Combinations of estrogen receptor degraders and KAT6 inhibitors

Abstract

Disclosed herein are methods for treating cancer comprising administering to a subject an estrogen receptor degrader in combination with a KAT6 inhibitor.

Description

[0001] PC073243A

[0002] - 1 -

[0003] COMBINATIONS OF ESTROGEN RECEPTOR DEGRADERS AND KAT6 INHIBITORS

[0004] Background of the Invention

[0005] Certain bifunctional compounds target specific cellular proteins for degradation via the 5 ubiquitin-proteasome system. Examples of such proteolysis targeting chimeric compounds ( / .e., “PROTAC protein degraders”) that target the Estrogen Receptor (ER) for ubiquitination and subsequent degradation are disclosed in International Publication No. WO 2018 / 102725, which is incorporated herein by reference in its entirety. Such bifunctional molecules exhibit a range of pharmacological activities consistent with the degradation of the ER including, but not limited to, 10 treatment or amelioration of a disease condition such as cancer (e.g., breast cancer, uterine cancer, ovarian cancer, prostate cancer, endometrial cancer), or endometriosis.

[0006] A bifunctional molecule of particular interest is vepdegestrant (i.e., (S)-3-(5-(4-((1-(4- ((1 R,2S)-6-hydroxy-2-phenyl-1 ,2,3,4-tetrahydronaphthalen-1 -yl)phenyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione or (3S)-3-[1 ,3-dihydro-1-oxo- 5-[4-[[1 -[4-[(1 R,2S)-1 ,2,3,4-tetrahydro-6-hydroxy-2-phenyl-1 -naphthalenylphenyl]-4- piperidinyl]methyl]-1 -piperazinyl]-2 / - / -isoindol-2-yl]-2,6-piperidinedione (referred to herein as “Compound A” of “Compd A”), which has the molecular formula of C45H49N5O4 and the following structure:

[0007]

[0008] 20 Compound A is under development as a PROTAC protein degrader that targets estrogen receptor (ER) for the potential treatment of breast cancer and has been shown to be a useful modulator of targeted protein ubiquitination and degradation via the ubiquitin-proteasome pathway.

[0009] Compound A and pharmaceutically acceptable salts thereof are disclosed in 25 International Publication No. WO 2018 / 102725 and U.S. Patent Nos. 10,647,698, 10,899,742 and 11 ,104,666; International Publication No. WO 2021 / 041348; U.S. Serial No. 17 / 472,847; U.S. Serial No. 17 / 548,842; and U.S. Serial No. 17 / 873,748. The contents of each of the foregoing references are incorporated herein by reference in their entirety.KAT6A and KAT6B are histone lysine acetyltransferases that acetylate H3K23, and their enzymatic functions are involved in fundamental cellular processes, including gene transcription, cellular 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 a variety of cancers with KAT6A amplifications and over-expression observed in breast cancer, prostate cancer, ovarian cancer, uterine cervix cancer, lung adenocarcinoma, colon & rectal adenocarcinomas and medulloblastoma (Yu, L., et al., Identification of MYST3 as a novel epigenetic activator of ERa frequently amplified in breast cancer. Oncogene 20 7. 36(20) :2910-8; Tsherniak, A., et al., Defining a cancer dependency map. Ce / / 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 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 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 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, prostate and NSCLC.

[0010] Prifestrastat, 2-methoxy- / V-{4-methoxy-6-[(1 / 7-pyrazol-1-yl)methyl]-1 ,2-benzoxazol-3-yl}benzene-1 -sulfonamide, also known by its synonym M-(6-((1 H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-2-methoxybenzenesulfonamide (referred to herein as “Compound B” or “Compd B”), having the following structure:

[0011]

[0012] that is useful in the treatment of cancer. Compound A is a potent and selective catalytic inhibitor of KAT6 histone acetyltransferases, KAT6A and KAT6B. In an ongoing phase 1 / 2 study, Compound B in combination with fulvestrant demonstrated a tolerable safety profile and durable anti-tumor activity in patients with heavily pretreated estrogen receptor positive (ER+) human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer(Mukohara et al., Nat Med. 2024; 30(8):2242-2250). Compound B in combination with fulvestrant is currently in a phase 3 clinical trial.

[0013] Preparation of Compound B, including an anhydrous crystalline Form 1 of Compound B free acid, is described in International Publication No. WO 2020 / 254946 and in U.S. Patent No.

[0014] 11 ,492,346. Combination therapies including Compound B are described in International Publication No. WO 2022 / 013369. The contents of each of the foregoing documents are incorporated herein by reference in their entireties.

[0015] There remains a need for new therapeutic methods and improved therapies for the treatment of cancers, particularly for the treatment of breast cancer. The combinations of the present invention are believed to have one or more advantages, such as an increase in objective response rate or an increase in survival, including progression free survival or overall survival, as compared to treatment of either therapeutic agent alone or as compared to a comparator in a clinical trial; potential to reduce adverse events or an adverse event profile, as compared to treatment of either therapeutic agent alone or as compared to a comparator in a clinical trial; greater efficacy as compared to treatment with either therapeutic agent alone or as compared to a comparator in a clinical trial; potential to enable an improved dosing schedule; potential to overcome resistance mechanisms, and the like.

[0016] Summary of the Invention

[0017] The present invention provides, in part, methods for administering an estrogen receptor degrader, such as Compound A, or a pharmaceutically acceptable salt thereof, and a KAT6 inhibitor, such as Compound B, or a pharmaceutically acceptable salt thereof, in combination therapies, for the treatment of cancer, and particularly, breast cancer. This summary is provided to introduce a selection of concepts in a simplified form that are further described below in the detailed description. This summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used in isolation as an aid in determining the scope of the claimed subject matter.

[0018] According to Embodiment 1 of the invention, there is provided a method for treating cancer comprising administering to a subject in need thereof an amount of Compound A:

[0019]

[0020] (Compound A), or a pharmaceutically acceptable salt thereof, and an amount of Compound B:

[0021]

[0022] (Compound B), or a pharmaceutically acceptable salt thereof,

[0023] wherein the amounts together are therapeutically effective in treating cancer.

[0024] Described below are embodiments of the invention, where for convenience Embodiment 1 (E1) is identical to the embodiments provided above.

[0025] 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.

[0026] Detailed Description of the Invention

[0027] The present invention may be understood more readily by reference to the following detailed description of the embodiments of the invention. It is to be also understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to be limiting.

[0028] E1 A method of treating cancer, as defined thereof.

[0029] E2 A method of embodiment 1 , wherein the amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 200 mg.E3 A method of embodiment 1 , wherein the amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 100 mg.

[0030] E4 A method of any one of embodiments 1 to 3, wherein the amount of Compound A, or a pharmaceutically acceptable salt thereof, is administered once a day (QD).

[0031] E5 A method of any one of embodiments 1 to 4, wherein the amount of Compound B, or a pharmaceutically acceptable salt thereof, is about 1 mg, about 2 mg, about 3 mg, about 4 mg, or about 5 mg.

[0032] E6 A method of any one of embodiments 1 to 5, wherein the amount of Compound B, or a pharmaceutically acceptable salt thereof, is about 5 mg.

[0033] E7 A method of any one of embodiments 1 to 6, wherein the amount of Compound B, or a pharmaceutically acceptable salt thereof, is administered once a day (QD).

[0034] E8 A method of any one of embodiments 1 to 7, wherein the Compound B is administered concurrently or sequentially.

[0035] E9 A method of any one of embodiments 1 to 7, wherein the Compound B is administered concurrently or sequentially with the administration of Compound A.

[0036] E10 A method of any one of embodiments 1 to 7, wherein the Compound B is administered intermittently.

[0037] E11 A method of any one of embodiments 1 to 7, wherein the Compound B is administered intermittently with the administration of Compound A.

[0038] E12 A method of any one of embodiments 1 to 11 , wherein the Compound A, or a pharmaceutically acceptable salt thereof, is administered orally to the subject.

