Dosage regimens containing KAT6 inhibitors for the treatment of cancer

Abstract

The present invention relates to a dosing regimen for the treatment of cancer comprising administering to a subject in need thereof a daily dose of a lysine acetyltransferase 6 (KAT6) inhibitor, either as a single agent or in combination with a) a cyclin-dependent kinase 4 (CDK4) inhibitor, b) an antiestrogen, or c) a CDK4 inhibitor and an antiestrogen. [Figure 1] TIFF2025533719000013.tif188121

Description

[Technical Field]

[0001] [Background technology]

[0002] KAT6A and KAT6B are histone lysine acetyltransferases that acetylate H3K23, and their enzymatic function is involved in fundamental cellular processes, including gene transcription, cellular senescence, tissue development, and the maintenance of normal hematopoietic stem cells (Huang, F. et al., Regulation of KAT6 Acetyltransferases and Their Roles in Cell Cycle Progression, Stem Cell Maintenance, and Human Disease, Mol Cell Biol. 2016, 36(14):1900-7). KAT6A has been implicated in promoting tumorigenesis in various cancers, with KAT6A amplification and overexpression observed in breast cancer, prostate cancer, ovarian cancer, cervical cancer, lung adenocarcinoma, colon and rectal adenocarcinoma, and medulloblastoma (Yu, L. et al., Identification of MYST3 as a novel epigenetic activator of ERα frequently amplified in breast cancer, Oncogene, 2017, 36(20):2910-8; Tsherniak, A. et al., Defining a cancer dependency map, Cell, 2017;170(3)(Jul):564-576.e16; Zack, T. I. et al., Pan-cancer patterns of somatic copy number alteration, Nat Genet. 2013, 45:1134-1140; and Northcott, P. A. et al., Multiple recurrent genetic events converge on the control of histone lysine methylation in medulloblastoma, Nat Genet.2009, 41(4):465~72).KAT6A chromosomal translocations have been observed in AML (see Huang F et al.; Borrow, J. et al., The translocation t(8;16)(p11;p13) of acute myeloid leukemia fuses a putative acetyltransferase to the CREB-binding protein, Nat. Genet. 1996;14(1):33-41; and Shima, H. et al., Bromodomain-PHD finger protein 1 is critical for leukemogenesis associated with MOZ-TIF2 fusion, Int J Hematol. 2014;99(1):21-31). KAT6 inhibition has therapeutic potential in multiple disease settings, including breast cancer, prostate cancer, and NSCLC.

[0003] 2-Methoxy-N-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-yl}benzene-1-sulfonamide (referred to herein as "COMPOUND A," "Compound A," or "COMPD A") is a potent and selective catalytic inhibitor of KAT6 histone acetyltransferases, KAT6A, and KAT6B. Compound A is currently in Phase I clinical trials for the treatment of cancer and has the following structure:

[0004] [ka]

[0005] The preparation of Compound A, including the anhydrous crystalline form of Compound A free acid, is described in WO 2020 / 254946. Combination therapies including Compound A are described in WO 2022 / 013369. The contents of each of the foregoing documents are incorporated herein by reference in their entirety.

[0006] Cyclin-dependent kinases (CDKs) and related serine / threonine protein kinases are important cellular enzymes that play essential roles in regulating eukaryotic cell division and proliferation. The CDK catalytic unit is activated by regulatory subunits known as cyclins. At least 16 mammalian cyclins have been identified (Johnson DG, Walker CL, Cyclins and Cell Cycle Checkpoints, Annu. Rev. Pharmacol. Toxicol. (1999) 39:295-312). Cyclin B / CDK1, cyclin A / CDK2, cyclin E / CDK2, cyclin D / CDK4, cyclin D / CDK6, and other similar heterodynes are key regulators of cell cycle progression. Additional functions of cyclin / CDK heterodynes include regulation of transcription, DNA repair, differentiation, and apoptosis (Morgan DO, Cyclin dependent kinases: engines, clocks, and microprocessors, Annu. Rev. Cell. Dev. Biol. (1997) 13:261-291).

[0007] CDK inhibitors have been demonstrated to be useful in the treatment of cancer. Hyperactivity or transient aberrant activation of cyclin-dependent kinases has been shown to lead to the development of human tumors, which are generally associated with alterations in either the CDK proteins themselves or their 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; and Hall M, Peters G., Genetic alterations of cyclins, cyclin-dependent kinases, and Cdk inhibitors in human cancer, Adv. Cancer Res. (1996) 68:67-108).

[0008] CDK4 and CDK6 are key regulators of cell cycle progression at the G1-S checkpoint, along with D-type cyclins, and p16 INK4a It is regulated by endogenous CDK inhibitors such as INK4 (CDKN2A). Dysregulation of the cyclin D-CDK4 / 6-INK4-retinoblastoma (Rb) pathway has been reported to be associated with the development of endocrine therapy resistance. Furthermore, CDK4 has been identified as a unique tumorigenic driver in many breast cancers, and emerging data suggest that cyclin D3-CDK6 inhibition is associated with hematologic toxicity, suggesting a possible role for CDK4-selective inhibitors.

[0009] Clinical trials of the CDK4 / 6 inhibitors palbociclib, ribociclib, and abemaciclib are ongoing in breast cancer and other cancers, both as monotherapy and in combination with other therapies. The use of CDK4 / 6 inhibitors in combination with endocrine therapy has shown significant efficacy in the treatment of hormone receptor (HR)-positive, human epidermal growth factor 2 (HER2)-negative advanced or metastatic breast cancer, and CDK4 / 6 inhibitors, including palbociclib, ribociclib, and abemaciclib, are approved for use in combination with endocrine therapy in the first- or second-line setting. Palbociclib, ribociclib, and abemaciclib are approved for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer in combination with aromatase inhibitors, such as letrozole, in the first-line setting and in combination with fulvestrant in the second-line or later setting for certain patients. (O'Leary et al., Treating cancer with selective CDK4 / 6 inhibitors, Nature Reviews (2016) 13:417~430).

[0010] 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 and has the following structure:

[0011] [ka]

[0012] 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. 2003 / 062236 and U.S. Patent Nos. 6,936,612, 7,456,168 and RE47,739; International Publication No. 2005 / 005426 and U.S. Patent Nos. 7,345,171 and 7,863,278; International Publication No. 2008 / 032157 and U.S. Patent No. 7,781,583; and International Publication No. 2014 / 128588. The contents of each of the above-mentioned references are incorporated herein by reference in their entirety.

[0013] The compound 1,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol (also known as "PF-07220060") is a potent and selective inhibitor of CDK4 and has the following structure:

[0014] [ka]

[0015] PF-07220060 and pharmaceutically acceptable salts thereof are disclosed in International Publication No. WO 2019 / 207463, published October 31, 2019, U.S. Patent Nos. 10,766,884 and 11,220,494, and U.S. Patent Application Publication No. 2022 / 0089580, and International Publication No. WO 2022 / 058871, published March 24, 2022, the contents of which are incorporated herein by reference in their entireties. Unless otherwise indicated, all references herein to PF-07220060 include references to salts, solvates, hydrates, and complexes thereof, and solvates, hydrates, and complexes of salts thereof, including polymorphs, stereoisomers, and isotopically labeled versions thereof.

[0016] CDK4 / 6 inhibitors have shown significant clinical efficacy in ER-positive metastatic breast cancer, but, as with other kinases, their effectiveness can be limited over time by the development of primary or acquired resistance.The selective CDK4 / 6 inhibitor palbociclib has proven clinically effective in breast cancer (DeMichele A, Clark AS, Tan KS, et al., CDK4 / 6 inhibitor palbociclib (PD-0332991) in Rb+ advanced breast cancer: phase II activity, safety, and predictive biomarker assessment, Clin Cancer Res 2015;21(5):995-1001; Finn RS, Martin M, Rugo HS, et al., Palbociclib and Letrozole in Advanced Breast Cancer, New Engl J Med 2016;375(20):1925-36; and Cristofanilli M, Turner NC, Bondarenko I, et al., Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy). Palbociclib 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 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). Summary of the Invention [Problem to be solved by the invention]

[0017] Appropriate dosing regimens for oral Compound A as monotherapy and combination therapy for treating cancer are needed to improve patient benefit and convenience while minimizing adverse events and risks to patients. [Means for solving the problem]

[0018] The present invention provides, in part, dosing regimens for administering Compound A or a pharmaceutically acceptable salt thereof to a subject as a single agent and in combination therapy to treat cancer. This Summary is provided to introduce in a simplified form a selection of concepts further described below in the Detailed Description. This Summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended for use alone as an aid in determining the scope of the claimed subject matter.

