WO2021034631A1 - Methods and pharmaceutical compositions containing 4,6-bis(benzylthio)hexanoic acid for treating cancer - Google Patents

Abstract

The invention provides methods, compositions, and medical kits for treating cancer using 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically acceptable salt thereof.

Description

METHODS AND PHARMACEUTICAL COMPOSITIONS CONTAINING 4,6- BIS(BENZYLTHIO)HEXANOIC ACID FOR TREATING CANCER

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to United States Provisional Patent Application serial number 62/887,754, filed August 16, 2019; the contents of which are hereby incorporated by reference.

FIELD OF THE INVENTION

[0001] The invention provides methods, compositions, and medical kits for treating cancer using 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically acceptable salt thereof.

BACKGROUND

[0002] CPI-613 (6,8-bis-benzylthio-octanoic acid) is a first-in-class investigational small- molecule (lipoate analog), which targets the altered energy metabolism unique to many cancer cells. CPI-613 is currently being evaluated in two phase III clinical trials, and has been granted orphan drug designation for the treatment of pancreatic cancer, acute myeloid leukemia (AML), peripheral T-cell lymphoma (PTCL), Burkitt lymphoma and myelodysplastic syndromes (MDS).

[0003] A limitation of CPI-613 is that it is rapidly metabolized. After IV dosing the half-life of bis-benzylthio-octanoic acid is only about 1-2 hours (Pardee, T.S. et ah, Clin Cancer Res. 2014,

20, 5255-64). The short half-life limits the overall drug exposure and necessitates the administration of relatively high doses. For safety reasons, CPI-613 is administered via a central venous catheter as an IV infusion over 30-120 minutes, with higher doses requiring longer infusion times.

[0004] A need exists for new derivatives of CPI-613 with improved pharmacokinetic properties. The present invention addresses this need and provides other related advantages.

SUMMARY

[0005] The invention provides methods, compositions, and medical kits for treating cancer using 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically acceptable salt thereof. In particular, one aspect of the invention provides a method of treating cancer in a patient. The method comprises administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically acceptable salt thereof to treat the cancer. The cancer may be a lymphoma, leukemia, carcinoma, sarcoma, melanoma, myeloma, brain or spinal cord cancer, blastoma, germ cell tumor, cancer of the pancreas, colorectal cancer, myelodysplastic syndrome, or cancer of the prostate. In certain embodiments, the cancer is a lymphoma, leukemia, carcinoma, sarcoma, melanoma, or myeloma.

[0006] Another aspect of the invention provides a pharmaceutical composition. The pharmaceutical composition comprises a pharmaceutically acceptable carrier and 4,6- bis(benzylthio)hexanoic acid or a pharmaceutically acceptable salt thereof. The pharmaceutical composition may be, for example, in the form of tablet, capsule, or isotonic aqueous mixture for intravenous injection.

BRIEF DESCRIPTION OF FIGURES

[0007] Figure l is a graph depicting average tumor volumes in mice bearing a NCI-H460 Human NSCLC xenograft treated with 4,6-bis(benzylthio)hexanoic acid at 25 mg/kg (IP) for three weeks, as further described in Example 2.

[0008] Figure 2 is a graph depicting mean body weight values of mice treated with 4,6- bis(benzylthio)hexanoic acid or dextrose solution, as further described in Example 2.

DETAILED DESCRIPTION

[0009] The invention provides methods, compositions, and medical kits for treating cancer using 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically acceptable salt thereof. The practice of the present invention employs, unless otherwise indicated, conventional techniques of organic chemistry, pharmacology, molecular biology (including recombinant techniques), cell biology, biochemistry, and immunology. Such techniques are explained in the literature, such as in “Comprehensive Organic Synthesis” (B.M. Trost & I. Fleming, eds., 1991-1992); “Handbook of experimental immunology” (D.M. Weir & C.C. Blackwell, eds.); “Current protocols in molecular biology” (F.M. Ausubel et al ., eds., 1987, and periodic updates); and “Current protocols in immunology” (J.E. Coligan et al. , eds., 1991), each of which is herein incorporated by reference in its entirety. [00010] Various aspects of the invention are set forth below in sections; however, aspects of the invention described in one particular section are not to be limited to any particular section. Further, when a variable is not accompanied by a definition, the previous definition of the variable controls.

I. Definitions

[00011] To facilitate an understanding of the present invention, a number of terms and phrases are defined below.

[00012] The term “6,8-bis-benzylthio-octanoic acid” refers to the compound known as CPI-613, having the chemical structure

[00013] Certain compounds contained in compositions of the present invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, R- and ^-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention.

[00014] As used herein, the term “patient” refers to a human being in need of medical treatment.

[00015] As used herein, the term “treating” includes any effect, e.g., lessening, reducing, modulating, ameliorating or eliminating, that results in the improvement, stabilization, or slowing progression of a condition, disease, disorder, or the like, or a symptom thereof. For example, treatment can include diminishment of a symptom of a disorder or complete eradication of a disorder. As another example, treatment can include slowing the progression of a disease, or preventing or delaying its recurrence, such as maintenance treatment to prevent or delay relapse.

[00016] “Therapeutically effective amount” refers to an amount of a compound sufficient to inhibit, halt, or cause an improvement in a disorder or condition being treated in a particular patient or patient population. For example, a therapeutically effective amount can be an amount of drug sufficient to slow the progression of a disease, or to prevent or delay its recurrence, such as maintenance treatment to prevent or delay relapse. In a human or other mammal, a therapeutically effective amount can be determined experimentally in a laboratory or clinical setting, or may be the amount required by the guidelines of the United States Food and Drug Administration, or equivalent foreign agency, for the particular disease and subject being treated. It should be appreciated that determination of proper dosage forms, dosage amounts, and routes of administration is within the level of ordinary skill in the pharmaceutical and medical arts.

[00017] As used herein, the term “pharmaceutical composition” refers to the combination of an active agent with an excipient, inert or active, suitable for administration to a human being.

[00018] The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound judgment, suitable for use in contact with the tissues of human beings with acceptable toxicity, irritation, allergic response, and other problems or complications commensurate with a reasonable benefit/risk ratio.

[00019] As used herein, the term “pharmaceutically acceptable excipient” refers to any of the standard pharmaceutical excipients suitable for use in humans. For examples of excipients, see e.g., Martin, Remington's Pharmaceutical Sciences, 15th Ed., MackPubl. Co., Easton, PA [1975]

[00020] As used herein, the term “pharmaceutically acceptable salt” refers to any salt (e.g., acid or base) of a compound of the present invention which is suitable for administration to a human being. “Salts” of the compounds of the present invention may be derived from inorganic or organic acids and bases. Examples of acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene- p-sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic, benzenesulfonic acid, and the like. Examples of bases include, but are not limited to, alkali metals (e.g, sodium) hydroxides, alkaline earth metals (e.g, magnesium), hydroxides, ammonia, and compounds of formula NR3, wherein R is C1-4 alkyl, and the like.