[0039] E13 A method of any one of embodiments 1 to 12, wherein the Compound B, or a pharmaceutically acceptable salt thereof, is administered orally to the subject.

[0040] E14 A method of any one of embodiments 1 to 13, wherein the subject is in a fed state.E15 A method of any one of embodiments 1 to 14, 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.

[0041] E16 A method of embodiment 15, wherein the cancer is breast cancer, lung cancer, prostate cancer, pancreatic cancer, or ovarian cancer.

[0042] E17 A method of embodiment 16, wherein the cancer is breast cancer, lung cancer, or prostate cancer.

[0043] E18 A method of embodiment 17, wherein the cancer is breast cancer.

[0044] E19 A method of embodiment 18, wherein the breast cancer is metastatic or locally advanced.

[0045] E20 A method of embodiment 18 or embodiment 19, wherein the breast cancer is estrogen receptor positive (ER+) breast cancer.

[0046] E21 A method of embodiment 18 or embodiment 19, wherein the estrogen receptor positive (ER+) breast cancer is ESR1 -mutant ER+ breast cancer.

[0047] E22 A method of embodiment 18 or embodiment 19, wherein the estrogen receptor positive (ER+) breast cancer is ESR1 wildtype ER+ breast cancer.

[0048] E23 A method of embodiment 20, wherein the estrogen receptor positive (ER+) breast cancer is human epidermal growth factor receptor 2 negative (HER2-).

[0049] E24 A method of any one of embodiments 1 to 23, wherein the subject is human.

[0050] E25 A method of embodiment 24, wherein the human is an adult human.

[0051] The methods of the present invention may be beneficial for treating cancer (e.g., breast cancer), and, indeed, may have one or more advantages or increased benefits when Compound A is used in combination with another therapy, specifically a KAT6 inhibitor. For example, it is believed that the combination of Compound A and Compound B may showimproved safety and efficacy; potential to reduce side effects, including adverse events; potential to overcome resistance mechanisms, such as resistance to endocrine therapy; and potential to achieve similar or improved safety and efficacy through dose modification or dosing regimens; over the monotherapies of Compound A and Compound B alone, or over standard of care therapies.

[0052] In ER+ breast cancer, KAT6A is a direct transcriptional regulator of ESR1 and promotes growth of ER+ breast cancer cells by driving ER signaling (See Yu L, et al.). KAT6A may also promote cell proliferation by upregulating MYC transcriptional programs along with inhibition of cellular senescence via the INK4A-ARF pathway (Baell JB, Leaver DJ, Hermans SJ, et al., Inhibitors of histone acetyltransferases KAT6A / B induce senescence and arrest tumour growth. Nature. 2018;560(7717):253- 57; Sheikh BN, Phipson B, El-Saafin F, et al., MOZ (MYST3, KAT6A) inhibits senescence via the INK4A-ARF pathway. Oncogene.

[0053] 2015;34(47):5807-20; Hu Z, Zhou J, Jiang J, et al. Genomic characterization of genes encoding histone acetylation modulator proteins identifies therapeutic targets for cancer treatment. Nat Common. 2019;10(1 ):733; and Scher HI, Morris MJ, Stadler WM, et al., Trial Design and Objectives for Castration- Resistant Prostate Cancer: Updated Recommendations from the Prostate Cancer Clinical Trials Working Group 3. J Clin Oncol. 2016;34(12) :1402-18) . Based on the mechanistic overlap of KAT6A activity in breast cancer with cell cycle inhibitors or endocrine therapy, along with its other distinct mechanisms of action, treatment with the combination of a KAT6 inhibitor, such as Compound B, and ER antagonists or degraders, such as fulvestrant or Compound A, may have increased benefit in ER+ breast cancer patients. While fulvestrant is a selective ER degrader that has demonstrated meaningful efficacy in patients with WT ESR1, emergence of ESR1 mutations (Y537S, D538G) in patients frequently results in fulvestrant resistance. Compound B has demonstrated, in non-clinical studies, potent and robust ER degradation and inhibited, tumor growth in multiple mouse xenograft models in vivo, including in an ESR1 mutant patient-derived xenograft model. Compound B has demonstrated greater ER degradation compared to other novel SERDs in clinical development such as elacestrant / RAD1901.

[0054] Definitions

[0055] Unless otherwise defined herein, scientific, and technical terms used in connection with the present invention have the meanings that are commonly understood by those of ordinary skill in the art.

[0056] The invention described herein suitably may be practiced in the absence of any element(s) not specifically disclosed herein.As used herein, the singular form “a,” “an,” and “the” include plural references unless indicated otherwise. For example, “a” substituent includes one or more substituents.

[0057] As used herein, the term “about” when used to modify a numerically defined parameter (e.g., the dose of a compound) means that the parameter may vary by as much as 10% below or above the stated numerical value for that parameter. For example, a dose of about 5 mg means 5 mg ± 10%, i.e., it may vary from 4.5 mg to 5.5 mg.

[0058] As used herein, terms, including, but not limited to, “agent,” “composition,” “compound,” “drug,” and “therapeutic agent”, “study intervention”, and “study treatment” may be used interchangeably to refer to compounds included in the methods and uses of the present disclosure.

[0059] As used herein, the terms, “subject,” “participant,” and “patient,” are used interchangeably, to refer to any animal, including mammals. Mammals according to the disclosure include canine, feline, bovine, caprine, equine, ovine, porcine, rodents, lagomorphs, primates, humans, and the like, and encompass mammals in utero. In embodiments, humans are suitable subjects. Human subjects may be of any gender and at any stage of development.

[0060] The term “standard of care” therapy refers to the widely accepted, evidence-based treatment that medical experts consider the most effective for a specific type and stage of cancer. One of skill in the art would be able to identify the standard of care therapy for a particular type and stage of cancer.

[0061] The term “endocrine therapy”, which is also known as hormone therapy, as used herein, relates to treatment that adds, blocks or removes hormones. In the treatment of breast cancer, there are two types of endocrine therapy: drugs that stop estrogen and progesterone from helping breast cancer cells grow and drugs that keep to ovaries from making the hormones. Endocrine therapy drugs used in the treatment of breast cancer include, but are not limited to, anastrozole, exemestane, fulvestrant, goserelin, letrozole, leuprorelin, megestrol, tamoxifen, and toremifene.

[0062] 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 spectrum of CDKs or selective CDK inhibitors that target specific CDK(s). 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).

[0063] As used herein, the term “locally advanced or metastatic second line (2L) ER+HER2-breast cancer” refers to breast cancers in subjects who have received prior hormonal / endocrine therapy and chemotherapy in the locally advanced / metastatic setting and whose breast cancers have progressed. The term “(2L+)”, as related to lines of treatment for cancer, refers to secondline and move advanced lines of treatment. The term “(2-4L)”, as related to lines of treatment for cancer, refers to second to forth lines of treatment.

[0064] Compound A, having the structure:

[0065]

[0066] Compound A is a Biopharmaceutics Classification System Class IV compound (low solubility / low permeability). Compound A may interconvert to its epimer, Compound C (or “Compd C”):

[0067]

[0068] Preclinical data demonstrates that the exposure of Compound C is limited compared to Compound A (<26%). Compound C does not degrade the estrogen receptor; however, Compound C shows similar antagonism of ER-dependent transcription compared to Compound A.

[0069] As used herein, a “KAT6 inhibitor” includes an inhibitor of KAT6A, an inhibitor of KAT6B, and an inhibitor of KAT6A and KAT6B. KAT6 inhibitors are disclosed in International Publication No. WO2019 / 043139A1 ; International Publication No WO2019 / 243491 A1 ; International Publication No. W02020 / 002587; and International Application Serial No. PCT / IB2020 / 055667. The contents of each of the foregoing references are incorporated herein by reference in their entirety.

