Dosing regimens comprising KAT6 inhibitors for 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 as a single agent or in combination with: a) a cyclin dependent kinase 4 (CDK4) inhibitor; b) an anti-estrogen; or c) a CDK4 inhibitor and an antiestrogen.

Description

Background of the Invention

[0002] KAT6A and KAT6B are histone lysine acetyltransferases that acetylate H3K23, and their enzymatic functions are involved in basic cellular processes, including gene transcription, cell senescence, tissue development, and 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, TI et al., Pan-cancer patterns of somatic copy number alteration. Nat Genet. 2013, 45:1134-1140; and Northcott, PA et al., Multiple recurrent genetic events converge on control of histone lysine methylation in medulloblastoma. Nat Genet. 2013, 45:1134-1140). Genet. 2009, 41(4):465-72).KAT6A chromosomal translocation has been observed in AML (see Huang F et al.; Borrow, J. et al., The translocation t(8;16)(p11;p13)of acute myeloid leukaemia fuses a putative acetyltransferase to the CREB-binding protein. Nat. Genet. 1996; 14(1):33-41; and Shima, H. et al., Bromodomain-PHD finger protein1is critical for leukemogenesis associated with MOZ-TIF2 fusion. Int J Hematol. 2014; 99(1):21-31). KAT6 inhibition has therapeutic potential in a variety of 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]

[0005] The preparation of Compound A (including anhydrous crystalline forms of Compound A free acid) is described in International Publication No. WO2020 / 254946. Combination therapies including Compound A are described in International Patent Publication No. 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 perform 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 determined (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 possible other heterogeneous proteins are important regulatory factors for cell cycle progression. Additional functions of cyclin / CDK heteroproteins 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 shown to be useful for treating cancer. Increased activity or transient abnormal activation of cyclin-dependent kinases has been shown to lead to the development of human tumors, and human tumor development is often associated with changes in 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 important regulators of cell cycle progression at the G1-S checkpoint, which is regulated by D-type cyclins and endogenous CDK inhibitors such as p16 INK4a (CDKN2A)). 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. In addition, CDK4 has been identified as a single oncogenic driver in many breast cancers and emerging data suggest that cyclin D3-CDK6 inhibition may be associated with hematologic toxicity, suggesting a role for CDK4 selective inhibitors.

[0009] Clinical trials of CDK4 / 6 inhibitors palbociclib, ribociclib, and abemaciclib as single agents or in combination with other therapeutic agents for breast cancer and other cancers are ongoing. The combination of CDK4 / 6 inhibitors and endocrine therapy has demonstrated significant efficacy in the treatment of hormone receptor (HR)-positive, human epidermal growth factor 2 (HER2)-negative advanced or metastatic breast cancer, and CDK4 / 6 inhibitors (including palbociclib, ribociclib, and abemaciclib) have been approved for first-line or second-line treatment in combination with endocrine therapy. Palbociclib, ribociclib, and abemaciclib have been approved for first-line treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer in combination with an aromatase inhibitor such as letrozole and in certain patients in combination with fulvestrant for second or subsequent line treatment (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 having the structure:

[0011]

[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. 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.

[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]

[0015] PF-07220060 and pharmaceutically acceptable salts thereof are disclosed in International Publication No. WO 2019 / 207463, published on October 31, 2019, U.S. Pat. Nos. 10,766,884 and 11,220,494, and U.S. Pat. No. US2022 / 0089580; and International Publication No. WO 2022 / 058871, published on March 24, 2022, the contents of which are incorporated herein by reference in their entirety. Unless otherwise indicated, all references to PF-07220060 herein include references to its salts, solvates, hydrates and complexes, and solvates, hydrates and complexes of its salts (including polymorphs, stereoisomers and isotopically labeled forms thereof).

[0016] Although CDK4 / 6 inhibitors have shown significant clinical efficacy in ER-positive metastatic breast cancer, like other kinases, their effects can 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; 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 (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 can occur after the initial clinical benefit (Knudsen Erik S., Witkiewicz Agnieszka K., The Strange Case of CDK4 / 6 Inhibitors: Mechanisms, Resistance, and Combination Strategies. Trends Cancer 2017; 3(1): 39-55).

[0017] There is a need for suitable dosing regimens for the oral drug Compound A as a single agent and in combination therapy for the treatment of cancer to enhance the benefit and convenience to the patient while minimizing adverse events and risks to the patient. Summary of the invention

[0018] The present invention provides, in part, a dosing regimen for administering Compound A or a pharmaceutically acceptable salt thereof as a single agent and in combination therapy to a subject to treat cancer. This summary of the invention is provided to introduce a series of concepts in a simplified form, which are further described in the detailed description below. This summary of the invention is not intended to identify the key features or essential features of the claimed subject matter, nor is it intended to be used in isolation as an auxiliary means for determining the scope of the claimed subject matter.

[0019] According to one embodiment of the present invention, a method for treating cancer is provided, comprising administering to a subject in need thereof a daily dose of about 0.1 mg to about 15 mg of a lysine acetyltransferase 6 (KAT6) inhibitor having the following structure or a pharmaceutically acceptable salt thereof

[0020]

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

[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 DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 The overall study design of an open-label, multicenter, multiple-dose Phase 1 clinical trial in adult patients is shown 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.

[0025] Figure 2A Shown are median Compound A plasma concentration-time profiles on Day 1 following administration of a single oral dose of Compound A (either as a single agent or in combination with fulvestrant).

[0026] Figure 2B Shown are median Compound A plasma concentration-time profiles on Day 15 following administration of multiple oral doses of Compound A (as a single agent or in combination with fulvestrant).

[0027] Figure 3Shown are steady-state concentration-time profiles of Compound A on Cycle 1 Day 15 for Compound A as a single agent or in combination with fulvestrant. Abbreviations: Fulv = fulvestrant; hr = hours; QD = once daily; and StD = standard deviation.

[0028] Figure 4 Waterfall plot showing the 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

[0030] The present invention may be understood more readily by reference to the following detailed description of embodiments of the invention and the examples included therein.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.

[0031] E1 A method for treating cancer as defined above.

[0032] E2 A method according to embodiment E1, 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 combination with:

[0033] a) Cyclin-dependent kinase 4 (CDK4) inhibitors;

[0034] b) anti-estrogen; or

[0035] c) CDK4 inhibitors and anti-estrogens.

[0036] E3 A method as in 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 a day (QD).

[0037] E4 A method as described in 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.

[0038] E5 A method as described in 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.

[0039] E6 A method as described in 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.

[0040] E7 A method as described in 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.

[0041] E8 A method as described in 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.

[0042] E9 A method as described in 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.

[0043] E10 A method as described in 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.

[0044] E11 A method as described in 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.

[0045] E12 A method as described in 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.

[0046] E13 A method as described in 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.

