EP4687903A1 - Methods of treating cancer using hsf1 pathway inhibitors - Google Patents

Abstract

The disclosure is in part directed to a method of treating a cancer, for example ovarian cancer, in a patient in need thereof, comprising administering to the patient a fixed-dose amount of a HSF1 pathway inhibitor, wherein the cancer comprises solid tumors identified as having an ARID1A mutation.

Description

METHODS OF TREATING CANCER USING HSF1 PATHWAY INHIBITORS

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of, and priority to, U.S. Provisional Patent Application No. 63/456,033 filed on March 31, 2023; the content of which is hereby incorporated by reference herein in its entirety.

BACKGROUND

[0002] Cancer is caused by uncontrolled and unregulated cellular proliferation. Precisely what causes a cell to become malignant and proliferate in an uncontrolled and unregulated manner has been the focus of intense research over recent decades. This research has led to the identification of a number of molecular targets associated with key metabolic pathways that are known to be associated with malignancy.

[0003] Heat shock factor 1 pathway (HSF1 pathway) is one target pathway that is of interest. HSF1 is the primary regulator of the heat shock response, in which multiple genes are induced in response to temperature increase and other stresses. At non-shock temperatures in humans and other vertebrates, HSF1 is produced constitutively, but is inactive and bound by protein HSP90. At an elevated temperature, HSF1 is released by HSP90, moves from the cytoplasm to the nucleus, and trimerizes. This active HSF1 form binds to sequences called heat shock elements (HSE) in DNA and activates transcription of heat shock genes by RNA polymerase II. During cessation of the heat shock response, HSF1 is phosphorylated by mitogen -activated protein kinases (MAPKs) and glycogen synthase kinase 3 (GSK3) and returns to an inactive state.

[0004] HSF1 pathway activity has been implicated in several diseases, including cancer, and autoimmune, and viral diseases. HSF1 and other heat shock proteins (whose expression is increased by HSF1) are over-expressed in, or have otherwise been implicated in, breast, endometrial, fibrosarcoma, gastric, kidney, liver, lung, lymphoma, neuroectodermal, neuroblastoma, Ewing's sarcoma, prostate, skin, squamous cell, and testicular cancers, leukemia (e.g., promyelocytic leukemia), and Hodgkin's disease.

[0005] ARID! A is a member of the SWI/SNF family, whose members have helicase and ATPase activities and are thought to regulate transcription of certain genes by altering the chromatin structure around those genes. ARID 1 A controls the expression of key components of the metabolic pathway leading to increased cancer cell survival by enhanced generation of glutathione (GSH) and protection from metabolic stress induced by reactive oxygen species (ROS).

[0006] ARID 1 A is mutated in multiple solid tumor types at varying frequencies. For example, ARID 1 A mutations are commonly found to be present across cancer and solid tumor types including, for example, breast, lung, esophageal, pancreatic, urothelial, uterine, ovarian, gastrointestinal and liver. ARID 1 A mutations are associated with an aberrant cell cycle leading to reduced GSH levels, which results in decreased protection against stress. The cancer cells compensate for this by overactivation of the HSF-1 pathway.

[0007] Protein loss associated with ARID 1 A mutations can be used as a patient selection strategy in solid tumor types. Methodologies to detect the ARID 1 A mutations are known in the art. Accordingly, there is a need for methods for the treatment of diseases or conditions in which HSF1 pathway activity is mediated, e.g., for the treatment cancers manifested as solid tumors in which ARID 1 A mutations are present.

SUMMARY

[0008] The present disclosure is directed, at least in part, to methods of treating cancer using compounds that modulate, e.g., inhibit, the HSF1 pathway. For example, disclosed herein is a method of treating a cancer in a patient in need thereof, comprising administering to the patient about 50 mg, or about 75 mg, of a HSF1 pathway inhibitor, wherein the cancer harbors an ARID 1 A mutation, e.g., the cancer is identified as having an ARID 1 A mutation. In some embodiments, the cancer may be selected from the group consisting of, for example, an ovarian cancer, fallopian tube cancer, and primary peritoneal cancer. In some embodiments, the HSF1 pathway inhibitor is administered orally. In other embodiments, the HSF1 pathway inhibitor is administered once daily. In other embodiments, the HSF1 pathway inhibitor is administered in a weekly regimen comprising five consecutive days wherein the HSF1 pathway inhibitor is administered, and two consecutive days wherein the HSF1 pathway inhibitor is not administered.

[0009] For example, further disclosed herein is a method of treating an ovarian cancer in a patient in need thereof, comprising orally administering to the patient about 50 mg, or about 75 mg of a HSF1 pathway inhibitor, wherein the cancer harbors an ARID 1 A mutation, e.g., the cancer is identified as having an ARID1 A mutation. In some embodiments, the ovarian cancer is, for example, endometrioid ovarian cancer or ovarian clear cell carcinoma.

[0010] In some embodiments, the HSF1 pathway inhibitor is, for example, 7V-(5-(2,3- dihydrobenzofb] [ 1 ,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-((4-ethylpiperazin- 1 - yl)methyl)quinoline-6-carboxamide, and is represented by:

[0011] For example, disclosed herein is a method of treating an ovarian cancer in a patient in need thereof, comprising orally administering to the patient about 50 mg, or about 75 mg of a compound represented by pharmaceutically acceptable salt thereof; wherein the cancer harbors an ARID1 A mutation, e.g., the cancer is identified as having an ARID 1 A mutation.

[0012] Also disclosed herein is a method of treating an ovarian cancer in a patient in need thereof, comprising orally administering to the patient a pharmaceutical composition comprising: about 50 mg, or about 75 mg, of a compound represented by or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient; wherein the cancer harbors an ARID 1 A mutation, e.g., the cancer is identified as having an ARID 1 A mutation. [0013] In some embodiments, the cancer is endometrioid ovarian cancer, for example, cancer is relapsed or refractory endometrioid ovarian cancer. In other embodiments, the cancer is clear cell ovarian cancer. In certain embodiments, the ovarian cancer is substantially resistant to platinum-based chemotherapy, taxane-based chemotherapy, or a combination thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

[0014] FIG. 1 depicts the antitumor activity (e.g., tumor growth inhibition) of Compound A in an ovarian cancer xenograft model (SKOV-3). The tumor was identified as harboring an ARID1A mutation. Cr nude mice were injected with 5 x 10⁶ SK-OV-3 cells and, once the tumor was established, administered vehicle control (DCC) or 35 mg/kg Compound A in DCC once daily (or as described in the text) by oral gavage. Graph shows mean tumor volume over the dosing period of the study; error bars represent standard error of the mean. Control and 35 mg/kg group n=10. Horizontal black line is 35 mg/kg group tumor volume on Day 0.