[0070] Another embodiment relates to the pharmaceutically acceptable salts of the compounds described herein. Pharmaceutically acceptable salts of the compounds described herein include the acid addition and base addition salts thereof.Another embodiment also relates to the pharmaceutically acceptable acid addition salts of the compounds described herein. Suitable acid addition salts are formed from acids which 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, the acetate, acid citrate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulphate / sulphate, bitartrate, borate, camsylate, citrate, cyclamate, edisylate, esylate, ethanesulfonate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methanesulfonate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, p-toluenesulfonate, tosylate, trifluoroacetate and xinofoate salts.

[0071] Additional embodiments relate to base addition salts of the compounds described herein. Suitable base addition salts are formed from bases which form non-toxic salts. Nonlimiting examples of suitable base salts include the aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.

[0072] The compounds described herein that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may 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 the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1 ,1’-methylene-bis-(2-hydroxy-3-naphthoate)] salts. The compounds described herein that include a basic moiety, such as an amino group, may form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above.

[0073] The chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of those compounds of the 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 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 suchas N-methylglucamine-(meglumine), and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines.

[0074] Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.

[0075] For a review on 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 compounds described herein are known to one of skill in the art.

[0076] Administration and Dosina

[0077] The terms “treat” and “treating” a cancer or a cancer-associated disease, as used herein, mean to administer a combination therapy according to the present disclosure to a subject, participant or patient having a cancer, or diagnosed with a cancer, to achieve at least one positive therapeutic effect, such as, for example, reduced number of cancer cells, reduced tumor size, reduced rate of cancer cell infiltration into peripheral organs, or reduced rate of tumor metastasis or tumor growth, reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The terms “treatment” and “therapy,” as used herein, unless otherwise indicated, refer to the act of treating as “treating” is defined immediately above. For the purposes of this disclosure, beneficial or desired clinical results include, but are not limited to, one or more of the following: reducing the proliferation of (or destroying) neoplastic or cancerous cell; inhibiting metastasis or neoplastic cells; shrinking or decreasing the size of tumor; remission of the cancer; decreasing symptoms resulting from the cancer; increasing the quality of life of those suffering from the cancer; decreasing the dose of other medications required to treat the cancer; delaying the progression the cancer; curing the cancer; overcoming one or more resistance mechanisms of the cancer; and / or prolonging survival of patients the cancer.

[0078] Positive therapeutic effects in cancer may be measured in a number of ways (see, for example, W. A. Weber, J. Nucl. Med. (2009) 50:1S-10S).

[0079] “Fed condition” or “fed state” as used to describe a subject herein, means that the subject has eaten less than 4 hours before a time point of interest, such as the time of administering Compound A or Compound B. In embodiments, a subject in the fed state has not eaten for at most any of 4, 3, 2, 1 , or 0.5 hours prior to administration of Compound A or Compound B.

[0080] An “amount” for use and for treating a subject refers to an amount that provides, in single or multiple doses, in combination with one or more other agents, a detectable responseof any duration of time (transient, medium, or long term), a desired outcome in or an objective or subjective benefit to a subject of any measurable or detectable degree or for any duration of time (e.g., for hours, days, months, years, in remission or cured). Such amounts typically are effective to ameliorate a disease, or one, multiple or all adverse effects / symptoms, consequences, or complications of the disease, to a measurable extent, although reducing or inhibiting a progression or worsening of the disease, or providing stability (i.e., not worsening) state of the disease, is considered a satisfactory outcome. The term “therapeutically effective amount” also means an amount of an agent in combination with one or more other agents, effective for producing a desired therapeutic effect upon administration to a subject, for example, to stem the growth, or result in the shrinkage, of a cancerous tumor. In reference to the treatment of cancer, a therapeutically effective amount refers to that amount that has the effect of (1) reducing the size of the tumor, (2) inhibiting (that is, slowing to some extent, preferably stopping) tumor metastasis emergence, (3) inhibiting to some extent (that is, slowing to some extent, preferably stopping) tumor growth or tumor invasiveness, and / or (4) relieving to some extent (or, preferably, eliminating) one or more signs or symptoms associated with the cancer. Therapeutic or pharmacological effectiveness of the doses and administration regimens also may be characterized as the ability to induce, enhance, maintain, or prolong disease control and / or overall survival in patients with these specific tumors, which may be measured as prolongation of the time before disease progression.

[0081] As used herein, “ameliorate” refers to any reduction 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 disease or of a subject’s condition.

[0082] As used herein, “daily dose” refers to a dose that is administered each day, such as an amount of Compound A that is administered each day or an amount of Compound B that is administered each day.

[0083] The daily dose or daily dosage of Compound A, or a pharmaceutically acceptable salt thereof, is the free base equivalent of Compound A. Dosage amounts provided herein refer to the dose of the free base form of Compound A, or are calculated as the free base equivalent of an administered Compound A salt form. For example, a dosage or amount of Compound A, such as about 100 mg or about 200 mg refers to the free base equivalent.

[0084] The daily dose or daily dosage of Compound B, or a pharmaceutically acceptable salt thereof, is the free base equivalent of Compound B. Dosage amounts provided herein refer to the dose of the free base form of Compound B, or are calculated as the free base equivalent of an administered Compound B salt form. For example, a dosage or amount of Compound B, such as about 1 mg, about 2 mg, about 3 mg, about 4 mg or about 5 mg refers to the free base equivalent.Embodiments of the present invention provide a dose, dosage, and dosing regimen comprising administering to a subject an amount, or an effective amount of Compound A, or a pharmaceutically acceptable salt thereof. The amount, or the therapeutically effective amount, may be a daily dose of about 200 mg. In another embodiment, a daily dose is about 100 mg. A daily dose of 200 mg is a preferred starting dose. A daily dose of 100 mg is a preferred dose for a dose reduction.

[0085] Embodiments of the present invention provide a dose, dosage and dosing regimen comprising administering to a subject an amount, or a therapeutically effective amount, of Compound B, or a pharmaceutically acceptable salt thereof. The amount, or the therapeutically effective amount, may be a daily dose in the range of from about 0.1 mg to about 15 mg. In another embodiment, a daily dose is from about 1 mg to about 15 mg, a daily dose is from about 1 mg to about 10 mg, from about 1 mg to about 8 mg, a daily dose is from about 0.1 mg to about 8 mg, from about 1 mg to about 5 mg, from about 0.1 mg to about 5 mg, or from about 0.5 mg to about 5 mg. In another embodiment, a daily dose is from about 0.1 mg to less than 1 mg or from about 0.1 mg to about 0.75 mg. In preferred embodiments, 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 more preferred embodiments, 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 preferred embodiments, 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 more preferred embodiments, the daily dose is 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, or 5 mg.

[0086] In embodiments, the daily dose of Compound A, or a pharmaceutically acceptable salt thereof, is administered once a day (QD).

[0087] In embodiments, the daily dose of Compound B, or a pharmaceutically acceptable salt thereof, is administered once a day (QD).

[0088] The compounds disclosed herein may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the bloodstream directly from the mouth.

[0089] In embodiments, the daily dose of Compound A, or a pharmaceutically acceptable salt thereof, is administered orally.

[0090] In embodiments, the daily dose of Compound B, or a pharmaceutically acceptable salt thereof, is administered orally.

[0091] Compound A, or a pharmaceutically acceptable salt thereof, may be present in a pharmaceutical composition, which includes a pharmaceutically acceptable excipient.

[0092] Compound B, or a pharmaceutically acceptable salt thereof, may be present in a pharmaceutical composition, which includes a pharmaceutically acceptable excipient. A“pharmaceutically acceptable excipient” refers to a component that may be included in the compositions described herein, is physiologically suitable for pharmaceutical use, and causes no significant adverse effects nor therapeutic effects to a subject. The term “excipient” is used herein to describe any ingredient other than the compound(s) of the invention. The choice of excipient will to a large extent 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.

[0093] The compounds of the methods, uses, or combinations of the present invention may be formulated prior to administration. The formulation preferably will be adapted to the particular mode of administration. These compounds may be formulated with pharmaceutically acceptable excipients as known in the art and administered in a wide variety of dosage forms as known in the art. Dosage unit forms or pharmaceutical compositions suitable for oral administration include, but are not limited to tablets, capsules, such as gelatin capsules, pills, powders, granules, aqueous, and nonaqueous oral solutions and suspensions, packaged in containers adapted for subdivision into individual doses.