[0019] According to an embodiment of the present invention, a daily dose of about 0.1 mg to about 15 mg of

[0020] [ka] or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0021] The following describes embodiments of the present invention, but for convenience, embodiment 1 (E1) is the same as the above embodiment.

[0022] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed. [Brief explanation of the drawings]

[0023] [Figure 1]FIG. 1 shows the overall study design of an open-label, multicenter, multiple-dose Phase 1 clinical trial in adult patients to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of Compound A in locally advanced or metastatic selected solid tumors, as well as early signs of clinical efficacy of Compound A as a single agent, in combination with antiestrogen, and in combination with a CDK4 inhibitor and antiestrogen. [Figure 2A] FIG. 1 shows the median plasma concentration-time profile of Compound A on day 1 after administration of a single oral dose of Compound A alone or in combination with fulvestrant. [Figure 2B] FIG. 1 shows the median plasma concentration-time profile of Compound A on day 15 after administration of multiple oral doses of Compound A as a single agent or in combination with fulvestrant. [Figure 3] Figure 1 shows the steady-state concentration-time profile of Compound A as a single agent or in combination with fulvestrant on day 15 of cycle 1. Abbreviations: Fulv = fulvestrant, hr = hour, QD = once daily, and StD = standard deviation. [Figure 4] Figure 1 shows a waterfall plot of best percent change from baseline in target lesions by tumor type for the safety analysis set (n=22). Abbreviations: CRPC = castration-resistant prostate cancer, ERBC = ER+ / HER2- breast cancer, Fulv = fulvestrant, NSCLC = non-small cell lung cancer, PD = progressive disease, PR = partial response, QD = once daily, and SD = stable disease. DETAILED DESCRIPTION OF THE INVENTION

[0024] The present invention may be understood more readily by reference to the following detailed description of the embodiments of the invention and the examples contained herein. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0025] E1 A method for treating cancer, as defined above.

[0026] E2 2-methoxy-N-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-yl}benzene-1-sulfonamide, or a pharmaceutically acceptable salt thereof, a) cyclin-dependent kinase 4 (CDK4) inhibitors, b) anti-estrogens, or c) CDK4 inhibitors and antiestrogens The method of embodiment E1, wherein the patient is administered in combination with

[0027] E3 The method of embodiment E1 or E2, wherein the daily dose of 2-methoxy-N-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-yl}benzene-1-sulfonamide, or a pharmaceutically acceptable salt thereof, is administered once daily (QD).

[0028] E4 The method of any one of embodiments E1 to E3, wherein 2-methoxy-N-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-yl}benzene-1-sulfonamide, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 1 mg to about 15 mg QD.

[0029] E5 The method of any one of embodiments E1 to E3, wherein 2-methoxy-N-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-yl}benzene-1-sulfonamide, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 1 mg to about 8 mg QD.

[0030] E6 The method of any one of embodiments E1 to E3, wherein 2-methoxy-N-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-yl}benzene-1-sulfonamide, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 0.5 mg to about 5 mg QD.

[0031] E7 The method of any one of embodiments E1 to E3, wherein 2-methoxy-N-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-yl}benzene-1-sulfonamide, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 0.1 mg to about 8 mg QD.

[0032] E8 The method of any one of embodiments E1 to E3, wherein 2-methoxy-N-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-yl}benzene-1-sulfonamide, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 0.1 mg to less than 1 mg QD.

[0033] E9 The method of any one of embodiments E1 to E3, wherein 2-methoxy-N-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-yl}benzene-1-sulfonamide, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 0.1 mg to about 0.75 mg QD.

[0034] E10 The method of any one of embodiments E1 to E3, wherein 2-methoxy-N-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-yl}benzene-1-sulfonamide, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 0.5 mg to about 5 mg QD.

[0035] E11 The method of any one of embodiments E1 to E3, wherein 2-methoxy-N-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-yl}benzene-1-sulfonamide, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 0.5 mg QD.

[0036] E12 The method of any one of embodiments E1 to E3, wherein 2-methoxy-N-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-yl}benzene-1-sulfonamide, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 1 mg QD.

[0037] E13 The method of any one of embodiments E1 to E3, wherein 2-methoxy-N-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-yl}benzene-1-sulfonamide, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 2 mg QD.

[0038] E14 The method of any one of embodiments E1 to E3, wherein 2-methoxy-N-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-yl}benzene-1-sulfonamide, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 3 mg QD.

[0039] E15 The method of any one of embodiments E1 to E3, wherein 2-methoxy-N-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-yl}benzene-1-sulfonamide, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 4 mg QD.

[0040] E16 The method of any one of embodiments E1 to E3, wherein 2-methoxy-N-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-yl}benzene-1-sulfonamide, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 5 mg QD.

[0041] E17 The method of any one of embodiments E1 to E3, wherein 2-methoxy-N-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-yl}benzene-1-sulfonamide, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 6 mg QD.

[0042] E18 The method of any one of embodiments E1 to E3, wherein 2-methoxy-N-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-yl}benzene-1-sulfonamide, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 7 mg QD.

[0043] E19 The method of any one of embodiments E1 to E3, wherein 2-methoxy-N-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-yl}benzene-1-sulfonamide, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 8 mg QD.

[0044] E20 The method of any one of embodiments E1 to E19, wherein 2-methoxy-N-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-yl}benzene-1-sulfonamide, or a pharmaceutically acceptable salt thereof, is administered orally.

[0045] E21 The method of any one of embodiments E2 to E20, wherein the CDK4 inhibitor is a CDK4 selective inhibitor or a CDK4 / 6 inhibitor.

[0046] E22 The method of embodiment E21, wherein the CDK4 inhibitor is a CDK4 selective inhibitor.

[0047] E23 The method of embodiment E22, wherein the CDK4 selective inhibitor is 1,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol, or a pharmaceutically acceptable salt thereof.

[0048] E24 The method of embodiment E21, wherein the CDK4 inhibitor is a CDK4 / 6 inhibitor.

[0049] E25 The method of embodiment E24, wherein the CDK4 / 6 inhibitor is abemaciclib, ribociclib, or palbociclib, or a pharmaceutically acceptable salt thereof.

[0050] E26 The method of embodiment E25, wherein the CDK4 / 6 inhibitor is palbociclib, or a pharmaceutically acceptable salt thereof.

[0051] E27 The method of any one of embodiments E2 to E20, wherein the anti-estrogen agent is an aromatase inhibitor, a selective estrogen receptor degrader (SERD), or a selective estrogen receptor modulator (SERM).

[0052] E28 The method of embodiment E27, wherein the anti-estrogen is fulvestrant or letrozole.

[0053] E29 The method of embodiment E28, wherein the anti-estrogen is fulvestrant.

[0054] E30 The method of embodiment E28, wherein the anti-estrogen is letrozole.

[0055] E31 The method of any one of embodiments E1 to E30, wherein 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.

[0056] E32 The method of embodiment E31, wherein the cancer is breast cancer, lung cancer, prostate cancer, pancreatic cancer, or ovarian cancer.

[0057] E33 The method of embodiment E32, wherein the cancer is breast cancer, lung cancer, or prostate cancer.

[0058] E34 The method of embodiment E33, wherein the cancer is breast cancer.

[0059] E35 The method of embodiment E34, wherein the breast cancer is hormone receptor positive (HR+) breast cancer.

[0060] E36 The method of embodiment E35, wherein the hormone receptor positive (HR+) breast cancer is selected from the group consisting of progesterone receptor positive (PR+) breast cancer and estrogen receptor positive (ER+) breast cancer.

[0061] E37 The method of embodiment E36, wherein the breast cancer is progesterone receptor positive (PR+) breast cancer.

[0062] E38 The method of embodiment E36, wherein the breast cancer is estrogen receptor positive (ER+) breast cancer.

[0063] E39 The method of embodiment E38, wherein the estrogen receptor positive (ER+) breast cancer is human epidermal growth factor receptor 2 negative (HER2-) or the estrogen receptor positive (ER+) breast cancer is human epidermal growth factor receptor 2 positive (HER2+).

[0064] E40 The method of embodiment E39, wherein the estrogen receptor positive (ER+) breast cancer is human epidermal growth factor receptor 2 negative (HER2-).

[0065] E41 2-Methoxy-N-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-yl}benzene-1-sulfonamide, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments E1 to E40.

[0066] E42 Use of 2-methoxy-N-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-yl}benzene-1-sulfonamide, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament according to any one of embodiments E1 to E41.

[0067] Each of the embodiments described herein can be combined with any other embodiment described herein unless it is inconsistent with the embodiment with which it is combined.

[0068] definition Unless otherwise defined herein, scientific and technical terms used in connection with the present invention shall have the meanings that are commonly understood by those skilled in the art.

