inc. (Palbociclib). US FDA Package Insert. Capsules, for oral use: Full Prescribing Information. New York, NY: Pfizer Laboratories; Revised: 04 / 2019. Available from: www.accessdata.fda.gov / drugsatfda_docs / label / 2019 / 207103s008lbl.pdf).

[0302] Based on the data cutoff date of June 6, 2022, a total of 24 of 27 patients (88.9%) in Part C reported at least 1 TEAE.

[0303] The most common TEAEs observed in ≥20% of patients (regardless of whether attributed to study drug) included decreased neutrophil count (51.9%), fatigue (44.4%), neutropenia (37.0%), decreased platelet count (33.3%), anemia (29.6%), nausea (25.9%), cough (22.2%), diarrhea (22.2%), and leukopenia (22.2%).

[0304] Compound A combination therapy - Part C - Combination of Compound A + Palbociclib :

[0305] Based on the data cutoff date of June 6, 2022, a total of 7 SAEs were reported by 5 of 27 patients. All SAEs reported in Part C were assessed by the investigator as not related to Compound A. One SAE of Grade 3 bacteremia was assessed by the investigator as possibly related to palbociclib treatment.

[0306] II. Efficacy in patients with breast cancer (FIH study)

[0307] Efficacy data collection for Part C is ongoing.

[0308] in conclusion

[0309] Without wishing to be bound by theory, based on the foregoing examples, a 200 mg daily dose may be beneficial for the combination of administration of Compound A with a CDK4 / 6 inhibitor.

[0310] Example 5: TACTIVE-U: A Phase 1b / 2 Umbrella Study of the Proteolysis Targeting Chimera (PROTAC) Estrogen Receptor (ER) Degrader Compound A in Combination with Other Anticancer Therapies in ER+ Advanced or Metastatic Breast Cancer

[0311] Patients eligible for substudies A and B are ≥18 years of age, have histologically or cytologically confirmed ER+ / HER2- advanced or metastatic breast cancer that is not amenable to surgical resection, have ≥1 measurable lesions, and have received ≤2 lines of prior therapy for advanced or metastatic disease, including 1 line of any CDK4 / 6 inhibitor-based regimen. In substudy A, patients will receive compound A taken orally once daily (QD) in a dose-escalating / decreasing manner and abemaciclib taken orally twice daily (BID). In substudy B, patients will receive compound A taken orally once daily and ribociclib taken orally once daily in a dose-escalating / decreasing manner; compound A will be given continuously, and ribociclib will be given for 21 days, followed by 7 days of intermittent treatment. For both substudies, the primary endpoint of the Phase 1b portion is dose-limiting toxicity to determine the recommended Phase 2 dose for the combination of compound A with abemaciclib or ribociclib. Secondary endpoints for Phase 1b are progression-free survival (PFS), antitumor activity (overall response rate [ORR], clinical benefit rate [CBR], and duration of response [DOR]), safety (type, frequency, and severity of adverse events and laboratory abnormalities), and plasma concentrations of study drug; for Substudy B, the AUC of Compound A + / - ribociclib will be determined tau and C max Phase 2 further evaluated the antitumor activity of the combination; the primary endpoint was ORR, and secondary endpoints included overall survival, PFS, antitumor activity (CBR and DOR), safety, plasma concentrations of study drug, and changes in circulating tumor DNA.

[0312] As of the data cutoff date of June 6, 2023, 4 patients have received 200 mg of compound A once daily and 150 mg of abemaciclib twice daily in substudy A, and 2 patients have received 100 mg of compound A once daily and 600 mg of ribociclib once daily in substudy B.

[0313] Example 6: Enhanced efficacy of the combination of compound A and a CDK4 / 6 inhibitor in an ER+ breast cancer model

[0314] method

[0315] Live cell imaging proliferation assay

[0316] MCF7 or T47D cells were seeded in 6-well plates and treated with the indicated concentrations of compounds. The plates were then placed The S3 Live Cell Analysis System was used and images were collected every 4 hours for 5 days. Data were analyzed using the software v2020C, which quantified cell surface area coverage as confluence values. Relative growth ( Figure 1A and 1C Graphpad Prism (GraphPad Software) was used for graphing and statistical analysis.