[0015] FIG. 2 depicts the antitumor activity (e.g., tumor growth inhibition) of Compound A in an ovarian cancer xenograft model (TOV-21G). The tumor was identified as harboring an ARID1A mutation. NCr nude mice were injected with 3 x 10⁶ TOV-21G cells and, once the tumor was established, administered vehicle control (DCC) or 35 mg/kg Compound A in DCC once daily for 5 days out of every 7 by oral gavage. Graph shows mean tumor volume over the dosing period of the study; error bars represent standard error of the mean. Vehicle control group n=8 and 35 mg/kg dose group n=ll.

[0016] FIG. 3 depicts the antitumor activity (e.g., tumor growth inhibition) of Compound A in an ovarian cancer xenograft model (OVISE). NCr nude mice were injected with 5 x 10⁶ OVISE cells and, once the tumor was established, administered vehicle control (DCC) or 35 mg/kg Compound A in DCC once daily for 5 days out of every 7 by oral gavage. Graph shows mean tumor volume over the dosing period of the study; error bars represent standard error of the mean. Vehicle control group n=10 and 35 mg/kg Compound A group n=l 1.

[0017] FIG. 4 depicts the antitumor activity (e.g., tumor growth inhibition) of Compound A in an ovarian cancer xenograft model (IGROV-1). NCr nude mice were injected with 3 x 10⁶ IGROV-1 cells and, once the tumor was established, administered vehicle control (DCC) or 35 mg/kg Compound A in DCC once daily by oral gavage in an intermittent schedule. Graph shows mean tumor volume over the dosing period of the study; error bars represent standard error of the mean. Vehicle control group n=5 and 35 mg/kg Compound A group n=6.

[0018] FIG. 5 depicts a summary of tumor xenograft experiments. Established tumor xenografts were treated (35 mg/kg Compound A oral schedule as in Table 1 once daily as indicated). TGI>50% was considered significant and is indicated by the dotted line. All experiments were conducted with at least n=9 mice control and treated (except IGROV-1 n=6 treated and n=5 control).

DETAILED DESCRIPTION

[0019] The features and other details of the disclosure will now be more particularly described. Before further description of the present disclosure, certain terms employed in the specification, examples and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and as understood by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art.

Definitions

[0020] “Treating” includes any effect, e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the condition, disease, disorder and the like. For example, "treating" or "treatment" of a state, disorder or condition therefore includes: ( 1 ) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms. It is to be appreciated that references to "treating" or "treatment" include prophylaxis as well as the alleviation of established symptoms of a condition.

[0021] The term “disorder” refers to and is used interchangeably with, the terms “disease,” “condition,” or “illness,” unless otherwise indicated. [0022] “Pharmaceutically or pharmacologically acceptable” include molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate. For human administration, preparations should meet sterility, pyrogenicity, and general safety and purity standards as required by FDA Office of Biologies standards.

[0023] The phrases “pharmaceutically acceptable carrier” and “pharmaceutically acceptable excipient,” as used herein, refer to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. Pharmaceutical acceptable carriers can include phosphate buffered saline solution, water, emulsions (e.g., such as an oil/water or water/oil emulsions), and various types of wetting agents. The compositions also can include stabilizers and preservatives.

[0024] The phrase “pharmaceutical composition,” as used herein, refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers. The pharmaceutical compositions can also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.

[0025] “Individual,” “patient,” or “subject” are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans. The compounds of the present disclosure can be administered to a mammal, such as a human, but can also be administered to other mammals such as an animal in need of veterinary treatment, e.g., domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like). The mammal treated in the methods of the present disclosure is desirably a mammal in which treatment, for example, of a cancer or a blood disorder is desired. “Modulation” includes antagonism (e.g., inhibition), agonism, partial antagonism and/or partial agonism.

[0026] In the present specification, the terms “effective amount” or “therapeutically effective amount” means the amount of the subject compound that will elicit the biological or medical response of a tissue, system or animal, (e.g., mammal or human) that is being sought by the researcher, veterinarian, medical doctor or other clinician. The compounds of the present disclosure are administered in therapeutically effective amounts to treat a disease. Alternatively, a therapeutically effective amount of a compound is the quantity required to achieve a desired therapeutic and/or prophylactic effect.

[0027] The term “pharmaceutically acceptable salt(s)” as used herein refers to salts of basic groups that may be present in compounds used in the compositions. Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.

[0028] The term “and/or” is used in this disclosure to mean either “and” or “or” unless indicated otherwise.

[0029] As used herein, the words “a” and “an” are meant to include one or more unless otherwise specified. For example, the term “an agent” encompasses both a single agent and a combination of two or more agents.

[0030] Where the use of the term “about” is before a quantitative value, the present disclosure also includes the specific quantitative value itself, unless specifically stated otherwise. As used herein, the term “about” refers to a ± 10% variation from the nominal value unless otherwise indicated or inferred.

Methods

[0031] Disclosed herein, for example, is a method of treating a cancer in a patient in need thereof, comprising administering to the patient about 50 mg, or about 75 mg, of a HSF1 pathway inhibitor, wherein the cancer harbors an ARID1 A mutation, e.g., the cancer is identified as having an ARID1 A mutation. In some embodiments, the HSF1 pathway inhibitor is administered orally. In certain embodiments, the cancer is selected from the group consisting of an ovarian cancer, fallopian tube cancer, and primary peritoneal cancer.

[0032] In some embodiments, a contemplated HSF1 pathway inhibitor is represented by Formula I: or a pharmaceutically acceptable salt and/or a stereoisomer thereof, wherein: R¹ and R² are each independently selected from the group consisting of hydrogen and halogen;

R³ is selected from the group consisting of fluoro, hydrogen, chloro, cyano, -CH3, - CF3, -OCH3, and -OCF3; and

R⁴ is a 5, 6 or 7-membered nitrogen-linked heterocyclyl optionally comprising one further nitrogen atom; wherein R⁴ may optionally be substituted on the further nitrogen atom by a substituent selected from the group consisting of methyl, ethyl, propyl, and cyclopropylmethyl; and wherein R⁴ may optionally be substituted on a carbon atom by a substituent selected from the group consisting of methyl, fluoro, and chloro.

[0033] In certain embodiments, for example, R⁴ is nitrogen-linked piperazinyl substituted on the further nitrogen atom by methyl, ethyl, or propyl, or cyclopropylmethyl.

[0034] In some embodiments, the HSF1 pathway inhibitor is, for example, or a pharmaceutically acceptable salt thereof.

[0035] For example, in certain embodiments the HSF1 pathway inhibitor is

[0036] In some embodiments, the methods disclosed herein comprise administering to the patient about 50 mg of the HSF1 pathway inhibitor. In other embodiments, the methods disclosed herein comprise administering to the patient about 75 mg of the HSF1 pathway inhibitor. [0037] For example, disclosed herein is a method of treating an ovarian cancer in a patient in need thereof, comprising orally administering to the patient about 50 mg, or about 75 mg of a compound represented by or a pharmaceutically acceptable salt thereof; wherein the cancer harbors an ARID 1 A mutation, e.g., the cancer is identified as having an ARID1 A mutation.