[0069] The invention described herein may suitably be practiced in the absence of any element not specifically disclosed herein.

[0070] As used herein, the singular forms "a," "an," and "the" include plural references unless otherwise indicated. For example, "a" substituent includes one or more substituents.

[0071] As used herein, the term "about," when used to modify a parameter defined by a numerical value (e.g., the dose of a KAT6 inhibitor), means that the parameter may vary by about 10% below or above the numerical value specified for that parameter. For example, a dose of about 5 mg means that it may vary by 5 mg ± 10%, i.e., between 4.5 mg and 5.5 mg.

[0072] As used herein, the 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 invention, specifically KAT6 inhibitors, CDK4 inhibitors, and antiestrogens.

[0073] As used herein, "KAT6 inhibitor" includes KAT6A inhibitors, KAT6B inhibitors, and KAT6A and KAT6B inhibitors. KAT6 inhibitors are disclosed in International Publication No. 2019 / 043139A1, International Publication No. 2019 / 243491A1, International Publication No. 2020 / 002587, and International Application No. PCT / IB2020 / 055667. The contents of each of the aforementioned references are incorporated herein by reference in their entirety.

[0074] Cyclin-dependent kinases (CDKs) and related serine / threonine kinases are important cellular enzymes that play essential roles in regulating cell division and proliferation. CDK inhibitors include pan-CDK inhibitors that target a wide range of CDKs, and selective CDK inhibitors that target specific CDKs.

[0075] As used herein, "CDK4 inhibitor" includes CDK4 selective inhibitors and CDK4 / 6 inhibitors. CDK4 selective inhibitors are disclosed in International Publication No. 2019 / 207463. Examples of CDK4 / 6 inhibitors include, but are not limited to, abemaciclib, ribociclib, and palbociclib. Further examples of CDK4 / 6 inhibitors include relociclib (also known as G1T38) and trilaciclib (also known as GTI128).

[0076] In one embodiment, a CDK4 selective inhibitor of the present invention comprises 1,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol, or a pharmaceutically acceptable salt thereof.

[0077] In one embodiment, the CDK4 / 6 inhibitor of the present invention comprises palbociclib. Unless otherwise indicated herein, palbociclib (also referred to herein as "palbo" or "Palbo") refers to 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof.

[0078] As used herein, "endocrine therapy" refers to an aromatase inhibitor, a selective estrogen receptor degrader (SERD), or a selective estrogen receptor modulator (SERM). In certain embodiments, endocrine therapy includes fulvestrant, tamoxifen, toremifene, anastrozole, exemestane, or letrozole.

[0079] The term "antiestrogen" as used herein refers to a class of drugs that prevent estrogens, such as estradiol, from mediating biological effects in the body.Antiestrogens act by blocking estrogen receptors (ER) and / or inhibiting or suppressing estrogen production.In other embodiments, the antiestrogen is an aromatase inhibitor, a selective estrogen receptor degrader (SERD), or a selective estrogen receptor modulator (SERM).Examples of aromatase inhibitors include, but are not limited to, anastrozole.Examples of SERDs include, but are not limited to, fulvestrant. Other SERDs include elacestrant (RAD-1901, Radius Health), SAR439859 (Sanofi), RG6171 (Roche), AZD9833 (AstraZeneca), AZD9496 (AstraZeneca), lintodestrant (G1 Therapeutics), ZN-c5 (Zentalis), LSZ102 (Novartis), D-0502 (Inventisbio), LY3484356 (Lilly), and SHR9549 (Jiansu Hengrui Medicine).Examples of SERMs include, but are not limited to, tamoxifen, clomiphene, and raloxifene.Other SERMs include toremifene, lasofoxifene, bazedoxifene, and afimoxifene.

[0080] In one embodiment, aromatase inhibitors include letrozole, exemestane, and anastrozole.In one embodiment, SERMs include tamoxifen, clomiphene, and raloxifene.

[0081] In one embodiment, antiestrogen agents of the present invention include fulvestrant and letrozole. In one embodiment, antiestrogen agents of the present invention include fulvestrant. In one embodiment, antiestrogen agents of the present invention include letrozole.

[0082] Another embodiment pertains to pharmaceutically acceptable salts of the compounds described herein. Pharmaceutically acceptable salts of the compounds described herein include acid addition and base addition salts thereof.

[0083] Another embodiment also relates 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 acetate, acid citrate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, bitartrate, borate, camsylate, citrate, cyclamate, edisylate, esylate, ethanesulfonate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybenzate, hydrochloride / chloride, hydrobromide / bromide, and hydroiodide. The salts include, but are not limited to, acid salt / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methanesulfonate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, p-toluenesulfonate, tosylate, trifluoroacetate, and xinofoate.

[0084] Another embodiment relates 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, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, and zinc salts.

[0085] The compounds described herein that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. Acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds described herein are those that form non-toxic acid addition salts, e.g., 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 salts [i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)]. The compounds described herein that include a basic moiety, such as an amino group, can form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above.

[0086] Chemical bases that can be used as reagents to prepare pharmaceutically acceptable base salts of compounds described herein that are acidic in nature are those that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to, those derived from pharmacologically acceptable cations, such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-soluble amine addition salts, such as N-methylglucamine (meglumine), and lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines.

[0087] Hemi-salts of acids and bases may also be formed, for example, hemisulfate and hemicalcium salts.

[0088] For a review of suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002). Methods for making pharmaceutically acceptable salts of the compounds described herein are known to those skilled in the art.

[0089] Administration and Dosage "Treating" or "treating" cancer and / or cancer-related diseases, as used herein, means administering a monotherapy or combination therapy according to the present invention to a subject, participant, or patient having or diagnosed with cancer to achieve at least one positive therapeutic effect, such as a reduction in cancer cell count, a reduction in tumor size, a reduction in the rate of cancer cell invasion into peripheral organs, or a reduction in the rate of tumor metastasis or tumor growth, a reversal, alleviation, inhibition, or prevention of the progression of the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The terms "treatment" or "therapy," as used herein, unless otherwise indicated, refer to the act of treatment as defined immediately above as "treating." For purposes of this invention, beneficial or desirable clinical results include, but are not limited to, one or more of the following: reducing (or destroying) the proliferation of neoplastic or cancerous cells, inhibiting metastasis or neoplastic cells, shrinking or reducing tumor size, cancer remission, reducing symptoms caused by cancer, improving the quality of life of people with cancer, reducing the dose of other drugs required to treat cancer, delaying cancer progression, curing cancer, overcoming one or more resistance mechanisms in cancer, and / or extending the survival of cancer patients. Positive therapeutic effects in cancer can be measured in several ways (see, e.g., W.A. Weber, J. Nucl. Med. 50:1S-10S (2009)).

[0090] As used herein, the terms "subject," "participant," and "patient" are used interchangeably to refer to a human. A human subject can be of either gender. In one embodiment, the human is an adult.

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

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

[0093] Embodiments of the present invention provide doses, administration amounts, and dosing regimens that include administering to a subject an amount or therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof. The amount or therapeutically effective amount can be a daily dose ranging from about 0.1 mg to about 15 mg. In another embodiment, the daily dose is about 1 mg to about 15 mg, the daily dose is about 1 mg to about 10 mg, about 1 mg to about 8 mg, about 0.1 mg to about 8 mg, about 1 mg to about 5 mg, about 0.1 mg to about 5 mg, or about 0.5 mg to about 5 mg. In another embodiment, the daily dose is about 0.1 mg to less than 1 mg, or about 0.1 mg to about 0.75 mg. In a preferred embodiment, the daily dose is about 0.5 mg, 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, or about 8 mg. In a preferred embodiment, the daily dose is about 0.5 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, or about 5 mg. In a preferred embodiment, the daily dose is 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, or 8 mg. In a preferred embodiment, the daily dose is 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, or 5 mg.

[0094] In another embodiment, Compound A or a pharmaceutically acceptable salt thereof, alone or in combination with an antiestrogen, is administered orally in a subject at a dose of, for example, 2 mg, 5 mg, 8 mg, or 15 mg of Compound A per day, to achieve a peak steady-state plasma concentration (C max ) can be administered in an amount sufficient to achieve a concentration of 400 to 13,000 ng / mL, e.g., 500 to 700 ng / mL, 1,400 to 2,800 ng / mL, 2,000 to 4,400 ng / mL, or 4,000 to 12,000 ng / mL.