[0094] Repetition of the administration or dosing regimens may be conducted as necessary to achieve the desired reduction or diminution of cancer cells. A “continuous dosing schedule,” as used herein, is an administration or dosing regimen without dose interruptions, e.g., without days off treatment. Repetition of 28-day treatment cycles without dose interruptions between the treatment cycles is an example of a continuous dosing schedule. In embodiments, the compounds of the combination of the present invention may be administered in a continuous dosing schedule. In embodiments, the compounds of the combination disclosed herein may be administered concurrently in a continuous dosing schedule.

[0095] Also disclosed herein are kits comprising the therapeutic agents of the combination of the present disclosure and written instructions for administration of the therapeutic agents. In embodiments, the written instructions elaborate and qualify the modes of administration of the therapeutic agents, for example, for simultaneous or sequential administration of the therapeutic agents of the present disclosure. In embodiments, the written instructions elaborate and qualify the modes of administration of the therapeutic agents, for example, by specifying the days of administration for each of the therapeutic agents during a 28-day treatment cycle.

[0096] Methods of Treatment

[0097] In embodiments, provided herein are methods for treating cancer in a subject comprising administering to the subject an amount of an estrogen receptor degrader, such as Compound A, as described herein in combination with an amount of a KAT6 inhibitor, such as Compound B.The term “combination,” or “combination therapy” as used herein, unless otherwise indicated, refers to the use of Compound A with one or more therapeutic agents, wherein Compound A and the one or more therapeutic agents are administered intermittently, concurrently, or sequentially, according to the same or different route of administration and according to the same or different dosage schedules.

[0098] The term “sequential” or “sequentially” refers to the administration of each therapeutic agent of the combination therapy of the invention, either alone or in a medicament, one after the other, wherein each therapeutic agent may be administered in any order. Sequential administration is particularly useful when the therapeutic agents in the combination therapy are in different dosage forms, for example, one agent is a tablet and another agent is a sterile liquid, and I or are administered according to different dosing schedules, for example, one agent is administered daily, and the second agent is administered less frequently such as weekly.

[0099] The term “concurrently” refers to the administration of each therapeutic agent in the combination therapy of the invention, either alone or in separate medicaments, wherein the second therapeutic agent is administered immediately after the first therapeutic agent, but that the therapeutic agents may be administered in any order. In a preferred embodiment the therapeutic agents are administered concurrently.

[0100] The term “intermittent” or “intermittently” refers to the administration of each therapeutic agent in the combination therapy of the invention, either alone or in separate medicaments, wherein one of the therapeutic agents is stopped and then restarted. Intermittent dosing may utilize regular "drug holidays" in which a patient is not exposed to drug.

[0101] The term “locally advanced,” as used herein, as it relates to cancer, may or may not be treated with curative intent. For example, locally advanced breast cancer (LABC) is defined by the U.S. National Comprehensive Cancer Network as a subset of breast cancer characterized by the most advanced breast tumors in the absence of distant metastasis, wherein the tumors are more than 5 cm in size with regional lymphadenopathy; tumors of any size with direct extension to the chest wall or skin, or both (including ulcer or satellite nodules), regardless of regional lymphadenopathy; presence of regional lymphadenopathy (clinically fixed or matted axillary lymph nodes, or any of infraclavicular, supraclavicular, or internal mammary lymphadenopathy) regardless of tumor stage. (Garg et al. Curr Oncol. 2015 Oct; 22(5): e409-10; National Comprehensive Cancer Network NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. Fort Washington, PA: NCCN; 2015. Ver. 2.2015.)

[0102] The term “metastatic” as used herein, as it relates to cancer, cannot be treated with curative intent. For example, metastatic breast cancer refers to breast cancer that has spreadbeyond the breast and nearby lymph nodes to other parts of the body, e.g., bones, liver, lungs, brain, (www.cancer.org / cancer / breast-cancer.)

[0103] Those skilled in the art will be able to recognize and diagnose locally advanced and metastatic cancer in a patient or subject.

[0104] 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).

[0105] In embodiments, the cancer is selected from lung cancer, mesothelioma, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, hepatic carcinoma, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin’s disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, hematology malignancy, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumors, glioblastoma, brain stem glioma, pituitary adenoma, head and neck cancer, and combinations of two or more of the foregoing cancers.

[0106] Also disclosed herein are methods of treating cancer in a subject. In embodiments, the methods comprise treating cancer in a subject comprising administering to the subject an amount of the compounds described herein that are effective in treating the cancer.

[0107] In embodiments, the cancer is breast, lung, colon, brain, head and neck, prostate, stomach, pancreatic, ovarian, melanoma, endocrine, uterine, testicular, orbladder.

[0108] In embodiments, the cancer is breast, lung, prostate, pancreatic, or ovarian.

[0109] In embodiments, the cancer is breast, lung, or prostate.

[0110] In embodiments, the cancer is breast cancer.

[0111] In embodiments, the breast cancer is metastatic breast cancer.

[0112] In embodiments, the breast cancer is locally advanced breast cancer.

[0113] In embodiments, the breast cancer is HR+ breast cancer.

[0114] In embodiments, the breast cancer is HR+ HER2- breast cancer.

[0115] In embodiments, the breast cancer is HR+ HER2+ breast cancer.

[0116] In embodiments, the HR+ breast cancer is PR+ and / or ER+ breast cancer.In some embodiments, the breast cancer is PR+ breast cancer.

[0117] In embodiments, the breast cancer is ER+ breast cancer.

[0118] In embodiments, the breast cancer is ER+ HER2- breast cancer.

[0119] In embodiments, the breast cancer is ER+ HER2+ breast cancer.

[0120] In embodiments, the breast cancer is locally advanced or metastatic HR+ breast cancer. In embodiments, the breast cancer is locally advanced or metastatic HR+ HER2- breast cancer.

[0121] In embodiments, the breast cancer is locally advanced or metastatic HR+ HER2+ breast cancer.

[0122] In embodiments, the breast cancer is metastatic, HR+, HER2- breast cancer.

[0123] In embodiments, the breast cancer is metastatic, HR+, HER2- breast cancerthat is also locally advanced.

[0124] In embodiments, the breast cancer is locally advanced or metastatic ER+ breast cancer. In embodiments, the breast cancer is locally advanced or metastatic ER+ HER2- breast cancer.

[0125] In embodiments, the breast cancer is locally advanced or metastatic ER+ HER2+ breast cancer.

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

[0127] In embodiments, the breast cancer is metastatic, ER+, HER2- breast cancerthat is also locally advanced.

[0128] In embodiments, the lung cancer is non-small cell lung cancer.

[0129] In embodiments, the lung cancer is locally advanced or metastatic non-small cell lung cancer.

[0130] In embodiments, the prostate cancer is CRPC.

[0131] In embodiments, the prostate cancer is locally advanced or metastatic CRPC.

[0132] Also disclosed herein are methods of treating solid tumors in a subject. In embodiments, disclosed herein are methods of treating solid tumors in a subject comprising administering to the subject an amount of the compounds described herein that are effective in treating the solid tumor.

[0133] In embodiments, the solid tumor is breast, lung, colon, brain, head and neck, prostate, stomach, pancreatic, ovarian, melanoma, endocrine, uterine, testicular, orbladder.

[0134] In embodiments, the solid tumor is breast, lung, prostate, pancreatic, or ovarian.

[0135] In embodiments, the solid tumor is breast, lung, or prostate.

[0136] In embodiments, the solid tumor is breast cancer. For example, in certain embodiments the breast cancer is HR+ breast cancer. In other embodiments, the HR+ breast cancer is PR+ and / or ER+ breast cancer ER+ breast cancer.In embodiments, the solid tumor is breast cancer. For example, in certain embodiments, the breast cancer is HR+ HER2- breast cancer or ER+ HER2- breast cancer.