[0038] In some embodiments, a compound of the present disclosure, for example, a disclosed HSF1 pathway inhibitor, is administered once daily. In other embodiments, a compound of the present disclosure, for example, a disclosed HSF1 pathway inhibitor, is administered in a weekly regimen comprising five consecutive days wherein the inhibitor is administered, and two consecutive days wherein the inhibitor is not administered. In still other embodiments, a compound of the present disclosure, for example, a disclosed HSF1 pathway inhibitor, is administered in a weekly regimen comprising four consecutive days wherein the inhibitor is administered, and three consecutive days wherein the inhibitor is not administered.

[0039] Also disclosed herein, for example, is a method of treating an ovarian cancer in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising: a compound represented by or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient; wherein the cancer harbors an ARID 1 A mutation, e.g., the cancer is identified as having an ARID 1 A mutation. [0040] Tn some embodiments, the methods disclosed herein comprise administering to the patient a pharmaceutical composition comprising about 50 mg of the HSF1 pathway inhibitor and a pharmaceutically acceptable excipient. In other embodiments, the methods disclosed herein comprise administering to the patient a pharmaceutical composition comprising about 75 mg of the HSF1 pathway inhibitor and a pharmaceutically acceptable excipient. In certain embodiments, a disclosed pharmaceutical composition is administered orally.

[0041] Further disclosed herein, for example, is a method of treating an ovarian cancer in a patient in need thereof, comprising orally administering to the patient a pharmaceutical composition comprising: about 50 mg, or about 75 mg, of a compound represented by or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient; wherein the cancer harbors an ARID 1 A mutation, e.g., the cancer is identified as having an ARID 1 A mutation.

[0042] In some embodiments, a pharmaceutical composition of the present disclosure, for example, a pharmaceutical composition comprising a disclosed HSF1 pathway inhibitor and a pharmaceutically acceptable excipient, is administered once daily. In other embodiments, a pharmaceutical composition of the present disclosure, for example, a pharmaceutical composition of the present disclosure, for example, a pharmaceutical composition comprising a disclosed HSF1 pathway inhibitor and a pharmaceutically acceptable excipient, is administered in a weekly regimen comprising five consecutive days wherein the inhibitor is administered, and two consecutive days wherein the inhibitor is not administered. In still other embodiments, a pharmaceutical composition of the present disclosure, for example, a pharmaceutical composition of the present disclosure, for example, a pharmaceutical composition comprising a disclosed HSF1 pathway inhibitor and a pharmaceutically acceptable excipient, is administered in a weekly regimen comprising four consecutive days wherein the inhibitor is administered, and three consecutive days wherein the inhibitor is not administered.

[0043] For example, in some embodiments, a cancer disclosed herein is selected from the group consisting of, for example, an ovarian cancer, fallopian tube cancer, and primary peritoneal cancer. In other embodiments, the cancer is stomach cancer and pancreatic cancer. In certain embodiments, the cancer is endometrioid ovarian cancer, for example, the cancer is relapsed or refractory endometrioid ovarian cancer. In other embodiments, the cancer is ovarian clear cell carcinoma. In some embodiments, the cancer is relapsed or refractory ovarian clear cell cancer. In certain embodiments, a cancer disclosed herein, for example ovarian cancer, is substantially resistant to platinum-based chemotherapy, taxane-based chemotherapy, or a combination thereof. In some embodiments, a cancer disclosed herein comprises solid tumors.

[0044] In some embodiments, the ARID 1 A mutation is a heterozygous ARID 1 A mutation. In other embodiments, the ARID1 A mutation is a homozygous ARID1 A mutation.

[0045] In further embodiments, the HSF1 pathway inhibitor is administered orally or subcutaneously. In some embodiments, the administration results in, for example, about a 2- 5 fold decrease in the mean GFo in ARID 1 A mutant cancer cells compared to wild type ARID 1 A cells. In other embodiment, the administration results in, for example, about a 4-5 fold decrease in the mean Gbo in ARID 1 A mutant ovarian cancer cells compared to wild type ARID 1 A ovarian cells.

[0046] In some embodiments, the method further and optionally comprises administering one or more additional cancer chemotherapeutic agents. For example, in other embodiments, the method further and optionally comprises administering an additional cancer chemotherapeutic agent.

[0047] Also disclosed herein, for example, is a method of treating platinum-resistant ovarian carcinoma in a patient in need thereof, comprising orally administering to the patient about 50 mg, or about 75 mg, a compound represented by: or a pharmaceutically acceptable salt thereof; wherein the cancer harbors an ARID 1 A mutation, e.g., the cancer is identified as having an ARID1 A mutation.

[0048] In some embodiments, the compound is administered once daily. In other embodiments, the compound is administered in a weekly regimen comprising five consecutive days wherein the inhibitor is administered, and two consecutive days wherein the inhibitor is not administered. In still other embodiments, the compound is administered in a weekly regimen comprising four consecutive days wherein the inhibitor is administered, and three consecutive days wherein the inhibitor is not administered.

[0049] In addition, disclosed herein is a method of treating platinum-resistant ovarian carcinoma in a patient in need thereof, comprising orally administering to the patient a pharmaceutical composition comprising: about 50 mg, or about 75 mg, of a compound represented by: or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient; wherein the cancer harbors an ARID 1 A mutation, e.g., the cancer is identified as having an ARID 1 A mutation.

[0050] In some embodiments, the composition is administered once daily. In other embodiments, the composition is administered in a weekly regimen comprising five consecutive days wherein the inhibitor is administered, and two consecutive days wherein the inhibitor is not administered. In still other embodiments, the composition is administered in a weekly regimen comprising four consecutive days wherein the inhibitor is administered, and three consecutive days wherein the inhibitor is not administered.

[0051] In some embodiments, a cancer type or solid tumor type disclosed herein has been identified as having an ARID 1 A mutation. Methodologies to detect the ARID 1 A mutations are known in the art. For example, protein loss associated with ARID 1 A mutations can be used as a patient selection strategy in solid tumor types. [0052] In particular, in certain embodiments, the disclosure provides a method of treating the above medical indications comprising administering to a patient in need thereof an effective amount of a HSF1 pathway inhibitor disclosed herein. In certain other embodiments, the disclosure provides a method of treating the above medical conditions in a patient in need thereof, comprising orally, subcutaneously, or intravenously administering to the patient a composition comprising a disclosed HSF1 pathway inhibitor.

[0053] By way of example only, the dose of the compound described herein for methods of treating a disease as described herein is about 0.001 to about 1 mg/kg body weight of the subject per day, for example, about 0.001 mg, about 0.002 mg, about 0.005 mg, about 0.010 mg, 0.015 mg, about 0.020 mg, about 0.025 mg, about 0.050 mg, about 0.075 mg, about 0.1 mg, about 0.15 mg, about 0.2 mg, about 0.25 mg, about 0.5 mg, about 0.75 mg, or about 1 mg/kg body weight per day. In some embodiments, the dose of compound described herein for the described methods is about 1 to about 1000 mg/kg body weight of the subject being treated per day, for example, about 1 mg, about 2 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, about 80 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 500 mg, about 750 mg, or about 1000 mg per day of a compound described herein, for example, 2V-(5-(2,3- dihydrobenzo[b] [ 1 ,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-((4-ethylpiperazin- 1 - yl)methyl)quinoline-6-carboxamide.