[0047] E14 A method as described in 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.

[0048] E15 A method as described in 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.

[0049] E16 A method as described in 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.

[0050] E17 A method as described in 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.

[0051] E18 A method as described in 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.

[0052] E19 A method as described in 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.

[0053] E20 A method according to 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.

[0054] E21 The method according to any one of embodiments E2 to E20, wherein the CDK4 inhibitor is a CDK4 selective inhibitor or a CDK4 / 6 inhibitor.

[0055] E22 A method according to embodiment E21, wherein the CDK4 inhibitor is a CDK4 selective inhibitor.

[0056] E23 A method as described in 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.

[0057] E24 A method according to embodiment E21, wherein the CDK4 inhibitor is a CDK4 / 6 inhibitor.

[0058] E25 The method of embodiment E24, wherein the CDK4 / 6 inhibitor is abemaciclib, ribociclib or palbociclib or a pharmaceutically acceptable salt thereof.

[0059] E26 According to the method of embodiment E25, the CDK4 / 6 inhibitor is palbociclib or a pharmaceutically acceptable salt thereof.

[0060] E27 The method of any one of embodiments E2 to E20, wherein the anti-estrogen is an aromatase inhibitor, a selective estrogen receptor degrader (SERD) or a selective estrogen receptor modulator (SERM).

[0061] E28 A method according to embodiment E27, wherein the anti-estrogen is fulvestrant or letrozole.

[0062] E29 A method according to embodiment E28, wherein the anti-estrogen is fulvestrant.

[0063] E30 A method according to embodiment E28, wherein the anti-estrogen is letrozole.

[0064] 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, stomach cancer, pancreatic cancer, ovarian cancer, melanoma, endocrine cancer, uterine cancer, testicular cancer or bladder cancer.

[0065] E32 A method according to embodiment E31, wherein the cancer is breast cancer, lung cancer, prostate cancer, pancreatic cancer or ovarian cancer.

[0066] E33 The method of embodiment E32, wherein the cancer is breast cancer, lung cancer or prostate cancer.

[0067] E34 A method according to embodiment E33, wherein the cancer is breast cancer.

[0068] E35 The method of embodiment E34, wherein the breast cancer is hormone receptor positive (HR+) breast cancer.

[0069] 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.

[0070] E37 The method of embodiment E36, wherein the breast cancer is progesterone receptor positive (PR+) breast cancer.

[0071] E38 The method of embodiment E36, wherein the breast cancer is estrogen receptor positive (ER+) breast cancer.

[0072] 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+).

[0073] E40 The method of embodiment E39, wherein the estrogen receptor positive (ER+) breast cancer is human epidermal growth factor receptor 2 negative (HER2-).

[0074] 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.

[0075] 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 preparation of a medicament according to any one of Embodiments E1 to E41.

[0076] Each of the embodiments described herein may be combined with any other embodiment described herein that is not inconsistent with the embodiment with which it is combined.

[0077] definition

[0078] 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.

[0079] The invention described herein suitably may be practiced in the absence of any element not specifically disclosed herein.

[0080] 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.

[0081] As used herein, the term "about" when used to modify a numerically defined parameter (e.g., the dosage of a KAT6 inhibitor) means that the parameter may vary within a range of up to 10% below or above the stated value of the parameter. For example, a dosage of about 5 mg means 5 mg ± 10%, i.e., it may vary between 4.5 mg and 5.5 mg.

[0082] As used herein, terms (including but not limited to "agent," "composition," "compound," "drug," and "therapeutic agent") are used interchangeably to refer to compounds included in the methods and uses of the present invention, particularly KAT6 inhibitors, CDK4 inhibitors, and antiestrogens.

[0083] As used herein, "KAT6 inhibitors" include inhibitors of KAT6A, inhibitors of KAT6B, and inhibitors of KAT6A and KAT6B. KAT6 inhibitors are disclosed in International Publication No. WO2019 / 043139A1; International Publication No. WO2019 / 243491A1; International Publication No. WO2020 / 002587; and International Application No. PCT / IB2020 / 055667. The contents of each of the foregoing references are incorporated herein by reference in their entirety.

[0084] Cyclin-dependent kinases (CDKs) and related serine / threonine kinases are important cellular enzymes that perform essential functions in regulating cell division and proliferation.CDK inhibitors include pan-CDK inhibitors that target a broad range of CDKs or selective CDK inhibitors that target specific CDKs.

[0085] As used herein, "CDK4 inhibitors" include CDK4 selective inhibitors and CDK4 / 6 inhibitors. CDK4 selective inhibitors are disclosed in International Publication No. WO 2019 / 207463. Examples of CDK4 / 6 inhibitors include, but are not limited to, abemaciclib, ribociclib, and palbociclib. Additional examples of CDK4 / 6 inhibitors include lerociclib (also known as G1T38) and trilaciclib (also known as GTI128).

[0086] In one embodiment, the CDK4 selective inhibitor of the present invention includes 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.

[0087] In one 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 or a pharmaceutically acceptable salt thereof.

[0088] As used herein, "endocrine therapy" means 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.

[0089] The term "anti-estrogen" as used herein refers to a class of drugs that prevent estrogen (such as estradiol) from mediating biological effects in the body. Anti-estrogen works by blocking estrogen receptors (ER) and / or inhibiting (inhibiting) or curbing (suppressing) estrogen production. In other embodiments, the anti-estrogen 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), rintodestrant (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, clomifene and raloxifene. Other SERMS include toremifene, lasofoxifene, bazedoxifene and afimoxifene.

[0090] In one embodiment, the aromatase inhibitors include letrozole, exemestane, and anastrozole. In one embodiment, the SERMs include tamoxifen, clomiphene, and raloxifene.

[0091] In one embodiment, the antiestrogens of the invention include fulvestrant and letrozole. In one embodiment, the antiestrogens of the invention include fulvestrant. In one embodiment, the antiestrogens of the invention include letrozole.

[0092] Another embodiment relates 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.

[0093] 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, but are not limited to, acetate, acid citrate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate / carbonate, bisulfate / sulfate, bitartrate, borate, camphorsulfonate, citrate, cyclamate, edisylate, esylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride

[0013] The invention also includes but is not limited to the following salts: hydrobromide / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methanesulfonate, methylsulfate, naphthylate, 2-naphthylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, pyroglutamate, sucrose, stearate, succinate, tannate, tartrate, p-toluenesulfonate, toluenesulfonate, trifluoroacetate, and xinafoate.

[0094] 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, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, and zinc salts.