[00021] Further examples of salts include salts made using the ion pairing agents described in U.S. Patent No. 8,263,653, the entire disclosure of which is incorporated by reference herein. Still further ion pairing agents can be selected with guidance from Handbook of Pharmaceutical Salts Properties, Selection and Use, IUPAC, Wiley-VCH, P.H. Stahl, ed., the entire disclosure of which is incorporated by reference herein.

[00022] For therapeutic use, salts of the compounds of the present invention are contemplated as being pharmaceutically acceptable. However, salts of acids and bases that are non- pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.

[00023] Throughout the description, where compositions are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited steps.

[00024] As a general matter, compositions specifying a percentage are by weight unless otherwise specified.

II. Therapeutic Applications

[00025] One aspect of the invention provides a method of treating cancer in a patient. The method comprises administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and 4,6- bis(benzylthio)hexanoic acid or a pharmaceutically acceptable salt thereof to treat the cancer. 4,6- bis(benzylthio)hexanoic acid, also known as CPI-2850, is a compound having the following chemical structure:

4,6-Bis(benzylthio)hexanoic acid is an active metabolite of CPI-613, which is rapidly converted to CPI-2850 within minutes of administration by beta-oxidation (Alistar A. et al., Lancet Onol. 2017, 18, 770-78, incorporated herein by reference).

Cancers

[00026] In certain embodiments, the cancer is associated with altered energy metabolism. As used herein, the term “cancer” is intended to include myelodysplastic syndromes, and in certain embodiments of the present invention the cancer is a myelodysplastic syndrome. In certain embodiments, the cancer is high risk myelodysplastic syndrome (MDS). In certain embodiments, the cancer is high risk MDS in patients who have failed to respond, progressed, or relapsed while on hypomethylating therapy.

[00027] The method may be further characterized according to the severity or type of cancer. In certain embodiments, the cancer is Stage I or early stage cancer, in which the cancer is small and only in one area. In certain embodiments, the cancer is Stage II or III, in which the cancer is larger and has grown into nearby tissues or lymph nodes. In certain embodiments, the cancer is Stage IV or advanced or metastatic, in which the cancer has spread to other parts of the body.

[00028] In certain embodiments, the cancer is Stage I lymphoma, in which the cancer is found in one lymph node region or the cancer has invaded one extra-lymphatic organ or site but not any lymph node regions. In certain embodiments, the cancer is Stage II lymphoma, in which the cancer is found in two or more lymph node regions on the same side of the diaphragm or the cancer involves one organ and its regional lymph nodes, with or without cancer in other lymph node regions on the same side of the diaphragm. In certain embodiments, the cancer is Stage III lymphoma, in which there is cancer in lymph nodes on both sides of the diaphragm. In certain embodiments, the cancer is Stage IV lymphoma, in which the cancer has spread one or more organs beyond the lymph nodes.

[00029] In certain embodiments, the cancer is progressive or refractory. In certain embodiments, the cancer is a metastatic. In certain embodiments, the cancer is recurrent or relapsed. In certain embodiments, the cancer is relapsed or refractory. In certain embodiments, the cancer is a T-cell lymphoma. In certain embodiments, the cancer is a B-cell lymphoma. In certain embodiments, the cancer is previously untreated. In certain embodiments, the patient has not received hematopoietic cell transplant. In certain embodiments, the patient has received hematopoietic cell transplant.

[00030] In certain embodiments, the cancer is a lymphoma. In certain embodiments, the cancer is mantle cell lymphoma. In certain embodiments, the cancer is a leukemia. In certain embodiments, the cancer is an acute myeloid leukemia. In certain embodiments, the cancer is chronic myeloid leukemia. In certain embodiments, the cancer is acute lymphoblastic leukemia. In certain embodiments, the cancer is a carcinoma. In certain embodiments, the cancer is a sarcoma. In certain embodiments, the cancer is a myeloma. In certain embodiments, the cancer is a clear cell cancer. In certain embodiments, the cancer is a clear cell sarcoma. In certain embodiments, the cancer is a clear cell carcinoma. In certain embodiments, the cancer is a brain or spinal cord cancer. In certain embodiments, the cancer is a melanoma. In certain embodiments, the cancer is a blastoma. In certain embodiments, the cancer is a germ cell tumor. In certain embodiments, the cancer is a cancer of the pancreas. In certain embodiments, the cancer is a metastatic pancreatic cancer. In certain embodiments, the cancer is a locally advanced pancreatic cancer. In certain embodiments, the cancer is a cancer of the prostate. In certain embodiments, the cancer is a castration resistant prostate cancer. In certain embodiments, the cancer is a cancer of the lung. In certain embodiment, the cancer is non-small cell lung cancer. In certain embodiments, the cancer is a cancer of the colon. In certain embodiments, the cancer is a cancer of the rectum. In certain embodiments, the cancer is a colorectal cancer. In certain embodiments, the cancer is a cancer of the cervix. In certain embodiments, the cancer is a neuroendocrine tumor. In certain embodiments, the cancer is a gastroenteropancreatic neuroendocrine tumor. In certain embodiments, the cancer is a cancer of the liver. In certain embodiments, the cancer is a cancer of the uterus. In certain embodiments, the cancer is a cancer of the cervix. In certain embodiments, the cancer is a cancer of the bladder. In certain embodiments, the cancer is a cancer of the kidney. In certain embodiments, the cancer is a cancer of the breast. In certain embodiments, the cancer is a cancer of the ovary.