[0054] Further, by way of example only, the dose of the compound for methods of treating a disease as described herein may be a fixed dose, e.g., a fixed dose of 10 mg, 12.5 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 m g, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, or 150 mg of a compound described herein, for example, 2V-(5-(2,3- dihydrobenzofb] [ 1 ,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-((4-ethylpiperazin- 1 - yl)methyl)quinoline-6-carboxamide.

[0055] In addition, by way of example only, the dose of the compound for methods of treating a disease as described herein comprises about 30 mg to about 300 mg, about 60 mg to about 300 mg, about 90 mg to about 300 mg, about 120 mg to about 300 mg, about 150 mg to about 300 mg, about 180 mg to about 300 mg, about 210 mg to about 300 mg, about 240 mg to about 300 mg, about 270 mg to about 300 mg, about 30 mg to about 270 mg, about 60 mg to about 270 mg, about 90 mg to about 270 mg, about 120 mg to about 270 mg, about 150 mg to about 270 mg, about 180 mg to about 270 mg, about 210 mg to about 270 mg, about 240 mg to about 270 mg, about 30 mg to about 240 mg, about 60 mg to about 240 mg, about 90 mg to about 240 mg, about 120 mg to about 240 mg, about 150 mg to about 240 mg, about 180 mg to about 240 mg, about 210 mg to about 240 mg, about 30 mg to about 210 mg, about 60 mg to about 210 mg, about 90 mg to about 210 mg, about 120 mg to about 210 mg, about 150 mg to about 210 mg, about 180 mg to about 210 mg, about 30 mg to about 180 mg, about 60 mg to about 180 mg, about 90 mg to about 180 mg, about 120 mg to about 180 mg, about 150 mg to about 180 mg, about 30 mg to about 150 mg, about 60 mg to about 150 mg, about 90 mg to about 150 mg, about 120 mg to about 150 mg, about 30 mg to about 120 mg, about 60 mg to about 120 mg, about 90 mg to about 120 mg about 30 mg to about 90 mg, about 60 mg to about 90 mg, or about 30 mg to about 60 mg of a compound described herein, for example, 2V-(5-(2,3-dihydrobenzo[b][l,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-((4- ethylpiperazin- 1 -yl)methyl)quinoline-6-carboxamide.

[0056] In some embodiments, the dose of the compound for methods of treating a disease as described herein comprises about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, or about 300 mg of a compound described herein, for example, 7V-(5-(2,3-dihydrobenzo[b][l,4]dioxine-6-carboxamido)-2- fluorophenyl)-2-((4-ethylpiperazin-l-yl)methyl)quinoline-6-carboxamide.

[0057] In other embodiments, the dose of the compound for methods of treating a disease as described herein comprises about 5 mg to about 80 mg, about 5 mg to about 70 mg, about 5 mg to about 60 mg, about 5 mg to about 50 mg, about 5 mg to about 40 mg, about 5 mg to about 30 mg, about 5 mg to about 20 mg, about 5 mg to about 10 mg, about 2 mg to about 40 mg, about 2 mg to about 35 mg, about 2 mg to about 30 mg, about 2 mg to about 25 mg, about 2 mg to about 20 mg, about 2 mg to about 15 mg, about 2 mg to about 10 mg, about 2 mg to about 5 mg, about 10 mg to about 100 mg, about 10 mg to about 90 mg, about 10 mg to about 80 mg, about 10 mg to about 70 mg, about 10 mg to about 60 mg, about 10 mg to about 50 mg, about 10 mg to about 40 mg, about 10 mg to about 30 mg, about 10 mg to about 20 mg, and about 10 mg to about 15 mg of a compound described herein, for example, 7V-(5-(2,3-dihydrobenzo[b][l ,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-((4- ethylpiperazin- 1 -yl)methyl)quinoline-6-carboxamide.

[0058] In certain embodiments, the dose of the compound for methods of treating a disease as described herein comprises about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, about 50 mg, about 52.5 mg, about 55 mg, about 57.5 mg, about 60 mg, about 62.5 mg, about 65 mg, about 67.5 mg, about 70 mg, about 72.5 mg, about 75 mg, about 77.5 mg, about 80 mg, about 82.5 mg, about 85 mg, about 87.5 mg, about 90 mg, about 92.5 mg, about 95 mg, about 97.5 mg, or about 100 mg of a compound described herein, for example, 7V-(5-(2,3-dihydrobenzo[b][l ,4]dioxine-6-carboxamido)-2- fluorophenyl)-2-((4-ethylpiperazin-l-yl)methyl)quinoline-6-carboxamide.

[0059] In some embodiments, a compound of the present disclosure, for example, a disclosed HSF1 pathway inhibitor, is administered once daily. In other embodiments, a compound of the present disclosure, for example, a disclosed HSF1 pathway inhibitor, is administered in a weekly regimen comprising five consecutive days wherein the inhibitor is administered, and two consecutive days wherein the inhibitor is not administered. In still other embodiments, a compound of the present disclosure, for example, a disclosed HSF1 pathway inhibitor, is administered in a weekly regimen comprising four consecutive days wherein the inhibitor is administered, and three consecutive days wherein the inhibitor is not administered.

[0060] In some embodiments, a method of treatment disclosed herein may produce an antiproliferative effect. In some embodiments, a method of treatment disclosed herein may be a method of treating a proliferative disease or a proliferative disorder. The terms “proliferative disease” and "proliferative disorder" are used interchangeably herein and pertain to an unwanted or uncontrolled cellular proliferation of excessive or abnormal cells which is undesired, such as, neoplastic or hyperplastic growth, whether in vitro or in vivo. Examples of proliferative conditions include, but are not limited to, pre-malignant and malignant cellular proliferation, including but not limited to, cancers and solid tumors. Any type of cell may be treated, including but not limited to, lung, liver, stomach, colon, breast, ovarian, prostate, liver, pancreas, brain, and skin. [0061] The anti-proliferative effects of the methods disclosed herein have particular application in the treatment of human cancers by virtue of their HSF1 inhibitory properties. The anti-cancer effect may arise through one or more mechanisms, including but not limited to, the regulation of cell proliferation, the inhibition of angiogenesis (the formation of new blood vessels), the inhibition of metastasis (the spread of a tumor from its origin), the inhibition of invasion (the spread of tumor cells into neighboring normal structures), or the promotion of apoptosis (programmed cell death). The anti-proliferative and anti-cancer effects may be observed in cancer and solid tumor types identified as having an ARID 1 A mutation.