[0317] Relative to control cells, the 50 In MCF7 and T47D cells treated with Compound A or fulvestrant as a single agent or in combination with abemaciclib at concentrations of 100 mg / kg for 5 days, MCF7 cell growth was reduced by an average of 41%, 49%, and 65% for Compound A, abemaciclib, and the combination, respectively ( Figure 1A-1B ). For fulvestrant and fulvestrant plus abemaciclib, MCF7 cell growth was reduced by an average of 48% and 68%, respectively. For Compound A, abemaciclib, and the combination, T47D cell growth was reduced by an average of 42%, 32%, and 63%, respectively, and for fulvestrant and fulvestrant plus abemaciclib, by an average of 16% and 50%, respectively ( Figure 1C-1D ). Similar results were obtained with single agent or combination of Compound A and Ribociclib. 50 After 5 days of treatment with the concentration of , the growth of MCF7 cells was reduced by 41%, 44% and 63% for compound A, ribociclib and the combination, respectively ( Figure 1E-1F ); the mean changes in T47D cell growth were 41%, 32%, and 61% for compound A, ribociclib, and the combination, respectively ( Figure 1G-1H ). When compared to any single agent alone, the combination of Compound A with abemaciclib or ribociclib showed significantly greater inhibition of the growth of both MCF7 and T47D cells. These results are similar to those observed with fulvestrant in combination with abemaciclib or ribociclib.

[0318] When compared to the activity of single agent Compound A in this model (105% TGI) ( Figure 5 ), the combination of Compound A and palbociclib resulted in tumor regression (131% TGI). In contrast, subcutaneously administered single-agent fulvestrant produced only a modest TGI (46% TGI), while the combination of fulvestrant and palbociclib resulted in improved inhibition of tumor growth (108% TGI), but not to the level achieved by Compound A and palbociclib. Similar results were observed in a tamoxifen-resistant xenograft model, where the combination of Compound A and palbociclib resulted in a greater TGI than any single agent alone.

[0319] 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 produced 88% and 50% TGI, respectively, while the combination produced greater growth inhibition (111% TGI) than either single agent alone ( Figure 3A Fulvestrant showed a modest TGI as a single agent (42%) and an enhanced TGI when combined with abemaciclib (77%). 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.

[0320] Treatment of MCF7 tumor-bearing mice with Compound A and ribociclib as single agents resulted in 87% TGI and 58% TGI, respectively, while the combination resulted in a greater TGI (124%) compared to either single agent alone ( Figure 3B Fulvestrant showed a modest TGI as a single agent (31%), and the combination with ribociclib showed an enhanced TGI (76%), but not to the level achieved by the combination of Compound A and ribociclib, which is similar to what was observed with the combination of fulvestrant and abemaciclib.

[0321] In summary, these results indicate that in BC tumor models, Compound A exhibits antitumor activity as a single agent and in combination with the CDK4 / 6 inhibitors abemaciclib and ribociclib, and exhibits greater antitumor activity than that observed with the combination of fulvestrant and either of these CDK4 / 6 inhibitors.

[0322] Dose-response matrix assay

[0323] Cells were plated at 2 x 10 3 Cells were seeded in 200 μl of medium per well of a 96-well plate and incubated overnight at 37°C. For an 8-point concentration curve ranging from 100 to 0.046 nM, the Compound A and abemaciclib concentration curves started at 100 nM ( Figure 2A , 2C and B). For the 8-point concentration curve ranging from 3000 to 1.37 nM, the ribociclib concentration curve started at 3000 nM ( Figure 2B). On day 5, cell viability was measured using Cell-Titer Glo, and CTG data were analyzed using Combenefit software (Veroli GYD, Fornari C, Wang D, Mollard S, Bramhall JL, Richards FM et al. Combenefit: an interactive platform for the analysis and visualization of drug combinations. Bioinformatics. 2016; 32: 2866–8). The combination of abemaciclib or ribociclib with Compound A showed enhanced cell growth inhibition compared to single agent treatment and produced synergistic effects through the Bliss, Loewe, and HSA models, except for the Bliss model for T47D cells.