[0095] Compounds described herein that are basic in nature are capable of forming a variety of salts with various inorganic and organic acids. Acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds described herein are acids that form non-toxic acid addition salts, such as salts containing pharmacologically acceptable anions, such as hydrochlorides, hydrobromides, hydroiodides, nitrates, sulfates, bisulfates, phosphates, acid phosphates, isonicotinates, acetates, lactates, salicylates, citrates, acid citrates, tartrates, pantothenates, bitartrates, ascorbates, succinates, maleates, gentisates, fumarates, gluconates, glucuronates, sucrose salts, formates, benzoates, glutamates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, and pamoates [i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)] salts. In addition to the acids mentioned above, the compounds described herein that include a basic moiety, such as an amino group, can form pharmaceutically acceptable salts with various amino acids.

[0096] Chemical bases useful as reagents for preparing pharmaceutically acceptable base salts of those compounds described herein that are acidic in nature are those chemical bases that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to, those 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 lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines.

[0097] Hemisalts of acids and bases can also be formed, for example hemisulphate and hemicalcium salts.

[0098] For a review of suitable salts, see Stahl and Wermuth, Handbook of 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.

[0099] Administration and dosing

[0100] As used herein, "treat" or "treating" cancer and / or cancer-related diseases means administering a monotherapy or combination therapy according to the present invention to a subject, participant, or patient suffering from or diagnosed with cancer to achieve at least one positive therapeutic effect, such as, for example, 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 tumor metastasis or tumor growth rate, reversal, alleviation, inhibition of progression of the disorder or condition to which the term applies, or prevention of one or more symptoms of the disorder or condition to which the term applies. Unless otherwise indicated, the term "treatment" or "therapy" as used herein refers to the act of treating, such as "treating" as defined immediately above. For purposes of the present invention, beneficial or desired clinical results include, but are not limited to, one or more of the following: reducing the proliferation of tumors or cancer cells (or destroying tumors or cancer cells); inhibiting metastasis or tumor cells; shrinking or reducing the size of tumors; alleviating cancer; reducing symptoms caused by cancer; improving the quality of life of those suffering from 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 cancer patients. Positive therapeutic effects in cancer can be measured in several ways (see, e.g., WA Weber, J. Nucl. Med. 50: 1S-10S (2009)).

[0101] As used herein, the terms "subject," "participant," and "patient" are used interchangeably for humans. A human subject may be of any gender. In one embodiment, a human is an adult human.

[0102] "Amount" for use and for treating a subject refers to an amount that provides a detectable response of any duration (short-term, medium-term or long-term), any measurable or detectable degree or any duration (e.g., hours, days, months, years, in a state of remission or cure) to the subject in a single or multiple doses alone or in combination with one or more other agents, or an amount of an objective or subjective benefit to the subject. Although reducing or inhibiting the progression or deterioration of a disease, or providing a stable (i.e., non-deteriorating) state of a disease is considered a satisfactory result, such an amount is generally effective to improve one, multiple or all adverse reactions / symptoms, consequences or complications of a disease or disease to a measurable extent. The term "therapeutically effective amount" also means an amount of an agent that is effective to produce a desired therapeutic effect (e.g., preventing the growth of a cancerous tumor or causing the shrinkage of a cancerous tumor) after being administered to a subject, either alone or in combination with one or more other agents. With respect 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 metastasis, (3) inhibits (i.e., slows to some extent, preferably stops) tumor growth or tumor invasion, 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.

[0103] As used herein, "improvement" refers to any decrease in the extent, severity, frequency, and / or likelihood of a symptom or clinical sign characteristic of a particular disease. "Symptom" refers to any subjective evidence of a disease or condition in a subject.

[0104] Embodiments of the present invention provide dosage, dosage and dosing regimen, which include administering a certain amount or therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof to a subject. The amount or therapeutically effective amount may be a daily dose in the range of 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, the daily dose is 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.

[0105] In another embodiment, Compound A or a pharmaceutically acceptable salt thereof may be administered as a single agent or in combination with an anti-estrogen in an amount sufficient to produce a maximum plasma concentration (C ) of 400 to 13000 ng / mL, e.g., 500 to 700 ng / mL, 1400 to 2800 ng / mL, 2000 to 4400 ng / mL, or 4000 to 12000 ng / mL in a subject, e.g., following daily oral administration of 2 mg, 5 mg, 8 mg, or 15 mg of Compound A. max ).

[0106] In another embodiment, Compound A or a pharmaceutically acceptable salt thereof may be administered as a single agent or in combination with an anti-estrogen in an amount that provides a maximum plasma concentration (C ) of 400 to 13000 ng / mL, e.g., 500 to 700 ng / mL, 1400 to 2800 ng / mL, 2000 to 4400 ng / mL, or 4000 to 12000 ng / mL in a subject at steady state. max ). In one embodiment, the compound A is administered at a daily dose of about 1 mg to about 15 mg. In one embodiment, the 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.

[0107] In a preferred embodiment, the daily dose of Compound A or a pharmaceutically acceptable salt thereof is administered once a day (QD).

[0108] The compounds of the invention may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or may employ buccal or sublingual administration, whereby the compound enters the bloodstream directly from the mouth.

[0109] In a preferred embodiment, the daily dose of Compound A or a pharmaceutically acceptable salt thereof is administered orally.

[0110] Compound A or a pharmaceutically acceptable salt may be present in a pharmaceutical composition comprising a pharmaceutically acceptable excipient. "Pharmaceutically acceptable excipient" refers to a component that can be included in the composition described herein, is physiologically suitable for pharmaceutical use, and does not cause significant adverse reactions or therapeutic effects to the subject. The term "excipient" is used herein to describe any ingredient other than the compound 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.

[0111] The amount of Compound A or a pharmaceutically acceptable salt in the pharmaceutical composition can be any amount disclosed herein.

[0112] The compounds of the methods, uses or combinations of the present invention can be formulated prior to administration. Preferably, the preparation is adapted to a specific mode of administration. These compounds can be formulated with pharmaceutically acceptable excipients known in the art and administered in various dosage forms 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, which are packaged in containers adapted to be subdivided into single doses.

[0113] In another embodiment, the dosage of the compound or pharmaceutical composition described herein may vary within a range determined by the dosage form used. In another embodiment, the amount of the compound or pharmaceutical composition described herein administered to the subject may be determined according to factors known to the skilled artisan. In addition, it should be understood that the specific dosage of the pharmaceutical composition comprising the compound as disclosed herein may be determined according to a variety of factors, including the subject's physical condition (e.g., age, sex, weight) and the subject's medical history (e.g., medications being taken, health conditions, other diseases or disorders).

[0114] In one embodiment, Palbociclib or its pharmaceutically acceptable salt 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 daily, or about 25 mg daily. In one embodiment (which is a recommended starting dose), Palbociclib or its pharmaceutically acceptable salt is administered at a daily dose of about 125 mg once a day. For example, Palbociclib or its pharmaceutically acceptable salt 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 its pharmaceutically acceptable salt is administered at a dose of about 100 mg once a day. In one embodiment, Palbociclib or its pharmaceutically acceptable salt is administered at a dose of about 75 mg once a day. In one embodiment, Palbociclib or its pharmaceutically acceptable salt is administered at a dose of about 50 mg once a day. The amount of the dosage provided herein refers to the dosage of the free base form of Palbociclib, or is 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.