[0062] The treatments defined herein may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery, radiotherapy, gene therapy or therapy with a chemotherapeutic agent or a molecularly targeted agent. Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. The term "combination" as used herein refers to simultaneous, separate or sequential administration. In some embodiments, "combination" refers to simultaneous administration. In other embodiments, "combination" refers to separate administration. In further embodiments, "combination" refers to sequential administration. Where the administration is sequential or separate, the delay in administering the second component should not be such as to lose the beneficial effect of the combination.

[0063] In certain embodiments, a compound described herein is administered as a pure chemical. In some embodiments, the compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration (e.g., oral administration) and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21 st Ed. Mack Pub. Co., Easton, PA (2005)).

[0064] In certain embodiments, the compound provided herein is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method. [0065] Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity). Optimal doses are generally determined using experimental models and/or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.

[0066] In some embodiments, the pharmaceutical composition comprises about 10 mg, 12.5 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 m g, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, or 150 mg of a compound described herein, for example, A-(5-(2,3- dihydrobenzo[b][l,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-((4-ethylpiperazin-l- yl)methyl)quinoline-6-carboxamide.

[0067] In some embodiments, the pharmaceutical composition comprises about 30 mg to about 300 mg, about 60 mg to about 300 mg, about 90 mg to about 300 mg, about 120 mg to about 300 mg, about 150 mg to about 300 mg, about 180 mg to about 300 mg, about 210 mg to about 300 mg, about 240 mg to about 300 mg, about 270 mg to about 300 mg, about 30 mg to about 270 mg, about 60 mg to about 270 mg, about 90 mg to about 270 mg, about 120 mg to about 270 mg, about 150 mg to about 270 mg, about 180 mg to about 270 mg, about 210 mg to about 270 mg, about 240 mg to about 270 mg, about 30 mg to about 240 mg, about 60 mg to about 240 mg, about 90 mg to about 240 mg, about 120 mg to about 240 mg, about 150 mg to about 240 mg, about 180 mg to about 240 mg, about 210 mg to about 240 mg, about 30 mg to about 210 mg, about 60 mg to about 210 mg, about 90 mg to about 210 mg, about 120 mg to about 210 mg, about 150 mg to about 210 mg, about 180 mg to about 210 mg, about 30 mg to about 180 mg, about 60 mg to about 180 mg, about 90 mg to about 180 mg, about 120 mg to about 180 mg, about 150 mg to about 180 mg, about 30 mg to about 150 mg, about 60 mg to about 150 mg, about 90 mg to about 150 mg, about 120 mg to about 150 mg, about 30 mg to about 120 mg, about 60 mg to about 120 mg, about 90 mg to about 120 mg about 30 mg to about 90 mg, about 60 mg to about 90 mg, or about 30 mg to about 60 mg of a compound described herein, for example, 7V-(5-(2,3- dihydrobenzo[b][l,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-((4-ethylpiperazin-l- yl)methyl)quinoline-6-carboxamide..

[0068] In some embodiments, the pharmaceutical composition comprises about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, or about 300 mg of a compound described herein, for example, JV-(5-(2,3- dihydrobenzo[b] [ 1 ,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-((4-ethylpiperazin- 1 - yl)methyl)quinoline-6-carboxamide.

[0069] In some embodiments, the pharmaceutical composition comprises about 5 mg to about 80 mg, about 5 mg to about 70 mg, about 5 mg to about 60 mg, about 5 mg to about 50 mg, about 5 mg to about 40 mg, about 5 mg to about 30 mg, about 5 mg to about 20 mg, about 5 mg to about 10 mg, about 2 mg to about 40 mg, about 2 mg to about 35 mg, about 2 mg to about 30 mg, about 2 mg to about 25 mg, about 2 mg to about 20 mg, about 2 mg to about 15 mg, about 2 mg to about 10 mg, about 2 mg to about 5 mg, about 10 mg to about 100 mg, about 10 mg to about 90 mg, about 10 mg to about 80 mg, about 10 mg to about 70 mg, about 10 mg to about 60 mg, about 10 mg to about 50 mg, about 10 mg to about 40 mg, about 10 mg to about 30 mg, about 10 mg to about 20 mg, and about 10 mg to about 15 mg of a compound described herein, for example, 2V-(5-(2,3-dihydrobenzo[b][l,4]dioxine-6- carboxamido)-2-fluorophenyl)-2-((4-ethylpiperazin-l-yl)methyl)quinoline-6-carboxamide.

[0070] In some embodiments, the pharmaceutical composition comprises about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, about 50 mg, about 52.5 mg, about 55 mg, about 57.5 mg, about 60 mg, about 62.5 mg, about 65 mg, about 67.5 mg, about 70 mg, about 72.5 mg, about 75 mg, about 77.5 mg, about 80 mg, about 82.5 mg, about 85 mg, about 87.5 mg, about 90 mg, about 92.5 mg, about 95 mg, about 97.5 mg, or about 100 mg of a compound described herein, for example, 2V-(5-(2,3- dihydrobenzofb] [ 1 ,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-((4-ethylpiperazin- 1 - yl)methyl)quinoline-6-carboxamide. [0071] For example, in some embodiments a disclosed compound or composition may be administered once daily to the patient. In other embodiments, a disclosed compound or composition may be administered twice daily to the patient.

[0072] In some embodiments, a pharmaceutical composition of the present disclosure, for example, a pharmaceutical composition comprising a disclosed HSF1 pathway inhibitor and a pharmaceutically acceptable excipient, is administered once daily. In other embodiments, a pharmaceutical composition of the present disclosure, for example, a pharmaceutical composition of the present disclosure, for example, a pharmaceutical composition comprising a disclosed HSF1 pathway inhibitor and a pharmaceutically acceptable excipient, is administered in a weekly regimen comprising five consecutive days wherein the inhibitor is administered, and two consecutive days wherein the inhibitor is not administered. In still other embodiments, a pharmaceutical composition of the present disclosure, for example, a pharmaceutical composition of the present disclosure, for example, a pharmaceutical composition comprising a disclosed HSF1 pathway inhibitor and a pharmaceutically acceptable excipient, is administered in a weekly regimen comprising four consecutive days wherein the inhibitor is administered, and three consecutive days wherein the inhibitor is not administered.

[0073] For example, the pharmaceutical compositions of the present disclosure can be formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets (e.g., those targeted for buccal, sublingual, and/or systemic absorption), capsules, boluses, powders, granules, and pastes for application to the tongue;

(2) parenteral administration by, for example, subcutaneous, intramuscular, intraperitoneal, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; (3) topical administration, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin; (4) intravaginal or intrarectal administration, for example, as a pessary, cream or foam; (5) sublingual administration; (6) ocular administration; (7) transdermal administration; or (8) nasal administration. In certain embodiment, pharmaceutical compositions of the disclosure may be formulated for oral administration.

