WO2020236667A1

WO2020236667A1 - Methods of treating cancer

Info

Publication number: WO2020236667A1
Application number: PCT/US2020/033311
Authority: WO
Inventors: Jakob Dupont; Lei Zhou; Nihar BHAKTA; Deborah Helen Slee; Caryn Peterson; Jean-Marie Bruey; David Nickle
Original assignee: Gb006, Inc.; Msd International Gmbh
Priority date: 2019-05-17
Filing date: 2020-05-16
Publication date: 2020-11-26
Also published as: WO2020236668A1

Abstract

Disclosed herein are methods for treating cancer by administration to a patient in need thereof, an effective amount of (Z)-4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5-ylidene) methyl) furan-2-yl) benzoic acid or pharmaceutically acceptable salts thereof and pembrolizumab. In some embodiments, the choline salt Z)-4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5-ylidene) methyl) furan-2-yl) benzoic acid is administered. In some embodiments, the patient has a solid tumor.

Description

METHODS OF TREATING CANCER

TECHNICAL FIELD

Described herein are methods of treating cancer by administration of (Z)-4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5-ylidene)methyl)furan-2-yl)benzoic acid or pharmaceutically acceptable salts thereof and pembrolizumab.

INCORPORATION BY REFERENCE

All publications, patents and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and

individually indicated to be incorporated by reference.

BACKGROUND

Cancer is the second leading cause of mortality worldwide. Current treatments for cancer, including systemic chemotherapy, radiation and surgery, offer limited benefit for many patients with locally advanced or metastatic disease that is not amendable to curative surgical resections. There is a need for effective novel therapies for patients with advanced solid tumors.

Myeloid cells are among the most abundant normal cells in the tumor microenvironment and are present at all stages of tumor progression. Such myeloid cells are polarized in the tumor microenvironment into tumor-associated

macrophages (TAMs), found in both in primary and metastatic sites. TAMs shield and enhance tumor growth and as such they represent an important therapeutic target for cancer treatment (Noy at al , "Tumor-associated macrophages: from mechanisms to therapy" Immunity 2014, 41(1): 49-61.)

Several approaches for targeting TAMs to treat cancer have been attempted. For example, inhibition of tumor-derived factors, suppression of generation and expansion of TAMs from hematopoietic progenitors, blockade of TAM trafficking and infiltration, harnessing immune suppressive activities of TAMs, facilitating differentiation of TAMs into mature non-suppressive cells and blocking TAM cell recruitment to the tumor site.

Tumors secrete chemokines, notably colony stimulating factor 1 (CSF1), C-C motif ligand 2 (CCL2) and C-X-C motif chemokine 12 (CXCL12). The secreted chemokines upregulate the endothelial ligands, to slow down and induce myeloid cells transmigration from the lumen of blood vessels to the tumor matrix and enhance their recruitment to tumor sites and their polarization into TAMs. Strategies targeting CSF1R, CCL2/CCR2 axis and CXCL12 have shown promise in reducing TAM recruitment to tumors, and in decreasing tumor growth.

Myeloid-derived suppressor cells (MDSC's) are a heterogeneous population of myeloid cells in the tumor microenvironment that also negatively regulate adaptive and innate immune responses to cancer. Upregulation of certain subsets of MDSCs (e.g., granulocytic MDSCs) at the tumor site is a compensatory mechanism for therapies that specifically target TAMs leading to treatment resistance and eventual tumor progression.

CD1 lb is an integrin receptor predominantly expressed on myeloid cell types. It is highly expressed on the cells of the immune system and mediates their biological functions, and is also highly expressed on both TAMs and MDSCs. CD1 lb expression is upregulated in many tumor types and the presence of CD1 lb+ cells is associated with poor prognosis in multiple cancer types. Genetic deletion of CD1 lb, or targeting it with various agents, significantly reduces CD1 lb+ cells in the tumor and is associated with enhanced immune response to the tumor, suppression of tumor growth and of metastases (Zhang et al , "CD1 lb deficiency suppresses intestinal tumor growth by reducing myeloid cell recruitment." Scientific Reports 5, 2015, 15948.)

In oncology settings, influx of CD1 lb expressing MDSCs and M2 TAMs creates an immunosuppressive microenvironment that suppresses the adaptive immune response, promotes angiogenesis and tumor growth and is associated with resistance/relapse to therapy in nonclinical syngeneic tumor models and in the clinic.

Modulation of CD1 lb results in increased CD 1 lb-dependent cell adhesion, reduced leukocyte migration in vitro and tissue influx in vivo , as well as repolarization of immunosuppressive M2 macrophages towards the anti -turn or Ml phenotype. For a number of different cancers, systemic chemotherapy offers only limited benefit for patients with locally advanced or metastatic disease which is not amenable to surgical resection. Novel therapies which are efficacious and well- tolerated are urgently needed for patients with advanced and previously treated solid tumors, including pancreatic ductal adenocarcinoma (PD AC), prostate cancer, malignant melanoma, breast cancer and soft tissue sarcomas. While advantages have been made in the treatment of cancer, there remains a significant need in the art for methods of treating this condition. The present invention fulfills this need and provides further related advantages.

SUMMARY OF THE INVENTION

Provided herein are methods for treating cancer by administration to a patient in need thereof an effective amount of (Z)-4-(5-((3-benzyl-4-oxo-2- thioxothiazolidin-5-ylidene)methyl)furan-2-yl)benzoic acid, (herein after referred to as Compound 1), or a pharmaceutically acceptable salt thereof, and pembrolizumab. Compound 1 may also be depicted as a compound according to Formula (I)

As depicted above, Compound 1 is shown as the "free acid". In one embodiment, the pharmaceutically acceptable salt is the choline salt or crystalline form thereof.

In another embodiment, the pharmaceutically acceptable salt of Compound 1 is the meglumine salt or crystalline form thereof.

Meglumine salt of Compound 1

Compound 1 is disclosed in US Patents 9,023,876, 9,328,105 and

10,239,871. The choline and meglumine salts of Compound 1 and crystalline forms thereof are described in published Application US 2018/0354938 (all of which are incorporated by reference herein in their entirety).

In another embodiment, a method of treating a cancer is provided, comprising administering to a patient identified as having a cancer with a BRCA mutation: a compound according to Formula (I)

or a pharmaceutically acceptable salt thereof; and pembrolizumab.

In yet another embodiment, a method of treating a cancer is provided, comprising (a) administering to a patient having cancer (i) a compound according to Formula (I)

or a pharmaceutically acceptable salt thereof; and (ii) pembrolizumab; (b) obtaining at least two measurements of neutrophil to lymphocyte ratio for the patient post treatment and comparing the at least two measurements of neutrophil to lymphocyte ratio for the patient post-treatment with a baseline neutrophil to lymphocyte ratio at day 0, wherein the at least two measurements are obtained every one week, two weeks, three weeks, or four weeks; (c) wherein administration of the compound and pembrolizumab is continued if a decrease in neutrophil to lymphocyte ratio compared to the baseline neutrophil to lymphocyte ratio at day 0 is maintained for at least four weeks, or administration of the compound and pembrolizumab is discontinued if a decrease in neutrophil to lymphocyte ratio compared to the baseline neutrophil to lymphocyte ratio at day 0 is not maintained for at least four weeks.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 represents a Schematic for Phase 1, the Dose Escalation Phase, of the clinical study. Doses are expressed with respect to Compound 1 free acid; lOOmg free acid is equivalent to 124.48mg choline salt.

FIG. 2 represents a Schematic for Phase 2, the Basket Expansion Phase, of the clinical study.

FIG. 3 represents Schematic for Phase 1 and Phase 2 of the clinical study. Doses are expressed with respect to Compound 1 free acid; lOOmg free acid is equivalent to 124.48mg choline salt.

FIG. 4 shows baseline demographics and disease characteristics of 22 patients enrolled in dose escalation study as of March 27, 2020. Continuous data are presented as median (range); categorical data are presented as n (%). Doses are expressed with respect to Compound 1 free acid; lOOmg free acid is equivalent to 124.48mg choline salt.

FIG. 5 shows treatment emergent adverse events (TEAE) reported in > one patient. Data as of March 27, 2020. *Disease progression included disease progression and worsening pancreatic cancer.

FIG. 6 shows choline salt of Compound 1 treatment-related adverse events. Data as of March 27, 2020.

FIG. 7 shows plasma concentration of choline salt of choline salt Compound 1 vs. time. Doses are expressed with respect to Compound 1 free acid; lOOmg free acid is equivalent to 124.48mg choline salt. Data as of March 27, 2020. FIG. 8 depicts patient exposure and response evaluation criteria in solid tumors (RECIST) for Regimens A and B. Data as of March 27, 2020.

FIG. 9 shows medical history of CRPC patient enrolled in Regimen

B. FIG. 10 shows heatmap of per patient gene expression changes in serial blood biopsies and correlation with tumor type. Doses are expressed with respect to Compound 1 free acid; lOOmg free acid is equivalent to 124.48mg choline salt. Data as of March 27, 2020.

FIG. 11 shows blood transcriptomics of Regimen A (Choline salt of Compound 1 alone) vs. Regimen B (Choline salt of Compound 1 +

Pembrolizumab). Doses are expressed with respect to Compound 1 free acid;

lOOmg free acid is equivalent to 124.48mg choline salt. Data as of March 27, 2020.

FIG. 12 shows blood transcriptomics of choline salt of Compound 1 dose-dependent cluster. Doses are expressed with respect to Compound 1 free acid; lOOmg free acid is equivalent to 124.48mg choline salt. Data as of March 27, 2020.