[0115] 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 preferably administered at a dose of about 25 mg to about 300 mg per day on a BID schedule. In another embodiment, the CDK4 inhibitor is administered at a dose of about 100 mg to about 300 mg 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, 2, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450 45, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 260, 270, 275, 280, 290, 300, 325, 350, 375, 400, 425, 450, 475 or 500 mg.

[0116] Can carry out administration or dosing regimen repetition as needed to realize the desired reduction or reduction of cancer cells.As used herein, " continuous dosing schedule " is administration or dosing regimen without dosage interruption, for example, without drug withdrawal (daysoff) treatment.Repeating 28 days treatment cycle under the situation of no dosage interruption between treatment cycles is an example of continuous dosing schedule.In one embodiment, the compound of the combination of the present invention can be administered with continuous dosing schedule.In one embodiment, the compound of the combination of the present invention can be administered simultaneously in continuous dosing schedule.

[0117] 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 comprise a complete cycle of 28 days. During treatment with the combination of the present invention, the 28-day cycle continues to be repeated.

[0118] The standard recommended dosing regimen of palbociclib or its pharmaceutically acceptable salt (which includes the standard dosing schedule) is once daily administration for 21 consecutive days, followed by 7 days of rest treatment to include a complete cycle of 28 days. During treatment with the combination of the present invention, the 28-day cycle continues to be repeated.

[0119] The standard clinical dosing regimen of palbociclib or its pharmaceutically acceptable salt is 125 mg once daily for 21 consecutive days, followed by 7 days of rest treatment to include a complete cycle of 28 days. During treatment with the combination of the present invention, the 28-day cycle continues to be repeated.

[0120] In other embodiments of the present 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 wherein letrozole is administered orally at 2.5 mg daily.

[0121] The invention also relates to a kit comprising a therapeutic agent of the combination of the invention and written instructions for administering the therapeutic agent. In one embodiment, the written instructions detail and define the mode of administration of the therapeutic agent, e.g., for simultaneous or sequential administration of the therapeutic agent of the invention. In one embodiment, the written instructions detail and define the mode of administration of the therapeutic agent, e.g., by specifying the number of days for administration of each therapeutic agent during a 28-day cycle.

[0122] Treatment

[0123] In one embodiment, the present invention provides a method for treating cancer in a subject in need thereof, comprising administering to the subject an amount of Compound A as described herein. In another embodiment, the present invention also provides a method for treating cancer in a subject, comprising administering to the subject an amount of Compound A as described herein in combination with: 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 anti-estrogen.

[0124] Unless otherwise indicated, the term "combination" as used herein means a fixed dose combination, or a combination of medicaments administered intermittently, simultaneously or sequentially according to the same or different routes of administration and according to the same or different dosage schedules. As used herein, an "effective" or "therapeutically effective" amount refers to an amount of a medicament, a compound or a composition, an amount sufficient to cause a decrease in the severity of disease symptoms, an increase in the frequency and duration of disease-free symptom periods, or prevention of damage or disability caused by disease ailments - as a single dose or according to a multiple dose regimen, alone or in combination with other medicaments. One of ordinary skill in the art will be able to determine the amount based on such factors (such as the size of the patient, the severity of the patient's symptoms, and the specific combination, composition or route of administration selected). The patient or subject may be a human or non-human mammal in need of treatment. In one embodiment, the patient is human.

[0125] As used herein, the term "locally advanced" may or may not be treated with curative intent when it is associated with cancer. As used herein, the term "metastatic" may not be treated with curative intent when it is associated with cancer. One skilled in the art will be able to identify and diagnose locally advanced and metastatic cancer in a patient.

[0126] 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). The abbreviations ER+HER2-, ER+HER2-, and ER+ / HER2- are equivalent and interchangeable when they are related to breast cancer indications.

[0127] In one embodiment, the cancer is selected from the group consisting of lung cancer, mesothelioma, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, hepatic carcinoma, 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, hematology malignancy, 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 (spinal axis tumors), tumor), glioblastoma, brain stem glioma, pituitary adenoma, head and neck cancer, or a combination of two or more of the foregoing cancers.

[0128] Another embodiment is directed to a method of treating cancer in a patient.Another embodiment is directed to treating cancer in a patient comprising administering to the patient an amount of a compound described herein that is effective in treating cancer.

[0129] In one embodiment, 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.

[0130] In one embodiment, the cancer is breast cancer, lung cancer, prostate cancer, pancreatic cancer, or ovarian cancer.

[0131] In one embodiment, the cancer is breast cancer, lung cancer, or prostate cancer.

[0132] In one embodiment, the cancer is breast cancer.

[0133] In one embodiment, the breast cancer is HR+ breast cancer.

[0134] In one embodiment, the HR+ breast cancer is PR+ and / or ER+ breast cancer.

[0135] In one embodiment, the breast cancer is a PR+ breast cancer.

[0136] In one embodiment, the breast cancer is ER+ breast cancer.

[0137] In one embodiment, the breast cancer is ER+HER2- breast cancer.

[0138] In one embodiment, the breast cancer is ER+HER2+ breast cancer.

[0139] In one embodiment, the breast cancer is locally advanced or metastatic ER+ breast cancer.

[0140] In one embodiment, the breast cancer is locally advanced or metastatic ER+HER2- breast cancer.

[0141] In one embodiment, the breast cancer is locally advanced or metastatic ER+HER2+ breast cancer.

[0142] In one embodiment, the lung cancer is non-small cell lung cancer.

[0143] In one embodiment, the lung cancer is locally advanced or metastatic non-small cell lung cancer.

[0144] In one embodiment, the prostate cancer is castration-resistant prostate cancer.

[0145] In one embodiment, the prostate cancer is locally advanced or metastatic castration-resistant prostate cancer.

[0146] Another embodiment is directed to a method of treating a solid tumor in a patient.Another embodiment is directed to treating a solid tumor in a patient comprising administering to the patient an amount of a compound described herein that is effective in treating a solid tumor.

[0147] In one embodiment, 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.

[0148] In one embodiment, the solid tumor is breast cancer, lung cancer, prostate cancer, pancreatic cancer, or ovarian cancer.

[0149] In one embodiment, the solid tumor is breast cancer, lung cancer, or prostate cancer.

[0150] In one embodiment, the solid tumor is breast cancer, and in another embodiment, the breast cancer is HR+ breast cancer, and in yet another embodiment, the HR+ breast cancer is PR+ and / or ER+ breast cancer.