[00031] In certain embodiments, the cancer is Burkitt’s Lymphoma. In certain embodiments, the cancer is relapsed or refractory Burkitt’s Lymphoma. In certain embodiments, the cancer is relapsed or refractory Burkitt’s Lymphoma in which the patient has failed at least one previous line of therapy. In certain embodiments, the cancer is relapsed or refractory Burkitt’s Lymphoma in which the patient has failed prior bone marrow transplant. In certain embodiments, the cancer is double hit diffuse large B cell lymphoma. In certain embodiments, the cancer is high-grade B cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6 (DHL/THL). In certain embodiments, the cancer is Hodgkin lymphoma. In certain embodiments, the cancer is non- Hodgkin lymphoma. In certain embodiments, the cancer is T-cell non-Hodgkin lymphoma. In certain embodiments, the cancer is relapsed or refractory Hodgkin lymphoma. In certain embodiments, the cancer is relapsed or refractory non-Hodgkin lymphoma. In certain embodiments, the cancer is relapsed or refractory T-cell non-Hodgkin lymphoma. In certain embodiments, the cancer is Hodgkin lymphoma in which the patient has not received hematopoietic cell transplant. In certain embodiments, the cancer is Hodgkin lymphoma in which the patient has received hematopoietic cell transplant. In certain embodiments, the cancer is non- Hodgkin lymphoma in which the patient has not received hematopoietic cell transplant. In certain embodiments, the cancer is non-Hodgkin lymphoma in which the patient has received hematopoietic cell transplant. In certain embodiments, the cancer is T-cell non-Hodgkin lymphoma in which the patient has not received hematopoietic cell transplant. In certain embodiments, the cancer is T-cell non-Hodgkin lymphoma in which the patient has received hematopoietic cell transplant. In certain embodiments, the cancer is relapsed or refractory Hodgkin lymphoma in which the patient has not received hematopoietic cell transplant. In certain embodiments, the cancer is relapsed or refractory Hodgkin lymphoma in which the patient has received hematopoietic cell transplant. In certain embodiments, the cancer is relapsed or refractory non- Hodgkin lymphoma in which the patient has not received hematopoietic cell transplant. In certain embodiments, the cancer is relapsed or refractory Hodgkin lymphoma in which the patient has or has not received hematopoietic cell transplant. In certain embodiments, the cancer is relapsed or refractory Hodgkin lymphoma in which the patient has failed brentuximab vedotin and a PD-1 inhibitor. In certain embodiments, the cancer is relapsed or refractory Hodgkin lymphoma in which the patient has failed brentuximab vedotin and a PD-1 inhibitor and has received hematopoietic cell transplant. In certain embodiments, the cancer is relapsed or refractory Hodgkin lymphoma in which the patient has failed brentuximab vedotin and a PD-1 inhibitor and has not received hematopoietic cell transplant. In certain embodiments, the cancer is relapsed or refractory non- Hodgkin lymphoma in which the patient has received hematopoietic cell transplant. In certain embodiments, the cancer is relapsed or refractory T-cell non-Hodgkin lymphoma in which the patient has not received hematopoietic cell transplant. In certain embodiments, the cancer is relapsed or refractory T-cell non-Hodgkin lymphoma in which the patient has received hematopoietic cell transplant. In certain embodiments, the cancer is relapsed or refractory T-cell non-Hodgkin lymphoma in which the patient has or has not received hematopoietic cell transplant.

[00032] In certain embodiments, the cancer is a carcinoma, sarcoma, or myeloma. In certain embodiments, the cancer is lymphoma. In certain embodiments, the cancer is leukemia. In certain embodiments, the cancer is a solid tumor.

[00033] In certain embodiments, the cancer is bladder cancer, colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, esophagus cancer, lung cancer, stomach cancer, cervical cancer, testicular cancer, skin cancer, rectal cancer, thyroid cancer, kidney cancer, uterus cancer, or liver cancer.

[00034] In certain embodiments, the cancer is an acoustic neuroma, oligodendroglioma, meningioma, neuroblastoma, or retinoblastoma. In certain embodiments, the cancer is Burkitt's lymphoma. In certain embodiments, the cancer is a T-cell lymphoma. In certain embodiments, the cancer is acute lymphocytic leukemia or acute myeloid leukemia. In certain embodiments, the cancer is chronic lymphocytic leukemia or chronic myeloid leukemia. In certain embodiments, the cancer is myelodysplastic syndrome or hairy cell leukemia.

[00035] In certain embodiments, the cancer is a solid tumor or leukemia. In certain other embodiments, the cancer is colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, lung cancer, leukemia, bladder cancer, stomach cancer, cervical cancer, testicular cancer, skin cancer, rectal cancer, thyroid cancer, kidney cancer, uterus cancer, espophagus cancer, liver cancer, an acoustic neuroma, oligodendroglioma, meningioma, neuroblastoma, or retinoblastoma. In certain other embodiments, the cancer is small cell lung cancer, non-small cell lung cancer, melanoma, cancer of the central nervous system tissue, brain cancer, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, cutaneous T-Cell lymphoma, cutaneous B-Cell lymphoma, or diffuse large B-Cell lymphoma. In certain other embodiments, the cancer is breast cancer, colon cancer, small-cell lung cancer, non-small cell lung cancer, prostate cancer, renal cancer, ovarian cancer, leukemia, melanoma, or cancer of the central nervous system tissue. In certain other embodiments, the cancer is colon cancer, small-cell lung cancer, non-small cell lung cancer, renal cancer, ovarian cancer, renal cancer, or melanoma.

[00036] Additional exemplary cancers include fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, Ewing’s tumor, leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms’ tumor, epithelial carcinoma, glioma, astrocyto a, medulloblastoma, and hemangioblastoma. [00037] In certain embodiments, the cancer is a neuroblastoma, meningioma, hemangiopericytoma, multiple brain metastase, glioblastoma multiforms, glioblastoma, brain stem glioma, poor prognosis malignant brain tumor, malignant glioma, anaplastic astrocytoma, anaplastic oligodendroglioma, neuroendocrine tumor, rectal adeno carcinoma, Dukes C & D colorectal cancer, unresectable colorectal carcinoma, metastatic hepatocellular carcinoma,

Kaposi’s sarcoma, karotype acute myeloblastic leukemia, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, cutaneous T-Cell lymphoma, cutaneous B-Cell lymphoma, diffuse large B-Cell lymphoma, low grade follicular lymphoma, metastatic melanoma, localized melanoma, malignant mesothelioma, malignant pleural effusion mesothelioma syndrome, peritoneal carcinoma, papillary serous carcinoma, gynecologic sarcoma, soft tissue sarcoma, scelroderma, cutaneous vasculitis, Langerhans cell histiocytosis, leiomyosarcoma, fibrodysplasia ossificans progressive, hormone refractory prostate cancer, resected high-risk soft tissue sarcoma, unrescectable hepatocellular carcinoma, Waldenstrom’s macroglobulinemia, smoldering myeloma, indolent myeloma, fallopian tube cancer, androgen independent prostate cancer, androgen dependent stage IV non-metastatic prostate cancer, hormone-insensitive prostate cancer, chemotherapy-insensitive prostate cancer, papillary thyroid carcinoma, follicular thyroid carcinoma, medullary thyroid carcinoma, or leiomyoma.

[00038] In certain embodiments, the cancer is a carcinoma, sarcoma, lymphoma, leukemia, germ cell tumor, or blastoma. In certain embodiments, the cancer is a primary or metastatic melanoma, lung cancer, liver cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, uterine cancer, cervical cancer, bladder cancer, kidney cancer, colon cancer, or adenocarcinomas such as breast cancer, prostate cancer, ovarian cancer, or pancreatic cancer.