FIGS. 13A-13B show change from baseline in (FIG. 12 A) monocytic myeloid-derived suppressor cells (mMDSCs) and (FIG. 12B)

granulocytic myeloid-derived suppressor cells (gMDSCs) by regimen and overall. Data as of March 27, 2020. FIG. 14 shows a line plot for neutrophils: lymphocyte ratio (LNR) percent change from baseline over time (Regimen B only).

DETAILED DESCRIPTION

Compound 1 is a CDl lb modulator. In nonclinical syngeneic models, Compound 1 reduced tumor influx of CD1 lb positive MDSCs and tumor- associated macrophages (TAMs), while increasing influx of activated CD8+ T cells. It also re-polarizes immuno-suppressive (M2) TAMs towards the Ml phenotype, which is associated with improved antigen presentation and anti-tumor activity (Schmid et al, "Integrin CD1 lb activation drives anti -tumor innate immunity", Nature Communications 2018, 9:5379.) Thus Compound 1, unlike other myeloid cell targeted therapies, impacts not just TAMs and monocytic MDSCs, but also granulocytic MDSCs that are often upregulated at the tumor site as part of a compensatory immune evasion mechanism.

The pleiotropic mechanisms - targeting both migration and polarization of the different myeloid cell subtypes within the tumor

microenvironment - translates into improved anti-tumor efficacy in vivo, especially in combination settings. For example, in syngeneic orthotopic pancreatic tumor models, Compound 1 demonstrated strong synergy in combination with

chemotherapeutic agents, leading to tumor regression, long-term survival and lasting immunologic memory.

Pembrolizumab (KEYTRUDA®) is a humanized IgG4 antibody approved for the treatment of advanced solid tumors (U.S. Patent 8,354,509, incorporated by reference in its entirety). Clinical outcomes with pembrolizumab remain variable; many patients do not respond to therapy or experience relapse after initial therapy due to extensive immunosuppression. The immunosuppression is mediated in part by MDSCs that inhibit the anti -tumor activities of T and natural killer cells and contribute to pembrolizumab resistance. Frequency of MDSCs in cancer patients is a predictive marker for pembrolizumab response where depletion of MDSCs leads to improved outcomes to pembrolizumab treatment.

Compound 1 offers potential treatment options to patients with sub- optimal treatment benefit from pembrolizumab due to MDSC mediated

immunosuppression. Compound 1 is under development for the treatment of advanced solid tumors. Described herein is a Phase 1/2 clinical trial, evaluating Compound 1 as monotherapy or in combination, comprising a Phase 1 Dose Escalation phase, followed by a Phase 2 Basket Expansion phase, for the treatment of various cancers. Described herein are methods of treating cancer by administration to a patient having cancer (Z)-4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5- ylidene)methyl)furan-2-yl)benzoic acid or pharmaceutically acceptable salts thereof and pembrolizumab.

In some embodiments, (Z)-4-(5-((3-benzyl-4-oxo-2- thioxothiazolidin-5-ylidene)methyl)furan-2-yl)benzoic acid is administered.

In some embodiments, a pharmaceutically acceptable salt of (Z)-4- (5-((3-benzyl-4-oxo-2-thioxothiazolidin-5-ylidene)methyl)furan-2-yl)benzoic acid is administered. A“salt” refers to a base addition salt prepared by combining Compound 1 free acid with a pharmaceutically acceptable base. A number of pharmaceutically acceptable bases can be used to prepare salts of (Z)-4-(5-((3- benzyl-4-oxo-2-thioxothiazolidin-5-ylidene)methyl)furan-2-yl)benzoic acid.

Pharmaceutically acceptable bases include, but are not limited to, ammonia, L- arginine, calcium hydroxide, choline, meglumine, magnesium hydroxide, benethamine, benzathine, betaine, deanol, diethylamine, 2-diethylaminoethanol, hydrabamine, 1 -(2-hydroxy ethyl)-pyrrolidine, t-butylamine, tromethamine, piperazine, imidazole, ethylenediamine, ethanolamine, diethanolamine, and triethanolamine. In some embodiments, the salt of (Z)-4-(5-((3-benzyl-4-oxo-2- thioxothiazolidin-5-ylidene)methyl)furan-2-yl)benzoic acid comprises a cation derived from a pharmaceutically acceptable base selected from ammonia, L- arginine, calcium hydroxide, choline, meglumine, and magnesium hydroxide. In some embodiments, the choline salt of (Z)-4-(5-((3-benzyl-4-oxo-2- thioxothiazolidin-5-ylidene)methyl)furan-2-yl)benzoic acid is administered. In some embodiments, the meglumine salt of (Z)-4-(5-((3-benzyl-4-oxo-2- thioxothiazolidin-5-ylidene)methyl)furan-2-yl)benzoic acid is administered.

In some embodiments, a crystalline form of a choline salt of (Z)-4- (5-((3-benzyl-4-oxo-2-thioxothiazolidin-5-ylidene)methyl)furan-2-yl)benzoic acid is administered. In some embodiments, a crystalline form of a meglumine salt of (Z)-4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5-ylidene)methyl)furan-2-yl)benzoic acid is administered. A“crystalline form” refers to a solid form of a compound wherein the constituent molecules are packed in a regularly ordered, repeating pattern. A crystalline form can be triclinic, monoclinic, orthorhombic, tetragonal, trigonal, hexagonal, or cubic. A crystalline form can contain one or more regions, i.e., grains, with distinct crystal boundaries. A crystalline solid can contain two or more crystal geometries. In some embodiments, the crystalline form G of a choline salt of a compound of Formula I is administered. In some embodiments, the crystalline form O of a choline salt of a compound of Formula I is administered. In some embodiments, the crystalline form Q of a choline salt of a compound of Formula I is administered. In some embodiments, the crystalline form R of a choline salt of a compound of Formula I is administered. In some embodiments, the crystalline form S of a choline salt of a compound of Formula I is administered. In some embodiments, a crystalline form H of a meglumine salt of a compound of Formula I is administered. In some embodiments, a crystalline form L of a meglumine salt of a compound of Formula I is administered. In some

embodiments, a crystalline form M of a meglumine salt of a compound of Formula I is administered. In some embodiments, a crystalline form N of a meglumine salt of a compound of Formula I is administered. In some embodiments, a crystalline form T of a meglumine salt of a compound of Formula I is administered. Choline or megulimine salts of a compound of Formula I and crystalline salts thereof are described in US2018/0354938 (incorporated by reference in its entirety).

In some embodiments, (Z)-4-(5-((3-benzyl-4-oxo-2- thioxothiazolidin-5-ylidene)methyl)furan-2-yl)benzoic acid, or a pharmaceutically acceptable salt thereof, is administered orally.

In some embodiments, the choline salt of (Z)-4-(5-((3-benzyl-4-oxo- 2-thioxothiazolidin-5-ylidene)methyl)furan-2-yl)benzoic acid or crystalline form thereof is administered orally. In some embodiments, the meglumine salt of (Z)-4- (5-((3-benzyl-4-oxo-2-thioxothiazolidin-5-ylidene)methyl)furan-2-yl)benzoic acid or crystalline form thereof is administered orally. In some embodiments, (Z)-4-(5-((3-benzyl-4-oxo-2- thioxothiazolidin-5-ylidene)methyl)furan-2-yl)benzoic acid, or a pharmaceutically acceptable salt thereof, is administered as a tablet. In some embodiments, the choline salt of (Z)-4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5- ylidene)methyl)furan-2-yl)benzoic acid is administered as a tablet. In some embodiments, the meglumine salt of (Z)-4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin- 5-ylidene)methyl)furan-2-yl)benzoic acid is administered as a tablet. In some embodiments, a crystalline form of meglumine salt or choline salt of (Z)-4-(5-((3- benzyl-4-oxo-2-thioxothiazolidin-5-ylidene)methyl)furan-2-yl)benzoic acid is administered as a tablet. In some embodiments, the tablet is coated. In some embodiments, the tablet is uncoated.

In some embodiments, the tablet comprises from 25mg to about 500mg of(Z)-4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5-ylidene)methyl)furan-2- yl)benzoic acid. In some embodiments, the tablet comprises about 50mg of(Z)-4-(5- ((3-benzyl-4-oxo-2-thioxothiazolidin-5-ylidene)methyl)furan-2-yl)benzoic acid. In some embodiments, the tablet comprises about lOOmg of(Z)-4-(5-((3-benzyl-4-oxo- 2-thioxothiazolidin-5-ylidene)methyl)furan-2-yl)benzoic acid. In some

embodiments, the tablet comprises about 150mg of(Z)-4-(5-((3-benzyl-4-oxo-2- thioxothiazolidin-5-ylidene)methyl)furan-2-yl)benzoic acid. In some embodiments, the tablet comprises about 200mg of(Z)-4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin- 5-ylidene)methyl)furan-2-yl)benzoic acid. In some embodiments, the tablet comprises about 300mg of(Z)-4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5- ylidene)methyl)furan-2-yl)benzoic acid. In some embodiments, the tablet comprises about 400mg of(Z)-4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5- ylidene)methyl)furan-2-yl)benzoic acid. In some embodiments, the tablet comprises about 500mg of(Z)-4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5- y li dene)methy l)furan-2-y l)b enzoi c aci d .

In some embodiments, the tablet comprises from about 25mg to about 750mg of the choline salt of (Z)-4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5- ylidene)methyl)furan-2-yl)benzoic acid or a crystalline form thereof. In some embodiments, the tablet comprises from about 60 to about 500mg of the choline salt of (Z)-4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5-ylidene)methyl)furan-2- yl)benzoic acid or a crystalline form thereof.

In some embodiments, the tablet comprises about 62mg of the choline salt of (Z)-4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5- ylidene)methyl)furan-2-yl)benzoic acid. In some embodiments, the tablet comprises about 124mg of the choline salt of (Z)-4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5- ylidene)methyl)furan-2-yl)benzoic acid. In some embodiments, the tablet comprises about 248mg of the choline salt of (Z)-4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5- ylidene)methyl)furan-2-yl)benzoic acid. In some embodiments, the tablet comprises about 498mg of the choline salt of (Z)-4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5- y li dene)methy l)furan-2-y l)b enzoi c aci d .