[0151] In one embodiment, the solid tumor is breast cancer, and in another embodiment, the breast cancer is ER+HER2- breast cancer.

[0152] In one embodiment, the solid tumor is breast cancer, and in another embodiment, the breast cancer is ER+HER2+ breast cancer.

[0153] In one embodiment, the solid tumor is breast cancer, and in another embodiment, the breast cancer is locally advanced or metastatic ER+HER2- breast cancer.

[0154] In one embodiment, the solid tumor is breast cancer, and in another embodiment, the breast cancer is locally advanced or metastatic ER+HER2+ breast cancer.

[0155] In one embodiment, the solid tumor is lung cancer, and in another embodiment, the lung cancer is non-small cell lung cancer.

[0156] In one embodiment, the solid tumor is lung cancer, and in another embodiment, the lung cancer is locally advanced or metastatic non-small cell lung cancer.

[0157] In one embodiment, the solid tumor is prostate cancer, and in another embodiment, the prostate cancer is castration-resistant prostate cancer.

[0158] In one embodiment, the solid tumor is prostate cancer, and in another embodiment, the prostate cancer is locally advanced or metastatic castration-resistant prostate cancer.

[0159] Another embodiment is directed to a method of treating a hematological neoplasm in a patient.Another embodiment is directed to treating a hematological neoplasm in a patient comprising administering to the patient an amount of a compound described herein that is effective in treating a hematological neoplasm.

[0160] In one embodiment, the hematological tumor is leukemia, lymphoma or multiple myeloma.

[0161] In one embodiment, the hematological tumor is a leukemia or a lymphoma.

[0162] Another embodiment is directed to a method of treating cancer in a patient with locally advanced or metastatic ER+HER2- breast cancer, CRPC, or NSCLC whose disease has progressed on or is intolerant to standard therapy.

[0163] Another embodiment is directed to a method of treating cancer in a patient with locally advanced or metastatic ER+HER2- breast cancer, CRPC, or NSCLC whose disease has progressed on or is intolerant to standard therapy.

[0164] Another embodiment relates to a method of treating cancer in a patient with locally advanced or metastatic 2L+ER+HER2 breast cancer who has progressed after at least 1 prior line of endocrine therapy and a CDK4 / 6 inhibitor. In one embodiment thereof, a combination of Compound A and Fulvestrant is administered to the patient.

[0165] Another embodiment relates to a method of treating cancer in a patient with locally advanced or metastatic 2L+ER+HER2 breast cancer who has progressed after at least 1 prior line of endocrine therapy and a CDK4 / 6 inhibitor. In one embodiment thereof, the patient is administered a combination of Compound A with letrozole and palbociclib.

[0166] Another embodiment relates to a method of treating cancer in a patient with advanced or metastatic 2L+ER+HER2- breast cancer who has progressed after at least 1 prior line of CDK4 / 6 inhibitor and 1 line of endocrine therapy. In one embodiment thereof, Compound A is administered to the patient.

[0167] Another embodiment relates to a method of treating cancer in a patient with advanced or metastatic 2 to 4L fulvestrant-untreated ER+HER2- breast cancer whose disease has progressed after 1 line of CDK4 / 6 inhibitor and 1 line of endocrine therapy and who must not have received more than 3 lines of systemic therapy in the advanced or metastatic setting. In one embodiment thereof, Compound A and fulvestrant are administered to the patient. Example

[0168] In order to better understand the present invention, the following examples are listed below. These examples are for illustrative purposes only and should not be interpreted as limiting the scope of the present invention in any way.

[0169] Phase 1 Compound A Clinical Trial

[0170] Overview

[0171] Compound A is being studied in an ongoing open-label, multicenter, multi-dose Phase 1 study in adult patients to evaluate the safety, tolerability, PK and PD of Compound A in locally advanced or metastatic selected solid tumors (ER+HER2- breast cancer, CRPC or NSCLC) and early signs of clinical efficacy of Compound A as a single agent in combination with anti-estrogen; and in combination with CDK4 inhibitors and anti-estrogen. Patients in this trial are intolerant or resistant to standard therapy.

[0172] Research Design: The overall research design is depicted in Figure 1 This study consists of two parts, dose escalation (Part 1) followed by dose expansion (Part 2). Figure 1 Part 1D and Part 2D, which are additional groups in Part 1 and Part 2 of the study design, are not shown in the figure and are described below.

[0173] As of the data cutoff date of March 23, 2022, 31 participants were treated with Compound A and early signs of clinical efficacy of Compound A were observed.

[0174] Example 1: Pharmacokinetic (PK) study - data cutoff date is March 23, 2022

[0175] Compound A was orally administered at 2 mg, 5 mg, 8 mg and 15 mg QD alone or at 5 mg QD in combination with 500 mg fulvestrant.

[0176] Figure 2A Shown are median Compound A plasma concentration-time profiles on Day 1 following a single oral dose of Compound A at 2 mg, 5 mg, 8 mg and 15 mg QD alone and at 5 mg QD in combination with 500 mg fulvestrant. Figure 2BShown are median Compound A plasma concentration-time profiles on Day 15 following multiple oral doses of Compound A at 2 mg, 5 mg, 8 mg and 15 mg QD alone and at 5 mg QD in combination with 500 mg fulvestrant.

[0177] Preliminary pharmacokinetic parameters after the first oral dose (Day 1 of Cycle 1) and at steady-state (Day 15 of Cycle 1) were available from 23 participants and are presented in Table 1.

[0178] Table 1. Summary of preliminary plasma pharmacokinetic parameters of Compound A after the first dose (Day 1 of Cycle 1) and at steady state (Day 15 of Cycle 1).

[0179]

[0180]

[0181] *Only minimum and maximum values ​​for 2 mg are presented;

[0182] **Median (minimum, maximum).

[0183] Abbreviations: C1D1: cycle 1 day 1; C1D15: cycle 1 day 15; CV: coefficient of variation; N: number of patients; Cmax: maximum concentration after administration; T max : time when maximum concentration is achieved; AUC 24 : Area under the curve from 0 to 24 hours after administration; CL / F: Apparent clearance of compound A; Rac: AUC on day 15 of cycle 1 24 Compared with the AUC on day 1 of cycle 1 24 ratio

[0184] After repeated daily dosing up to day 15, Compound A showed a median T of 3 hours. max Absorption. Compound A accumulated after repeated daily oral administration, with Rac ranging from 2.3 to 5.8. Based on a dose range of 2 mg to 15 mg administered alone or in combination with fulvestrant, Compound A exposure (i.e., AUC 24 ) increased proportionally with increasing doses. The apparent clearance CL / F at each dose level was similar, indicating that the pharmacokinetics of Compound A was linear and there was no apparent drug-drug interaction between Compound A and Fulvestrant. The inter-patient variability of the drug was low to moderate, i.e., AUC on day 15 of cycle 1 24 The CV% ranged from 9.7% to 43.2% and on Day 15 of Cycle 1, C max The CV% ranged from 12.6% to 43.2%.