General Aspects of Administering 4, 6-bis(benzylthio)hexanoic acid to a Patient

[00039] Generally, the 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically acceptable salt thereof is delivered to the patient in a therapeutically effective amount, sufficient to treat cancer. The treatment may involve one or several administrations on one or more days, and the dosage may be adjusted by the individual practitioner to achieve a desired effect. Preferably, the dosage amount should be sufficient to interact primarily with disease cells, leaving normal cells comparatively unharmed.

[00040] The dosage amount may be administered in a single dose or in the form of individual divided doses, such as one, two, three, or four times per day. In certain embodiments, the daily dosage amount is administered in a single dose. In the event that the response in a patient is insufficient at a certain dose, higher or more frequent doses may be employed to the extent of patient tolerance.

[00041] For combination therapy, each agent may be administered in a particular order and/or on the same or different days according to a treatment cycle. For example, a dose of a 4,6- bis(benzylthio)hexanoic acid or a pharmaceutically acceptable salt thereof may be administered to the patient prior to administering a second therapeutic agent, such as immediately prior, earlier in the day, or on an earlier day in a treatment cycle. In certain embodiments, the active agents may be administered on the same day of a treatment cycle, for example being co-administered simultaneously or one right after the other. In certain embodiments, a dose of a second therapeutic agent is administered to the patient prior to administering the 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically acceptable salt thereof, such as immediately prior, earlier in the day, or on an earlier day in a treatment cycle. In certain embodiments, treatment cycles may be repeated one or more times in order to maximize benefit to the patient.

[00042] The invention may be further characterized according to the patient to be treated. In the present invention, the patient is a human being. In certain embodiments, the patient is an adult. In certain embodiments, the patient is an adult at least 50 years of age. In certain embodiments, the patient is an adult at least 60 years of age. In certain embodiments, the patient is a child.

4, 6-Bis(benzylthio)hexanoic acid

[00043] 4,6-Bis(benzylthio)hexanoic acid may be administered in any suitable form, including as a solid or liquid, a free acid or salt. The 4,6-bis(benzylthio)hexanoic acid may be crystalline, amorphous, or dissolved in solution. In certain embodiments, the 4,6-bis(benzylthio)hexanoic acid is administered to the patient as a salt or ion pair. In certain embodiments, the 4,6- bis(benzylthio)hexanoic acid is administered to the patient as a salt or ion pair with triethanolamine. Exemplary ion pairing agents that may be used include, for example, a tertiary amine (such as triethylamine or triethanolamine), other amines such as diethylamine, diethanolamine, monoethanolamine, meglumine, mefenamic acid and tromethamine, and combinations thereof. In certain embodiments, the ion pairing agent is an organic Bronsted base. In certain other embodiments, the ion pairing agent is an amine compound. In yet other embodiments, the ion pairing agent is a monoalkylamine, dialkylamine, trialkylamine, amino-substituted aliphatic alcohol, hydroxymonoalkylamine, hydroxydi alkyl amine, hydroxytrialkylamine, amino-substituted heteroaliphatic alcohol, alkyl diamine, substituted alkyldiamine, or optionally substituted heteroaryl group containing at least one ring nitrogen atom. In certain embodiments, the therapeutic agent is a salt of a 4,6-bis(benzylthio)hexanoic acid as described above with an ion pairing agent selected with guidance from Berge et ak, "Pharmaceutical Salts," J. of Pharmaceutical Science , 1977; 66:1- 19 or Handbook of Pharmaceutical Salts Properties, Selection and Use, IUPAC, Wiley-VCH, P. H. Stahl, ed., the entire disclosures of which are incorporated by reference herein. Ion pairing agents of particular note in the latter include, without limitation, those listed in Table 5, p. 342.

[00044] Additional exemplary ion pairing agents include, for example, polyethyleneimine, polyglutamic acid, ammonia, L-arginine, benethamine benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine(2,2’-iminobis(ethanol)), diethylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylenediamine, N-methyl-glucamine, hydrabamine, lH-imidazole, lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide, l-(2- hydroxyethyl)-pyrrolidine, sodium hydroxide, triethanolamine (2,2’,2”-nitrilotris(ethanol)), tromethamine, and zinc hydroxide. In certain other embodiments, the ion pairing agent is diisopropanolamine, 3 -amino- 1 -propanol, meglumine, morpholine, pyridine, niacinamide, tris(hydroxymethyl)aminomethane, 2-((2-dimethylamino)ethoxy)ethanol, 2- (dimethylamino)ethanol, l-(2-hydroxyethyl)pyrrolidine, or ammonium hydroxide. In certain other embodiments, the ion pairing agent is an alkali metal hydroxide or alkaline earth metal hydroxide, such as, for example, cesium hydroxide.

Route of Administration

[00045] 4,6-Bis(benzylthio)hexanoic acid or a pharmaceutically acceptable salt thereof may be administered to the patient by any suitable route. For example, in certain embodiments, the 4,6- bis(benzylthio)hexanoic acid or pharmaceutically acceptable salt thereof is administered orally to the patient. In certain embodiments, the 4,6-bis(benzylthio)hexanoic acid or pharmaceutically acceptable salt thereof is administered subcutaneously to the patient. In certain embodiments, the 4,6-bis(benzylthio)hexanoic acid or pharmaceutically acceptable salt thereof is administered intravenously to the patient. In certain embodiments, the 4,6-bis(benzylthio)hexanoic acid or pharmaceutically acceptable salt thereof is administered as an IV infusion over two hours. In certain embodiments, the 4,6-bis(benzylthio)hexanoic acid or pharmaceutically acceptable salt thereof is administered as an IV infusion over two hours via a central venous catheter. Pharmaceutical Composition

[00046] Any suitable pharmaceutical composition may be used to administer the 4,6- bis(benzylthio)hexanoic acid or pharmaceutically acceptable salt thereof to the patient. In combination therapy, the therapeutic agents may be administered together in the same pharmaceutical composition (e.g., fixed dose combination) or separately in different pharmaceutical compositions. There is a wide variety of suitable formulations of pharmaceutical compositions of the present invention (see, e.g., Remington: The Science and Practice of Pharmacy , 20th ed., Gennaro et al. Eds., Lippincott Williams and Wilkins, 2000). In certain embodiments, the 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically acceptable salt thereof is administered in a pharmaceutical composition that is a dry oral dosage form. In certain embodiments, the pharmaceutical composition is an oral dosage form chosen from tablet, pill, capsule, caplet, powder, granule, solution, suspension, and gel. Oral dosage forms may include pharmaceutically acceptable excipients, such as carriers, diluents, stabilizers, plasticizers, binders, glidants, disintegrants, bulking agents, lubricants, plasticizers, colorants, film formers, flavoring agents, preservatives, dosing vehicles, and any combination of any of the foregoing.