In some embodiments, (Z)-4-(5-((3-benzyl-4-oxo-2- thioxothiazolidin-5-ylidene)methyl)furan-2-yl)benzoic acid is administered in an amount of from about 50mg to about 1200mg.

In some embodiments, (Z)-4-(5-((3-benzyl-4-oxo-2- thioxothiazolidin-5-ylidene)methyl)furan-2-yl)benzoic acid is administered in an amount of about 50mg, about lOOmg, about 200mg, about 400mg, about 800mg, or about 1200mg.

In some embodiments, the choline salt of (Z)-4-(5-((3-benzyl-4-oxo- 2-thioxothiazolidin-5-ylidene)methyl)furan-2-yl)benzoic acid or a crystalline form thereof is administered in an amount of from about 50mg to about 1500mg. In some embodiments, the choline salt of (Z)-4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5- ylidene)methyl)furan-2-yl)benzoic acid is administered in an amount of about 62mg, about 125mg, about 258mg, about 499mg, about 998mg or about 1497mg.

In some embodiments, the meglumine salt of (Z)-4-(5-((3-benzyl-4- oxo-2-thioxothiazolidin-5-ylidene)methyl)furan-2-yl)benzoic acid or a crystalline form thereof is administered in an amount of from about 50mg to about 1800mg. In some embodiments, the meglumine salt of (Z)-4-(5-((3-benzyl-4-oxo-2- thioxothiazolidin-5-ylidene)methyl)furan-2-yl)benzoic acid is administered in an amount of about 73mg, about 146mg, about 292mg, about 584mg, about l,168mg or about l,752mg.

In some embodiments, (Z)-4-(5-((3-benzyl-4-oxo-2- thioxothiazolidin-5-ylidene)methyl)furan-2-yl)benzoic acid, or a pharmaceutically acceptable salt thereof, is administered once daily. In some embodiments, the choline salt of (Z)-4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5- ylidene)methyl)furan-2-yl)benzoic acid or a crystalline form thereof is administered once daily. In some embodiments, the meglumine salt of (Z)-4-(5-((3-benzyl-4-oxo- 2-thioxothiazolidin-5-ylidene)methyl)furan-2-yl)benzoic acid or a crystalline form thereof is administered once daily. In some embodiments, (Z)-4-(5-((3-benzyl-4- oxo-2-thioxothiazolidin-5-ylidene)methyl)furan-2-yl)benzoic acid, or a

pharmaceutically acceptable salt thereof, is administered twice daily. In some embodiments, the choline salt of (Z)-4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5- ylidene)methyl)furan-2-yl)benzoic acid or a crystalline form thereof is administered twice daily. In some embodiments, the meglumine salt of (Z)-4-(5-((3-benzyl-4- oxo-2-thioxothiazolidin-5-ylidene)methyl)furan-2-yl)benzoic acid or a crystalline form thereof is administered twice daily. In some embodiments, (Z)-4-(5-((3- benzyl-4-oxo-2-thioxothiazolidin-5-ylidene)methyl)furan-2-yl)benzoic acid, or a pharmaceutically acceptable salt thereof, is administered three times daily. In some embodiments, the choline salt of (Z)-4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5- ylidene)methyl)furan-2-yl)benzoic acid or a crystalline form thereof is administered three times daily. In some embodiments, the meglumine salt of (Z)-4-(5-((3-benzyl- 4-oxo-2-thioxothiazolidin-5-ylidene)methyl)furan-2-yl)benzoic acid or a crystalline form thereof is administered three times daily.

In some embodiments, the patient has a solid tumor. In some embodiments, the cancer is pancreatic, breast, prostate, esophageal,

gastric/gastroesophageal junction (GEJ), or colorectal cancer. In some

embodiments, the patient has locally advanced cancer. In some embodiments, the patient has metastatic cancer. In some embodiments, the patient has recurrent cancer. In some embodiments, the patient has metastatic cancer and has not received prior systemic therapy for the metastatic disease. In some embodiments, the patient has metastatic cancer and has received prior systemic therapy for the metastatic disease.

In some embodiments, the patient has metastatic pancreatic adenocarcinoma, wherein the patient has not received prior systemic therapy for the metastatic pancreatic adenocarcinoma.

In some embodiments, the patient has locally advanced pancreatic adenocarcinoma, esophageal adenocarcinoma, esophageal squamous cell carcinoma, gastric/GEJ adenocarcinoma, triple negative breast cancer (TNBC), castration resistant prostate cancer, or MSS colorectal adenocarcinoma. In some embodiments, the patient has metastatic pancreatic adenocarcinoma, esophageal adenocarcinoma, esophageal squamous cell carcinoma, gastric/GEJ

adenocarcinoma, triple negative breast cancer (TNBC), castration resistant prostate cancer, or MSS colorectal adenocarcinoma. In some embodiments, the patient has recurrent pancreatic adenocarcinoma, esophageal adenocarcinoma, esophageal squamous cell carcinoma, gastric/GEJ adenocarcinoma, triple negative breast cancer (TNBC), castration resistant prostate cancer, or MSS colorectal adenocarcinoma.

Further described herein are methods of treating a patient suffering from colorectal cancer, comprising administering to the patient a combination of (Z)-4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5-ylidene)methyl)furan-2-yl)benzoic acid, or a pharmaceutically acceptable salt thereof, and pembrolizumab. In some embodiments, the colorectal cancer is recurrent colorectal cancer, refractory colorectal cancer, or both recurrent and refractory colorectal cancer.

Further described herein are methods of treating a patient suffering from gastric cancer, comprising administering to the patient a combination of (Z)-4- (5-((3-benzyl-4-oxo-2-thioxothiazolidin-5-ylidene)methyl)furan-2-yl)benzoic acid, or a pharmaceutically acceptable salt thereof, and pembrolizumab. In some embodiments, the gastric cancer is PDL1 positive. In some embodiments, the gastric cancer is recurrent gastric cancer, refractory gastric cancer, or both recurrent and refractory gastric cancer.

Further described herein are methods for treating a cancer comprising administering to a patient identified as having a cancer with a BRCA mutation: a compound according to Formula (I)

or a pharmaceutically acceptable salt thereof; and pembrolizumab.

In some embodiments, a BRCA mutation comprises a BRCAl mutation, a BRCA2 mutation or both. BRCA1 refers to a tumor suppressor gene located encoding breast cancer type 1 susceptibility protein. BRCA2 refers to tumor suppressor gene encoding breast cancer type 2 susceptibility protein. In some embodiments, a BRCA mutation refers to a human BRCA mutation. In some embodiments, the sequence set forth in NG_005905.2 or NM_007294 from the National Center for Biotechnology Information (NCBI) database

(http://www.ncbi.nlm.nih.gov) is used as a reference BRCA1 sequence. In some embodiments, the sequence set forth in NG_012772.3 or NM_000059 from the NCBI database is used as a reference BRCA2 sequence. In some embodiments, a BRCA mutation is a deleterious mutation. A BRCA mutation may be present in an exon, intron, exon/intr on junction, or untranslated region. A BRCA mutation may be a germline mutation or a somatic mutation. A BRCA mutation may be a missense mutation, a nonsense mutation, frameshift mutation, splice site mutation, large deletion (e.g., 1 or more exons), large duplication (e.g., 1 or more exons). Non-limiting examples of BRCA mutations include: BRCA1 c.68_69delAG (BIC: 185delAG); BRCA1 c.5266dupC (BIC: 5382insC); BRCA1 c.211A>G (BIC: R71G); BRCA1 C.130T>A (BIC: C44S); BRCA1 c 181T>G (BIC: C61G);

BRCA1 c.5095C>T (BIC: R1699W); BRCA1 c.5123C>A (BIC: A1708E); BRCA1 c.5213G>A (BIC: G1738E); BRCA1 c.5324T>G (BIC: M1775R); BRCA1 c.5558dupA (BIC: 5677insA); BRCA2 c.5946delT (BIC: 6174delT); BRCA2 c.9501+3A>T (BIC: IVS25+3A>T); BRCA2 c.3G>A (BIC: Mil); and

BRCA2 c.9541_9554dell4 (BIC: 9769dell4). In some embodiments, a cancer with a BRCA mutation is breast cancer, ovarian cancer, cervical cancer, uterine cancer, colon cancer, Fallopian tube cancer, peritoneal cancer, prostate cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, or melanoma.

BRCA mutations may be identified by obtaining genomic DNA from a patient specimen and performing a variety of methods, including but not limited to sequencing, polymerase chain reaction, comparative genomic hybridization, Southern blotting, and multiplex ligation-dependent probe amplification (MLPA).

In some embodiments, the patient identified as having a cancer with a BRCA mutation has locally advanced cancer, metastatic cancer, refractory cancer, or relapsing or recurrent cancer. In some embodiments, the patient has metastatic cancer and has not received prior systemic therapy for the metastatic cancer. In some embodiments, the patient has metastatic cancer and has received prior systemic therapy for the metastatic cancer. Systemic therapy refers to drugs that spread throughout the body to treat cancer cells, and includes chemotherapy, hormonal therapy, targeted therapy, and immunotherapy.

In some embodiments, pembrolizumab is administered intravenously. In some embodiments, pembrolizumab is administered every week, two weeks, three weeks, four weeks, five weeks, or six weeks. In some embodiments, pembrolizumab is administered in an amount of about 200mg to about 500mg. In some embodiments, pembrolizumab is administered in an amount of about 200mg every three weeks. In some

embodiments, pembrolizumab is administered in an amount of about 400mg every six weeks.

