LEUKADHERIN-1 ALONE OR IN COMBINATION FOR USE IN THE TREATMENT OF 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)fur an-2-yl)benzoic acid or pharmaceutically acceptable salts thereof.

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 anti-PD-1 antibody 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. Compound 1 may also be depicted as a compound according to Formula (I)

(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 are described in published Application US 2018/0354938 (all of which are incorporated by reference herein in their entirety).

In some embodiments, Compound 1 or the pharmaceutically acceptable salt thereof is administered in an amount of about 50mg to about 1800mg.

In some embodiments, the method further comprises administering an inhibitor of an immune checkpoint molecule, wherein the inhibitor of the immune checkpoint molecule does not comprise pembrolizumab.

In some embodiments, the method further comprises administering gemcitabine, nab-paclitaxel, or both. 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.

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 or anti- PD-1 antibody, leading to tumor regression, long-term survival and lasting immunologic memory.

Several anti -PD- 1 antibodies are approved for the treatment of advanced solid tumors, e.g., nivolumab (OPDIVO®), and cemiplimab (LIBTAYO®). Clinical outcomes with these anti PD-1 therapies remain highly 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 immune checkpoint resistance. Frequency of MDSCs in cancer patients is a predictive marker for checkpoint blockade response where depletion of MDSCs leads to improved outcomes to anti -PD- 1 antibody treatment.

Compound 1 offers potential treatment options to patients with sub-optimal treatment benefit from anti -PD- 1 antibodies 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.

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)f uran-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)fur an-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)fur an-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)meth yl)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)meth yl)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)meth yl)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)meth yl)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)meth yl)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-ylidene)meth yl)furan-2-yl)benzoic acid.

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 to the patient in an amount of from about 50mg to about 1800mg In some embodiments, (Z)-4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5- ylidene)methyl)furan-2-yl)benzoic acid is administered to the patient 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 to the patient 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 to the patient 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)fur an-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)fur an-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)meth yl)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 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 refractory cancer. In some embodiments, the patient has recurrent and refractory 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. 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, 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/gastroesophageal junction (GEJ) adenocarcinoma, triple negative breast cancer (TNBC), castration resistant prostate cancer (CRPC), or microsatellite stable (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. In some embodiments, the gastric/GEJ adenocarcinoma is PD-L1 positive. In some embodiments, the metastatic gastric/GEJ adenocarcinoma is PD-L1 positive. In some embodiments, the recurrent gastric/GEJ adenocarcinoma is PD-L1 positive.

In some embodiments, methods of the present disclosure further comprise administration with a second agent. In some embodiments, the second agent is an anti-cancer agent. In some embodiments, the second agent is an inhibitor of an immune checkpoint molecule, wherein the inhibitor of the immune checkpoint molecule does not comprise pembrolizumab. In some embodiments, the immune checkpoint molecule is Programmed cell death protein 1 (PD-1), Programmed death-ligand 1 (PD-L1), or (cytotoxic T-lymphocyte-associated protein 4) CTLA-4. In some embodiments, the inhibitor of the immune checkpoint molecule is a protein, a compound, ribozyme, or a nucleic acid (e.g., antisense oligonucleotide, RNAi molecule). In some embodiments, the inhibitor of the immune checkpoint molecule is an antibody or antigen binding fragment thereof. In some embodiments, the inhibitor of the immune checkpoint molecule comprises an anti-PD-1 antibody selected from nivolumab, pidilizumab, cemiplimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostarlimab, INCMGA00012, AMP-224, AMP-514, or any combination thereof. In some embodiments, the inhibitor of the immune checkpoint molecule comprises an anti-PD-Ll antibody selected from atezolizumab, avelumab, durvalumab, envafolimab, BMS-936559 (MDX-1105), CK-301, CS-1001, SHR-1316 (HTI-1088), CBT-502 (TQB-2450), BGB-A333, or any combination thereof. In some embodiments, the inhibitor of the immune checkpoint molecule comprises an anti-CTLA-4 antibody selected from ipilimumab and tremelimumab.

In some embodiments, the inhibitor of the immune checkpoint molecule (e.g., antibody) is administered intravenously. In some embodiments, the inhibitor of the immune checkpoint molecule (e.g., antibody) is administered every week, two weeks, three weeks, four weeks, five weeks, or six weeks.