[00047] The pharmaceutical composition will generally include at least one inert excipient. Excipients include pharmaceutically compatible binding agents, lubricants, wetting agents, disintegrants, and the like. Tablets, pills, capsules, troches and the like can contain any of the following excipients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a dispersing agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. When the dosage unit form is a capsule, it can contain a liquid excipient such as a fatty oil. In addition, dosage unit forms can contain various other materials that modify the physical form of the dosage unit, for example, coatings of sugar, shellac, or enteric agents. Further, a syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes, colorings, and flavorings. In certain embodiments, the pharmaceutical composition comprises an excipient in an amount of about 5% to about 99%, such as about 10% to about 85%, by weight of the composition, with the therapeutic agent comprising the remainder. In certain embodiments, pharmaceutically acceptable excipients comprise about 20% to about 80% of the total weight of the composition. In certain embodiments, the pharmaceutical composition comprises the therapeutic agent in an amount of at least about 40% by weight of the composition, with one or more excipients comprising the remainder. In certain embodiments, the pharmaceutical composition comprises the therapeutic agent in an amount of at least about 50% by weight of the composition. In certain embodiments, the pharmaceutical composition comprises the therapeutic agent in an amount of at least about 60% by weight of the composition. In certain embodiments, the pharmaceutical composition comprises the therapeutic agent in an amount of at least about 70% by weight of the composition. In certain embodiments, the pharmaceutical composition comprises the therapeutic agent in an amount of at least about 80% by weight of the composition. In certain embodiments, the pharmaceutical composition comprises the therapeutic agent in an amount of at least about 90% by weight of the composition.

[00048] Diluents for solid compositions include, but are not limited to, microcrystalline cellulose (e.g. AVICEL®), microfme cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g. Eudragit), potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc.

[00049] Binders for solid pharmaceutical compositions include, but are not limited to, acacia, tragacanth, sucrose, glucose, alginic acid, carbomer (e.g. Carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. KLUCEL®), hydroxypropyl methyl cellulose (e.g. METHOCEL®), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g. KOLLIDON®, PLASDONE®), pregelatinized starch, sodium alginate and starch. In certain embodiments, the pharmaceutical composition comprises a binder in an amount of about 0.5% to about 25%, such as about 0.75% to about 15%, by weight of the composition. In certain embodiments, the pharmaceutical composition comprises a binder in an amount of about 1% to about 10% by weight of the composition.

[00050] The dissolution rate of a compacted solid pharmaceutical composition in a patient's stomach may be increased by the addition of a disintegrant to the composition. Disintegrants include, but are not limited to, alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g. AC -DI-SOL®, PRIMELLOSE®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g. KOLLIDON®, POLYPLASDONE®), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g. EXPLOTAB®) and starch. In certain embodiments, the pharmaceutical composition comprises a disintegrant in an amount of about 0.2% to about 30%, such as about 0.2% to about 10%, by weight of the composition. In certain embodiments, the pharmaceutical composition comprises a disintegrant in an amount of about 0.2% to about 5% by weight of the composition.

[00051] The pharmaceutical composition optionally comprises one or more pharmaceutically acceptable wetting agents. Such wetting agents are preferably selected to maintain the API in close association with water, a condition that is believed to improve bioavailability of the composition. Non-limiting examples of surfactants that can be used as wetting agents include quaternary ammonium compounds, for example benzalkonium chloride, benzethonium chloride and cetylpyridinium chloride, dioctyl sodium sulfosuccinate, polyoxyethylene alkylphenyl ethers, for example nonoxynol 9, nonoxynol 10, and octoxynol 9, poloxamers (polyoxyethylene and polyoxypropylene block copolymers), polyoxyethylene fatty acid glycerides and oils, for example polyoxyethylene, caprylic/capric mono- and diglycerides (e.g., Labrasol™ of Gattefosse), polyoxyethylene castor oil and polyoxyethylene hydrogenated castor oil; polyoxyethylene alkyl ethers, for example polyoxyethylene cetostearyl ether, polyoxyethylene fatty acid esters, for example polyoxyethylene stearate, polyoxyethylene sorbitan esters, for example polysorbate 20 and polysorbate 80 (e.g., Tween™ 80 of ICI), propylene glycol fatty acid esters, for example propylene glycol laurate (e.g., Lauroglycol™ of Gattefosse), sodium lauryl sulfate, fatty acids and salts thereof, for example oleic acid, sodium oleate and triethanolamine oleate, glyceryl fatty acid esters, for example glyceryl monostearate, sorbitan esters, for example sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate and sorbitan monostearate, tyloxapol, and mixtures thereof. In certain embodiments, the pharmaceutical composition comprises a wetting agent in an amount of about 0.25% to about 15%, such as about 0.4% to about 10%, by weight of the composition. In certain embodiments, the pharmaceutical composition comprises a wetting agent in an amount of about 0.5% to about 5% by weight of the composition. In certain embodiments, the pharmaceutical composition comprises a wetting agent that is an anionic surfactant. In certain embodiments, the pharmaceutical composition comprises sodium lauryl sulfate as a wetting agent. In certain embodiments, the pharmaceutical composition comprises sodium lauryl sulfate in an amount of about 0.25% to about 7%, such as about 0.4% to about 4%, by weight of the composition. In certain embodiments, the pharmaceutical composition comprises sodium lauryl sulfate in an amount of about 0.5% to about 2% by weight of the composition.

[00052] Lubricants (e.g., anti-adherents or glidants) can be added to improve the flow properties of solid compositions and/or to reduce friction between the composition and equipment during compression of tablet formulations. Excipients that may function as lubricants include, but are not limited to, colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate. Suitable lubricants further include glyceryl behapate (e.g., Compritol™ 888 of Gattefosse); stearic acid and salts thereof, including magnesium, calcium and sodium stearates; zinc stearate; glyceryl monostearate; glyceryl palmitostearate; hydrogenated castor oil; hydrogenated vegetable oils (e.g., Sterotex™ of Abitec); waxes; boric acid; sodium benzoate; sodium acetate; sodium stearyl fumarate; sodium fumarate; sodium chloride; DL-leucine; PEG (e.g., Carbowax™ 4000 and Carbowax™ 6000 of the Dow Chemical Company); sodium oleate; sodium lauryl sulfate; and magnesium lauryl sulfate. In certain embodiments, the pharmaceutical compositions comprises a lubricant in an amount of about 0.1% to about 10%, such as about 0.2% to about 8%, by weight of the composition. In certain embodiments, the pharmaceutical composition comprises a lubricant in an amount of about 0.25% to about 5% by weight of the composition. In certain embodiments, the pharmaceutical composition comprises magnesium stearate as a lubricant. In certain embodiments, the pharmaceutical composition comprises colloidal silicon dioxide. In certain embodiments, the pharmaceutical composition comprises talc. In certain embodiments, the composition comprises magnesium stearate or talc in an amount of about 0.5% to about 2% by weight of the composition.