[0095] In another embodiment, Compound A or a pharmaceutically acceptable salt thereof, alone or in combination with an antiestrogen, is effective in increasing the peak plasma concentration at steady state (C max ) is 400 to 13,000 ng / mL, for example, 500 to 700 ng / mL, 1,400 to 2,800 ng / mL, 2,000 to 4,400 ng / mL, or 4,000 to 12,000 ng / mL. In this embodiment, Compound A is administered at a daily dose of about 1 mg to about 15 mg. In this embodiment, Compound A is administered at a daily dose of 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, or 8 mg.

[0096] In a preferred embodiment, a daily dose of Compound A or a pharmaceutically acceptable salt thereof is administered once daily (QD).

[0097] The compounds of the present invention can be administered orally either by swallowing, so that the compound enters the gastrointestinal tract, or by employing buccal or sublingual administration by which the compound enters the blood stream directly from the mouth.

[0098] In a preferred embodiment, a daily dose of Compound A or a pharmaceutically acceptable salt thereof is administered orally.

[0099] Compound A or a pharmaceutically acceptable salt can be present in a pharmaceutical composition containing a pharmaceutically acceptable excipient. "Pharmaceutically acceptable excipient" refers to a component that can be included in the compositions described herein, and refers to a component that is physiologically suitable for pharmaceutical use and does not cause significant adverse effects or therapeutic effects in subjects. The term "excipient" is used herein to describe any component other than the compound of the present invention. The selection of an excipient will largely depend on factors such as the mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

[0100] The amount of Compound A or a pharmaceutically acceptable salt in the pharmaceutical composition can be any amount disclosed herein.

[0101] The compound of the method, use or combination of the present invention can be formulated before administration.Preferably, the formulation is adapted to specific administration mode.These compounds can be formulated with pharmaceutically acceptable excipients known in the art and administered in a variety of dosage forms known in the art.The unit dosage form or pharmaceutical composition suitable for oral administration includes but is not limited to tablets, capsules such as gelatin capsules, pills, powders, granules, aqueous and non-aqueous oral solutions and suspensions, which are packaged in suitable containers for dividing into individual doses.

[0102] In another embodiment, the dosage of the compound or pharmaceutical composition described herein can vary within a range depending on the dosage form used.In another embodiment, the amount of the compound or pharmaceutical composition described herein administered to a subject can depend on factors known to those skilled in the art.In addition, it will be understood that the specific dosage of the pharmaceutical composition comprising the compound described herein can depend on various factors, including the subject's physical condition (e.g., age, sex, weight) and the subject's medical history (e.g., medications being taken, health condition, other diseases or disorders).

[0103] In one embodiment, palbociclib or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 125 mg once daily, about 100 mg once daily, about 75 mg once daily, about 50 mg once daily, or about 25 mg once daily. In an embodiment that is the recommended starting dose, palbociclib or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 125 mg once daily. For example, palbociclib or a pharmaceutically acceptable salt thereof is administered at a dose of about 100 mg once daily, about 75 mg once daily, or about 50 mg once daily. In one embodiment, palbociclib or a pharmaceutically acceptable salt thereof is administered at a dose of about 100 mg once daily. In one embodiment, palbociclib or a pharmaceutically acceptable salt thereof is administered at a dose of about 75 mg once daily. In one embodiment, palbociclib or its pharmaceutically acceptable salt is administered at a dose of about 50mg once a day.The dosage provided herein refers to the dosage of palbociclib free base form or is calculated as the free base equivalent of the administered palbociclib salt form.For example, the dosage or amount of palbociclib such as 100mg, 75mg or 50mg refers to the free base equivalent.

[0104] In one embodiment, 1,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol, or a pharmaceutically acceptable salt thereof, is administered at a daily dose of about 1 mg to about 1000 mg per day. In another embodiment, the CDK4 inhibitor is administered at a daily dose of about 10 mg to about 500 mg per day. In another embodiment, the CDK4 inhibitor is administered at a dose of about 25 mg to about 300 mg per day, preferably on a BID schedule. In another embodiment, the CDK4 inhibitor is administered at a dose of about 100 mg to about 300 mg per day, preferably on a BID schedule. In another embodiment, the CDK4 inhibitor is administered at a dose of about 100 mg on a BID schedule. In another embodiment, the CDK4 inhibitor is administered at a dose of about 300 mg on a BID schedule. In another embodiment, the CDK4 inhibitor is administered at a dose of about 1, about 2, about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, about 100, about 105, about 110, about 115, about 120, about 125, about 130, about 135, about 140, about 145, about 150, about 160, about 170, about 180, about 190, about 210, about 220, about 230, about 240, about 250, about 260, about 270, about 280, about 290, about 310, about 320, about 330, about 340, about 350, about 360, about 370, about 380, about 390, about 410, about 420, about 430, about 440, about 450, about 460, about 470, about 480, about 490, about 510, about 520, about 530, about 540, about 550, about 560, about 570, about 580, about 590, about 610, about 611, about 620, about 630, about 640, about 65 about 55, about 160, about 165, about 170, about 175, about 180, about 185, about 190, about 195, about 200, about 205, about 210, about 215, about 220, about 225, about 230, about 235, about 240, about 245, about 250, about 260, about 270, about 275, about 280, about 290, about 300, about 325, about 350, about 375, about 400, about 425, about 450, about 475, or about 500 mg.

[0105] Repeated administration or administration regimens can be performed as needed to achieve the desired reduction or shrinkage of cancer cells. As used herein, a "continuous administration schedule" refers to an administration or administration regimen without a break in administration, e.g., without days off treatment. Repeated 28-day treatment cycles without a break in administration between treatment cycles is an example of a continuous administration schedule. In one embodiment, the compounds of the combination of the present invention can be administered in a continuous administration schedule. In one embodiment, the compounds of the combination of the present invention can be administered concurrently in a continuous administration schedule.

[0106] In one embodiment, 2-methoxy-N-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-yl}benzene-1-sulfonamide, or a pharmaceutically acceptable salt thereof, is administered once daily to constitute a complete 28-day cycle, with recurrence of the 28-day cycle continuing throughout treatment with the combination of the present invention.

[0107] The standard recommended dosing regimen for palbociclib or a pharmaceutically acceptable salt thereof comprises a standard dosing schedule of once daily administration for 21 consecutive days, followed by 7 days off treatment, constituting a complete 28-day cycle, with repetition of the 28-day cycle continuing throughout treatment with the combination of the present invention.

[0108] The standard clinical dosing regimen for palbociclib or a pharmaceutically acceptable salt thereof is 125 mg administered once daily for 21 consecutive days, followed by 7 days off treatment, constituting a complete 28-day cycle, with repeated 28-day cycles continuing throughout treatment with the combination of the present invention.

[0109] In a further embodiment of the invention, 2-methoxy-N-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-yl}benzene-1-sulfonamide, or a pharmaceutically acceptable salt thereof, is administered in combination with palbociclib and letrozole, wherein palbociclib is administered orally at 125 mg once daily for 21 days followed by 7 days off, and letrozole is administered orally at 2.5 mg daily.

[0110] The present invention also relates to kits comprising a combination therapeutic agent of the present invention and written instructions for administering the therapeutic agents. In one embodiment, the written instructions detail and limit the mode of administration of the therapeutic agents, e.g., for simultaneous or sequential administration of the therapeutic agents of the present invention. In one embodiment, the written instructions detail and limit the mode of administration of the therapeutic agents, e.g., by specifying the number of days each therapeutic agent is administered during a 28-day cycle.

[0111] Treatment method In one embodiment, the present disclosure provides a method for treating cancer in a subject in need thereof, comprising administering to the subject an amount of Compound A described herein. In another embodiment, the present disclosure also provides a method for treating cancer in a subject, comprising administering to the subject an amount of Compound A described herein in combination with: a) an amount of a cyclin-dependent kinase 4 (CDK4) inhibitor; b) an amount of an antiestrogen; or c) an amount of a CDK4 inhibitor and an amount of an antiestrogen.

[0112] The term "combination," as used herein, unless otherwise indicated, refers to a fixed-dose combination of drugs, or a combination of drugs administered intermittently, in parallel, or sequentially, according to the same or different administration routes and according to the same or different dosage schedules. As used herein, an "effective" or "therapeutically effective" amount refers to an amount of a drug, compound, or composition, alone or in combination with other drugs, as a single dose or according to a multiple-dose regimen, sufficient to reduce the severity of disease symptoms, increase the frequency and duration of disease symptom-free periods, or prevent damage or disability caused by disease affliction. One skilled in the art would be able to determine such amounts based on factors such as the size of the patient, the severity of the patient's symptoms, and the specific combination, composition, or administration route selected. The patient or subject may be a human or non-human mammal in need of treatment. In one embodiment, the patient is a human.