Further described herein are methods for treating a cancer comprising: (a) administering to a patient having cancer (i) a compound according to Formula (I)

or pharmaceutically acceptable salt thereof, and (ii) pembrolizumab; (b) obtaining at least two measurements of neutrophil to lymphocyte ratio (NLR) for the patient post treatment and comparing the at least two measurements of neutrophil to lymphocyte ratio for the patient post-treatment with a baseline neutrophil to lymphocyte ratio at day 0, wherein the at least two measurements are obtained every one week, two weeks, three weeks, or four weeks; and (c) wherein administration of the compound and pembrolizumab to the patient is continued if a decrease in neutrophil to lymphocyte ratio compared to the baseline neutrophil to lymphocyte ratio at day 0 is maintained for at least four weeks, or administration of the compound and pembrolizumab is discontinued if a decrease in neutrophil to lymphocyte ratio compared to the baseline neutrophil to lymphocyte ratio at day 0 is not maintained for at least four weeks. Neutrophil to lymphocyte ratio may be measured by obtaining a peripheral blood sample from the patient and dividing neutrophil count by lymphocyte count.

In some embodiments, administration of the compound and pembrolizumab is continued if a decrease in neutrophil to lymphocyte ratio compared to the baseline neutrophil to lymphocyte ratio at day 0 is maintained for at least five weeks, or administration of the compound and pembrolizumab is discontinued if a decrease in neutrophil to lymphocyte ratio compared to the baseline neutrophil to lymphocyte ratio at day 0 is not maintained for at least five weeks.

In some embodiments, administration of the compound and pembrolizumab is continued if a decrease in neutrophil to lymphocyte ratio compared to the baseline neutrophil to lymphocyte ratio at day 0 is maintained for at least six weeks, or administration of the compound and pembrolizumab is discontinued if a decrease in neutrophil to lymphocyte ratio compared to the baseline neutrophil to lymphocyte ratio at day 0 is not maintained for at least six weeks.

In some embodiments, administration of the compound and pembrolizumab is continued if a decrease in neutrophil to lymphocyte ratio compared to the baseline neutrophil to lymphocyte ratio at day 0 is maintained for at least seven weeks, or administration of the compound and pembrolizumab is discontinued if a decrease in neutrophil to lymphocyte ratio compared to the baseline neutrophil to lymphocyte ratio at day 0 is not maintained for at least seven weeks.

In some embodiments, administration of the compound and pembrolizumab is continued if a decrease in neutrophil to lymphocyte ratio compared to the baseline neutrophil to lymphocyte ratio at day 0 is maintained for at least eight weeks, or administration of the compound and pembrolizumab is discontinued if a decrease in neutrophil to lymphocyte ratio compared to the baseline neutrophil to lymphocyte ratio at day 0 is not maintained for at least eight weeks.

In some embodiments, administration of the compound and pembrolizumab is continued if a decrease in neutrophil to lymphocyte ratio compared to the baseline neutrophil to lymphocyte ratio at day 0 is maintained for at least nine weeks, or administration of the compound and pembrolizumab is discontinued if a decrease in neutrophil to lymphocyte ratio compared to the baseline neutrophil to lymphocyte ratio at day 0 is not maintained for at least nine weeks. In some embodiments, administration of the compound and pembrolizumab is continued if a decrease in neutrophil to lymphocyte ratio compared to the baseline neutrophil to lymphocyte ratio at day 0 is maintained for at least ten weeks, or administration of the compound and pembrolizumab is discontinued if a decrease in neutrophil to lymphocyte ratio compared to the baseline neutrophil to lymphocyte ratio at day 0 is not maintained for at least ten weeks.

In some embodiments, the decrease in neutrophil to lymphocyte ratio compared to the baseline neutrophil to lymphocyte ratio is observed at about day 7, day 8, day 9, day 10, day 11, day 12, day 13, day 14, day 15, day 16, day 17, day 18, day 19, day 20, or day 21 of treatment.

In some embodiments, a maximum decrease in neutrophil to lymphocyte ratio compared to the baseline neutrophil to lymphocyte ratio is at least about 30%, 35%, 40%, 45%, 50%, 55%, or 60%.

In some embodiments, pembrolizumab is administered intravenously. In some embodiments, pembrolizumab is administered every week, two weeks, three weeks, four weeks, five weeks, or six weeks.

In some embodiments, pembrolizumab is administered in an amount of about 200mg to about 500mg. In some embodiments, pembrolizumab is administered in an amount of about 200mg every three weeks. In some

In some embodiments, the cancer is pancreatic, breast, prostate, esophageal, gastric/gastroesophageal junction (GEJ), or colorectal cancer.

In some embodiments, the cancer is locally advanced cancer, metastatic cancer, refractory cancer, or relapsing or recurrent cancer. In some embodiments, the cancer is locally advanced pancreatic adenocarcinoma, esophageal adenocarcinoma, esophageal squamous cell carcinoma, gastric/GEJ adenocarcinoma, triple negative breast cancer (TNBC), castration resistant prostate cancer, or microsatellite stable (MSS) colorectal adenocarcinoma.

In some embodiments, the cancer is metastatic pancreatic adenocarcinoma, esophageal adenocarcinoma, esophageal squamous cell carcinoma, gastric/GEJ adenocarcinoma, triple negative breast cancer (TNBC), castration resistant prostate cancer, or MSS colorectal adenocarcinoma. In some embodiments, the metastatic gastric/GEJ adenocarcinoma is PD-L1 positive.

In some embodiments, the metastatic gastric/GEJ adenocarcinoma is PD-L1 positive, the cancer is recurrent pancreatic adenocarcinoma, esophageal adenocarcinoma, esophageal squamous cell carcinoma, gastric/GEJ

adenocarcinoma, triple negative breast cancer (TNBC), castration resistant prostate cancer, or MSS colorectal adenocarcinoma. In some embodiments, the recurrent gastric/GEJ adenocarcinoma is PD-L1 positive.

In some embodiments, the patient has metastatic cancer and has not received prior systemic therapy for the metastatic disease. In some embodiments, the patient has metastatic cancer and has received prior systemic therapy for the metastatic cancer. In some embodiments, systemic therapy comprises

chemotherapy, hormonal therapy, targeted therapy, immunotherapy, or any combination thereof. EXAMPLES

Example 1 : Clinical Trial Protocols

Described herein is a Phase 1/2 clinical trial, evaluating the choline salt Compound 1 as monotherapy or in combination, comprising a Phase 1 Dose Escalation phase, followed by a Phase 2 Basket Expansion phase.

In general, study patients are male or female, at least 18 years of age, with a diagnosis of locally advanced or metastatic pancreatic adenocarcinoma, or esophageal adenocarcinoma, or esophageal squamous cell carcinoma, or

gastric/gastroesophageal junction adenocarcinoma, or triple negative breast cancer (TNBC), or metastatic castrate resistant prostate cancer (mCRPC), or microsatellite stable colorectal adenocarcinoma (Regimen C requires a diagnosis of

adenocarcinoma of the pancreas), with a disease site amenable to biopsy. Patients have exhausted potential curative options and are relapsed or refractory to, or intolerant of, or refuse approved / standard of care established therapy. Study patients do not have a history of another malignancy within the prior 2 years, central nervous system (CNS) metastases, cardiovascular disease, active infections, HIV, Hepatitis B, Hepatitis C, any serious nonmalignant disease (e.g., psychiatric, substance abuse) or have undergone organ transplant.

The study population for Phase 1 are patients with no potential curative options available for the tumor types specified, i.e. locally advanced or metastatic pancreatic adenocarcinoma, esophageal adenocarcinoma, esophageal squamous cell carcinoma, gastric/GEJ adenocarcinoma, triple negative breast cancer (TNBC), castration resistant prostate cancer and microsatellite stable (MSS) colorectal adenocarcinoma. The study population for Phase 2 are patients with newly diagnosed metastatic / stage IV pancreatic adenocarcinoma, adenocarcinoma originating from the colon or rectum, microsatellite stable metastatic colorectal adenocarcinoma, or recurrent/metastatic gastric/GEJ adenocarcinoma with documented PD-L1 expression.

For each patient, in either study phase, the study comprises a screening period of up to 28 days, followed by a treatment period of up to 2 years, unless radiographic disease progression, unacceptable toxicity, or other reasons for arise for discontinuation. An end of treatment visit occurs within 30 days of the last dose, and long-term follow-up continues approximately every 3 months, to a maximum of 18 months

Choline salt of compound 1 is administered orally, twice daily, (morning and evening), as whole tablets, under fasted conditions, with water (8oz). Choline salt of compound 1 is provided in three dosage strengths (shown with equivalent amount of Compound 1-free acid):

Compound 1 is administered in six dosage levels - 50mg, lOOmg, 200mg, 400mg, 800mg and 1200mg. Doses are expressed with respect to

Compound 1 free acid; lOOmg free acid is equivalent to 124.48mg choline salt. Intermediate dose levels, higher dose levels or different dosing schedules, (e.g., once daily, three times daily) may also be explored.

The tablets are uncoated, light yellow to orange in color, containing the following inactive excipients: Microcrystalline cellulose, Pregelatinised starch, Crospovidone, Colloidal silicon dioxide, Sodium stearyl fumarate.

Dose Escalation Phase

The primary objective of the Dose Escalation phase of the study is to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of choline salt of Compound 1, administered orally, through evaluation of safety and PK.