[00053] Flavoring agents and flavor enhancers make the dosage form more palatable to the patient. Common flavoring agents and flavor enhancers for pharmaceutical products that may be included in the composition of the present invention include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid ethyl maltol, and tartaric acid.

[00054] Compositions may also be colored using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level. The formulations of the invention may be buffered by the addition of suitable buffering agents. [00055] In certain embodiments of the present invention, the 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof may be formulated as a pharmaceutically-acceptable oil; liposome; oil-water or lipid-oil-water emulsion or nanoemulsion; or liquid. To facilitate such formulations, the 4,6-bis(benzylthio)hexanoic acid or pharmaceutically acceptable salt thereof may be combined with a pharmaceutically-acceptable excipient therefor.

[00056] As described in detail below, the pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation.

[00057] Further examples of pharmaceutical formulations suitable for administration of a 4,6- bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof are described in U.S. Patent No. 8,263,653, the entire disclosure of which is incorporated by reference herein.

[00058] Methods of preparing pharmaceutical formulations or pharmaceutical compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[00059] Pharmaceutical compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[00060] In certain embodiments, one or more of the therapeutic agents are administered by intraparenteral administration. In certain other embodiments, one or more of the therapeutic agents are formulated for inhalational, oral, topical, transdermal, nasal, ocular, pulmonary, rectal, transmucosal, intravenous, intramuscular, subcutaneous, intraperitoneal, intrathoracic, intrapleural, intrauterine, intratumoral, or infusion methodologies or administration, or combinations of any thereof, in the form of aerosols, sprays, powders, gels, lotions, creams, suppositories, ointments, and the like. As indicated above, if such a formulation is desired, other additives known in the art may be included to impart the desired consistency and other properties to the formulation.

[00061] In certain embodiments, the pharmaceutical composition of the present invention is a unit dose composition. In certain embodiments, the pharmaceutical composition contains about 1 mg to about 5000 mg of the 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof. In certain embodiments, the pharmaceutical composition contains about 100 mg to about 3000 mg of the 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof. In certain embodiments, the pharmaceutical composition contains about 200 mg to about 2000 mg of the 4,6- bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof. In certain embodiments, the pharmaceutical composition contains about 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg, 2000 mg, 2500 mg, or 3000 mg of the 4,6- bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof. In certain embodiments, the pharmaceutical composition contains about 300 mg, 500 mg, 700 mg, or 1000 mg of the 4,6- bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof.

[00062] In certain embodiments, the pharmaceutical composition of the present invention comprises an emulsion, particle, or gel as described in U.S. Patent No. 7,220,428. In certain embodiments, the pharmaceutical composition is a solid or liquid formulation having from about 0.1% to about 75% w/w lipids or fatty acid components. In certain embodiments, the formulation contains about 0.1% to about 15% w/v lipids and fatty acid components. In certain embodiments, the fatty acid component comprises saturated or unsaturated C4, C5, C6, C7, C8, C9, CIO, Cl 1, or C12 fatty acids and/or salts of such fatty acids. Lipids may include cholesterol and analogs thereof.

[00063] In certain embodiments, the pharmaceutical composition of the 4,6- bis(benzylthio)hexanoic acid comprises triethanolamine and 4,6-bis(benzylthio)hexanoic acid in a mole ratio of triethanolamine to 4,6-bis(benzylthio)hexanoic acid of about 10:1 to about 1:10. In certain embodiments, the mole ratio of triethanolamine to 4,6-bis(benzylthio)hexanoic acid is about 10:1 to about 5:1. In certain embodiments, the mole ratio of triethanolamine to 4,6- bis(benzylthio)hexanoic acid is about 8:1. In certain embodiments, the pharmaceutical composition comprises a 50 mg/mL solution of a 4,6-bis(benzylthio)hexanoic acid in 1M aqueous triethanolamine. In certain embodiments, the pharmaceutical composition comprises a solution of a 4,6-bis(benzylthio)hexanoic acid in 1M aqueous triethanolamine diluted from 50 mg/mL to as low as 12.5 mg/mL with sterile aqueous 5% dextrose for injection (D5W). In certain embodiments, the pharmaceutical composition comprises a solution of a 4,6-bis(benzylthio)hexanoic acid in 1M aqueous triethanolamine diluted from 50 mg/mL to about 12.5 mg/mL with sterile aqueous 5% dextrose for injection (D5W).

Dosing Amounts & Schedules

[00064] The 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof may be administered to the patient in a therapeutically effective dose according to any suitable schedule. The therapeutically effective dose and schedule will vary based on the cancer being treated and can be readily determined by those of ordinary skill in the art in view of the 6,8-bis-benzylthio- octanoic acid doses and schedules used in the prior art when administered alone or in combination with other agents, the relative potencies and pharmacokinetics of the compounds, as well as the guidance provided herein. In certain embodiments, the dose is the maximum tolerated dose.

[00065] In certain embodiments, the 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 25 mg/m² to about 5000 mg/m². In certain embodiments, the 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 50 mg/m² to about 4000 mg/m². In certain embodiments, the first 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 100 mg/m² to about 3000 mg/m². In certain embodiments, the 4,6- bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 150 mg/m² to about 3000 mg/m². In certain embodiments, the 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 250 mg/m² to about 2500 mg/m². In certain embodiments, the first 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 500 mg/m² to about 2000 mg/m². In certain embodiments, the 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 25 mg/m². In certain embodiments, the 4,6- bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 500 mg/m². In certain embodiments, the 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 100 mg/m². In certain embodiments, the 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 150 mg/m². In certain embodiments, the 4,6- bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 200 mg/m². In certain embodiments, the 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 250 mg/m². In certain embodiments, the 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 300 mg/m². In certain embodiments, the 4,6- bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 350 mg/m². In certain embodiments, the 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 400 mg/m². In certain embodiments, the 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 450 mg/m². In certain embodiments, the 4,6- bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 500 mg/m². In certain embodiments, the 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 600 mg/m². In certain embodiments, the 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 700 mg/m². In certain embodiments, the 4,6- bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 800 mg/m². In certain embodiments, the 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 900 mg/m². In certain embodiments, the 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 1000 mg/m². In certain embodiments, the 4,6- bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 1100 mg/m². In certain embodiments, the 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 1200 mg/m². In certain embodiments, the 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 1300 mg/m². In certain embodiments, the 4,6- bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 1400 mg/m². In certain embodiments, the 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 1500 mg/m². In certain embodiments, the 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 1600 mg/m². In certain embodiments, the 4,6- bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 1700 mg/m². In certain embodiments, the 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 1800 mg/m². In certain embodiments, the 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 1900 mg/m². In certain embodiments, the 4,6- bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 2000 mg/m². In certain embodiments, the 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 2500 mg/m². In certain embodiments, the 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 3000 mg/m².