[0113] The term "locally advanced," as used herein, refers to cancer that may or may not be treated with curative intent. The term "metastatic," as used herein, refers to cancer that may not be treated with curative intent. One skilled in the art would be able to recognize and diagnose locally advanced and metastatic cancer in a patient.

[0114] For convenience, several 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). The abbreviations ER+HER2-, ER+ HER2-, and ER+ / HER2- are equivalent and interchangeable when they relate to the indication of breast cancer.

[0115] In one embodiment, the cancer is selected from the group consisting of lung cancer, mesothelioma, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, 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 gland cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, hematological malignancies, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumors, glioblastoma, brain stem glioma, pituitary adenoma, head and neck cancer, or a combination of two or more of the foregoing cancers.

[0116] Another embodiment relates to a method of treating cancer in a patient, comprising administering to the patient a compound described herein in an amount effective to treat the cancer.

[0117] In one embodiment, the cancer is breast, lung, colon, brain, head and neck, prostate, stomach, pancreatic, ovarian, melanoma, endocrine, uterine, testicular, or bladder cancer.

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

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

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

[0121] In one embodiment, the breast cancer is HR+ breast cancer.

[0122] In one embodiment, the HR+ breast cancer is PR+ and / or ER+ breast cancer.

[0123] In one embodiment, the breast cancer is PR+ breast cancer.

[0124] In one embodiment, the breast cancer is ER+ breast cancer.

[0125] In one embodiment, the breast cancer is ER+ HER2- breast cancer.

[0126] In one embodiment, the breast cancer is ER+ HER2+ breast cancer.

[0127] In one embodiment, the breast cancer is locally advanced or metastatic ER+ breast cancer.

[0128] In one embodiment, the breast cancer is locally advanced or metastatic ER+ HER2- breast cancer.

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

[0130] In one embodiment, the lung cancer is non-small cell lung cancer.

[0131] In one embodiment, the lung cancer is locally advanced or metastatic non-small cell lung cancer.

[0132] In one embodiment, the prostate cancer is castration-resistant prostate cancer.

[0133] In one embodiment, the prostate cancer is locally advanced or metastatic castration-resistant prostate cancer.

[0134] Another embodiment relates to a method of treating a solid tumor in a patient, comprising administering to the patient a compound described herein in an amount effective to treat the solid tumor.

[0135] In one embodiment, the solid tumor is a breast, lung, colon, brain, head and neck, prostate, stomach, pancreatic, ovarian, melanoma, endocrine, uterine, testicular, or bladder solid tumor.

[0136] In one embodiment, the solid tumor is a breast, lung, prostate, pancreatic, or ovarian solid tumor.

[0137] In one embodiment, the solid tumor is a breast, lung, or prostate solid tumor.

[0138] In one embodiment, the solid tumor is breast cancer, in a further embodiment the breast cancer is HR+ breast cancer, and in yet a further embodiment the HR+ breast cancer is PR+ and / or ER+ breast cancer.

[0139] In one embodiment, the solid tumor is breast cancer, and in a further embodiment, the breast cancer is ER+ HER2- breast cancer.

[0140] In one embodiment, the solid tumor is breast cancer, and in a further embodiment, the breast cancer is ER+ HER2+ breast cancer.

[0141] In one embodiment, the solid tumor is breast cancer, and in a further embodiment, the breast cancer is locally advanced or metastatic ER+ HER2- breast cancer.

[0142] In one embodiment, the solid tumor is breast cancer, and in a further embodiment, the breast cancer is locally advanced or metastatic ER+ HER2+ breast cancer.

[0143] In one embodiment, the solid tumor is lung cancer, and in a further embodiment, the lung cancer is non-small cell lung cancer.

[0144] In one embodiment, the solid tumor is lung cancer, and in a further embodiment, the lung cancer is locally advanced or metastatic non-small cell lung cancer.

[0145] In one embodiment, the solid tumor is prostate cancer, and in a further embodiment, the prostate cancer is castration-resistant prostate cancer.

[0146] In one embodiment, the solid tumor is prostate cancer, and in a further embodiment, the prostate cancer is locally advanced or metastatic castration-resistant prostate cancer.

[0147] Another embodiment relates to a method of treating a hematological tumor in a patient, comprising administering to the patient a compound described herein in an amount effective to treat the hematological tumor.

[0148] In one embodiment, the hematological tumor is leukemia, lymphoma, or multiple myeloma.

[0149] In one embodiment, the hematological tumor is a leukemia or lymphoma.

[0150] Another embodiment relates to a method of treating cancer in patients with locally advanced or metastatic ER+HER2- breast cancer, CRPC, or NSCLC who have progressed on or are intolerant to standard therapy.

[0151] Another embodiment relates to a method of treating cancer in patients with locally advanced or metastatic ER+HER2- breast cancer, CRPC, or NSCLC who have progressed on or are intolerant to standard therapy.

[0152] Another embodiment relates to a method of treating cancer in patients with locally advanced or metastatic 2L+ ER+ HER2 breast cancer that has progressed after at least one line of prior endocrine therapy and a CDK4 / 6 inhibitor, in which the patient is administered a combination of Compound A and fulvestrant.

[0153] Another embodiment is a method of treating cancer in patients with locally advanced or metastatic 2L+ ER+ HER2 breast cancer that has progressed after at least one line of prior endocrine therapy and a CDK4 / 6 inhibitor, in which the patient is administered Compound A in combination with letrozole and palbociclib.

[0154] Another embodiment relates to a method of treating cancer in patients with advanced or metastatic 2L+ ER+ HER2- breast cancer that has progressed after at least one line of prior CDK4 / 6 inhibitor and one line of endocrine therapy. In this embodiment, the patient is administered Compound A.

[0155] Another embodiment relates to a method of treating cancer in patients with advanced or metastatic 2-4L fulvestrant-naive ER+ HER2- breast cancer whose disease has progressed after one line of CDK4 / 6 inhibitor and one line of endocrine therapy and who should not receive more than three lines of systemic therapy in the advanced or metastatic setting. In this embodiment, the patient is administered Compound A and fulvestrant. [Example]

[0156] In order that the present invention may be better understood, the following examples are set forth, which are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way.

[0157] Phase 1 Compound A Clinical Trial overview Compound A is being investigated in an ongoing, open-label, multicenter, multiple-dose Phase 1 study in adult patients to evaluate the safety, tolerability, PK, and PD of Compound A, as well as early signs of clinical efficacy of Compound A as a single agent, in combination with antiestrogen, and in combination with a CDK4 inhibitor and antiestrogen, in locally advanced or metastatic selected solid tumors (ER+ HER2- breast cancer, CRPC, or NSCLC). Patients in this study are intolerant or resistant to standard therapy.

[0158] Study Design: The overall study design is shown in Figure 1. The study included two parts: dose escalation (Part 1) followed by dose expansion (Part 2). Parts 1D and 2D, not shown in Figure 1, are additional arms of Parts 1 and 2 in the study design and are described below.

[0159] As of the data cutoff date of March 23, 2022, 31 participants had been treated with Compound A and early signs of Compound A's clinical efficacy had been observed.

[0160] Example 1 Pharmacokinetic (PK) study - Data cutoff date: March 23, 2022 Compound A was orally administered at 2 mg, 5 mg, 8 mg, and 15 mg QD alone or 5 mg QD in combination with 500 mg of fulvestrant.

[0161] Figure 2A shows the median plasma concentration-time profiles of Compound A on day 1 after administration of a single oral dose of 2 mg, 5 mg, 8 mg, and 15 mg QD of Compound A alone, and in combination with 5 mg QD and 500 mg of fulvestrant. Figure 2B shows the median plasma concentration-time profiles of Compound A on day 15 after administration of multiple oral doses of 2 mg, 5 mg, 8 mg, and 15 mg QD of Compound A alone, and in combination with 5 mg QD and 500 mg of fulvestrant.

[0162] Preliminary pharmacokinetic parameters were available for 23 participants after the first oral dose (Day 1 of Cycle 1) and at steady state (Day 15 of Cycle 1) and are shown in Table 1.

[0163] [Table 1]

[0164] After repeated daily administration up to day 15, Compound A max Compound A was absorbed within a median time of 3 hours. After repeated daily administration, Compound A accumulated with an Rac ranging from 2.3 to 5.8. When administered alone or in combination with fulvestrant at doses ranging from 2 mg to 15 mg, Compound A exposure, i.e., AUC 24increased proportionally with increasing dose. The apparent clearance (CL / F) at each dose level was similar, suggesting that the pharmacokinetics of Compound A was linear and that there was no obvious drug-drug interaction between Compound A and fulvestrant. The inter-patient variability of the drug was low to moderate, i.e., AUC 24 The CV% of C on Day 15 of Cycle 1 ranged from 9.7% to 43.2%. max The CV% ranged from 12.6% to 43.2%.