[0074] In some embodiments, the pharmaceutical composition is formulated as a tablet, a pill, a capsule, a liquid, an inhalant, a nasal spray solution, a suppository, a suspension, a gel, a colloid, a dispersion, a suspension, a solution, an emulsion, an ointment, a lotion, an eye drop, or an ear drop. In some embodiments, the pharmaceutical composition is formulated as a tablet, for example, a tablet formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated as a capsule, for example, a capsule formulated for oral administration.

[0075] Amounts of a disclosed compound, or amounts of a disclosed compound as described herein in a pharmaceutical composition, may vary according to factors such as the disease state, age, sex, and weight of the individual. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.

EXAMPLES

[0076] The following non-limiting examples illustrate the disclosure.

[0077] W(5-(2,3-Dihydrobenzo[b][l,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-

((4-ethylpiperazin-l-yl)methyl)quinoline-6-carboxamide (Compound A) can be prepared according to the synthetic procedures in WO 2015/049535, which is incorporated by reference herein.

Example 1

[0078] A study of Compound A in subjects with advanced solid tumors and in subjects with ovarian cancer is conducted.

Primary Objective: To generate efficacy data and safety data in subjects with ARIDla mutated, platinum-resistant ovarian carcinoma.

Primary Endpoints: Estimates of objective response rate, duration of response, and disease control rate per response criteria in solid tumors.

Secondary Objective: To further characterize the PK profile of Compound A. Secondary Endpoints: Estimates of PK parameters such as area under the curve, maximum concentration, time to maximum concentration, elimination half-life, volume of distribution at steady state, and total plasma clearance at steady state.

Exploratory Objectives: To describe the treatment effect of Compound A on pharmacodynamic markers; to evaluate the correlation between ARIDla mutation and ARID la protein loss; to evaluate the concordance of next generation sequencing and circulating free deoxyribonucleic acid for ARIDla mutation.

Exploratory Endpoints: Estimation of change in expression of CHAC1, ATF3, ATF4, HSP27 and other proteins at RNA or protein level pre and post treatment with Compound A; estimates of ARIDla mutation by next generation sequencing and ARIDla protein loss by immunohistochemistry; Estimates of ARIDla mutation by next generation sequencing and ARIDla mutation by circulating free deoxyribonucleic acid.

Study Design:

[0079] The study population will be subjects with platinum-resistant, ARID la- mutated ovarian, fallopian tube and primary peritoneal carcinoma. Compound A will be supplied as 12.5 mg and 75 hydroxypropyl methylcellulose capsules. Two cohorts are planned: Cohort 1 : Compound A will be administered orally as a 50 mg/day fixed dose, once daily, every day, of a 28-day treatment cycle; and Cohort 2: Compound A will be administered orally as a 75 mg/day fixed dose, once daily, every day of a 28-day treatment cycle. The doses will be taken with food, suggested at the end of a meal and no longer than 2 hours after a meal. Each subject will participate in the study until progression, discontinuation due to unacceptable toxicity, initiation of another anticancer therapy, or subject choice, subjects will remain on study for up to 18 months post discontinuation of treatment with Compound A. During the study, disease assessments will be performed at 8- 12-week intervals, (depending on time on study) using a computed tomography (CT) or magnetic resonance imaging (MRI) scan. PET-CT is not to be used for disease assessment or reassessment. Two cohorts will enroll a total of 22 evaluable subjects per cohort for initial assessment of the antitumor activity of Compound A. Table 1 provides information on selected doses.

Table 1.

[0080] Based on a rat 28-day repeat dose GLP toxicity study (the rat was considered the most sensitive of the 2 species), the MTD of Compound A was 12.5 mg/kg/day (75 mg/m²/day). Using surface area scaling, this dose equates to 2.0 mg/kg/day in man, or a clinical dose of approximately 120 mg/day for a 60- kg human. Based on in vitro and in vivo data, a dose of 50 mg/day represents the expected minimally effective dose, and since this dose is within the acceptable safety range (2.4-fold relative to the MTD) it is a suitable starting dose for this study. Model-based simulations demonstrated that Compound A exposures following 75 mg QD and 50 mg QD were pharmacokinetically distinguishable, with minimal overlap between the corresponding 50% prediction intervals for systemic exposure (area under the plasma concentration-time curve [AUC]). Systemic exposures obtained at these dose levels in patients were at, or higher than, the expected minimally effective dose.

[0081] Subjects must meet all of the following criteria to be eligible for study participation: Provide written informed consent; 18 years old or older; Subjects with the following ARID la mutated, ovarian/fallopian tube/primary peritoneal cancer histologies (ARID la mutation status determined by a DNA based Next Generation Sequencing test): a) Clear cell ovarian carcinoma (> 50% clear cell carcinoma with no serous differentiation) or b) Endometrioid ovarian carcinoma; Subjects must have disease progression within 6 months (182 days) from completion of platinum-based therapy (6 months should be calculated from the date of the last administered dose of platinum therapy to the date of radiographic imaging showing progression); Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 ; Subjects with a BRCA mutation must have received prior treatment with a PARP inhibitor; Subjects must have received at least 1 but not more than 3 prior systemic lines of anticancer therapy, including at least 1 line of therapy containing bevacizumab (Adjuvant + neoadjuvant are considered one line of therapy, Maintenance therapy (i.e., bevacizumab, PARP inhibitors) will be considered as part of the preceding line of therapy and are not counted independently); Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 ; Hematological and biochemical indices within the ranges as follows: a) Hemoglobin: > 9.0 g/dL or > 10.0 g/L if transfusion within last 4 weeks; b) Absolute neutrophil count: > 1.5xl09/L; c) Platelet count: > 100xl09/L; d) Bilirubin: < 1.5x the upper limit of normal (ULN), unless raised due to Gilbert’s syndrome in which case direct (not total) bilirubin will be used; e) Alanine and aspartate aminotransferase (ALT and AST): < x2.5 ULN unless raised due to tumor, in which case <5xULN is permissible; f) Calculated creatinine clearance (using the Cockcroft & Gault formula): >50 mL/min (uncorrected value); Subjects must have sufficient archival Formalin-Fixed Paraffin-Embedded (FFPE) tissue specimen, or be willing to consent to a fresh tissue biopsy during the study, for the following tests: a) All eligible subjects will have NGS testing performed using the Foundation One® CDx while on study. Eleven (11) unstained FFPE slides are needed for this test. Subjects who had the screening NGS using the Foundation One® CDx will not need to repeat the testing, b) Three FFPE slides are needed for immunohistochemistry (IHC) for all eligible subjects and able to swallow oral therapy.