[00066] In certain embodiments, the 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 1 mg to about 10,000 mg. In certain embodiments, the 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 10 mg to about 7,500 mg. In certain embodiments, the 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 100 mg to about 5,000 mg. In certain embodiments, the 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 200 mg to about 4,000 mg. In certain embodiments, the 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 300 mg to about 3,000 mg. In certain embodiments, the 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 400 mg to about 2,500 mg. In certain embodiments, the 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 500 mg to about 2,000 mg. In certain embodiments, the 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 100 mg. In certain embodiments, the 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 200 mg. In certain embodiments, the 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 300 mg. In certain embodiments, the 4,6- bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 400 mg. In certain embodiments, the 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 500 mg. In certain embodiments, the 4,6- bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 600 mg. In certain embodiments, the 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 700 mg. In certain embodiments, the 4,6- bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 800 mg. In certain embodiments, the 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 900 mg. In certain embodiments, the 4,6- bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 1,000 mg. In certain embodiments, the 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 1,250 mg. In certain embodiments, the 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 1,500 mg. In certain embodiments, the 4,6- bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 1,750 mg. In certain embodiments, the 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 2,000 mg. In certain embodiments, the 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 2,500 mg. In certain embodiments, the 4,6- bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 3,000 mg. In certain embodiments, the 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 3,500 mg. In certain embodiments, the 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 4,000 mg. In certain embodiments, the 4,6- bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 4,500 mg. In certain embodiments, the 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 5,000 mg. In certain embodiments, the 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 6,000 mg. In certain embodiments, the 4,6- bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 7,000 mg. In certain embodiments, the 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 8,000 mg. In certain embodiments, the 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 9,000 mg. In certain embodiments, the 4,6- bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered at a daily dose of about 10,000 mg.

[00067] The daily dose of 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof may be administered as one dose or divided into two or more doses - e.g., b.i.d. (two times a day), t.i.d. (three times a day), or q.i.d. (four times a day). At higher daily doses and/or when administered orally or subcutaneously, it will often be beneficial to administer the daily dose of 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof b.i.d., t.i.d., or q.i.d. Splitting the daily dose may improve efficacy by prolonging exposure time and may also improve safety by reducing peak plasma concentration.

[00068] The 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof may be administered pursuant to a treatment schedule that includes days in which a dose of 4,6- bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered and days in which a dose of 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is not administered. For example, the 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof may be administered pursuant to a schedule in which 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered during the early days of a cycle and then not administered during the latter portion of the cycle. In certain embodiments, the 4,6- bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered on days 1-5 of a 28 day cycle. In certain embodiments, the 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered on days 1, 8, and 15 of a four week cycle. In certain embodiments, the 4,6- bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered on days 1 and 3 of a two week cycle. In certain embodiments, the 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered on days 1-5 of a three week cycle. In certain embodiments, the 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered on days 1-5 of a two week cycle. In certain embodiments, the 4,6- bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered on days 1-3 of a three week cycle. In certain embodiments, the 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered on days 1-3 of a two week cycle. In certain embodiments, the 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered every day. In certain embodiments, the 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered every other day. In certain embodiments, the 4,6- bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered three days per week. In certain embodiments, the 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered two days per week. In certain embodiments, the 4,6- bis(benzylthio)hexanoic acid or a pharmaceutically salt thereof is administered one day per week. [00069] In certain embodiments, the dosing cycle is repeated at least once. In certain embodiments, the method of the present invention comprises treatment with 5 cycles or more. In certain embodiments, the method of the present invention comprises treatment with 6 cycles or more. In certain embodiments, the method of the present invention comprises treatment with 7 cycles or more. In certain embodiments, the method of the present invention comprises treatment with 8 cycles or more. In certain embodiments, the method of the present invention comprises treatment with 9 cycles or more. In certain embodiments, the method of the present invention comprises treatment with 10 cycles or more.

Safety & Efficacy Features

[00070] The therapeutic method of the present invention may be further characterized by the efficacy and safety of the treatment. Preferably, the method provides an acceptable safety profile, with the benefit of treatment outweighing the risk. When tested in a phase II or phase III clinical trial of at least 10 patients with pancreatic cancer, the method of the present invention preferably provides an overall response rate of at least about 10%, a duration of response of at least about 1 month, progression-free survival (PFS) of at least about 1 month, and/or overall survival (OS) of at least about 1 month. Preferably, the phase II or phase III clinical trial comprises at least 15 patients. More preferably, the phase II or phase III clinical trial comprises at least 20 patients.

More preferably, the phase II or phase III clinical trial comprises at least 25 patients. More preferably, the phase II or phase III clinical trial comprises at least 50 patients. More preferably, the phase II or phase III clinical trial comprises at least 100 patients. More preferably, the phase II or phase III clinical trial comprises at least 200 patients. More preferably, the phase II or phase III clinical trial comprises at least 300 patients. More preferably, the phase II or phase III clinical trial comprises at least 400 patients. More preferably, the phase II or phase III clinical trial comprises at least 500 patients. Preferably, the method of the present invention provides an overall response rate of at least about 20% in patients. More preferably, the method of the present invention provides an overall response rate of at least about 30%. More preferably, the method of the present invention provides an overall response rate of at least about 40%. More preferably, the method of the present invention provides an overall response rate of at least about 50%. More preferably, the method of the present invention provides an overall response rate of at least about 60%. More preferably, the method of the present invention provides an overall response rate of at least about 70%. More preferably, the method of the present invention provides an overall response rate of at least about 80%. More preferably, the method of the present invention provides an overall response rate of at least about 90%. Preferably, the method of the present invention provides a duration of response, PFS, and/or OS of at least about 2 months. Preferably, the method of the present invention provides a duration of response, PFS, and/or OS of at least about 3 months. Preferably, the method of the present invention provides a duration of response, PFS, and/or OS of at least about 4 months. Preferably, the method of the present invention provides a duration of response, PFS, and/or OS of at least about 5 months. Preferably, the method of the present invention provides a duration of response, PFS, and/or OS of at least about 6 months. Preferably, the method of the present invention provides a duration of response, PFS, and/or OS of at least about 7 months. Preferably, the method of the present invention provides a duration of response, PFS, and/or OS of at least about 8 months. Preferably, the method of the present invention provides a duration of response, PFS, and/or OS of at least about 9 months. Preferably, the method of the present invention provides a duration of response, PFS, and/or OS of at least about 10 months. Preferably, the method of the present invention provides a duration of response, PFS, and/or OS of at least about 11 months. Preferably, the method of the present invention provides a duration of response, PFS, and/or OS of at least about 12 months. Preferably, the method of the present invention provides a duration of response, PFS, and/or OS of at least about 14 months. Preferably, the method of the present invention provides a duration of response, PFS, and/or OS of at least about 16 months. Preferably, the method of the present invention provides a duration of response, PFS, and/or OS of at least about 18 months. Preferably, the method of the present invention provides a duration of response, PFS, and/or OS of at least about 20 months. Preferably, the method of the present invention provides a duration of response, PFS, and/or OS of at least about 24 months. In certain embodiments, the overall response rate, duration of response, and progression-free survival mentioned above are measured in a phase II clinical trial. In certain embodiments, the overall response rate, duration of response, and progression-free survival mentioned above are measured in a phase III clinical trial.