Dose escalation phase consists of 2 parallel dose escalation arms with a third dose escalation regimen initiated (in subjects with metastatic pancreatic adenocarcinoma) after the MTD/RP2D is determined. Three cohorts evaluate choline salt of Compound 1 monotherapy (Regimen A), choline salt of Compound 1 in combination with pembrolizumab (Regimen B) or choline salt of Compound 1 in combination with nab-paclitaxel and gemcitabine (Regimen C). Patients in the study have one of the following cancers:

- locally advanced pancreatic adenocarcinoma, esophageal adenocarcinoma, esophageal squamous cell carcinoma, gastric/GEJ

adenocarcinoma, triple negative breast cancer (TNBC), castration resistant prostate cancer, or microsatellite stable (MSS) colorectal adenocarcinoma;

- metastatic pancreatic adenocarcinoma, esophageal adenocarcinoma, esophageal squamous cell carcinoma, gastric/GEJ adenocarcinoma, triple negative breast cancer (TNBC), castration resistant prostate cancer, or microsatellite stable (MSS) colorectal adenocarcinoma;

- metastatic pancreatic adenocarcinoma who have not received prior systemic therapy for the metastatic disease.

Regimens A & B enroll patients with no potential curative options with either locally advanced or metastatic pancreatic adenocarcinoma, esophageal adenocarcinoma, esophageal squamous cell carcinoma, gastric/GEJ

adenocarcinoma, triple negative breast cancer (TNBC), castration resistant prostate cancer, or microsatellite stable (MSS) colorectal adenocarcinoma; Regimen C enrolls patients with metastatic pancreatic adenocarcinoma who have not received prior systemic therapy for the metastatic disease. The Dose Escalation phase consists of 2 dose escalation regimens, based on a standard 3+3 design. Cohorts of 3-6 subjects are sequentially assigned to one of three regimens:

- Regimen A receiving escalating doses of choline salt of Compound 1 as monotherapy

- Regimen B receiving escalating doses of choline salt of Compound 1 in combination with pembrolizumab

- Regimen C receiving escalating doses of choline salt of Compound 1 in combination with nab-paclitaxel and gemcitabine (referred to as standard of care).

Initially, subjects are enrolled into Regimen A. Regimen B is initiated after at least the first 2 cohorts in Regimen A have proven safe and dose escalation in Regimen A has proceeded to at least the third dose level if the MTD is not determined in the first 2 dose levels. Regimen B dose escalation may continue in parallel with Regiment A but the dose level of choline salt of Compound 1 in Regimen B does not exceed the highest dose level proven safe from Regimen A. When enrollment is open for both Regimens A and B, priority is given to enrollment in Regimen A over Regimen B.

Dose escalation for Regimen C begins after Regimen A is complete. Initially, at least 3 patients (with metastatic pancreatic adenocarcinoma) receive choline salt of Compound 1 starting at 1 dose level below the established monotherapy MTD/RP2D from Regimen A. Dose escalation for Regimen C stops at either choline salt of Compound 1 at the MTD/RP2D or one dose level below the MTD/RP2D determined from Regimen A dose escalation.

Up to approx. 82 patients are enrolled:

Regimen A: 6-35 patients for choline salt of Compound 1 monotherapy Regimen B: 3-35 patients for choline salt of Compound 1+ pembrolizumab combination

Regimen C: 6 to 12 patients for choline salt of Compound 1 + nab- paclitaxel / gemcitabine Doses - Regimen A, the starting dose is lOOmg BID. Dose escalation proceeds as follows:

QD = once daily; BID = twice per day

* Doses are expressed with respect to Compound 1 free acid; lOOmg free acid is equivalent to 124.48mg choline salt Regimen B, the starting dose is at least 1 dose level below the highest dose shown to have an acceptable toxicity profile in at least 3 subjects from Regimen A. Regimen C, the starting dose is 1 dose level below MTD/RP2D and stops at the MTD/RP2D from Regimen A.

The dose of choline salt of Compound 1 is not reduced during Cycle 1 unless the subject experiences a DLT event, where dose reductions by one dose level are permitted based on the event that occurs. Intra-subject dose escalation is allowed for subjects assigned to doses lower than the MTD/RP2D after the

MTD/RP2D is determined, if the subject has not experienced a significant choline salt of Compound 1 treatment-related AE after treatment for at least 3 cycles. Dose Escalation is described below:

he MTD is the highest dose that < 1 of 6 subjects experiences a DLT.

Subjects from cohort A and Regiment B receive a single dose of choline salt of Compound 1 on Cycle 1 Day 1 and are evaluated over the next 24 hours. A screening radiographic (baseline) assessment is conducted within 28 days of the first dose of choline salt of Compound 1. Radiographic assessments of chest, abdomen and pelvis are then performed every 6 weeks ±7 days for the first 6 months and every 12 weeks ±7 days thereafter.

Study drug(s) are administered until the occurrence of unequivocal radiographic disease progression or unacceptable toxicity or other discontinuation criteria, with a maximum treatment duration of 2 years. Dose Limiting Toxicity Criteria - Timing

During the Dose Escalation phase of the study, a dose limiting toxicity is the occurrence or start of any of the events listed below at any time - from Cycle 1, Day 1 through Cycle 1, Day 21, inclusive (Regimen A and B); from Cycle 1, Day 8 through Cycle 2, Day 8, inclusive

(Regimen C).

Dose Limiting Toxicity - Criteria (Regimens A and B)

The following events are considered DLTs Grade 4 neutropenia

Febrile neutropenia Grade 4 thrombocytopenia Grade 4 anemia

> Grade 3 non-hematologic toxicity Any Grade 3 or Grade 4 non-hematologic laboratory value

Any AE other than the events that are clearly associated with clinical or radiographic progression that prevents the subject from being able to complete >75% of the planned doses during Cycle 1

Any adverse event that leads to the permanent

discontinuation of choline salt of Compound 1

Dose Limiting Toxicity - Criteria (Regimen C)

The following events are considered DLTs Drug-induced liver toxicities as defined by laboratory parameters

> Grade 3 non-hematologic toxicity

Any adverse event preventing the subject from completing >75% of the planned doses during Cycle 1

Any adverse event that leads to permanent discontinuation Basket Expansion Phase

The primary objective of the Basket Expansion phase of the study is to assess the efficacy of choline salt of Compound 1 in combination with standard of care (SOC) or pembrolizumab through determination of objective response rate (ORR) within each basket expansion cohort. Each basket expansion cohort employs a Simon’s two-stage optimal design that evaluates the null hypothesis (HO) that the ORR is less than or equal to an uninteresting level of response (pO) versus the alternative hypothesis (HI) that the ORR is greater than or equal to a level of response (pi) that warrants further evaluation. Each of three cohorts evaluate three cancer types.

Cohort 1: in patients with newly diagnosed metastatic pancreatic adenocarcinoma who have never received systemic therapy. Once the tolerable dose of choline salt of Compound 1 in combination with nab-paclitaxel and gemcitabine is determined in Regimen C, and PK assessment is complete, recruitment of new subjects is initiated at this dose, as follows:

Stage 1 enrolls 19 subjects. If <3 of the first 19 subjects have an objective response, the enrollment of additional subjects is not warranted. If > 4 of the first 19 subjects have an objective response, the study proceeds to Stage 2 and enrolls an additional 20 subjects, for a total of 39 subjects. Each treatment cycle is 28 days. Cohort 2: in patients with microsatellite stable (MSS) metastatic colorectal adenocarcinoma who experienced disease progression or were intolerant to at least 1 systemic chemotherapy that must contain a fluoropyrimidine-, oxaliplatin- and irinotecan-containing regimen. Patients are treated with Compound 1 at MTD/RP2D with from Phase 1 Regimen B, and pembrolizumab. Recruitment is as follows:

Stage 1 enrolls 11 subjects. If no subjects out of the first 11 have an objective response, the enrollment of additional subjects is not warranted. If >1 of the first 11 subjects have an objective response, the study proceeds to Stage 2 and enrolls an additional 15 subjects, for a total of 26 subjects. Each treatment cycle is 21 days.

Cohort 3: in patients with recurrent/metastatic gastric/ gastroesophageal junction (GEJ) adenocarcinoma that have received at least 2 lines of chemotherapy, including fluoropyrimidine- and platinum-containing

chemotherapy. Patients are treated with choline salt of Compound 1 at MTD/RP2D with from Phase 1 Regimen B, and pembrolizumab. Recruitment is as follows:

Stage 1 enrolls 19 subjects. If <1 subject of the first 19 subjects has an objective response, the enrollment of additional subjects is not warranted. If > 2 of the first 19 subjects have an objective response, the study proceeds to Stage 2 and enrolls an additional 21 subjects for a total of 40 subjects. Each treatment cycle is 21 days.

nl = number of patients in stage 1; n2 = number of patients in stage 2; n = total number of patients

Cohort 1 receives choline salt of Compound 1 at MTD/RP2D from Regimen C, in combination with SOC. Cohorts 2 and 3 receive choline salt of Compound 1 at MTD/RP2D from Regimen B, in combination with pembrolizumab. Recruitment of patients into the expansion phase begins only after the MTD/RP2D from Phase 1 has been determined.

Up to approx. 120 patients are enrolled: the sample size for each of the three tumor type cohorts is determined using Simon’s two-stage optimal design for single-arm studies. If promising anti-tumor activity and acceptable safety is observed in the Expansion Phase, such that further investigation is warranted in any of the three tumor type cohorts, the respective cohort(s) may be expanded.

Therefore, the Basket Expansion Phase requires up to 120 patients in total. Patients receive study drug(s) starting on Day 1 of Cycle 1 until the occurrence of unequivocal radiographic disease progression or unacceptable toxicity, or other reasons for discontinuation with a maximum treatment duration of 2 years.