[0137] In embodiments, the solid tumor is breast cancer. For example, in certain embodiments, the breast cancer is HR+ HER2+ breast cancer or ER+ HER2+ breast cancer.

[0138] In embodiments, the solid tumor is breast cancer. For example, in certain embodiments, the breast cancer is locally advanced or metastatic HR+ HER2- breast cancer or ER+ HER2-breast cancer.

[0139] In embodiments, the solid tumor is breast cancer. For example, in certain embodiments, the breast cancer is locally advanced or metastatic HR+ HER2+ breast cancer or ER+ HER2+ breast cancer.

[0140] In embodiments, the solid tumor is lung cancer. For example, in certain embodiments, the lung cancer is non-small cell lung cancer.

[0141] In embodiments, the solid tumor is lung cancer. For example, in certain embodiments, the lung cancer is locally advanced or metastatic non-small cell lung cancer.

[0142] In embodiments, the solid tumor is prostate cancer. For example, in certain embodiments, the prostate cancer is CRPC.

[0143] In embodiments, the solid tumor is prostate cancer. For example, in certain embodiments, the prostate cancer is locally advanced or metastatic castration resistant prostate cancer.

[0144] Also disclosed herein are methods of treating hematologic tumors in a subject. In certain embodiments, the method comprises treating hematologic tumors in a subject comprising administering to the subject an amount of the compounds described herein that is effective in treating the hematologic tumor.

[0145] In embodiments, the hematologic tumor is leukemia, lymphoma, or multiple myeloma. In embodiments, the hematologic tumor is leukemia or lymphoma.

[0146] Also disclosed herein are methods of treating cancer in a subject with locally advanced or metastatic HR+HER2- breast cancer, ER+HER2- breast cancer, CRPC, or NSCLC whose disease progressed on or is intolerant to standard therapy.

[0147] Also disclosed herein are methods of treating cancer in a subject with locally advanced or metastatic HR+HER2- breast cancer, ER+HER2- breast cancer, CRPC, or NSCLC whose disease progressed on or is intolerant to standard therapy.

[0148] EXAMPLESIn order that this invention may be better understood, the following examples are set forth. These examples are for purposes of illustration only and are not to be construed as limiting the scope of the invention in any manner.

[0149] Abbreviations:

[0150] BID is twice a day;

[0151] mpk is mg / kg or milligrams per kilogram;

[0152] ns is not statistically significant;

[0153] PO is orally;

[0154] QD is once daily;

[0155] SC is subcutaneous;

[0156] SEM is standard error of the mean; and

[0157] TV is tumor volume.

[0158] Example 1: Compound B Demonstrated In Vivo Combinatorial Benefit with Compound A in an ESRf-mutant ER+ Breast Cancer Patient Derived Xenoqraft (PDX) Model

[0159] In vivo studies were performed in a clinically-relevant patient-derived xenograft (PDX) model of ER+ breast cancer to evaluate the potential for Compound B in combination with Compound A to overcome endocrine therapy resistance.

[0160] Materials and Methods:

[0161] Compound B was tested in combination with Compound A and benchmarked against the combination with fulvestrant in an ESRI-mutant ER+ breast cancer in vivo model ST2056. ST2056 harbors the activating mutation Y537S in the ligand-binding domain (LBD) of ESR1, associated with resistance to endocrine therapy in the clinic. The study was conducted by XenoSTART (San Antonio, Texas), where 6-12 week-old female athymic nude mice (JAX, stock #007850) were subcutaneously implanted with ~70mg tumor fragments. Tumor measurements and animal weights were measured twice per week, and animals were randomized into treatment groups when the mean tumor volume (TV = width2x length x 0.5) reached 150-300 mm3.

[0162] The study contained six treatment groups of n=10 animals per group. The groups were as follows: 1) vehicle 2) Compound B, 3) Compound A, 4) fulvestrant, 5) Compound B + Compound A, and 6) Compound B + fulvestrant. Compound A and Compound B were dosed once daily. Fulvestrant was dosed weekly with a loading dose given on day 3 of the first week in each 4-week cycle. A vehicle was used as a negative control. Group details for dose levels, routes, and regimens are listed in Table 1. Compound and formulation details are listed in Table 2. Animals remained on study and were continued on treatments until the mean tumorvolume of each group reached ~1500-2000mm3. At that point, the final dose was administered, animals were sacrificed, and terminal samples were collected. Blood microsamples were collected from each group for pharmacokinetics (PK) analysis at 0, 3, and 7 hrs (n=3 / group / timepoint) on day 10 of dosing and again on the terminal day of dosing.

[0163] Tumor growth inhibition (TGI) was calculated in relation to the vehicle group on day 45, where %TGI = (1 -(Vtx- Vto) / (VCX- Vco)) x 100%, and Vcand Vtare the means of control and treated groups respectively, X = day X on study and 0 = initial day of dosing. Analysis of covariance (ANCOVA) was used to determine statistical significance when comparing percent TGI between groups. Changes in bodyweights were calculated in relation to starting bodyweights at study initiation (day 0 of treatment).

[0164] Results:

[0165] This study showed that Compound A had a superior monotherapy efficacy as compared to fulvestrant (90% tumor growth inhibition (TGI) versus no TGI) and most importantly, there was a statistically significant additive combination benefit for Compound A + Compound B over either single agent (Tables 3 and 4). The combination of Compound B + fulvestrant did not provide any combination benefit over Compound B alone.

[0166] RECIST analysis revealed a statistically significant increase in partial responses in the combination groups of Compound B + Compound A relative to Compound B alone (Tables 5 and 6). Relative tumor volume (individual tumors normalized to their day 0 volume) were used to stratify response as per RECIST. Criteria were as follows: Progressive Disease (PD) = tumors with >20% growth; Stable Disease (SD) = 2 consecutive tumor measurements <20% but >-30%; Partial Response (PR) = 2 consecutive tumor measurements <-30% with no increase >-30%; Complete Response (CR) = no measureable tumor for 2 consecutive measurements at the end of the study.

[0167] All combinations of Compound B, fulvestrant, and Compound A were well-tolerated, and there were no treatment-related deaths (Table 7). Overall, these results demonstrated the safe and efficacious in vivo combination potential for co-treatment of Compound A + Compound B in an ESR1 mutant ER+ breast cancer model that is resistant to ER or CDK4 / 6 inhibition.

[0168] Table 1. Study Design and Dosing Details for ST2056 Study

[0169]

[0170]

[0171] *LD = loading dose administered on the 3rdday of each new 4 week dosing cycle

[0172] Table 2. Test Article and Formulation

[0173]

[0174] Table 3. ST2056 TGI Results

[0175] <

[0176] <

[0177] >

[0178] <

[0179] <

[0180]

[0181] Table 4. ST2056 Intergroup comparisons and statistical significance (day 45)

[0182] <

[0183] < <

[0184]

[0185] < < <

[0186] < < <

[0187]

[0188] Table 5. ST2056 responders using RECIST criteria (day 60)

[0189] < < < <

[0190]

[0191] Table 6. ST2056 efficacy response quantified by RECIST

[0192]

[0193] Table 7. ST2056 mouse body weight change

[0194]

[0195] Example 2: Compound B Demonstrated In Vivo Combinatorial Benefit with Compound A in an ESR1 wildtype (WT) ER+ Breast Cancer Patient-Derived Xenograft (PDX) Model In vivo studies were performed a clinically relevant ESR1 wildtype PDX model of ER+ breast cancer to determine whether Compound B provided additional anti-tumor efficacy benefit when used in combination with Compound A.

[0196] Materials and Methods:

[0197] Compound B was tested in combination with Compound A in one ESR1 wildtype ER+ breast cancer PDX model, ST3142. The study was conducted by XenoSTART (San Antonio, Texas), where 6-12-week-old female athymic nude mice (JAX, stock #007850) were subcutaneously implanted with ~70 mg tumor fragments. Tumor measurements and animal weights were measured twice per week, and animals were randomized into treatment groups when the mean tumor volume (TV = width2x length x 0.5) reached 150-300 mm3.