In some embodiments, the inhibitor of the immune checkpoint molecule is an antibody or antigen binding fragment thereof and is administered in an amount of about 200mg to about 1500mg. In some embodiments, the inhibitor of the immune checkpoint molecule is nivolumab and is administered in an amount of about 240mg every two weeks or about 480mg every four weeks. In some embodiments, the inhibitor of the immune checkpoint molecule is cemiplimab and is administered in an amount of about 350mg every three weeks. In some embodiments, the inhibitor of the immune checkpoint molecule is atezolizumab and is administered in an amount of about 840mg every two weeks, about 1200mg every three weeks, or about 1680mg every four weeks. In some embodiments, the inhibitor of the immune checkpoint molecule is avelumab and is administered in an amount of about 800mg every two weeks. In some embodiments, the inhibitor of the immune checkpoint molecule is durvalumab and is administered in an amount of about 750mg every two weeks or about l,500mg every four weeks.

In some embodiments, the second agent is nab-paclitaxel. In some embodiments, the second agent is gemcitabine. In some embodiments, the second agent is nab-paclitaxel and gemcitabine.

In some embodiments, methods of the present disclosure further comprise administration with standard of care for the treatment of the particular cancer.

Further described herein are methods of treating a patient having pancreatic 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, gemcitabine and nab-paclitaxel. In some embodiments, the pancreatic cancer is metastatic. In some embodiments, the methods further comprise administering a PD-L1 inhibitor. In some embodiments, the methods further comprise administering a PD-1 inhibitor, wherein the PD-1 inhibitor does not comprise pembrolizumab.

Also described herein are pharmaceutical compositions comprising 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 pharmaceutical compositions further comprise microcrystalline cellulose. In some embodiments, the pharmaceutical compositions further comprise pre-gelatinised starch. In some embodiments, the pharmaceutical compositions further comprise crospovidone. In some embodiments, the pharmaceutical compositions further comprise colloidal silicon dioxide. In some embodiments, the pharmaceutical compositions further comprise sodium stearyl fumarate. In some embodiments, the pharmaceutical compositions comprise the choline salt of (Z)-4-(5-((3-benzyl-4-oxo-2- thioxothiazolidin-5-ylidene)methyl)furan-2-yl)benzoic acid, microcrystalline cellulose, pre-gelatinised starch, Crospovidone, colloidal silicon dioxide and sodium stearyl fumarate.

In some embodiments, the pharmaceutical compositions are tablets. In some embodiments, the pharmaceutical compositions are coated tablets. In some embodiments, the pharmaceutical compositions are uncoated tablets. In some embodiments, the pharmaceutical compositions are tablets for oral administration.

In some embodiments, the pharmaceutical compositions comprise 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. 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 Regimen 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:

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

Subjects from cohort A and Regimen 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. Pembrolizumab (KEYTRUDA ^® ) is an anti -PD- 1 antibody.

Standard of Care (SOC) - for Regimen C and Expansion Cohort 1

(patients with Pancreatic Adenocarcinoma) is defined as Nab-Paclitaxel (125mg/m ² ) and Gemcitabine (1000mg/m ² ), 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 Dose limiting toxi cities (DLTs), (MTD) or recommended phase 2 dose adverse events (AEs) and serious (RP2D) of choline salt of Compound 1 in adverse events (SAEs) subjects with previously treated specified

Number and frequency of clinically advanced solid tumors

significant laboratory, electrocardiogram and vital sign abnormalities

To determine the PK profile of choline salt of

Compound 1 in subjects with previously PK

treated specified advanced solid tumors

Plasma concentrations and PK parameters of choline salt of Compound 1 and metabolites as appropriate

Exploratory

To evaluate anti -turn or activity of choline salt Overall Response Rate (ORR) of Compound 1 in subjects with previously

Duration of Response (DOR) treated specified advanced solid tumors

Time to Response (TTR)

Clinical Benefit Rate (CBR)

Progression-free Survival (PFS)

Time to Progression (TTP)

Overall Survival (OS)

To evaluate changes in disease biomarkers Change from baseline in the following treatment with choline salt of following target engagement Compound 1 in subjects with previously (TE) / pharmacodynamic assays: treated specified advanced solid tumors

Whole blood CD1 lb-TE assay

Whole blood tumor mutational burden (TMB) assessment from cell free DNA (cfDNA) Dose Escalation Phase: Regimen A & Regimen B