Tumor tissues from core needle biopsies are collected at pre- specified timepoints. Generalities for Both Phases

Pembrolizumab (200mg) is administered by intravenous (IV) infusion, over 30 minutes, once every 3 weeks (Q3W), which is the recommended dose for adults across all indications, regardless of tumor type. Standard of Care (SOC) - for Regimen C and Expansion Cohort 1

(patients with Pancreatic Adenocarcinoma) is defined as Nab-Paclitaxel (125mg/m²) and Gemcitabine (1000mg/m²), administered immediately after nab-paclitaxel intravenous infusion, over 30-40 minutes on days 1, 8 and 15 of each 28-day cycle. Patients first receive SOC on Cycle 1, Day 1. On Cycle 1, Day 8, subjects start daily choline salt of Compound 1. Patient baseline weight is used to calculate the doses of nab-paclitaxel and gemcitabine, and may be adjusted as follows:

Nab-paclitaxel (ABRAXANE^®; nanoparticle albumin-bound paclitaxel or protein-bound paclitaxel) is an injectable formulation of paclitaxel, which kills cancer cells by preventing the normal breakdown of microtubules during cell division.

Gemcitabine (GEMZAR^®) is a nucleoside analog that acts by replacing cytidine during DNA replication, which arrests tumor growth and results in apoptosis.

The Nab-Paclitaxel / Gemcitabine combination is designated as an orphan drug as first-line treatment for metastatic adenocarcinoma of the pancreas.

Safety is assessed by any or all of physical examinations, vital signs (pulse rate, respiratory rate, temperature and blood pressure), electrocardiogram, clinical safety laboratory assessments and / or Eastern cooperative oncology group (ECOG) performance status. Pharmacokinetics - Blood samples are collected in both study phases to evaluate plasma concentrations of choline salt of Compound 1.

Additionally, where relevant, blood samples are collected to evaluate plasma concentrations of gemcitabine (and metabolite difluorodeoxyuridine) and nab-paclitaxel. Pharmacokinetic parameters are estimated using standard noncompartmental methods. The primary parameters for analysis include maximum observed plasma concentration (Cmax), trough observed plasma concentration (Ctrough), time of maximum observed plasma concentration (Tmax), terminal phase elimination half-life (t½), area under the plasma concentration-time curve (AUC) and oral clearance (CL/F). Other noncompartmental parameters, such as oral apparent volume of distribution (Vd/F), may be reported.

The primary objectives and corresponding endpoints of the study, are as follows:

Dose Escalation Phase: Regimen A & Regimen B Objectives Endpoints

Primary

Safety

To determine the maximum tolerated Dose limiting toxi cities (DLTs), adverse dose (MTD) or recommended phase 2 events (AEs) and serious adverse dose (RP2D) of choline salt of events (SAEs)

Compound 1 in subjects with Number and frequency of clinically previously treated specified advanced significant laboratory,

solid tumors electrocardiogram and vital sign

abnormalities

To determine the PK profile of choline PK

salt of Compound 1 in subjects with Plasma concentrations and PK previously treated specified advanced parameters of choline salt of solid tumors Compound 1 and metabolites as appropriate

Exploratory

To evaluate anti -tumor activity of Overall Response Rate (ORR)

choline salt of Compound 1 in Duration of Response (DOR) subjects with previously treated Time to Response (TTR)

specified advanced solid tumors Clinical Benefit Rate (CBR)

Progression-free Survival (PFS) Dose Escalation Phase: Regimen A & Regimen B

Objectives Endpoints

Time to Progression (TTP)

Overall Survival (OS)

To evaluate changes in disease Change from baseline in the following biomarkers following treatment with target engagement (TE) / choline salt of Compound 1 in pharmacodynamic assays:

subjects with previously treated Whole blood CD1 lb-TE assay specified advanced solid tumors Whole blood tumor mutational burden

(TMB) assessment from cell free DNA (cfDNA)

Whole blood immune cell phenotyping

Plasma biomarkers

Tumor tissue target engagement / biomarker

Tumor tissue immunohistochemistry

Dose Escalation Phase: Regimen C

Objectives Endpoints

Primary

To determine safety of choline salt of Dose limiting toxi cities (DLTs), adverse Compound 1 in combination with events (AEs) and serious adverse standard of care (nab-paclitaxel and events (SAEs)

gemcitabine) in subjects with Number and frequency of clinically metastatic pancreatic adenocarcinoma significant laboratory,

electrocardiogram and vital sign abnormalities

Secondary

To assess the PK of choline salt of Plasma concentrations of choline salt of Compound 1 in subjects with Compound 1 and metabolites as metastatic pancreatic adenocarcinoma appropriate

To assess the PK of SOC (nab-paclitaxel Plasma concentrations and PK

and gemcitabine) alone and in parameters of gemcitabine (and combination with choline salt of metabolite difluorodeoxyuridine) and Compound 1 in subjects with nab-paclitaxel

metastatic pancreatic adenocarcinoma

Exploratory

To evaluate anti -tumor activity of Overall Response Rate (ORR)

choline salt of Compound 1 in Duration of Response (DOR) combination with standard of care Time to Response (TTR)

(nab-paclitaxel and gemcitabine) in Clinical Benefit Rate (CBR) subjects with metastatic pancreatic Dose Escalation Phase: Regimen C

Objectives Endpoints

adenocarcinoma Progression-free Survival (PFS)

Time to Progression (TTP)

Overall Survival (OS)

To evaluate changes in disease Proportion of subjects with a >50% biomarkers following treatment with reduction from baseline in cancer choline salt of Compound 1 in antigen 19-9 (CA19-9)

combination with standard of care Change from baseline in the following (nab-paclitaxel and gemcitabine) in TE/pharmacodynamic assays:

subjects with metastatic pancreatic Whole blood CD1 lb-TE assay adenocarcinoma Whole blood TMB assessment from cfDNA

Whole blood immune cell phenotyping Plasma biomarkers

Tumor tissue target engagement / biomarker

Tumor tissue IHC

Efficacy analyses may include the following:

Objective response rate (ORR) is the proportion of subjects with best overall confirmed response (BOCR) of either a complete response (CR) or partial response (PR).

Duration of response (DOR) is the time from the first date of objective response (CR or PR) to the first documented date of disease progression or the date of death due to any cause, whichever occurs first.

Time to response (TTR) is the time from the first dose of study drug to the first date of objective response (CR or PR).

Clinical benefit rate (CBR) is the proportion of subjects with a confirmed CR or PR or SD at 6 months.

Progression-free survival (PFS) is the time from the first dose of study drug to the first documented date of disease progression or the date of death due to any cause, whichever occurs first.

Time to progression (TTP) is the time from the first dose of study drug to the first documented date of disease progression.

Overall survival (OS) is the time from the first dose of study drug to the date of death due to any cause. Example 2: Phase 1/2 Clinical Trial Results

This is an ongoing phase 1/2 study to evaluate choline salt of Compound 1 alone and combined with pembrolizumab or standard of care chemotherapy in tumor types known to be immunotherapy resistant. Eligible patients are at least 18 years of age having ECOG PS 0 or 1 with pre-specified refractory tumors known to be resistant to cancer immunotherapy. Six tumor types (MSS-CRC, PDAC, TNBC, CRPC, gastric/GEJ, and esophageal cancer) will be studied in the dose escalation phase using Regimen A and B; Regimen C will be evaluated in patients with pancreatic ductal adenocarcinoma (PDAC). Choline salt of Compound 1 is given orally at 5 dose levels, alone and with pembrolizumab 200 mg IV every 3 weeks (Figure 3). Regimen A was initiated first, and followed by Regimen B after clearing the dose-limiting toxicities in the first few cohorts in Regimen A. A safety run-in with choline salt of Compound 1 plus nab-paclitaxel- gemcitabine will begin after the maximum tolerated dose is reached in Regimen A. Phase 2 basket expansion in three tumor types (metastatic PDAC, MSS mCRC, and metastatic gastric/GEJ adenocarcinoma with PD-L1 expression) is planned once a choline salt of Compound 1 dose is selected in the corresponding regimens. Dose escalation was based on a standard 3 + 3 design; phase 2 basket expansion utilized a Simon’s two-stage optimal design.

Study endpoints included: safety (dose-limiting toxicity, adverse events), pharmacokinetic (PK) profile, treatment response (tumor assessment by response evaluation criteria in solid tumors (RECIST) 1.1 every 2 cycles (~42 days for Regimens A and B)), pharmacodynamics (serial blood and tumor samples were collected for PK and biomarker analyses). Blood samples were collected from patients before treatment with Compound 1 and after 15 days of Compound 1 treatment; percentage of peripheral myeloid-derived suppressor cells (MDSCs) was measured using multicolor flow cytometry (Serametrix). Whole blood

transcriptome sequencing was performed at Fulgent Genetics.

Baseline demographics and disease characteristics of 22 patients enrolled in the dose escalation study as of March 27, 2020 is shown in Figure 4. Median (range) age: 68 years (37-79). 68% of patients had ECOG PS 1. Patient group composed primarily of pancreatic and colorectal cancers (in Regimen A);

68% received 3 or more lines of systemic treatment. No dose-limiting toxicities have been reported. Within this example, doses are expressed with respect to Compound 1 free acid; lOOmg free acid is equivalent to 124.48mg choline salt. Choline salt of Compound 1 as monotherapy (up to 1200 mg PO BID) and combined with pembrolizumab (up to 400 mg PO BID) was well tolerated (Figures 5 and 6). Most frequently reported treatment emergent adverse events were Grade 1 or Grade 2. Three patients discontinued study treatment due to death related to underlying disease. Treatment-related adverse events were reported in 9 patients; all were Grade 1. Incidence of was not dose-dependent (Figure 6). No immune-related adverse events were reported with Regimen A or B. Two patients receiving Regimen B (choline salt of Compound 1, 100 mg PO BID) reported Grade 1 fatigue and Grade 1 constipation considered related to both choline salt of Compound 1 and pembrolizumab.