[0324] MCF7 xenograft model

[0325] In brief, MCF7 cells are orthotopically implanted into the mammary fat pad of NOD / SCID female mice. 17β-estradiol 0.72mg 90-day precipitate (Innovative Research of America, USA) was implanted 2-3 days before MCF7 cells were implanted. For the combination group, Compound A was first applied, and then the combination partner was applied after 1 hour. The mice processed with Compound A and / or the combination partner were orally administered once a day. The mice processed with Fulvestrant were subcutaneously administered twice a week for 2 weeks, and then administered once a week for 2 weeks.

[0326] More specifically, the synergistic effect between Compound A and abemaciclib and ribociclib was followed in vivo using an MCF7 orthotopic xenograft model. Eight to ten week old female NOD / SCID mice were surgically implanted subcutaneously with 0.36 mg of a 90 day 17β-estradiol release pellet. One to two days later, 5 x 10 6 MCF7 cells were injected into one mammary fat pad per mouse at 25x10 in a 50 / 50 RPMI-1640 phenol red-free medium / Corning basement membrane matrix mixture. 6 Once tumors reach an average of 200 mm 3, administration was started. In the case of oral administration of the combination, Compound A (30 mg / kg) was first administered, and Abemacili (30 mg / kg) and Reboxib (75 mg / kg) were administered 30-60 minutes later. Fulvestrant (200 mg / kg, subcutaneous; twice a week for 2 weeks, then once a week for 2 weeks) was also evaluated as a single agent and in combination with Abemacili and Reboxib. The indicated drugs were administered to 10 mice / group as a single agent or in combination. Compound A and Abemacili and Reboxib were administered once a day at a volume of 5 ml / kg for 28 days (once a day for 28 days). The vehicle of Compound A was 2% Tween 80 / PEG400. The vehicle of Abemacili was 1% hydroxymethylcellulose (HEC) in 20mM HCl at a pH of 2. The vehicle of Reboxib was 0.5% methylcellulose. The vehicle for Fulvestrant was 10% w / v ethanol, 10% w / v benzyl alcohol, 15% w / v benzyl benzoate, formulated up to 100% w / v with castor oil. A single-day dosing holiday was implemented for all groups if any weight loss approached 10% (Days 11, 12, 19, and 20 of the ribociclib study). With the single-day dosing holiday, body weight was well maintained ( Figure 4A and 4B ). Tumor volume was measured twice weekly in the efficacy study and was measured using (width 2 x length) / 2, where all measurements are in millimeters (mm) and tumor volume is in 3 Body weights were recorded twice a week. At study termination, mice were euthanized 18 hours after the last dose and harvested tissues were snap-frozen on dry ice. Tumor growth inhibition (TGI) was calculated as follows, where tumor volume was expressed in mm 3 Unit:

[0327]

[0328] At the end of the abemaciclib study, single agent Compound A and fulvestrant inhibited tumor growth by 88% and 50%, respectively. The growth inhibition of the combination of Compound A and abemaciclib was 111%. Fulvestrant inhibited tumor growth by 42% as a single agent and by 77% when combined with abemaciclib.

[0329] At the end of the ribociclib study, single agent Compound A and ribociclib inhibited tumor growth by 87% and 58%, respectively. The growth inhibition of the combination of Compound A and ribociclib was 124%. Fulvestrant inhibited tumor growth by 31% as a single agent and by 76% when combined with ribociclib.

[0330] Data are presented as mean ± standard error of the mean.

[0331] Discover

[0332] 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 the combination of Compound A with CDK4 / 6 inhibitors (i.e., abemaciclib and ribociclib) showed enhanced efficacy and evidence of synergistic effects in vitro.

[0333] The combination of Compound A with the CDK4 / 6 inhibitors abemaciclib and ribociclib enhanced tumor regression in MCF7 xenografts compared to the single agents alone.

[0334] The combination of Compound A with these agents showed greater antitumor activity than that observed with the combination of fulvestrant with abemaciclib or ribociclib.

[0335] Together, these data highlight the potential utility of Compound A as a combination partner to clinically relevant targeted agents for the treatment of early and advanced ER+ disease.