[0082] Subjects screened for enrollment meeting any of the following criteria are not eligible for study participation: Subjects with disease that did not respond to, or has progressed during or within 4 weeks of the last dose of first-line platinum containing chemotherapy; Radiotherapy (except for palliative reasons), endocrine therapy, chemotherapy, or investigational agent within 28 days, (42 days for nitrosoureas, mitomycin- C) of first dose of Compound A; Ongoing toxic manifestations of previous treatments > Grade 2, with the exception of alopecia; Subjects with treated brain metastases are eligible if there is no evidence of progression for at least 12 weeks while off corticosteroids after central nervous system (CNS)-directed treatment, as ascertained by clinical examination and brain imaging (magnetic resonance imaging [MRI] or computed tomography [CT] scan) during the Screening period; Female subjects who can become pregnant (or are already pregnant or lactating). However, female subjects who have a negative serum or urine pregnancy test before enrollment and agree to use at least one highly effective form of contraception (such methods include: combined [estrogen and progestin containing] hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal); Intrauterine device; intrauterine hormone-releasing system; bilateral tubal occlusion; vasectomized partner [provided that partner is the sole sexual partner of the female study participant and that the vasectomized partner has received medical assessment of the surgical success]) or agree to sexual abstinence, effective from the first administration of Compound A, throughout the study and for 6 months afterwards can be eligible. (Note: abstinence is only considered to be an acceptable method of contraception when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence [e.g., calendar, ovulation, symptothermal, post- ovulation methods] and withdrawal are not acceptable methods of contraception.); Has a known additional malignancy that is progressing or has required active treatment within the past 3 years; Major surgery from which the subject has not yet recovered; At high medical risk because of non-malignant systemic disease including active uncontrolled infection; Known to be serologically positive for: a) Human immunodeficiency virus (HIV); b) Hepatitis B surface antigen or hepatitis B core antibody who have detectable hepatitis B virus DNA (unless immune due to vaccination, which is not exclusionary); c) Hepatitis C virus antibody or HCV ribonucleic acid (unless immune due to vaccination, which is not exclusionary); Clinical or radiographic evidence of bowel obstruction, history of bowel obstruction, abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 6 months of screening; Subjects requiring therapeutic paracentesis within 8 weeks of Cycle 1 Day 1; Severe cardiovascular abnormalities, including but not limited to, uncontrolled hypertension, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or myocardial infarction within 24 weeks of screening; QT/QTc interval 470 ms using Fredericia’s QT correction formula; Any other medical, psychiatric, or social condition that in the Investigator’s opinion would not make the subject a good candidate for the clinical study.

Example 2

In Vivo Efficacy Studies:

[0083] The in vivo efficacy of Compound A was investigated in xenograft tumors in athymic nude mice with a focus on ovarian cancers. The efficacy of Compound A was investigated in xenograft bearing mice with the following ovarian cancer cell lines: SK-OV- 3; TOV-21G, OVISE, IGROV1, OVCAR-5, ES-2, and RMG1. Of the seven cell lines, SK- OV-3; TOV-21G, OVISE, and IGROV1 were identified as harboring an ARID1A mutation, while OVCAR-5, ES-2, and RMG1 were ARID1A wildtype.

[0084] Once the tumors were established, mice were randomized into vehicle control and treatment groups. Mice in both the vehicle control and treatment groups that were removed during the course of the study due to spontaneous or treatment derived tumor regression, tumor growth approaching license limits, tumor ulceration or loss of condition were excluded from the final analysis of the mean tumor volume and standard error of the mean and up to the point they were removed from the study. The number of mice undergoing complete tumor regression in the treatment group is noted where applicable. [0085] Two groups of 12 female NCr nude mice (3 groups of 10 for SK-OV-3) were injected with 3-5 x 10⁶ cells of one of the above cancer cell lines, subcutaneously. Once the tumors had reached this size the groups were administered vehicle control (10% DMSO, 90% of 25% 2-hydroxypropyl-beta-cyclodextrin in 50 mM sodium citrate buffer pH5 [DCC]) or Compound A at 35 or 70 mg/kg orally in DCC once daily by gavage. Body weights were taken daily and animals were monitored for signs of toxicity. To evaluate drug levels the animals were euthanized in batches of 3 to 4 at 2, 6 and 24 hours after the last dose and terminal plasma and tumor samples collected for PK analysis. The difference in final tumor volume (p<0.005, Mann- Whitney test) in the Compound A dose group relative to the control group was recorded. The results are shown in Table 2.

Table 2. Details of the 35 mg/kg Compound A dose schedule and TGIs obtained in the studies

[0086] FIG. 1, FIG. 2, FIG. 3, and FIG. 4 depicts the antitumor activity (e.g., tumor growth inhibition) of Compound A in ovarian clear cell cancer xenograft models: SKOV-3, TOV-21G, OVISE, and IGROV1, each identified as harboring an ARID 1 A mutation.

[0087] FIG. 1 depicts the antitumor activity (e.g., tumor growth inhibition) of Compound A in an ovarian cancer xenograft model (SKOV-3). The tumor was identified as harboring an ARID1 A mutation. Cr nude mice were injected with 5 x 10⁶ SK-OV-3 cells and, once the tumor was established, administered vehicle control (DCC) or 35 mg/kg Compound A in DCC once daily (or as described in the text) by oral gavage. Graph shows mean tumor volume over the dosing period of the study; error bars represent standard error of the mean. Control and 35 mg/kg group n=10. Horizontal black line is 35 mg/kg group tumor volume on Day 0.

[0088] FIG. 2 depicts the antitumor activity (e.g., tumor growth inhibition) of Compound A in an ovarian cancer xenograft model (TOV-21G). The tumor was identified as harboring an ARID1A mutation. NCr nude mice were injected with 3 x 10⁶ TOV-21G cells and, once the tumor was established, administered vehicle control (DCC) or 35 mg/kg Compound A in DCC once daily for 5 days out of every 7 by oral gavage. Graph shows mean tumor volume over the dosing period of the study; error bars represent standard error of the mean. Vehicle control group n=8 and 35 mg/kg dose group n=ll.

[0089] FIG. 3 depicts the antitumor activity (e.g., tumor growth inhibition) of Compound A in an ovarian cancer xenograft model (OVISE). NCr nude mice were injected with 5 x 10⁶ OVISE cells and, once the tumor was established, administered vehicle control (DCC) or 35 mg/kg Compound A in DCC once daily for 5 days out of every 7 by oral gavage. Graph shows mean tumor volume over the dosing period of the study; error bars represent standard error of the mean. Vehicle control group n=10 and 35 mg/kg Compound A group n=l 1.

[0090] FIG. 4 depicts the antitumor activity (e.g., tumor growth inhibition) of Compound A in an ovarian cancer xenograft model (1GROV-1). NCr nude mice were injected with 3 x 10⁶ IGROV-1 cells and, once the tumor was established, administered vehicle control (DCC) or 35 mg/kg Compound A in DCC once daily by oral gavage in an intermittent schedule. Graph shows mean tumor volume over the dosing period of the study; error bars represent standard error of the mean. Vehicle control group n=5 and 35 mg/kg Compound A group n=6.