Objectives Endpoints

Whole blood immune cell phenotyping

Plasma biomarkers

Tumor tissue target engagement / biomarker

Tumor tissue

immunohi stochemi stry

Dose Escalation Phase: Regimen C

Objectives Endpoints

Primary

To determine safety of choline salt of Dose limiting toxi cities (DLTs),

Compound 1 in combination with standard adverse events (AEs) and of care (nab-paclitaxel and gemcitabine) in serious adverse events (SAEs) subjects with metastatic pancreatic

Number and frequency of adenocarcinoma

clinically significant laboratory, electrocardiogram and vital sign abnormalities

Secondary

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

To assess the PK of SOC (nab-paclitaxel and Plasma concentrations and PK gemcitabine) alone and in combination parameters of gemcitabine (and with choline salt of Compound 1 in metabolite

subjects with metastatic pancreatic difluorodeoxyuridine) and nab- adenocarcinoma paclitaxel

Exploratory

To evaluate anti -turn or activity of choline salt Overall Response Rate (ORR) of Compound 1 in combination with

Duration of Response (DOR) standard of care (nab-paclitaxel and

gemcitabine) in subjects with metastatic Time to Response (TTR) Dose Escalation Phase: Regimen C

Objectives Endpoints

pancreatic adenocarcinoma Clinical Benefit Rate (CBR)

Progression-free Survival (PFS) Time to Progression (TTP) Overall Survival (OS)

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

subjects with metastatic pancreatic

Change from baseline in the adenocarcinoma

following

TE/pharmacodynamic assays:

Whole blood CD1 lb-TE assay

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.

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. 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 6, wherein the tablet is coated. 8 The method of embodiment 6, wherein the tablet is uncoated.

9. The method of embodiment 6, 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 6, 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 6, wherein the tablet comprises about 400mg of (Z)-4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5- ylidene)methyl)furan-2-yl)benzoic acid.

12. The method of embodiment 6, 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 6, 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 6, 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)meth yl)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)meth yl)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, further comprising administering a second anti-cancer agent. 30. The method of embodiment 1, further comprising administering an anti-PD-1 antibody, wherein the anti-PD-1 antibody does not comprise pembrolizumab.

31. The method of embodiment 1, further comprising administering an anti -PD-L1 antibody.

32. The method of embodiment 1, further comprising administering nivolumab or atezolizumab.

33. The method of embodiment 1, further comprising administering nab-paclitaxel. 34. The method of embodiment 1, further comprising administering gemcitabine.

35. The method of embodiment 1, further comprising administering nab-paclitaxel and gemcitabine.

36. The method of embodiment 1, further comprising administering the standard of care.

37. A pharmaceutical composition comprising: the choline salt of (Z)-4-(5-((3-benzyl-4-oxo-2- thioxothiazolidin-5-ylidene)methyl)furan-2-yl)benzoic acid; microcrystalline cellulose ; pregelatinised starch; crospovidone; colloidal silicon dioxide; and sodium stearyl fumarate.

38. The pharmaceutical composition of embodiment 37, wherein the pharmaceutical composition is a tablet. 39. The pharmaceutical composition of embodiment 37, wherein the pharmaceutical composition is an uncoated tablet.

40. The pharmaceutical composition of embodiment 37, comprising about 62mg, about 124mg or about 498mg of the choline salt of (Z)-4- (5-((3-benzyl-4-oxo-2-thioxothiazolidin-5-ylidene)methyl)fur an-2-yl)benzoic acid. 41. A method of treating a patient suffering from pancreatic 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; gemcitabine; and nab-paclitaxel.

42. The method of embodiment 41, wherein the pancreatic cancer is metastatic.

43. The method of embodiment 41, further comprising administering a PD-L1 inhibitor.

44. The method of embodiment 1, wherein the cancer is colorectal cancer. 45. The method of embodiment 44, wherein the colorectal cancer is recurrent colorectal cancer, refractory colorectal cancer, or both recurrent and refractory colorectal cancer.

46. The method of embodiment 1, further comprising

administering a PD-L1 inhibitor.

47. The method of embodiment 1, further comprising

administering a PD-1 inhibitor, wherien the PD-1 inhibitor does not comprise pembrolizumab.

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

49. The method of embodiment 48, wherein the gastric cancer is

PDL1 positive.

50. The method of embodiment 48, wherein the gastric cancer is recurrent gastric cancer, refractory gastric cancer, or both recurrent and refractory gastric cancer.

51. The method of embodiment 48, further comprising administering a PD-L1 inhibitor.

52. The method of embodiment 48, further comprising administering a PD-1 inhibitor, wherien the PD-1 inhibitor does not comprise pembrolizumab. 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.