[0198] The ESR1 WT PDX study consisted of 7 treatment groups with n=10 animals per group. The groups were as follows: 1) Vehicle (5% DMSO / 40% PEG300 / 55% 1x PBS), 2) Compound B at 0.6 mg / kg, 3) Compound B at 3 mg / kg, 4) Compound A, 5) Compound B 0.6 mg / kg + Compound A, 6) Compound B 3 mg / kg + Compound A, and 7) Compound B 3 mg / kg + fulvestrant. Group details for dose levels, routes, and regimens are listed in Table 8. Compound and formulation details are listed in Table 2. Animals remained on study and were continued on treatments until the mean tumor volume of each group reached ~1500-2000mm3. At that point, the final dose was administered, animals were sacrificed, and terminal samples were collected. Blood microsamples were collected from each group for PK analysis at 0, 3, and 7 hrs (n=3 / group / timepoint) on day 10 of dosing and again on the terminal day of dosing.

[0199] TGI was calculated in relation to the vehicle group on day 23 for ST3142, where %TGI = (1-(Vtx - Vto) / (VCx - Vco)) x 100%, and where Vcand Vtare the means of control and treatedgroups respectively, X = day X on study and 0 = initial day of dosing. ANCOVA was used to determine statistical significance when comparing percent TGI between groups. Changes in bodyweights were calculated in relation to starting bodyweights at study initiation (day 0 of treatment).

[0200] Results:

[0201] Single agent Compound A showed strong efficacy (104% TGI, Table 9). Compound B efficacy was dose dependent (56% and 69% for 0.6 mg / kg and 3 mg / kg respectively. However, the strong Compound A single agent efficacy, minimized the window to see impact of combinations with Compound B (105% and 107%). While efficacy for both Compound B + Compound A combinations was quantitatively greater than Compound A alone, only the higher dose Compound B + Compound A was statistically significant from Compound A alone (Table 10).

[0202] At the conclusion of the 30-day treatment period, ST3142 tumors were allowed to grow untreated to determine if any of the combinations resulted in a more robust response than their single agent counterparts. Setting the TTE to when tumor volume = 1000 mm3 showed a statistically significant increase in TTE for Compound B 3 mg / kg + Compound A compared to both single agents (Table 11). The lower dose Compound B + Compound A TTE was statistically significant from single agent Compound B, but not so from single agent Compound A.

[0203] Health and bodyweight monitoring indicated that mean weight loss did not exceed 10% in any of the treatment groups (Table 12). Data are reported as % change in mean body weight relative to day 0 ± SEM. All combinations of Compound B, Compound A, and fulvestrant were well-tolerated, and there were no treatment-related deaths.

[0204] Table 8. Study Design and Dosing Details for the ESR1 Wildtype PDX Model, ST3142

[0205]

[0206] *LD = loading dose administered on the 3rdday of each new 4 week dosing cylce

[0207] Table 9. ST3142 TGI Results

[0208] <

[0209] <

[0210] <

[0211] <

[0212] <

[0213] <

[0214]

[0215] Table 10. ST3142 Intergroup comparisons and statistical significance (day 23)

[0216] < <

[0217] < <

[0218] < < < <

[0219] < < < < <

[0220]

[0221] Table 11. ST3142 Tumor Growth Delay Statistics (Time to Event = 1000 mm3)

[0222] <

[0223] <

[0224] <

[0225]

[0226] Table 12. ST3142 mouse body weight change

[0227]

[0228] Example 3: Phase 1 / 2a Study of Compound A in Combination with Compound B in Advanced or Metastatic Solid Tumors

[0229] Overview

[0230] Compound A in combination with Compound B is being investigated in a Phase 1 / 2a dose escalation and expansion study to evaluate safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) and anti-tumor activity in participants with advanced or metastatic solid tumors. (ER+HER2- breast cancer, CRPC, or NSCLC). The patients in this trial are intolerant of or resistant to standard therapy.

[0231] Abbreviations and Definitions:

[0232] “BOR” is best overall response.

[0233] “CBR” is clinical benefit rate.

[0234] “DOR” is duration of response.

[0235] “PFS” is progressive-free survival.“RP3D” is recommended phase 3 dose.

[0236] “RDE” is recommended dose for expansion.

[0237] “QD” is once-a-day or every day or once daily.

[0238] “TTP” is time to progression.

[0239] “Dose limiting toxicity” (DLT) refers to the dosage of study intervention that is contraindicative of a further increase in dosage. For combination dose escalation (Part 1 E), any of the following adverse events (AEs) occurring in the first cycle of treatment (28 days), which are attributable to Compound A or Compound B, as applicable, are classified as DLTs:

[0240] Hematological Dose-Limiting Toxicities:

[0241] • Grade 4 neutropenia regardless of intervention is a DLT.

[0242] • Febrile neutropenia (defined as an absolute neutrophil count (ANC)<1000 / mm3with a single temperature of >38.3°C [101 °F], or a sustained temperature of >38°C [100.4°F] for more than 1 hour) is a DLT.

[0243] • Grade 3 neutropenia with infection is a DLT. (Note: isolated Grade 3 neutropenia without accompanying fever or infection as defined above is not a DLT).

[0244] • Grade 4 thrombocytopenia is a DLT.

[0245] • Grade 3 thrombocytopenia with bleeding or requiring platelet transfusion is a DLT.

[0246] • Grade 4 anemia is a DLT.

[0247] • Grade 3 anemia requiring blood transfusion is a DLT.

[0248] Non-Hematologic Dose-Limiting Toxicities:

[0249] Any Grade >3 non-hematologic possibly treatment related AE is a DLT with the following clarifications:

[0250] • Grade >3 nausea, vomiting, or diarrhea lasting >3 days despite adequate antiemetic and other supportive care is a DLT.

[0251] • Grade >3 fatigue lasting >7 days is a DLT.

[0252] • Confirmed drug-induced liver injury (DILI) meeting Hy’s law criteria is a DLT.

[0253] • For participants with Grade 2 hepatic transaminase or alkaline phosphatase levels at baseline as a result of liver metastasis or bone metastasis, aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >8 x upper limit of normal (ULN) or AST or ALT >5 x ULN for >14 days will be considered as a DLT.

[0254] • Clinically important or persistent toxicities (e.g., toxicities responsible for significant dose delay) that are not included in the above criteria may also be considered a DLT following review by the investigators and the Sponsor. All DLTs need to represent a clinically significant shift from baseline.

[0255] • Grade >3 QTc prolongation is a DLT.• Grade >3 anaphylaxis is a DLT.

[0256] Any toxicity causing greater than 2 weeks of dose delay of either Compound A or Compound B is a DLT. In addition, any Grade 5 AE (death) not clearly due to either the underlying disease or other etiologies is a DLT.

[0257] Any dose reduction of either Compound A or Compound B due to a treatment-related AE (per protocol) during the first 28 days will be qualified as participant experiencing DLT.

[0258] As used herein “maximum tolerated dose” (MTD) is defined as a dose with true DLT rate from the target toxicity interval. The target interval for the DLT rate is defined as (0.16, 0.33).

[0259] Objectives and Endpoints

[0260] The objectives and endpoints for the combination dose escalation (Part 1 E) and combination dose expansion (Part 2E) is shown in Tables 13 and 14.

[0261] Table 13. Combination Dose Escalation (Part 1E)

[0262]

[0263]

[0264] Table 14. Combination Dose Expansion (Part 2E)

[0265]

[0266]

[0267] Study Design

[0268] Overall Design

[0269] This is an open-label, multi-center Phase 1 / 2a study in adult participants to evaluate safety, tolerability, PK, and PD of Compound B in combination with Compound A in ER+HER2-breast cancer. The study contains two parts, a dose escalation (Part 1 E) followed by a dose expansion (Part 2E).Part 1

[0270]

[0271] Part 1 dose escalation consists of: Part 1 A, Part 1B, Part 1 C, Part 1 D, and Part 1 E. Part 1 E (Combination Dose Escalation): Compound A in combination with Compound B will be evaluated for dose finding in participants with locally advanced or metastatic ER+HER2- breast cancer (2L+) whose disease has progressed after at least 1 line of treatment with an endocrine therapy and 1 line of CDK4 / 6 inhibitor, to determine the MTD and RDE(s) for this combination.