[0336] Example 6: Understanding the study of Compound 1 in Chinese patients with ER+ / HER2- advanced breast cancer

[0337] Brief Overview

[0338] The purpose of this clinical trial is to understand 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.

[0339] This study is seeking participants with -ER+ / HER2- advanced breast cancer

[0340] - Received at least 1 line of endocrine therapy with or without a CDK4 / 6 inhibitor

[0341] - Received up to 2 prior chemotherapy regimens for use in the advanced setting.

[0342] All participants in this study will receive Compound A.

[0343] Compound A will be administered orally once a day at home.

[0344] The experiences of people who receive the study drug will be examined. This will help to determine if the study drug is safe and effective.

[0345] Participants will participate in this study until their cancer no longer responds. During this time, the participants will be visited at the research clinic approximately every 4 weeks.

[0346] All participants will stay at the research clinic for 10 days and 9 nights.

[0347] Type of study: Intervention

[0348] Research phase: Phase 1

[0349] Study Group: A study group

[0350] Blind: No blind

[0351] Registration number: 9

[0352] Intervention

[0353]

[0354] Outcome Metrics

[0355]

[0356] Secondary outcome measures

[0357]

[0358]

[0359]

[0360] qualified

[0361]

[0362]

[0363] Example 6: Treatment-emergent AEs (TEAEs)

[0364] As of June 6, 2023, a total of 46 participants (100%) receiving the combination of Compound A with palbociclib 125 mg reported at least 1 TEAE.

[0365] The most common TEAEs observed in ≥20% of patients in combination with palbociclib 125 mg at all compound A doses are listed in descending order of frequency: neutropenia, fatigue, decreased platelet count, anemia, constipation, nausea, decreased white blood cell count, diarrhea, and electrocardiogram QT prolongation (Table 4). Grade 3 and 4 TEAEs occurred in 23 (50%) and 19 (41.3%) participants, respectively. Neutropenia was the most common grade 3 or 4 TEAE and occurred in 47.8% (grade 3) and 41.3% (grade 4) participants, respectively.

[0366] Table 3: TEAEs by Preferred Term and Maximum CTCAE Grade 3 or Higher ≥5% - Study ARV-471-mbc-101 (Part C)

[0367]

[0368] * Neutropenia is classified according to the MedDRA preferred terms neutropenia and neutrophil count decreased.

[0369] Please note: Treatment-emergent was defined as AEs occurring on / after the date of first study dose and within 30 days of the last study dose.

[0370] Please note: Patients are counted only once for each preferred term.

[0371] Please note: Adverse events were coded using MedDRA version 22.0.

[0372] Source: BDM TAE04C: TEAEs by Preferred Term and Maximum CTCAE Grade (Part C) - All Dose Groups Full Treatment Analysis Set and BDM TAE04RELC2: Compound A or Palbociclib TRAEs by Preferred Term and Maximum CTCAE Grade (Part C) - 200 mg Full Treatment Analysis Set

[0373] Data deadline: June 6, 2023

[0374] 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%), low back pain (23.8%), dizziness (23.8%), and decreased white blood cell count (23.8%).

[0375] In the Compound A 200mg and Palbociclib 125mg groups, all patients experienced neutropenia, with 8 participants (38.1%) reporting G4 neutropenia. For patients treated with a combination of Compound A 200mg and Palbociclib, the median time to the first neutropenic episode of any grade was 14.5 days, and was consistent with IBRANCE USPI. All neutropenic episodes were reversible, non-cumulative, and medically manageable with / without supportive care and / or dose reduction. Palbociclib dose reduction was reported in 13 participants (61.9%).

[0376] Table 4: Treatment-emergent adverse events ≥10% by preferred term (Part C) - All-As-Treatment Analysis Set (ARV-471-mBC-101)

[0377]

[0378]

[0379] * Neutropenia is classified according to the MedDRA preferred terms neutropenia and neutrophil count decreased.

[0380] Please note: Treatment-emergent was defined as AEs occurring on / after the first study dose date and within 30 days of the last study dose.

[0381] Please note: Patients are counted only once for each preferred term.