[0185] Example 1A: Pharmacokinetic (PK) study - data cutoff date is September 30, 2022

[0186] Compound A was orally administered at 1 mg, 2 mg, 5 mg, 8 mg and 15 mg QD alone or at 5 mg QD in combination with 500 mg fulvestrant.

[0187] A total of 29 participants had evaluable PK concentration data in Part 1A and Part 1B at the data cutoff date of September 30, 2022. Of these participants, two (2) in the 1 mg QD dose group were excluded from the Cycle 1 Day 15 pooling due to dosing interruptions that impacted PK analysis or sample collection after the data cutoff date.

[0188] Figure 3 The steady-state concentration-time curve of Compound A on Day 15 of Cycle 1 is shown. Compound A PK was linear between the 1 mg QD dosing regimen and the 15 mg QD dosing regimen and achieved steady state by Day 15 of Cycle 1, as shown in Figure 2. Figure 3 When administered at ≥1 mg, the steady-state concentration is close to or higher than C eff Target (defined by preclinical models).

[0189] Example 2: Safety and Efficacy - Data Cutoff March 23, 2022

[0190] 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 were treated with Compound A. Dose de-escalation for monotherapy is ongoing (Part 1A); the recommended dose expansion (RDE) for monotherapy is determined to be 5 mg QD and Part 1B is ongoing. The RDE in combination with Fulvestrant is also determined to be 5 mg QD and dose expansion is ongoing (Part 2B).

[0191] I. Research Design

[0192] Part 1 (Dose Escalation)

[0193] Part 1 dose escalation was further divided into Part 1A, Part 1B, Part 1C, and Part 1D.

[0194] Part 1A (monotherapy dose escalation) contains dose escalation as monotherapy in patients with locally advanced or metastatic ER+HER2- breast cancer, CRPC or NSCLC to determine the maximum tolerated dose (MTD) and select RDE, the patients are resistant or intolerant to standard therapy or no standard therapy is available. Participants received increasing doses of Compound A orally starting from 8 mg QD. Dose finding was performed using a 2-parameter Bayesian logistic regression model (BLRM).

[0195] Part 1B (combination dose escalation) evaluates the combination of Compound A and Fulvestrant for dose exploration in patients with locally advanced or metastatic ER+HER2- breast cancer (2L+) to determine the MTD and RDE of the combination, the patients progressing after at least one line of endocrine therapy and CDK4 / 6 inhibitor treatment. Due to potential toxicity overlap, the combination RDE may be different from the monotherapy RDE. A 5-parameter BLRM is used for dose exploration.

[0196] Part 1C (combination dose escalation), the combination of Compound A and letrozole + palbociclib was evaluated in patients with locally advanced or metastatic ER+HER2- breast cancer (2L+) to determine the MTD and RDE of the combination, who had progressed after at least one line of endocrine therapy and CDK4 / 6 inhibitor treatment.

[0197] In Part 1D (combination dose escalation), the combination of Compound A and Fulvestrant + PF-07220060 was evaluated in a dose-exploration study to determine the MTD and RDE of the combination in patients with locally advanced or metastatic ER+HER2- breast cancer (2L+) who had progressed after at least one line of endocrine therapy and CDK4 / 6 inhibitor treatment.

[0198] BLRMs developed specifically for double and triple combinations were used for dose finding in Parts 1B, 1C, and 1D.

[0199] Part 2 (Dose Expansion)

[0200] Part 2A (ER+HER2- breast cancer 2L+, monotherapy): Following the selection of monotherapy RDE in Part 1A, Compound A was evaluated as monotherapy in a dose expansion cohort to evaluate patients with locally advanced or metastatic ER+HER2- breast cancer (2L+) who had progressed after at least 1 prior line of CDK4 / 6 inhibitor and 1 line of endocrine therapy.

[0201] Part 2B (ER+HER2- breast cancer 2-4L, fulvestrant-naive, combination with fulvestrant): Following determination of the combination RDE from Part 1B, patients with advanced or metastatic 2-4L fulvestrant-naive ER+HER2- breast cancer whose disease progressed after 1 line of CDK4 / 6 inhibitor and 1 line of endocrine therapy and who have not received more than 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.

[0202] Part 2D (ER+HER2- breast cancer 2-4L, combination with PF-07220060 and fulvestrant): After determination of the combination RDE from Part 1D, patients with advanced or metastatic ER+HER2- breast cancer whose disease progressed after 1 line of CDK4 / 6 inhibitor and 1 line of endocrine therapy and who have not received more than 3 lines of systemic therapy (including up to 1 line of cytotoxic chemotherapy for visceral disease) in the advanced or metastatic setting were evaluated in a dose expansion combination cohort with Compound A and fulvestrant + PF-07220060.

[0203] As of March 23, 2022, 31 participants were treated with Compound A in both dose escalation (Part 1) and dose expansion (Part 2).

[0204] Application method

[0205] Based on preclinical data, Compound A is predicted to exhibit a low plasma CL of approximately 0.1 mL / min / kg and a low V of approximately 0.1 L / kg. ss , resulting in a t of about 12 hours 1 / 2 , which is suitable for QD dosing in humans with high oral bioavailability.

[0206] Compound A is orally administered alone or in combination with Fulvestrant at an increasing dose of 2, 5, 8 and 15 mg QD. Compound A is orally administered alone or in combination with Fulvestrant at 5 mg QD. Compound A is orally administered alone or in combination with Fulvestrant at 1 mg QD. Compound A is orally administered in combination with fixed doses of Fulvestrant and different doses of PF-07220060 at a dose of 0.5 mg, 1 mg, 2 mg and 5 mg QD. Compound A can be orally administered at a dose level (RDE-1) lower than monotherapy RDE, using fixed doses of Fulvestrant or letrozole + palbociclib and different doses of PF-07220060.

[0207] Furthermore, based on the safety findings in Part 1A, the starting dose of Compound A in the combination may be further adjusted to a lower dose.

[0208] Participants were to swallow the entire tablet of Compound A and not manipulate or chew the study intervention before swallowing. All cohorts were administered Compound A orally QD on a continuous basis. The once-daily dose was administered over a 24±3 hour period (i.e., intervals of no less than 21 hours and no more than 27 hours). All cycles were 28 days long.

[0209] Fulvestrant 500 mg was administered intramuscularly slowly into the buttocks as two 5 mL injections (1 to 2 minutes per injection), once in each buttock and monthly thereafter, according to the product label and following its local prescribing information.

[0210] According to the product label and following its local prescribing information, letrozole was administered orally at 2.5 mg once daily (QD) as a continuous daily dosing schedule.