[0272] Part 2 (Dose Expansion)

[0273] Part 2E (Combination Dose Escalation): After determination of the combination RDE from Part 1 E, Compound A in combination with Compound B will be evaluated in a combination dose-expansion cohort, Part 2E. Part 2E will consists of participants with advanced or metastatic 2-4L ER+HER2- breast cancer whose disease has progressed after at least 1 line of a CDK4 / 6 inhibitor and at least 1 line of endocrine therapy and who must not have received more than 3 lines of systemic therapies in advanced or metastatic settings (Part 2E).

[0274] Inclusion Criteria

[0275] Participants are eligible to be included in the study only if all of the following criteria apply: 1. Adult participants age >18 years (please follow local regulatory requirements if the legal age of consent for study participation is less than 18 years old). For participants enrolled at clinical sites in Japan: adult participants age >20 years. For participants enrolled at clinical sites in South Korea: adult participants age >19 years.

[0276] 2. Part 1 E (Combination Dose Escalation): Histological or cytological diagnosis of locally advanced or metastatic ER+HER2- breast cancer. Participants must have progressed after at least 1 prior line of treatment with an endocrine therapy and CDK4 / 6 inhibitor in the advanced or metastatic setting.

[0277] 3. Part 2E (Combination Dose Expansion):

[0278] • Histological or cytological diagnosis of advanced or metastatic ER+HER2- breast cancer. Participants must have progressive disease after at least 1 prior line of a CDK4 / 6 inhibitor and at least 1 prior line of endocrine therapy.

[0279] • Participants must have not received more than 3 lines of systemic therapies including up to 1 line of cytotoxic chemotherapy for visceral disease in advanced or metastatic setting;

[0280] • Participants may have received fulvestrant.

[0281] • Participants who had received approved oral selective estrogen receptor degrader (oral SERD) in advanced or metastatic setting should be discussedand approved by sponsor for participation.

[0282] 4. Participants with ER+HER2- advanced or metastatic breast cancer must have documentation of ER-positive tumor (>1% positive stained cells) based on most recent tumor biopsy (unless non-measurable disease where most recent documentation will be provided) utilizing an assay consistent with local standards. 5. Participants with ER+HER2- advanced or metastatic breast cancer must have documentation of HER2-negative tumor: HER2-negative tumor is determined as immunohistochemistry score 0 / 1+ or negative by in situ hybridization (FISH / CISH / SISH / DISH) defined as a HER2 / CEP17 ratio <2 or for single probe assessment a HER2 copy number <4.

[0283] 6. Female participants with ER+HER2- advanced or metastatic breast cancer considered to be of childbearing potential (or have tubal ligations only) must be willing to undergo medically induced menopause by treatment with the approved LHRH agonist such as goserelin, leuprolide or equivalent agents to induce chemical menopause.

[0284] 7. Female participants with ER+HER2- advanced or metastatic breast cancer of nonchildbearing potential must meet at least 1 of the following criteria of achieving postmenopausal status, defined as follows:

[0285] • Cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; [status may be confirmed with / and have] a serum follicle-stimulating hormone (FSH) level confirming the post menopausal state;

[0286] • Have undergone a documented hysterectomy and / or bilateral oophorectomy; • Have medically confirmed ovarian failure. All other female participants (including female participants with tubal ligations) are considered to be of childbearing potential.

[0287] 8. Participants must have at least 1 measurable lesion as defined by RECIST version 1.1 that has not been previously irradiated.

[0288] 9. ECOG Performance Status PS 0 or 1.

[0289] 10. Adequate Bone Marrow Function, including:

[0290] a. ANC >1 ,500 / mm3 or >1.5 x 109 / L;

[0291] b. Platelets >100,000 / mm3 or >100 x 109 / L;

[0292] c. Hemoglobin >9 g / dL.

[0293] 11. Adequate Renal Function, including:

[0294] a. Serum creatinine <1.5 x ULN or estimated creatinine clearance GFR >60 mL / min (>50 mL / min for Part 2 dose expansion is acceptable) as calculated using themethod standard for the institution. In equivocal cases, a 24 hour urine collection test can be used to estimate the creatinine clearance more accurately.

[0295] 12. Adequate Liver Function, including:

[0296] a. Total serum bilirubin <1.5 x ULN unless the participant has documented Gilbert syndrome;

[0297] b. AST and ALT <2.5 x ULN; AST and ALT <3.0 x ULN if there is liver involvement by the tumor for Part 1 dose escalation. AST and ALT <5.0 x ULN if there is liver involvement by the tumor for Part 2 dose expansion. 13. Resolved acute effects of any prior therapy to baseline severity or CTCAE Grade <1 except for AEs not constituting a safety risk by investigator judgment.

[0298] 14. Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures.

[0299] 15. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICD and in this protocol.

[0300] Exclusion Criteria

[0301] Participants are excluded from the study if any of the following criteria apply:

[0302] 1. Participants with known symptomatic brain metastases requiring steroids. Participants with previously diagnosed brain metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to study entry, have discontinued corticosteroid treatment for these metastases for at least 3 weeks and are neurologically stable for 2 months (requires MRI confirmation).

[0303] 2. Participants with advanced / metastatic, symptomatic, visceral spread, that are at risk of life-threatening complications in the short term (including participants with massive uncontrolled effusions [pleural, pericardial, peritoneal], pulmonary lymphangitis, and over 50% liver involvement). Note: Participants with indwelling catheter for drainage, or requirement for drainage no more frequently than monthly will be allowed.

[0304] 3. Participants with any other active malignancy within 3 years prior to enrollment, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ. Other indolent cancers that do not interfere with assessment of primary cancer under study may be allowed with prior sponsor approval.

[0305] 4. Major surgery within 3 weeks prior to study entry.

[0306] 5. Radiation therapy within 3 weeks prior to study entry. Any palliative radiotherapy must be completed within the 7 days prior to Day 1 of study intervention

[0307] administration.6. Previous administration of systemic anti-cancer therapy within 3 weeks or 5 half-life prior to first dose of study intervention used in this study (whichever is shorter), unless the last immediate anti-cancer treatment contained an antibody based agent(s) (approved or investigational), then an interval of 28 days or 5 half-life (whichever is shorter) of the agent(s) prior to receive the study intervention treatment is required.

[0308] 7. Prior irradiation to >25% of the bone marrow.

[0309] 8. Participants with active, uncontrolled bacterial, fungal, or viral infection, including (but not limited to) HBV, HCV, known HIV or AIDS related illness. HIV seropositive subjects who are healthy and low risk for AIDS-related outcomes could be considered eligible.

[0310] • Eligibility criteria for HIV-positive subjects should be evaluated and discussed with sponsor’s medical monitor and will be based on current and past CD4 and T-cell counts, history (if any) of AIDS-defining conditions (eg, opportunistic infections), and status of HIV treatment. Also, the potential for DDIs will be taken into consideration. In equivocal cases, with positive serology, those participants with a negative viral load are potentially eligible provided the other entry criteria are met.

[0311] • COVID-19 / SARS-CoV-2: This protocol excludes participants with active infections, as noted above. While SARS-CoV-2 testing is not mandated for entry into this protocol, testing should follow local clinical practice standards. If a participant has a positive test result for SARS-CoV-2 infection, is known to have asymptomatic infection or is suspected of having SARS-CoV-2, he / she is excluded but may be rescreened according to protocol requirements for rescreening if the participant subsequently tests negative.

[0312] 9. Unmanageable ascites (limited medical treatment to control ascites is permitted, but all participants with ascites require review by sponsor’s medical monitor).