[0165] Example 1A Pharmacokinetic (PK) study - Data cutoff date: September 30, 2022 Compound A was orally administered at 1 mg, 2 mg, 5 mg, 8 mg, and 15 mg QD alone or 5 mg QD in combination with 500 mg of fulvestrant.

[0166] As of the data cutoff date of September 30, 2022, a total of 29 participants had evaluable PK concentration data in Parts 1A and 1B. Of these participants, 2 in the 1 mg QD group were excluded from the Day 15 summary of Cycle 1 due to dose interruptions that affected PK analysis or sample collection after the data cutoff date.

[0167] Figure 3 shows the steady-state concentration-time profile of Compound A on Day 15 of Cycle 1. The PK of Compound A was linear between the 1 mg and 15 mg QD dosing regimens, as shown in Figure 3, and steady-state was achieved by Day 15 of Cycle 1. Steady-state concentrations were significantly higher at C eff Target values ​​(defined from preclinical models) were near or exceeded.

[0168] Example 2 Safety and Efficacy - Data Cut-off Date March 23, 2022 As of the data cutoff date of March 23, 2022, the safety and efficacy of Compound A are being evaluated in an ongoing first-in-human Phase 1 study. Overall, 31 participants have been treated with Compound A. Dose tapers in monotherapy are ongoing (Part 1A), and the recommended dose expansion (RDE) in monotherapy has been identified as 5 mg QD, with Part 1B ongoing. The RDE in combination with fulvestrant has also been identified as 5 mg QD, with dose expansion ongoing (Part 2B).

[0169] I. Study Design Part 1 (dose escalation) Part 1 dose escalation is further divided into Part 1A, Part 1B, Part 1C, and Part 1D.

[0170] Part 1A (monotherapy dose escalation) included dose escalation as monotherapy in patients with locally advanced or metastatic ER+HER2- breast cancer, CRPC, or NSCLC who are resistant or intolerant to standard therapy, or for whom standard therapy is unavailable, to determine the maximum tolerated dose (MTD) and select the RDE. Participants received Compound A orally in escalating doses starting at 8 mg QD. A two-parameter Bayesian logistic regression model (BLRM) was used for dose finding.

[0171] In Part 1B (combination dose escalation), compound A in combination with fulvestrant was evaluated for dose-finding in patients with locally advanced or metastatic ER+ HER2- breast cancer (2L+) who had progressed after at least one line of endocrine therapy and a CDK4 / 6 inhibitor to determine the MTD and RDE of this combination. The RDE of the combination may differ from that of monotherapy due to potential overlapping toxicities. A 5-parameter BLRM was used for dose-finding.

[0172] Part 1C (combination dose escalation) will evaluate dose-finding of compound A in combination with letrozole plus palbociclib in patients with locally advanced or metastatic ER+ HER2- breast cancer (2L+) that has progressed after at least one line of endocrine therapy and a CDK4 / 6 inhibitor to determine the MTD and RDE of this combination.

[0173] Part 1D (combination dose escalation) will evaluate dose-finding of compound A in combination with fulvestrant + PF-07220060 in patients with locally advanced or metastatic ER+ HER2- breast cancer (2L+) that has progressed after at least one line of endocrine therapy and a CDK4 / 6 inhibitor to determine the MTD and RDE of this combination.

[0174] Dose-finding in Parts 1B, 1C, and 1D will use BLRMs specifically developed for double- and triple-drug combinations.

[0175] Part 2 (dose expansion) Part 2A (ER+HER2- breast cancer 2L+, monotherapy): After selecting a monotherapy RDE in Part 1A, patients with locally advanced or metastatic ER+HER2- breast cancer (2L+) who have progressed after at least one line of prior CDK4 / 6 inhibitor and one line of endocrine therapy will be evaluated in a dose-expansion cohort with Compound A as monotherapy.

[0176] Part 2B (ER+ HER2- breast cancer 2-4L, fulvestrant-naive, in combination with fulvestrant): After determining the combination RDE from Part 1B, patients with advanced or metastatic 2-4L fulvestrant-naive ER+ HER2- breast cancer whose disease has progressed after 1 line of CDK4 / 6 inhibitor and 1 line of endocrine therapy and who have not received >3 lines of systemic therapy in the advanced or metastatic setting will be evaluated in a dose-expansion combination cohort with Compound A in combination with fulvestrant.

[0177] Part 2D (ER+ HER2- breast cancer 2-4L, in combination with PF-07220060 and fulvestrant): After determining the combination RDE from Part 1D, patients with advanced or metastatic ER+ HER2- breast cancer whose disease has progressed after 1 line of CDK4 / 6 inhibitor and 1 line of endocrine therapy and who have not received >3 lines of systemic therapy, including up to 1 line of cytotoxic chemotherapy for visceral disease in the advanced or metastatic setting, will be evaluated in a dose-expansion combination cohort using Compound A in combination with fulvestrant + PF-07220060.

[0178] As of March 23, 2022, 31 participants have been treated with Compound A in dose escalation (Part 1) and dose expansion (Part 2).

[0179] Administration method Based on preclinical data, Compound A has a low plasma CL of approximately 0.1 mL / min / kg and a low V of approximately 0.1 L / kg. ss It is predicted that t 1 / 2 The oral bioavailability was high, making it suitable for QD administration in humans.

[0180] Compound A was orally administered at escalating doses of 2, 5, 8, and 15 mg QD alone or in combination with fulvestrant at 5 mg QD. Compound A was orally administered at 1 mg QD alone or in combination with fulvestrant at 5 mg QD. Compound A was orally administered at doses of 0.5 mg, 1 mg, 2 mg, and 5 mg QD in combination with a fixed dose of fulvestrant and various doses of PF-07220060. Compound A can be initiated at one dose level below the monotherapy RDE (RDE-1) using a fixed dose of fulvestrant or letrozole plus palbociclib and various doses of PF-07220060.

[0181] Additionally, depending on safety findings in Part 1A, the starting dose of Compound A in the combination may be further modified to a lower dose.

[0182] Participants were required to swallow Compound A tablets whole and were not permitted to manipulate or chew the study intervention before swallowing. Compound A was administered by mouth QD continuously in all cohorts. One daily dose was administered 24 ± 3 hours apart (i.e., no less than 21 hours and no more than 27 hours apart). All cycles were 28 days in length.

[0183] Fulvestrant 500 mg was administered intramuscularly as two 5 mL injections, one into each buttock, slowly (1–2 min per injection) in the buttocks, according to the product label and depending on local prescribing information, and then monthly thereafter.

[0184] Letrozole was administered orally at 2.5 mg once daily (QD) on a daily dosing schedule according to the product label and depending on local prescribing information.

[0185] Palbociclib was administered orally at 125 mg / day once daily for 21 days, followed by 7 days off treatment, in each 28-day cycle, according to the product label and depending on local prescribing information.

[0186] PF-07220060 was administered orally at 100 mg or 300 mg twice daily (BID).

[0187] Treatment will continue until disease progression, uncontrollable toxicity, patient or investigator decision to discontinue treatment, or end of study.

[0188] Patients who experience toxicity, including dose-limiting toxicity (DLT), will be managed by dose modification or discontinuation of treatment.

[0189] Definition: As used herein, "dose-limiting toxicity" (DLT) refers to the dose of Compound A at which further dose escalation is contraindicated. In the monotherapy dose escalation (Part 1A) and combination dose escalation (Parts 1B and 1C), the following adverse events (AEs) occurring during the first cycle (28 days) of treatment and attributed to Compound A or any concomitant therapy, if applicable, were classified as DLTs:

[0190] Hematologic dose-limiting toxicities:

[0191] Any grade 4 or higher hematological AE potentially related to treatment is a DLT, as described below. Grade 4 neutropenia is a DLT regardless of intervention. Febrile neutropenia (defined as an absolute neutrophil count (ANC) less than 1000 / mm³ and a single temperature greater than 38.3°C [101°F] or a temperature greater than 38°C [100.4°F] sustained for more than 1 hour) is a DLT. Grade 3 neutropenia with infection is a DLT. Grade 3 neutropenia lasting more than 7 days is a DLT. Grade 4 thrombocytopenia is a DLT. Grade 3 thrombocytopenia associated with bleeding or requiring platelet transfusion is a DLT. Grade 4 anemia is a DLT. Grade 3 anemia requiring transfusion is a DLT.