[0091] As shown in Table 2, a small signal of efficacy was seen in the ARID 1 A wild type OVCAR-5 and ES-2 models (%TGI of 27% and 12%, respectively), however this did not meet the criteria for efficacy (%TGI.50%). No inhibition of xenograft tumor growth was seen in the ARID 1 A wildtype RMG1 model. Plasma Cmax in the OVCAR-5 and ES-2 models were within the range seen in successful efficacy studies, while the levels in the RMG1 model was less than half the lowest level seen in successful efficacy studies. The ARID 1 A mutated, SK-OV-3 ovarian cancer cell line was the most sensitive cell line in xenograft models. [0092] FIG. 5 depicts a comparative graph of the antitumor activity (e.g., tumor growth inhibition) of Compound A in the seven ovarian cancer xenograft models studied: SK-OV-3; TOV-21G, OVISE, IGROV1, OVCAR-5, ES-2, and RMG1. FIG. 5 depicts a summary of tumor xenograft experiments. Established tumor xenografts were treated (35 mg/kg Compound A oral schedule as in Table 1 once daily as indicated). TGI>50% was considered significant and is indicated by the dotted line. All experiments were conducted with at least n=9 mice control and treated (except IGROV-1 n=6 treated and n=5 control).

INCORPORATION BY REFERENCE

[0093] All publications and patents mentioned herein, including those items listed below, are hereby incorporated by reference in their entirety for all purposes as if each individual publication or patent was specifically and individually incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

EQUIVALENTS

[0094] While specific embodiments of the subject disclosure have been discussed, the above specification is illustrative and not restrictive. Many variations of the disclosure will become apparent to those skilled in the art upon review of this specification. The full scope of the disclosure should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

[0095] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present disclosure.

[0096] What is claimed is:

Claims

1. A method of treating a cancer in a patient in need thereof, comprising administering to the patient about 50 mg, or about 75 mg, of a HSF1 pathway inhibitor, wherein the cancer is identified as having an ARID 1 A mutation.

2. The method of claim 1, wherein the HSF1 pathway inhibitor is administered orally.

3. The method of claim 1 or 2, wherein the cancer is selected from the group consisting of an ovarian cancer, fallopian tube cancer, and primary peritoneal cancer.

4. The method of any one of claims 1-3, wherein the HSF1 pathway inhibitor is represented by Formula I: or a pharmaceutically acceptable salt and/or a stereoisomer thereof, wherein:

R¹ and R² are each independently selected from the group consisting of hydrogen and halogen;

R³ is selected from the group consisting of fluoro, hydrogen, chloro, cyano, -CH3, - CF3, -OCH3, and -OCF3; and

R⁴ is a 5, 6 or 7-membered nitrogen-linked heterocyclyl optionally comprising one further nitrogen atom; wherein R⁴ may optionally be substituted on the further nitrogen atom by a substituent selected from the group consisting of methyl, ethyl, propyl, and cyclopropylmethyl; and wherein R⁴ may optionally be substituted on a carbon atom by a substituent selected from the group consisting of methyl, fluoro, and chloro.

5. The method of claim 4, wherein R⁴ is nitrogen-linked piperazinyl substituted on the further nitrogen atom by methyl, ethyl, or propyl, or cyclopropylmethyl.

6. The method of any one of claims 1-5, wherein the HSF1 pathway inhibitor is or a pharmaceutically acceptable salt thereof.

7. The method of any one of claims 1-6, wherein the HSF1 pathway inhibitor is

8. The method of any one of claims 1-7, comprising administering to the patient about 50 mg of the HSF1 pathway inhibitor.

9. The method of any one of claims 1-8, comprising administering to the patient about 75 mg of the HSF1 pathway inhibitor.

10. A method of treating an ovarian cancer in a patient in need thereof, comprising orally administering to the patient about 50 mg, or about 75 mg, of an HSF1 pathway inhibitor represented by or a pharmaceutically acceptable salt thereof; wherein the cancer is identified as having an ARTD1 A mutation.

11. The method of any one of claims 1-10, wherein the HSF1 pathway inhibitor is administered once daily.

12. The method of any one of claims 1-11, wherein the HSF1 pathway inhibitor is administered in a weekly regimen comprising five consecutive days wherein the inhibitor is administered, and two consecutive days wherein the inhibitor is not administered.

13. A method of treating an ovarian cancer in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising: a compound represented by or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient; wherein the cancer is identified as having an ARID 1 A mutation.

14. The method of claim 13, wherein the pharmaceutical composition comprises about 50 mg of the compound.

15. The method of claim 13, wherein the pharmaceutical composition comprises about 75 mg of the compound.

16. The method of any one of claims 13-15, wherein the pharmaceutical composition is administered orally.

17. A method of treating an ovarian cancer in a patient in need thereof, comprising orally administering to the patient a pharmaceutical composition comprising: about 50 mg, or about 75 mg, of a compound represented by or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient; wherein the is identified as having an ARID 1 A mutation.

18. The method of any one of claims 13-17, wherein the pharmaceutical composition is administered once daily.

19. The method of any one of claims 1 -17, wherein the pharmaceutical composition is administered in a weekly regimen comprising five consecutive days wherein the pharmaceutical composition is administered, and two consecutive days wherein the pharmaceutical composition is not administered.

20. The method of any one of claims 1-19, wherein the cancer is endometrioid ovarian cancer.

21. The method of claim 20, wherein the cancer is relapsed or refractory endometrioid ovarian cancer.

22. The method of any one of claims 1-19, wherein the cancer is clear cell ovarian cancer.

23. The method of claim 22, wherein the cancer is relapsed or refractory clear cell ovarian cancer.

24. The method of any one of claims 1-23, wherein the cancer comprises solid tumors.

25. The method of any one of claims 1-24, wherein the ovarian cancer is substantially resistant to platinum-based chemotherapy, taxane-based chemotherapy, or a combination thereof.

26. The method of any one of claims 1-25, wherein the ARID 1 A mutation is a heterozygous ARID 1 A mutation.

27. The method of any one of claims 1-26, wherein the ARID 1 A mutation is a homozygous ARID 1 A mutation.

28. The method of any one of claims 1-27, wherein the administration results in about a 2-5 fold decrease in the mean Gbo in ARID 1 A mutant cancer cells compared to wild type ARID 1 A cells.

29. The method of any one of claims 1-28, wherein the administration results in about a 4-5 fold decrease in the mean GIso in ARID 1 A mutant ovarian cancer cells compared to wild type ARID 1 A ovarian cells.

30. The method of any one of claims 1-29, wherein the method further and optionally comprises administering one or more additional cancer chemotherapeutic agents.

31. The method of any one of claims 1-30, wherein the method further and optionally comprises administering an additional cancer chemotherapeutic agent.

32. A method of treating platinum-resistant ovarian carcinoma in a patient in need thereof, comprising orally administering to the patient about 50 mg, or about 75 mg, a compound represented by: or a pharmaceutically acceptable salt thereof; wherein the is identified as having an ARID 1 A mutation.

33. A method of treating platinum-resistant ovarian carcinoma in a patient in need thereof, comprising orally administering to the patient a pharmaceutical composition comprising: about 50 mg, or about 75 mg, of a compound represented by: or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient; wherein the is identified as having an ARID 1 A mutation.