[0313] 10. Baseline 12 -lead ECG that demonstrates clinically relevant abnormalities that may affect participant safety or interpretation of study results (eg, baseline QTc interval >470 msec, complete LBBB, signs of an acute myocardial infarction, ST changes suggestive of active myocardial ischemia, second- or third- degree AV block, or serious bradyarrhythmias or tachyarrhythmias). If the baseline uncorrected QT interval is >470 msec, this interval should be rate corrected using the Fridericia method and the resulting QTcF- should be used for decision making and reporting. If QTcF exceeds 470 msec, or QRS exceeds 120 msec, the ECG should be repeated 2 more times and the average of the 3 QTcF or QRS values should be used todetermine the participant’s eligibility. Computer -interpreted ECGs should be overread by a physician experienced in reading ECGs before excluding participants. Cases must be discussed in detail with sponsor’s medical monitor to judge eligibility. 11. Any of the following in the previous 6 months: myocardial infarction, long QT syndrome, Torsade de Pointes, clinically important atrial or ventricular arrhythmias (including sustained ventricular tachyarrhythmia and ventricular fibrillation), serious conduction system abnormalities (eg, bifascicular block [defined as right bundle branch and left anterior or posterior hemiblock], 3rd degree AV block), unstable angina, coronary / peripheral artery bypass graft, symptomatic CHF, New York Heart Association class III or IV, cerebrovascular accident, transient ischemic attack, symptomatic pulmonary embolism, and / or other clinical significant episode of thrombo embolic disease and ongoing cardiac dysrhythmias of NCI CTCAE > Grade 2. For Grade 2 atrial fibrillation, may be considered eligible with sponsor approval (eg, if improved to Grade 1 with non-urgent medical intervention or chronic Grade 2 atrial fibrillation with good rate control with non-urgent medical intervention). If a participant has a cardiac rhythm device / pacemaker placed and QTcF >470 msec, the participant can be considered eligible. Participants with cardiac rhythm device / pacemaker must be discussed in detail with sponsor’s medical monitor to judge eligibility.

[0314] 12. Hypertension that cannot be controlled by optimal medical therapy (eg, >160 / 100 mmHg).

[0315] 13. Participation in other studies involving investigational drug(s) within 3 weeks prior to study entry. Participation in long term follow-up of other studies is allowed if no procedures which may interfere with the interpretation of study results will be performed.

[0316] 14. Known or suspected hypersensitivity or severe allergy to active ingredient / excipients of study drug(s).

[0317] 15. Prior treatment with study drug(s).

[0318] 16. Current use or anticipated need for food or drugs that are known strong CYP3A4 / 5 inhibitors, including their administration within 10 days or 5 half-lives of the CYP3A4 / 5 inhibitor, whichever is longer prior to first dose of study intervention.

[0319] 17. Current use or anticipated need for food or drugs that are known strong CYP3A4 / 5 inducers, including their administration within 10 days or 5 half-lives of the CYP3A4 / 5 inducer, whichever is longer prior to the first dose of study.

[0320] 18. Current use or anticipated need for food or drugs that are known moderate / strong CYP2C9 inhibitors, including their administration within [10 days or 5 half-lives of the CYP2C9 inhibitor, whichever is longer] prior to first dose of investigational product (amiodarone, fluconazole, miconazole, oxandrolone).19. Current use or anticipated need for drugs that are known moderate / strong CYP2C9 inducers, including their administration within [10 days or 5 half-lives of the CYP2C9 inducer, whichever is longer] prior to the first dose of investigational product (carbamazepine, rifampin.

[0321] 20. Concurrent administration of medications, food or herb supplements that are strong inhibitors and inducers of CYP3A and drugs known to predispose to Torsade de Pointes or QT interval prolongation. Prior use of strong CYP3A inhibitors must be stopped 10 days and strong inducers of CYP3A must be stopped 14 days before randomization.

[0322] 21. Positive serum or urine pregnancy test (for females of childbearing potential) at screening.

[0323] 22. Other medical or psychiatric condition including recent (within the past year) or active suicidal ideation / behavior or laboratory abnormality that may increase the risk of study participation or, in the investigator’s judgment, make the participant inappropriate for the study.

[0324] 23. Investigator site staff or Pfizer employees directly involved in the conduct of the study, site staff otherwise supervised by the investigator, and their respective family members.

[0325] Method of Administration

[0326] The starting doses for the combination of Compound B with Compound A (Part 1 E) are Compound B at 3 mg QD and Compound A at 200 mg QD. Tables 15 and 16 show examples of Compound A and Compound B dose levels in Part 1 E.

[0327] Table 15. Example of Compound A Dose Levels in Part 1 E (mg)

[0328]

[0329] Table 16. Example of Compound B Dose Levels in Part 1 E (mg)

[0330]

[0331] Treatment continues until progression of disease, uncontrollable toxicity, a decision by the patient or investigator to discontinue treatment or the study is terminated.

[0332] Patients experiencing toxicity including a dose limiting toxicity (DLT) are managed with dose modification or discontinuation from treatment.

[0333] Statistical Methods

[0334] Bayesian adaptive approach:

[0335] The dose finding in Part 1 E of the study will be guided by a Bayesian analysis of Cycle 1 DLT data for the combination.

[0336] A more complex BLRM model specifically designed for combinations will be used to model the dose / DLT relationship of Compound A given in combination with Compound B.

[0337] Efficacy analysis:

[0338] Tumor response will be presented in the form of participant data listings that include, but are not limited to tumor type, dose on Day 1 , tumor response at each visit, clinical benefit response, and best overall response. Proportion of participants responding to the treatment will be presented for each dose level. Progression date, date of first response and last tumor assessment date, and date of last contact will be listed. The Kaplan-Meier methods will be used to analyze all time to event endpoints.

Claims

CLAIMSWe claim:

1. A method for treating cancer comprising administering to a subject in need thereof an amount of Compound A:(Compound A), or a pharmaceutically acceptable salt thereof, and an amount of Compound B:(Compound B), or a pharmaceutically acceptable salt thereof,wherein the amounts together are therapeutically effective in treating cancer.

2. The method of claim 1 , wherein the amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 200 mg.

3. The method of claim 1 , wherein the amount of Compound A, or a pharmaceutically acceptable salt thereof, is about 100 mg.

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

5. The method of any one of claims 1 to 4, wherein the amount of Compound B, or a pharmaceutically acceptable salt thereof, is about 1 mg, about 2 mg, about 3 mg, about 4 mg, or about 5 mg.

6. The method of any one of claims 1 to 5, wherein the amount of Compound B, or a pharmaceutically acceptable salt thereof, is about 5 mg.

7. The method of any one of claims 1 to 6, wherein the amount of Compound B, or a pharmaceutically acceptable salt thereof, is administered once a day (QD).

8. The method of any one of claims 1 to 7, wherein the Compound B is administered concurrently or sequentially with the administration of Compound A.

9. The method of any one of claims 1 to 7, wherein the Compound B is administered intermittently with the administration of Compound A.

10. The method of any one of claims 1 to 9, wherein the Compound A, or a pharmaceutically acceptable salt thereof, is administered orally to the subject.

11. The method of any one of claims 1 to 10, wherein the Compound B, or a pharmaceutically acceptable salt thereof, is administered orally to the subject.

12. The method of any one of claims 1 to 11 , 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.

13. The method of claim 12, wherein the cancer is breast cancer, lung cancer, or prostate cancer.

14. The method of claim 13, wherein the cancer is breast cancer.

15. The method of claim 14, wherein the breast cancer is metastatic or locally advanced.

16. The method of claim 14 or claim 15, wherein the breast cancer is estrogen receptor positive (ER+) breast cancer.

17. The method of claim 16, wherein the estrogen receptor positive (ER+) breast cancer is ESR1 -mutant ER+ breast cancer.

18. The method of claim 16, wherein the estrogen receptor positive (ER+) breast cancer is ESR1 wildtype ER+ breast cancer.

19. The method of claim 16, wherein the estrogen receptor positive (ER+) breast cancer is human epidermal growth factor receptor 2 negative (HER2-).

20. The method of any one of claims 1 to 19, wherein the subject is human.

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