[0211] For each 28-day cycle, palbociclib was administered orally once daily at 125 mg / day for 21 days, according to the product label and following its local prescribing information, followed by 7 days off treatment.

[0212] PF-07220060 was administered orally twice daily (BID) at 100 mg or 300 mg.

[0213] Treatment continued until disease progression, uncontrolled toxicity, patient or investigator decision to discontinue treatment, or study termination.

[0214] Patients who experienced toxicity, including dose-limiting toxicity (DLT), were managed by dose modification or treatment discontinuation.

[0215] definition:

[0216] As used herein, "dose-limiting toxicity" (DLT) refers to the dose of Compound A that prohibits further dose escalation. For monotherapy dose escalation (Part 1A) and combination dose escalation (Part 1B and Part 1C), any of the following adverse events (AEs) attributable to Compound A or any combination therapy agent (if applicable) occurring in the first treatment cycle (28 days) were classified as DLTs:

[0217] Blood dose-limiting toxicity:

[0218] Any grade ≥ 4 hematologic AE that may be related to treatment was considered a DLT, as described below:

[0219] ●Grade 4 neutropenia was a DLT regardless of intervention.

[0220] Febrile neutropenia (defined as an absolute neutrophil count (ANC) <1000 / mm3 with a single temperature >38.3°C [101°F] or a temperature ≥38°C [100.4°F] for more than one hour) is a DLT.

[0221] ●Grade 3 neutropenia with infection is a DLT.

[0222] ●Grade 3 neutropenia lasting for >7 days is a DLT.

[0223] ●Grade 4 thrombocytopenia is a DLT.

[0224] ●Grade 3 thrombocytopenia with bleeding or requiring platelet transfusion is a DLT.

[0225] ●Grade 4 anemia is a DLT.

[0226] ●Grade 3 anemia requiring transfusion is a DLT.

[0227] Non-hematologic dose-limiting toxicities:

[0228] Any non-hematologic AE of grade ≥3 that may be related to treatment was considered a DLT, as described below:

[0229] ●Grade ≥3 nausea, vomiting, or diarrhea that persists for ≥3 days despite adequate antiemetics and other supportive care is a DLT.

[0230] ● Grade ≥3 fatigue lasting ≥5 days is a DLT.

[0231] ●Confirmed drug-induced liver injury (DILI) that meets Hy's law criteria is a DLT.

[0232] ●For participants with grade 2 liver transaminase or alkaline phosphatase levels due to liver or bone metastases at baseline, aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >8x upper limit of normal (ULN) or AST or ALT >5x ULN for ≥14 days will be considered a DLT.

[0233] ●After review by the investigator and sponsor, clinically important or persistent toxicities not included in the above criteria (e.g., toxicities resulting in significant dose delays) may also be considered DLTs. All DLTs were required to represent a clinically significant change from baseline.

[0234] ●Grade 3 or higher QTc prolongation is considered a DLT.

[0235] ●Allergic reactions of grade 3 or higher are considered DLTs.

[0236] Any toxicity resulting in a dose delay of greater than 2 weeks was a DLT. In addition, any grade 5 AE (death) that was unclear due to underlying disease or other etiology was a DLT.

[0237] Any dose reduction (per protocol) due to a treatment-related AE during the first 28 days will be considered as a participant experiencing a DLT.

[0238] 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. MTD is defined as the dose with a true DLT rate from the target toxicity interval. The target interval for the DLT rate is defined as (0.16, 0.33).

[0239] II. Security

[0240] Dose-limiting toxicity (DLT)

[0241] Patients were classified as DLT evaluable if they experienced a DLT or received >75% of the planned dose and had received all pre-arranged safety assessments during the DLT window. As of March 23, 2022, 19 patients were treated with monotherapy dose escalation, 6 participants were treated with 15mg QD, 7 patients were treated with 8mg QD, 4 patients were treated with 5mg QD, and 2 participants were treated with 2mg QD. Four participants were treated with a combination dose escalation of 5mg QD+fulvestrant. Three dose-limiting toxicities (DLTs) were reported during this study. Among them, 1 DLT was reported at 2mg QD (monotherapy escalation), 1 DLT was reported at 8mgQD (monotherapy escalation), and 1 DLT was reported at 5mg QD+fulvestrant (combination escalation).

[0242] All 3 DLTs were grade 3 neutropenia (decreased neutrophil count).

[0243] Adverse Events

[0244] Adverse events (AEs) in patients administered Compound A in the Phase 1 clinical trial were coded according to the Medical Dictionary for Regulatory Activities (MedDRA) version 24.1. The severity of adverse events was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.

[0245] All-Causality Adverse Events Emerging from Treatment

[0246] As of March 23, 2022, 31 patients given Compound A experienced at least one treatment-emergent adverse event (TEAE). The most common TEAEs occurring in ≥20% of patients were taste disturbance (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%).

[0247] All-cause grade 3 TEAEs 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%).

[0248] One grade 4 (hypercalcemia) and one grade 5 (pneumonitis) (N=1, 3.2%) TEAE were reported.

[0249] Treatment-related adverse events due to treatment

[0250] As of March 23, 2022, 31 patients given Compound A experienced at least one treatment-related adverse event (TRAE). The most common TRAEs occurring in ≥20% 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%).

[0251] 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%).

[0252] One grade 5 treatment-related AE, pneumonitis, was reported (N=1, 3.2%). There were no grade 4 treatment-related AEs.

[0253] All-cause and treatment-related serious adverse events (SAEs)

[0254] As of March 23, 2022, a total of ten (10) all-cause SAEs were reported in eight (8) patients (Table 2). Two (2) treatment-related SAEs, pneumonia and hypotension, were reported (Table 3).

[0255] Table 2. Summary of Serious Adverse Events - All Causes (by Patient Frequency)

[0256] Preferred Events total COVID-19 2 Low blood pressure 2 Bone pain 1 Difficulty swallowing 1 embolism 1 Side pain 1 hematuria 1 pneumonia 1 Total number of cases 9 Total events 10 Total number of subjects 8

[0257] Table 3. Summary of Serious Adverse Events—Treatment-Related (by Patient Frequency)

[0258]

[0259]

[0260] III. Efficacy

[0261] As of March 23, 2022, signs of efficacy were observed in patients with ER+HER2- breast cancer during dose escalation. Additional analyses are ongoing in dose expansion.

[0262] IV. Patient Population

[0263] The demographic characteristics of patients treated with Compound A in the Phase I study are shown in Tables 4 and 5.