[0192] Non-hematologic dose-limiting toxicities:

[0193] Any grade 3 or higher non-hematologic AE potentially related to treatment is a DLT, as described below. Grade 3 or greater nausea, vomiting, or diarrhea lasting 3 days or more despite appropriate antiemetics and other supportive care is a DLT. Grade 3 or higher fatigue lasting 5 days or more is a DLT. Confirmed drug-induced liver injury (DILI) that meets the criteria of Hy's Law is a DLT. In participants with baseline grade 2 liver transaminase or alkaline phosphatase levels as a result of liver or bone metastases, an aspartate aminotransferase (AST) or alanine aminotransferase (ALT) level greater than 8 times the upper limit of normal (ULN), or an AST or ALT level greater than 5 times the ULN for 14 days or more, is considered a DLT. Clinically significant or persistent toxicities not included in the above criteria (e.g., toxicities that cause significant dosing delays) may also be considered DLTs after review by the investigator and sponsor. All DLTs must demonstrate a clinically significant change from baseline. Grade 3 or greater QTc prolongation is a DLT. Grade 3 or greater anaphylaxis is a DLT.

[0194] Any toxicity that causes a dose delay of more than 2 weeks is a DLT. Additionally, any grade 5 AE (death) not clearly attributable to the underlying disease or other etiology is a DLT.

[0195] Any dose reduction due to a treatment-related AE (per protocol) during the first 28 days will qualify as the participant experiencing a DLT.

[0196] As used herein, "maximum tolerated dose" (MTD) refers to the highest dose of Compound A that does not cause unacceptable side effects or intolerable toxicity. The MTD is defined as the dose that has a true DLT probability from the target toxicity interval. The target interval for DLT probability is defined as (0.16, 0.33).

[0197] II. Safety Dose-limiting toxicity (DLT) Patients were classified as DLT-evaluable if they experienced a DLT or if they received >75% of the planned dose and underwent all scheduled safety assessments during the DLT evaluation period. As of March 23, 2022, 19 patients were treated with monotherapy dose escalation: six participants at 15 mg QD, seven at 8 mg QD, four at 5 mg QD, and two at 2 mg QD. Four participants were treated with the combination dose escalation of 5 mg QD + fulvestrant. Three dose-limiting toxicities (DLTs) were reported during the study: one DLT was reported with 2 mg QD (monotherapy escalation), one DLT was reported with 8 mg QD (monotherapy escalation), and one DLT was reported with 5 mg QD + fulvestrant (combination escalation).

[0198] All three DLTs were grade 3 neutropenia (decreased neutrophil count).

[0199] Adverse events Adverse events (AEs) in patients receiving Compound A in Phase 1 clinical trials were coded according to the Medical Dictionary for Clinical Evaluation of Reproductive Health (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.

[0200] Treatment-emergent adverse events, regardless of causality As of March 23, 2022, 31 patients receiving Compound A experienced at least one treatment-emergent adverse event (TEAE). The most common TEAEs occurring in 20% or more of patients were dysgeusia (N=26, 83.9%), anemia (N=17, 54.8%), decreased neutrophil count / neutropenia (N=16, 51.6%), diarrhea (N=11, 35.5%), increased aspartate aminotransferase and decreased white blood cell count (N=9, 29.0% each), increased alanine aminotransferase and fatigue (N=8, 25.8%), and decreased platelet count (N=7, 22.6%).

[0201] Grade 3 TEAEs, regardless of causality, included decreased neutrophil count / neutropenia (N=9, 29.1%), anemia (N=5, 16.1%), decreased white blood cell count (N=3, 9.7%), increased alanine aminotransferase, decreased lymphocyte count, and hypotension (N=2, 6.5%), diarrhea, fatigue, thrombocytopenia, urinary tract infection, hematuria, anaphylactic reaction, COVID-19, embolism, flank pain, and pulmonary embolism (N=1, 3.2%).

[0202] One grade 4 (hypercalcemia) and one grade 5 (pneumonitis) TEAE (N=1, 3.2%) were reported.

[0203] Treatment-emergent adverse events As of March 23, 2022, 31 patients receiving Compound A experienced at least one treatment-related adverse event (TRAE). The most common TRAEs occurring in 20% or more of patients were dysgeusia (N=25, 80.6%), anemia (N=17, 54.8%), decreased neutrophil count / neutropenia (N=16, 51.6%), diarrhea and decreased white blood cell count (N=9, 29.0%), and decreased platelet count (N=7, 22.6%).

[0204] Grade 3 treatment-related AEs included decreased neutrophil count / neutropenia (N=9, 29.1%), anemia (N=5, 16.1%), decreased white blood cell count (N=3, 9.7%), diarrhea, decreased lymphocyte count, thrombocytopenia, and embolism (N=1, 3.2%).

[0205] One grade 5 treatment-related AE, pneumonia (N=1, 3.2%), was reported. There were no grade 4 treatment-related AEs.

[0206] Serious adverse events (SAEs) of any causality and treatment-related As of March 23, 2022, a total of 10 SAEs, regardless of causality, had been reported in eight patients (Table 2). Two treatment-related SAEs, pneumonia and hypotension, were reported (Table 3).

[0207] [Table 2]

[0208] [Table 3]

[0209] III. Effectiveness As of March 23, 2022, signals of efficacy were observed in patients with ER+ HER2- breast cancer during dose escalation. Additional analyses in dose expansion are ongoing.

[0210] IV. Patient Population The demographic characteristics of patients treated with Compound A in the Phase I study are shown in Tables 4 and 5.

[0211] [Table 4]

[0212] [Table 5]

[0213] Example 2A Updated Safety and Efficacy Data for Part 1A and Part 1B - Data Cutoff Date September 30, 2022 As of the data cutoff date of September 30, 2022, the safety and efficacy of Compound A are being evaluated in an ongoing first-in-human Phase 1 study described in Example 2. Overall, 29 patients have been enrolled: 25 patients in Part 1A (n=12, ER+HER2- breast cancer; n=11, CRPC; n=2, NSCLC) and 4 patients in Part 1B (all ER+HER2- breast cancer). Dose expansion cohorts in patients with ER+HER2- breast cancer as monotherapy and in combination with fulvestrant are ongoing.

[0214] I. Updated Safety Data for Part 1A and Part 1B - Data Cutoff Date September 30, 2022 As of September 30, 2022, 25 patients were treated with monotherapy dose escalation: 6 patients at 15 mg QD, 7 patients at 8 mg QD, 4 patients at 5 mg QD, 4 patients at 2 mg QD, and 4 patients at 1 mg QD. Four patients were treated with the combination dose escalation of 5 mg QD + fulvestrant.

[0215] Compound A was well tolerated. The MTD for Compound A was not identified. 5 mg QD was identified as the RDE for Compound A both as monotherapy and in combination with fulvestrant.

[0216] Dose-limiting toxicity (DLT) As of September 30, 2022, three dose-limiting toxicities (DLTs) had been observed among 29 patients receiving Compound A in Part 1A (monotherapy escalation) and Part 1B (combination escalation). Of these, one DLT was reported with 2 mg QD (monotherapy escalation), one DLT with 8 mg QD (monotherapy escalation), and one DLT with 5 mg QD + fulvestrant (combination escalation). All three DLTs were grade 3 neutropenia (decreased neutrophil count): two in Part 1A (8 mg and 2 mg QD) and one in Part 1B (5 mg QD).

[0217] Adverse events Adverse events (AEs) in patients receiving Compound A in Phase 1 clinical trials were coded according to the Medical Dictionary for Clinical Evaluation of Reproductive Health (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.

[0218] Treatment-emergent adverse events (TEAEs), regardless of causality As of September 30, 2022, 28 of 29 patients (96.6%) who received Compound A in Part 1A (monotherapy escalation) and Part 1B (combination escalation) experienced at least one treatment-emergent adverse event of any grade reported in ≥20% of patients. The most common TEAEs occurring in ≥20% of patients were dysgeusia (N=22, 75.9%), anemia (N=16, 55.2%), decreased neutrophil count / neutropenia (N=14, 48.3%), diarrhea (N=11, 37.9%), thrombocytopenia (N=9, 31.0%), fatigue (N=9, 31.0%), decreased white blood cell count (N=8, 27.6%), increased aspartate aminotransferase (N=8, 27.6%), increased alanine aminotransferase (ALT) (N=6, 20.7%), and decreased appetite (N=6, 20.7%).