[0382] Please note: Adverse events were coded using MedDRA version 22.0.

[0383] Data Cutoff: June 6, 2023 Source: BDM TAE02C3: Treatment-Emergent Adverse Events ≥10% by Preferred Term (Part C) – All-As-Treatment Analysis Set

[0384] All 46 participants (100%) experienced at least one adverse event related to Compound A or palbociclib, with neutropenia, fatigue, and decreased platelet count being the most frequently reported TRAEs (Table).

[0385] Thirty-nine (39) of the 46 participants (84.8%) reported Compound A treatment-related TEAEs (Table 6). The most common Compound A treatment-related TEAEs observed in ≥10% of patients (all doses) included fatigue (47.8%), neutropenia (28.3%), constipation (21.7%), electrocardiogram QT prolongation (19.6%), diarrhea (17.4%), hot flashes (15.2%), arthralgia (13%), nausea (13%), decreased platelet count (13%), and alopecia (10.9%). Neutropenia was the most common Grade 3 or 4 TRAE and occurred in 47.6% (Grade 3) and 38.1% (Grade 4) of participants, respectively.

[0386] The most common palbociclib treatment-related TEAEs observed in ≥10% of patients treated with all doses of Compound A and 125 mg palbociclib included neutropenia (100%), fatigue (60.9%), decreased platelet count (45.7%), anemia (34.8%), and decreased white blood cell count (26.1%), constipation (17.4%), diarrhea (17.4%), and nausea (17.4%) for all patients.

[0387] A total of 5 deaths (10.9%) were reported among the 46 participants. Of these, 3 (6.5%) were found to be related to the disease under study or its complications, and the remaining 2 (4.3%) deaths were reported as being related to "other".

[0388] Four patients (8.7%) experienced TEAEs that led to discontinuation of both Compound A and palbociclib:

[0389] • One patient dosed with 200 mg Compound A + 125 mg palbociclib once daily experienced Grade 1 weight loss that was considered by the investigator to be related to both Compound A and palbociclib.

[0390] - One patient dosed with 200 mg Compound A + 125 mg Palbociclib once daily experienced a grade 1 cough that was considered unrelated to Compound A or Palbociclib. The patient withdrew from the study and the reason for discontinuation was subject withdrawal.

[0391] • One patient dosed with 200 mg Compound A + 125 mg Palbociclib once daily experienced Grade 1 dizziness that was considered unrelated to Compound A or Palbociclib.

[0392] - One patient dosed with 500 mg Compound A + 125 mg Palbociclib once daily experienced grade 3 fatigue deemed by the investigator to be unrelated to Compound A and related to Palbociclib. The patient withdrew from the study and the reason for discontinuation was subject withdrawal.

[0393] Four patients (8.7%) experienced TEAEs that led only to discontinuation of palbociclib:

[0394] • One patient dosed with 200 mg Compound A + 125 mg palbociclib once daily experienced a grade 4 decrease in neutrophil count that the investigator considered to be possibly related to both Compound A and palbociclib.

[0395] • One patient dosed with 200 mg Compound A + 125 mg Palbociclib once daily experienced a grade 3 cerebrovascular accident that was considered unrelated to Compound A or Palbociclib.

[0396] • One patient dosed with 500 mg Compound A + 125 mg palbociclib once daily experienced a grade 4 decrease in neutrophil count that was considered by the investigator to be related to palbociclib alone.

[0397] • One patient dosed with 500 mg Compound A + 125 mg palbociclib once daily experienced a grade 3 decrease in neutrophil count that was considered by the investigator to be related to palbociclib alone.

[0398] Table 5: Compound A or Palbociclib Treatment-Related Adverse Events ≥ 10% by Preferred Term (Part C) - All-Assay Analysis Set (ARV-471-mBC-101)

[0399]

[0400] Please note: Adverse events were coded using MedDRA version 22.0.

[0401] Data cutoff: June 6, 2023 Source: BDM TAE03C: Compound A or palbociclib treatment-related adverse events ≥ 10% by preferred term (Part C) - All-Assay Analysis Set

[0402] Table 6: Compound A Treatment-Related Adverse Events in ≥10% of Patients by Preferred Term (Part C) - All-Assay Analysis Set (ARV-471-mBC-101)

[0403]

[0404] Please note: Adverse events were coded using MedDRA version 22.0.