A dose-dependent increase in choline salt of Compound 1 plasma concentration was observed over doses of 100 mg to 800 mg PO BID (Figure 7). The elimination half-life of choline salt of Compound 1 was estimated at ~7 hours. The addition of pembrolizumab (Regimen B) at the choline salt of Compound 1 100 mg PO BID dose level did not substantially alter the PK profile of choline salt of Compound 1.

To date, the best response observed is stable disease (Figure 8). 79 year-old male with mCRPC, Gleason score 5 at diagnosis, tumor mutation burden (TMB) 4, blood BRCAl-m, prostate specific antigen (PSA) 3730 ng/mL at study entry, >10 lines of treatment, and progressive disease to atezolizumab initiated Regimen B (choline salt of Compound 1, 100 mg PO BID + pembrolizumab) (Figure 9). After 8 weeks of treatment, the CRPC patient exhibited stable disease, serum PSA 1790 ng/mL (a 52% decrease), maximum decrease in neutrophil- tolymphocyte ratio (NLR) of 52% sustained for 4 cycles up to data cut. Subject continues on study treatment. Figure 10 shows a potential difference in gene expression in this patient than other subjects in the trial. mCRPC patient is resistant to atezolizumab. The CPRC subject had a notable anti -tumor response to the combination of choline salt of Compound 1 with pembrolizumab. One would not expect a response to pembrolizumab in this subject as the patient had already progressed on an in-class drug (atezolizumab). The anti-tumor response in this subject is likely attributable to the addition of choline salt of Compound 1.

Biomarker profiles differ with addition of pembrolizumab (Figure 11) and with 800 mg dose (Figure 12).

Modulation of peripheral MDSCs was observed in the majority of patients with serial samples (Figures 13A-13B). At doses of choline salt of Compound 1 above 400mg BID, there is a notable decrease of both mMDSCs and gMDSCs in the blood of the treated patients. This suppression is not observed consistently at doses lower than 400mg BID. This suppression speaks directly to one of the proposed mechanisms of action for choline salt of Compound 1— to impact and lower the immune suppressive MDSCs.

The mCRPC patient exhibited a precipitous drop in neutrophil to lymphocyte ratio (NLR) (52%) upon treatment with Regimen B. This decrease is associated with improved clinical outcome and has been sustained through the entire time on treatment with disease control (for 4 cycles, each cycle being 21 days). The early and sustained decrease in NLR may be a biomarker for treatment response to compound 1 (optionally with pembrolizumab).

Moreover, the mCRPC patient has a BRCA1 -mutation. The presence of this mutation may be a predictive biomarker for the benefit of treatment of a patient with choline salt of Compound 1 (optionally with pembrolizumab).

Clinical safety data to date suggest that choline salt of Compound 1 monotherapy (up to 1200 mg PO BID) and in combination with pembrolizumab (up to 400 mg PO BID) is well tolerated. The maximum tolerated dose of choline salt of Compound 1 has not been reached. Choline salt of Compound l’s elimination half-life of approximately 7 hours supports BID dosing. Modulation of peripheral MDSCs was observed in patients treated with Regimens A and B. Additional biomarker analysis in blood and tumor biopsies is ongoing. Preliminary anti-tumor activity was observed in one atezolizumab-resistant patient with mCRPC, supported by PSA and NLR data.

EMBODIMENTS

1. A method of treating a patient suffering from cancer, comprising administering to the patient (Z)-4-(5-((3-benzyl-4-oxo-2- thioxothiazolidin-5-ylidene)methyl)furan-2-yl)benzoic acid, or a pharmaceutically acceptable salt thereof, and pembrolizumab.

2. The method embodiment 1, comprising administering (Z)-4- (5-((3-benzyl-4-oxo-2-thioxothiazolidin-5-ylidene)methyl)furan-2-yl)benzoic acid.

3. The method embodiment 1, comprising administering a pharmaceutically acceptable salt of (Z)-4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin- 5-ylidene)methyl)furan-2-yl)benzoic acid.

4. The method embodiment 3, comprising administering the choline salt of (Z)-4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5- y li dene)methy l)furan-2-y l)b enzoi c aci d .

5. The method of embodiment 1, wherein (Z)-4-(5-((3-benzyl-4- oxo-2-thioxothiazolidin-5-ylidene)methyl)furan-2-yl)benzoic acid, or a

pharmaceutically acceptable salt thereof, is administered orally.

6. The method of embodiment 1, wherein (Z)-4-(5-((3-benzyl-4- oxo-2-thioxothiazolidin-5-ylidene)methyl)furan-2-yl)benzoic acid, or a

pharmaceutically acceptable salt thereof, is administered as a tablet.

7. The method of embodiment 0, wherein the tablet is coated.

8. The method of embodiment 0, wherein the tablet is uncoated.

9. The method of embodiment 0, wherein the tablet comprises about 50mg of (Z)-4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5- y li dene)methy l)furan-2-y l)b enzoi c aci d . 10. The method of embodiment 0, wherein the tablet comprises about lOOmg of (Z)-4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5- y li dene)methy l)furan-2-y l)b enzoi c aci d .

11. The method of embodiment 0, wherein the tablet comprises about 400mg of (Z)-4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5- y li dene)methy l)furan-2-y l)b enzoi c aci d .

12. The method of embodiment 0, wherein the tablet comprises about 62mg of the choline salt of (Z)-4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5- y li dene)methy l)furan-2-y l)b enzoi c aci d .

13. The method of embodiment 0, wherein the tablet comprises about 124mg of the choline salt of (Z)-4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5- y li dene)methy l)furan-2-y l)b enzoi c aci d .

14. The method of embodiment 0, wherein the tablet comprises about 498mg of the choline salt of (Z)-4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5- y li dene)methy l)furan-2-y l)b enzoi c aci d .

15. The method of embodiment 1, wherein (Z)-4-(5-((3-benzyl-4- oxo-2-thioxothiazolidin-5-ylidene)methyl)furan-2-yl)benzoic acid is administered in an amount of from about 50mg to about 1200mg.

16. The method of embodiment 1, wherein (Z)-4-(5-((3-benzyl-4- oxo-2-thioxothiazolidin-5-ylidene)methyl)furan-2-yl)benzoic acid is administered in an amount of about 50mg, about lOOmg, about 200mg, about 400mg, about 800mg or about 1200mg.

17. The method of embodiment 1, wherein the choline salt of (Z)-4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5-ylidene)methyl)furan-2-yl)benzoic acid is administered in an amount of from about 50mg to about 1500mg.

18. The method of embodiment 1, wherein the choline salt of (Z)-4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5-ylidene)methyl)furan-2-yl)benzoic acid is administered in an amount of about 62mg, about 125mg, about 258mg, about 499mg, about 998mg or about 1497mg.

19. The method of embodiment 1, wherein (Z)-4-(5-((3-benzyl-4- oxo-2-thioxothiazolidin-5-ylidene)methyl)furan-2-yl)benzoic acid, or a

pharmaceutically acceptable salt thereof, is administered once daily.

20. The method of embodiment 1, wherein (Z)-4-(5-((3-benzyl-4- oxo-2-thioxothiazolidin-5-ylidene)methyl)furan-2-yl)benzoic acid, or a

pharmaceutically acceptable salt thereof, is administered twice daily.

21. The method of embodiment 1, wherein (Z)-4-(5-((3-benzyl-4- oxo-2-thioxothiazolidin-5-ylidene)methyl)furan-2-yl)benzoic acid, or a

pharmaceutically acceptable salt thereof, is administered three times daily.

22. The method of embodiment 1, wherein the patient has a solid tumor.

23. The method of embodiment 1, wherein the patient has locally advanced cancer, metastatic cancer or recurrent cancer.

24. The method of embodiment 1, wherein the patient has metastatic cancer and has not received prior systemic therapy for the metastatic disease.

25. The method of embodiment 1, wherein the patient has metastatic pancreatic adenocarcinoma, wherein the patient has not received prior systemic therapy for the metastatic pancreatic adenocarcinoma.

26. The method of embodiment 1, wherein the patient has locally advanced pancreatic adenocarcinoma, esophageal adenocarcinoma, esophageal squamous cell carcinoma, gastric/GEJ adenocarcinoma, triple negative breast cancer (TNBC), castration resistant prostate cancer, or MSS colorectal adenocarcinoma.

27. The method of embodiment 1, wherein the patient has metastatic pancreatic adenocarcinoma, esophageal adenocarcinoma, esophageal squamous cell carcinoma, gastric/GEJ adenocarcinoma, triple negative breast cancer (TNBC), castration resistant prostate cancer, or MSS colorectal adenocarcinoma.

28. The method of embodiment 1, wherein the patient has recurrent pancreatic adenocarcinoma, esophageal adenocarcinoma, esophageal squamous cell carcinoma, gastric/GEJ adenocarcinoma, triple negative breast cancer (TNBC), castration resistant prostate cancer, or MSS colorectal adenocarcinoma.

29. The method of embodiment 1, wherein (Z)-4-(5-((3-benzyl-4- oxo-2-thioxothiazolidin-5-ylidene)methyl)furan-2-yl)benzoic acid, or a

pharmaceutically acceptable salt thereof is administered as a tablet.

30. The method of embodiment 1, wherein (Z)-4-(5-((3-benzyl-4- oxo-2-thioxothiazolidin-5-ylidene)methyl)furan-2-yl)benzoic acid, or a

pharmaceutically acceptable salt thereof is administered as an uncoated tablet.

31. The method of embodiment 29, wherein the tablet comprises about 62mg, about 124mg or about 498mg of the choline salt of (Z)-4-(5-((3- benzyl-4-oxo-2-thioxothiazolidin-5-ylidene)methyl)furan-2-yl)benzoic acid.

32. The method of embodiment 1, wherein the cancer is colorectal cancer.

33. The method of embodiment 32, wherein the colorectal cancer is recurrent colorectal cancer, refractory colorectal cancer, or both recurrent and refractory colorectal cancer.