[0264] Table 4. Demographic characteristics of the Phase I study

[0265]

[0266]

[0267] Table 5. Demographic characteristics of the Phase I study

[0268]

[0269] Example 2A: Safety and Efficacy Update for Parts 1A and 1B – Data Cutoff 2022 September 30

[0270] As of the data cutoff date of September 30, 2022, the safety and efficacy of Compound A are being evaluated in the ongoing first-in-human Phase 1 study described in Example 2. Overall, 29 patients were 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). In patients with ER+HER2- breast cancer, dose expansion cohorts as monotherapy and in combination with Fulvestrant are ongoing.

[0271] I. Safety Update for Part 1A and Part 1B – Data Cutoff Date is September 30, 2022

[0272] As of September 30, 2022, 25 patients were treated in dose escalation as monotherapy, 6 patients were treated at 15 mg QD, 7 patients were treated at 8 mg QD, 4 patients were treated at 5 mg QD, 4 patients were treated at 2 mg QD and 4 patients were treated at 1 mg QD. Four patients were treated in dose escalation of the combination of 5 mg QD + fulvestrant.

[0273] Compound A was well tolerated. The MTD for Compound A was not determined; 5 mg QD was determined to be the RDE for both Compound A monotherapy and in combination with fulvestrant.

[0274] Dose-limiting toxicity (DLT)

[0275] As of September 30, 2022, 3 dose-limiting toxicities (DLTs) were observed in 29 patients given Compound A in Part 1A (monotherapy escalation) and Part 1B (combination escalation). Among them, 1 DLT was reported at 2 mg QD (monotherapy escalation), 1 DLT was reported at 8 mg QD (monotherapy escalation), and 1 DLT was reported at 5 mg QD + Fulvestrant (combination escalation). All 3 DLTs were grade 3 neutropenia (decreased neutrophil count): 2 in Part 1A (8 mg and 2 mg QD) and 1 in Part 1B (5 mg QD).

[0276] Adverse Events

[0277] Adverse events (AEs) in patients administered Compound A in the Phase 1 clinical trial were coded according to the Medical Dictionary for Regulatory Activities (MedDRA) version 24.1. The severity of adverse events was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.

[0278] Treatment-emergent adverse events (TEAEs)

[0279] As of September 30, 2022, of the 29 patients administered Compound A in Part 1A (monotherapy escalation) and Part 1B (combination escalation), 28 (96.6%) patients 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 (AST) (N=8, 27.6%); increased alanine aminotransferase (ALT) (N=6, 20.7%); and decreased appetite (N=6, 20.7%).

[0280] All-cause Grade ≥3 TEAEs included decreased neutrophil count / 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, 3.4% each). Among Grade ≥3 neutropenia, 1 case (N=6, 16.7%) was reported at 15 mg QD (Part 1A), 2 cases (N=7, 28.6%) were reported at 8 mg QD (Part 1A), 1 case (N=4, 25%) was reported at 5 mg QD (Part 1A), 1 case (N=4, 25%) was reported at 2 mg QD (Part 1A), and 1 case (N=4, 25%) was reported at 5 mg QD (Part 1B). In Grade ≥3 anemia, 3 cases (N=6, 50.0%) were reported at 15 mg QD (Part 1A), 1 case (N=7, 14.3%) was reported at 8 mg QD (Part 1A), and 1 case (N=4, 25%) was reported at 5 mg QD (Part 1A). In Grade ≥3 leukopenia, 1 case (N=6, 16.7%) was reported at 15 mg QD (Part 1A) and 1 case (N=7, 14.3%) was reported at 8 mg QD (Part 1A). Grade ≥3 diarrhea, fatigue, thrombocytopenia, hypotension, decreased lymphocyte count, and pneumonia (N=1, 3.4%) were each reported at 15 mg QD (Part 1A).

[0281] Treatment-related adverse events (TRAEs)

[0282] As of September 30, 2022, of the 29 patients administered Compound A in Part 1A and Part 1B, 27 (93.1%) patients 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).

[0283] In Part 1A and Part 1B, TRAEs (any grade) 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%); most TRAEs were G1-2. TRAEs ≥G3 in >1 patient were neutropenia (6 / 29; 21%), anemia (5 / 29; 17%), and decreased WBC (2 / 29; 7%).

[0284] TRAEs ≥ Grade 3 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).

[0285] II. Efficacy

[0286] As of September 30, 2022, confirmed and durable clinical responses were observed in heavily treated patients with ER+HER2- breast cancer.

[0287] Confirmed 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.

[0288] Among response-evaluable patients (n=22), confirmed and durable partial responses (PR) were observed in 3 patients with ER+ / HER2- breast cancer, including 1 patient in Part 1A (8 mg monotherapy) and 2 patients in Part 1B (5 mg QD / fulvestrant 500 mg); Figure 4 ).

[0289] Duration of response (DOR): 19.4 months in 1 patient in Part 1A and 8.1 months and 10 months in 2 patients in Part 1B.

[0290] Stable disease (SD) was observed in 9 patients (out of 18) in Part 1A and 1 patient (out of 4) in Part 1B; of these, 5 had ER+ / HER2- breast cancer, 4 had CRPC, and 1 had NSCLC.

[0291] Three patients had SD lasting ≥6 months; the duration of SD was 11.3 months (patient with CRPC; 15 mg QD), 9.1 months (patient with CRPC; 5 mg QD), and 7.5 months (patient with ER+ / HER2- breast cancer; 8 mg QD).

[0292] III. Patient Population

[0293] Patient demographics and baseline characteristics of Part 1A patients as of September 30, 2022 are shown in Table 6.

[0294] Table 6. Demographics and Baseline Characteristics (Part 1A + Part 1B) (N=29)

[0295]

[0296] *Eastern Cooperative Oncology Group performance status

[0297] Most patients were white (48.3%) or Asian (27.6%); median age was 67 (range: 48 to 90) years. Among patients with advanced or metastatic ER+ / HER2- breast cancer, the majority (81.3%) received >3 prior lines of systemic anticancer therapy.

[0298] A total of 83% (Part 1A) and 75% (Part 1B) of patients with advanced or metastatic ER+ / HER2- breast cancer had received >3 prior lines of systemic anticancer therapy. All patients with advanced or metastatic ER+ / HER2- breast cancer (n=16) received prior endocrine therapy and 15 patients received prior CDK4 / 6 inhibitors.

Claims

1. A method for treating cancer comprising administering to a subject in need thereof a daily dose of about 0.1 mg to about 15 mg of a lysine acetyltransferase 6 (KAT6) inhibitor having the following structure or a pharmaceutically acceptable salt thereof 2. A method for treating cancer comprising administering to a subject in need thereof a daily dose of 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 in combination with: a) a certain amount of a cyclin-dependent kinase 4 (CDK4) inhibitor; b) an amount of an anti-estrogen; or c) a certain amount of a CDK4 inhibitor and a certain amount of an anti-estrogen.

3. The method of claim 1 or 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 a day (QD).

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

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

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

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

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

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

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

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

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

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

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

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