[0405] Data Cutoff: June 6, 2023 Source: BDM TAE03C1: Compound A Treatment-Related Adverse Events ≥ 10% by Preferred Term (Part C) - All-Assay Analysis Set

[0406] Equivalent form

[0407] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described specifically herein. Such equivalents are intended to be encompassed within the scope of the following claims.

[0408] The method of the present disclosure has been described herein by reference to certain preferred embodiments. However, since certain changes thereto will become apparent to those skilled in the art based on the disclosure described herein, the present disclosure should not be considered limited thereto.

[0409] 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 the present disclosure belongs. In the specification and claims, unless the context clearly dictates otherwise, the singular also includes the plural.

[0410] It should be understood 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, while for the sake of clarity, eliminating other elements that will be understood by those of ordinary skill in the art may also comprise a portion of the present disclosure. However, since such elements are well known in the art and because the elements do not necessarily promote a better understanding of the present disclosure, a description of such elements is not provided herein.

[0411] Additionally, the specific order of steps recited in the claims should not be construed as limitations on the claims to the extent that the method does not rely on the specific order of steps set forth herein.

[0412] All patents, patent applications, references, and publications cited herein are fully and completely incorporated by reference as if set forth in their entirety. No such documents are admitted to be prior art to the present disclosure.

Claims

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

2. The method of claim 1, wherein the CDK4 / 6 inhibitor is administered simultaneously or sequentially.

3. The method 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 method 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 method according to any one of claims 1 to 4, wherein the daily dose of Compound A or a pharmaceutically acceptable salt thereof is administered once a day (QD).

6. The method according to any one of claims 1 to 5, wherein the daily dose of Compound A or a pharmaceutically acceptable salt thereof is administered orally to the subject.

7. The method according to any one of claims 1 to 6, wherein the subject is in a fed state.

8. The method according to any one of claims 1 to 7, wherein the CDK4 / 6 inhibitor is dalpiciclib, palbociclib, lerociclib, AT7519M, dinaciclib, ribociclib, abemaciclib or palbociclib or a pharmaceutically acceptable salt thereof.

9. The method of claim 8, wherein the CDK4 / 6 inhibitor is abemaciclib, ribociclib or palbociclib or a pharmaceutically acceptable salt thereof.

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

11. The method of claim 9, wherein the CDK4 / 6 inhibitor is ribociclib or a pharmaceutically acceptable salt thereof.

12. The method of claim 9, wherein the CDK4 / 6 inhibitor is palbociclib or a pharmaceutically acceptable salt thereof.

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

14. The method of 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 orally administered at a daily dose of about 600 mg once a day for 21 days in each 28-day cycle, followed by an intermittent treatment for 7 days.

15. The method of 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 orally administered once daily at 125 mg / day for 21 days in each 28-day cycle, followed by an intermittent treatment for 7 days.

16. The method of claim 1, wherein the daily dose of Compound A or a pharmaceutically acceptable salt thereof is about 200 mg in combination with abemaciclib or a pharmaceutically acceptable salt thereof, and the abemaciclib or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of about 150 mg twice a day.

17. The method of claim 1, wherein the daily dose of Compound A or a pharmaceutically acceptable salt thereof is about 100 mg in combination with ribociclib or a pharmaceutically acceptable salt thereof, wherein ribociclib or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 600 mg.

18. The method of any one of claims 1 to 17, 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 method of claim 18, wherein the cancer is breast cancer, lung cancer, prostate cancer, pancreatic cancer, or ovarian cancer.

20. The method of claim 19, wherein the cancer is breast cancer, lung cancer, or prostate cancer.

21. The method of claim 20, wherein the cancer is breast cancer.

22. The method of claim 21, wherein the breast cancer is metastatic or locally advanced.

23. The method of claim 21 or 22, wherein the breast cancer is estrogen receptor positive (ER+) breast cancer.

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

25. The method of any one of claims 1 to 24, wherein the subject is a human.

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