34. The method of embodiment 1, wherein the cancer is gastric cancer.

35. The method of embodiment 34, wherein the gastric cancer is

PDL1 positive.

36. The method of embodiment 34, wherein the gastric cancer is recurrent gastric cancer, refractory gastric cancer, or both recurrent and refractory gastric cancer. This application claims the benefit of priority to U.S. Provisional Application No. 62/849,740, filed May 17, 2019, which application is hereby incorporated by reference in its entirety.

Claims

1. A method for treating a cancer comprising administering to a patient identified as having a cancer with a BRCA mutation:

(a) a compound according to Formula (I)

or pharmaceutically acceptable salt thereof; and (b) pembrolizumab.

2. The method of claim 1, wherein the compound is a choline or meglumine salt of the compound according to Formula (I) or a crystalline form thereof.

3. The method of claim 2, wherein the choline or meglumine salt is a choline salt of the compound according to Formula (I) or a crystalline form thereof.

4. The method of claim 2, wherein the choline or meglumine salt is a meglumine salt of the compound according to Formula (I) or a crystalline form thereof.

5. The method of any one of claims 1-4, wherein the BRCA mutation comprises a BRCAl mutation, a BRCA2 mutation, or both.

6. The method of claim 5, wherein the BRCA mutation is in an exon, intron, exon/intron junction, or untranslated region of the BRCA gene.

7. The method of claim 5, wherein the BRCA mutation comprises a missense mutation, a nonsense mutation, frameshift mutation, splice site mutation, large deletion, or large duplication.

8. The method of any one of claims 1-7, wherein the cancer is breast cancer, ovarian cancer, cervical cancer, uterine cancer, colon cancer, Fallopian tube cancer, peritoneal cancer, prostate cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, or melanoma.

9. The method of any one of claims 1-8, wherein the compound according to Formula (I) or pharmaceutically acceptable salt thereof is administered orally.

10. The method of claim 9, wherein the compound according to Formula (I) or pharmaceutically acceptable salt thereof is administered as a tablet.

11. The method of claim 10, wherein the tablet is uncoated.

12. The method of any one of claims 1 and 5-11, wherein the compound is a compound according to Formula (I) and is administered in an amount from about 50mg to about 1200mg.

13. The method of claim 12, wherein the compound is administered in an amount of about 50mg, about lOOmg, about 200mg, about 400mg, about 800mg or about 1200mg.

14. The method of any one of claims 1-3 and 5-11, wherein the compound is a choline salt of the compound according to Formula (I) or a crystalline form thereof and administered in an amount from about 50mg to about 1500mg.

15. The method of claim 14, wherein the choline salt of the compound according to Formula (I) or crystalline form thereof is administered in an amount of about 62mg, about 125mg, about 258mg, about 499mg, about 998mg or about 1497mg.

16. The method of any one of claims 1-15, wherein the compound is administered once daily.

17. The method of any one of claims 1-15, wherein the compound is administered twice daily

18. The method of any one of claims 1-17, wherein the patient has locally advanced cancer, metastatic cancer, or recurrent cancer.

19. The method of claim 18, wherein the patient has metastatic cancer and has not received prior systemic therapy for the metastatic cancer.

20. The method of claim 18, wherein the patient has metastatic cancer and has received prior systemic therapy for the metastatic cancer.

21. The method of any one of claims 1-20, wherein pembrolizumab is administered intravenously.

22. The method of any one of claims 1-21, wherein pembrolizumab is administered every one, two, three, four, five, or six weeks.

23. The method of any one of claims 1-22, wherein pembrolizumab is administered in an amount of about 200mg to about 500mg.

24. The method of any one of claims 1-23, wherein pembrolizmuab is administered in an amount of about 200mg every three weeks.

25. The method of any one of claims 1-24, wherein pembrolizmuab is administered in an amount of about 400mg every six weeks.

26. A method for treating a cancer comprising:

(a) administering to a patient having cancer:

(i) a compound according to Formula (I)

or pharmaceutically acceptable salt thereof; and (ii) pembrolizumab;

(b) obtaining at least two measurements of neutrophil to lymphocyte ratio for the patient post-treatment and comparing the at least two measurements of neutrophil to lymphocyte ratio for the patient post-treatment with a baseline neutrophil to lymphocyte ratio at day 0, wherein the at least two measurements are obtained every one week, two weeks, three weeks, or four weeks;

(c) wherein administration of the compound and pembrolizumab is continued if a decrease in neutrophil to lymphocyte ratio compared to the baseline neutrophil to lymphocyte ratio at day 0 is maintained for at least four weeks, or administration of the compound and pembrolizumab is discontinued if a decrease in neutrophil to lymphocyte ratio compared to the baseline neutrophil to lymphocyte ratio at day 0 is not maintained for at least four weeks.

27. The method of claim 26, wherein administration of the compound and pembrolizumab is continued if a decrease in neutrophil to lymphocyte ratio compared to the baseline neutrophil to lymphocyte ratio at day 0 is maintained for at least six weeks, or administration of the compound and pembrolizumab is discontinued if a decrease in neutrophil to lymphocyte ratio compared to the baseline neutrophil to lymphocyte ratio at day 0 is not maintained for at least six weeks.

28. The method of claim 26, wherein administration of the compound and pembrolizumab is continued if a decrease in neutrophil to lymphocyte ratio compared to the baseline neutrophil to lymphocyte ratio at day 0 is maintained for at least nine weeks, or administration of the compound and pembrolizumab is discontinued if a decrease in neutrophil to lymphocyte ratio compared to the baseline neutrophil to lymphocyte ratio at day 0 is not maintained for at least nine weeks.

29. The method of any one of claims 26-28, wherein the decrease in neutrophil to lymphocyte ratio compared to the baseline neutrophil to lymphocyte ratio is observed at about day 14 of treatment.

30. The method of any one of claims 26-29, wherein a maximum decrease in neutrophil to lymphocyte ratio compared to the baseline neutrophil to lymphocyte ratio is about 50%.

31. The method of any one of claims 26-30, wherein the neutrophil to lymphocyte ratio is measured from a peripheral blood sample from the patient.

32. The method of any one of claims 26-31, wherein the compound is a choline or meglumine salt of the compound according to Formula (I) or a crystalline form thereof.

33. The method of claim 32, wherein the choline or meglumine salt is a choline salt of the compound according to Formula (I) or a crystalline form thereof.

34. The method of claim 32, wherein the choline or meglumine salt is a meglumine salt of the compound according to Formula (I) or a crystalline form thereof.

35. The method of any one of claims 26-34, wherein the compound according to Formula (I) or pharmaceutically acceptable salt thereof is administered orally.

36. The method of claim 35, wherein the compound according to Formula (I) or pharmaceutically acceptable salt thereof is administered as a tablet.

37. The method of claim 36, wherein the tablet is uncoated.

38. The method of any one of claims 26-37, wherein the compound is a compound according to Formula (I) and is administered in an amount from about 50mg to about 1200mg.

39. The method of claim 38, wherein the compound is administered in an amount of about 50mg, about lOOmg, about 200mg, about 400mg, about 800mg or about 1200mg.

40. The method of any one of claims 26-39, wherein the compound is a choline salt of the compound according to Formula (I) or a crystalline form thereof and administered in an amount from about 50mg to about 1500mg.

41. The method of claim 40, wherein the choline salt of the compound according to Formula (I) or crystalline form thereof is administered in an amount of about 62mg, about 125mg, about 258mg, about 499mg, about 998mg or about 1497mg.

42. The method of any one of claims 26-41, wherein the compound is administered once daily.

43. The method of any one of claims 26-41, wherein the compound is administered twice daily

44. The method of any one of claims 26-43, wherein pembrolizumab is administered intravenously.

45. The method of any one of claims 26-44, wherein

pembrolizumab is administered every one, two, three, four, five, or six, weeks.

46. The method of any one of claims 26-45, wherein pembrolizumab is administered in an amount of about 200mg to about 500mg.

47. The method of any one of claims 26-46, wherein pembrolizmuab is administered in an amount of about 200mg every three weeks.

48. The method of any one of claims 26-46, wherein pembrolizmuab is administered in an amount of about 400mg every six weeks.

49. The method of any one of claims 26-48, wherein the cancer is pancreatic, breast, prostate, esophageal, gastric/gastroesophageal junction (GEJ), or colorectal cancer.

50. The method of any one of claims 26-49, wherein the cancer is locally advanced cancer, metastatic cancer, or recurrent cancer.

51. The method of claim 49 or 50, wherein the cancer is locally advanced pancreatic adenocarcinoma, esophageal adenocarcinoma, esophageal squamous cell carcinoma, gastric/GEJ adenocarcinoma, triple negative breast cancer (TNBC), castration resistant prostate cancer, or microsatellite stable (MSS) colorectal adenocarcinoma.

52. The method of claim 49 or 50, wherein the cancer is metastatic pancreatic adenocarcinoma, esophageal adenocarcinoma, esophageal squamous cell carcinoma, gastric/GEJ adenocarcinoma, triple negative breast cancer (TNBC), castration resistant prostate cancer, or MSS colorectal adenocarcinoma.

53. The method of claim 49 or 50, wherein the patient has recurrent pancreatic adenocarcinoma, esophageal adenocarcinoma, esophageal squamous cell carcinoma, gastric/GEJ adenocarcinoma, triple negative breast cancer (TNBC), castration resistant prostate cancer, or MSS colorectal adenocarcinoma.

54. The method of claim 49 or 50, wherein the patient has metastatic cancer and has not received prior systemic therapy for the metastatic disease.

55. The method of claim 49 or 50, wherein the patient has metastatic cancer and has received prior systemic therapy for the metastatic cancer.