[0219] Grade ≥3 TEAEs, regardless of causality, included neutropenia / neutropenia (N = 6, 20.7%), anemia (N = 5, 17.2%), decreased white blood cell count (N = 2, 6.9%), diarrhea, fatigue, thrombocytopenia, hypotension, decreased lymphocyte count, and pneumonia (N = 1, each 3.4%). Of the Grade ≥3 neutropenia events, 1 (N = 6, 16.7%) was reported in the 15 mg QD (Part 1A), 2 (N = 7, 28.6%) in the 8 mg QD (Part 1A), 1 (N = 4, 25%) in the 5 mg QD (Part 1A), 1 (N = 4, 25%) in the 2 mg QD (Part 1A), and 1 (N = 4, 25%) in the 5 mg QD (Part 1B). Of the Grade 3 or higher anemia events, three (N = 6, 50.0%) were reported in the 15 mg QD group (Part 1A), one (N = 7, 14.3%) in the 8 mg QD group (Part 1A), and one (N = 4, 25%) in the 5 mg QD group (Part 1A). Of the Grade 3 or higher white blood cell count decreased events, one (N = 6, 16.7%) was reported in the 15 mg QD group (Part 1A) and one (N = 7, 14.3%) in the 8 mg QD group (Part 1A). Grade 3 or higher diarrhea, fatigue, thrombocytopenia, hypotension, lymphocytopenia, and pneumonia (N = 1, 3.4%) were each reported in the 15 mg QD group (Part 1A).

[0220] Treatment-emergent adverse events (TRAEs) As of September 30, 2022, 27 of 29 patients (93.1%) who received Compound A in Part 1A and Part 1B experienced at least one TRAE of any grade reported in ≥10% of patients. The most common TRAEs occurring in ≥10% of patients were dysgeusia (N = 21, 72.4%), anemia (N = 15, 51.7%), decreased neutrophil count / neutropenia (N = 14, 48.2%), diarrhea (N = 9, 31.0%), decreased white blood cell count (N = 8, 27.6%), fatigue (N = 7, 24.1%), increased aspartate aminotransferase (AST) (N = 6, 20.7%), thrombocytopenia and decreased appetite (N = 5, 17.2% each), increased alanine aminotransferase (ALT), hypomagnesemia, and nausea (N = 4, 13.8% each), and vomiting and decreased lymphocyte count (N = 3, 10.3% each).

[0221] Across Parts 1A and 1B, TRAEs (any grade) occurring in ≥20% of patients were dysgeusia (72%), anemia (52%), neutropenia (48%), thrombocytopenia (31%), diarrhea (31%), decreased white blood cells (WBC) (28%), fatigue (24%), and increased aspartate aminotransferase (21%); the majority of TRAEs were Grade 1-2. Grade ≥3 TRAEs occurring in >1 patient were neutropenia (6 / 29, 21%), anemia (5 / 29, 17%), and decreased WBC (2 / 29, 7%).

[0222] Grade ≥3 TRAEs included decreased neutrophil count / neutropenia (N=6, 20.7%), anemia (N=5, 17.2%), decreased white blood cell count (N=2, 6.9%), and diarrhea and thrombocytopenia (N=1, 3.4% each).

[0223] II. Effectiveness As of September 30, 2022, definitive and durable clinical responses have been observed in heavily treated ER+ HER2- breast cancer patients.

[0224] Definite and durable partial responses were observed in 1 / 8 (Part 1A) and 2 / 4 (Part 1B) response-evaluable patients with ER+ / HER2- mBC who had progressed on prior ET+CDK4 / 6 inhibitor therapy.

[0225] Among response-evaluable patients (n=22), confirmed and durable partial responses (PRs) were observed in three patients with ER+ / HER2- breast cancer, including one patient in Part 1A (8 mg monotherapy) and two patients in Part 1B (5 mg QD / fulvestrant 500 mg) ( Figure 4 ).

[0226] Duration of response (DOR): 19.4 months in one patient in Part 1A and 8.1 and 10 months in two patients in Part 1B.

[0227] Stable disease (SD) was observed in 9 (of 18) patients in Part 1A and 1 (of 4) patient in Part 1B; of these, 5 had ER+ / HER2- breast cancer, 4 had CRPC, and 1 had NSCLC.

[0228] Three patients experienced SD for more than 6 months, with durations of SD of 11.3 months (CRPC patient, 15 mg QD), 9.1 months (CRPC patient, 5 mg QD), and 7.5 months (ER+ / HER2- breast cancer patient, 8 mg QD).

[0229] III. Patient Population Demographic and baseline characteristics of patients across Part 1A as of September 30, 2022 are shown in Table 6.

[0230] [Table 6]

[0231] Most patients were Caucasian (48.3%) or Asian (27.6%), with a median age of 67 years (range: 48-90 years). Most patients (81.3%) with advanced or metastatic ER+ / HER2- breast cancer had received more than three lines of prior systemic anticancer therapy.

[0232] Eighty-three percent (Part 1A) and 75% (Part 1B) of patients with advanced or metastatic ER+ / HER2- breast cancer had received more than three lines of prior systemic anticancer therapy. All patients (n=16) with advanced or metastatic ER+ / HER2- breast cancer had received prior endocrine therapy, and 15 patients had received prior treatment with a CDK4 / 6 inhibitor.

Claims

1. A daily dose of about 0.1 mg to about 15 mg of the following structure: 【Chemical 1】 or a pharmaceutically acceptable salt thereof to a subject in need thereof.

2. about 0.1 mg to about 15 mg of 2-methoxy-N-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-yl}benzene-1-sulfonamide, or a pharmaceutically acceptable salt thereof, a) an amount of a cyclin-dependent kinase 4 (CDK4) inhibitor; b) an amount of an anti-estrogen; or c) an amount of a CDK4 inhibitor and an amount of an antiestrogen 40. A method for treating cancer comprising administering to a subject in need thereof a compound comprising the steps of:

3. 3. The method of any one of claims 1 to 2, wherein the daily dose of 2-methoxy-N-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-yl}benzene-1-sulfonamide, or a pharmaceutically acceptable salt thereof, is administered once daily (QD).

4. 4. The method of any one of claims 1 to 3, wherein the 2-methoxy-N-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-yl}benzene-1-sulfonamide, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 0.5 mg to about 5 mg QD.

5. 4. The method of any one of claims 1 to 3, wherein the 2-methoxy-N-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-yl}benzene-1-sulfonamide, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 0.1 mg to less than 1 mg QD.

6. 6. The method of claim 5, wherein the 2-methoxy-N-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-yl}benzene-1-sulfonamide, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 0.1 mg to about 0.75 mg QD.

7. 7. The method of any one of claims 4 to 6, wherein the 2-methoxy-N-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-yl}benzene-1-sulfonamide, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 0.5 mg QD.

8. 5. The method of claim 4, wherein the 2-methoxy-N-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-yl}benzene-1-sulfonamide, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 1 mg QD.

9. 5. The method of claim 4, wherein the 2-methoxy-N-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-yl}benzene-1-sulfonamide, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 2 mg QD.

10. 5. The method of claim 4, wherein the 2-methoxy-N-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-yl}benzene-1-sulfonamide, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 3 mg QD.

11. 5. The method of claim 4, wherein the 2-methoxy-N-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-yl}benzene-1-sulfonamide, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 4 mg QD.

12. 5. The method of claim 4, wherein the 2-methoxy-N-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-yl}benzene-1-sulfonamide, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 5 mg QD.

13. 13. The method of any one of claims 1 to 12, wherein the 2-methoxy-N-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-yl}benzene-1-sulfonamide, or a pharmaceutically acceptable salt thereof, is administered orally.

14. 14. The method of any one of claims 2 to 13, wherein the CDK4 inhibitor is a CDK4 selective inhibitor or a CDK4 / 6 inhibitor.

15. 15. The method of claim 14, wherein the CDK4 inhibitor is a CDK4 selective inhibitor.

16. 16. The method of claim 15, wherein the CDK4 selective inhibitor is 1,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol, or a pharmaceutically acceptable salt thereof.

17. 15. The method of claim 14, wherein the CDK4 inhibitor is a CDK4 / 6 inhibitor.

18. 18. The method of claim 17, wherein the CDK4 / 6 inhibitor is abemaciclib, ribociclib, or palbociclib, or a pharmaceutically acceptable salt thereof.

19. 18. The method of claim 17, wherein the CDK4 / 6 inhibitor is palbociclib, or a pharmaceutically acceptable salt thereof.

20. 20. The method of any one of claims 2 to 19, wherein the anti-estrogen agent is an aromatase inhibitor, a selective estrogen receptor degrader (SERD), or a selective estrogen receptor modulator (SERM).

21. 21. The method of claim 20, wherein the anti-estrogen is fulvestrant.

22. 21. The method of claim 20, wherein the anti-estrogen is letrozole.

23. 23. The method of any one of claims 1 to 22, wherein the cancer is breast cancer, lung cancer, or prostate cancer.

24. 24. The method of claim 23, wherein the cancer is breast cancer.

25. 25. The method of claim 24, wherein the breast cancer is ER+ HER2- breast cancer.

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

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