[00071] The therapeutic method may be further characterized according to the effect of the treatment, such as (i) a reduction in the size of at least one solid tumor in the patient, and/or (ii) reduction in the number of solid tumors in the patient. Accordingly, in certain embodiments, the therapeutic method is characterized by at least a 20% reduction in the size of at least one solid tumor in the patient. In certain other embodiments, there is at least a 35% reduction in the size of at least one solid tumor in the patient. In certain other embodiments, there is at least a 50% reduction in the size of at least one solid tumor in the patient. In certain other embodiments, there is at least a 75% reduction in the size of at least one solid tumor in the patient. In certain embodiments, there is at least a 20% reduction in the number of solid tumors in the patient. In certain other embodiments, there is at least a 35% reduction in the number of solid tumors in the patient. In yet other embodiments, there is at least a 50% reduction in the number of solid tumors in the patient. In yet other embodiments, there is at least a 75% reduction in the number of solid tumors in the patient.

[00072] Another aspect of the invention provides for the use of a compound described herein in the manufacture of a medicament. In certain embodiments, the medicament is for treating a disorder described herein, such as cancer.

[00073] Another aspect of the invention provides for the use of a compound described herein for treating a medical disorder, such as a medical disorder described herein ( e.g ., cancer).

III. Medical Kits

[00074] Another aspect of the invention provides medical kits containing a therapeutic agent and/or pharmaceutical composition described herein, along with instructions for using the kits to treat a disorder described herein. In certain embodiments, the medical kit comprises (i) 4,6- bis(benzylthio)hexanoic acid or a pharmaceutically acceptable salt thereof, and (ii) instructions for treating cancer in a patient. In certain embodiments, the medical kit comprises (i) 4,6- bis(benzylthio)hexanoic acid or a pharmaceutically acceptable salt thereof, (ii) an additional therapeutic agent to treat cancer, and (iii) instructions for treating cancer in a patient. The medical kit may be further characterized according to one or more of the features described herein in connection with the Therapeutic Applications herein.

EXAMPLES

[00075] The invention now being generally described, will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention. Example 1 - In Vitro Anti-cancer Activity of 4,6-Bis(benzylthio)hexanoic Acid Towards H460, BxPC-3, SF539, AsPC-1, HT-29, COLO 205, and SW620 Cells

[00076] The anti-cancer activity of 4,6-bis(benzylthio)hexanoic acid was tested in an in vitro assay for activity against H460, BxPC-3, SF539, AsPC-1, HT-29, COLO 205, and SW620 cells. Experimental procedures and results are described below.

Part I - Experimental Procedures

[00077] 4,6-Bis(benzylthio)hexanoic acid may be purchased from commercial sources or prepared according to known procedures, such as described in Example 17 of U.S. Patent 10,246,444.

[00078] Human pancreatic cancer (BxPC-3, AsPC-1), human non-small cell lung carcinoma (H460), and human colon cancer (HT-29, COLO 205, SW620) cell lines were obtained from American Type Cell Culture, Manassas, VA. Human glioblastoma (SF539) cells were obtained from the National Cancer Institute (NCI), Fredrick, MD. All tumor cells were maintained at 37°C in a humidified atmosphere with 5% CO2 in T75 tissue culture flasks (except SW620), containing a)

10 mL RPMI1640 (BxPC-3, H460, SF539, COLO205), b) 10 mL of DMEM (AsPC-1), c) 10 mL McCoy (HT-29), or d) 10 mL L-15 (SW620) media, each containing L-glutamine (2 mM), fetal bovine serum (FBS, 10%), penicillin 100 IU/mL and streptomycin (100 pg/mL). SW620 cells were maintained at 37°C in a non-CCh incubator. The cells were split at a ratio of 1 :5 every 4-5 days by using trypsin and were re-suspended in fresh media in new flasks as mentioned above, in new flasks. Cells were harvested for experiments at 70-90% confluence.

[00079] Cancer cells were seeded (4,000 per well for H460 cells, 5,000 per well for AsPC-1, HT-29, COLO 205, and SW620 cells, and 6,000 per well for BxPC-3 and SF539 cells) in media containing 5% FBS (BxPC-3, H460, SF539), or 0.5% FBS, 25 mM glucose, and 2 mM glutamine (AsPC-1, HT-29, COLO 205, SW620). Cancer cell were treated in RPMI media containing 5.8 mM glucose, 2 mM glutamine and 10% FBS for 72 hours (AsPC-1, HT-29, COLO 205, SW620). The cell-kill activity of 4,6-bis(benzylthio)hexanoic acid was assayed at concentrations of 100, 50, 25, 12.5, 6.25, and 3.125 micromolar (BxPC-3, H460, SF539) or 300, 150, 75, 37.5, 18.75, 9.375, 4.6875, and 2.3 mM (AsPC-1, HT-29, COLO 205, SW620) along with a vehicle control. The cells were treated for 24 hours (BxPC-3, H460, SF539) or 72 hours (AsPC-1, HT-29, COLO 205, SW620) and the number of viable cells was determined by using the CELLTITERGLO® Assay (Promega, Inc., Fitchburg, WI). CELLTITERGLO® reagent (100 mE per well (BxPC-3, H460, SF539) or 60 pL per well (AsPC-1, HT-29, COLO 205, SW620)) was added and the cells were lysed for 5 minutes at room temperature, according to the instructions. The luminescence was measured using a FLUOstar OPTIMA plate reader (BMG Labtech Inc.) (BxPC-3, H460, SF539) or Micro plate reader (Molecular Device) (AsPC-1, HT-29, COLO 205, SW620). For BxPC-3, H460, and SF539 a separate set of cells was seeded at the same time in a clear 96 well plate and observed under the microscope at 24 hours, following addition of 4,6-bis(benzylthio)hexanoic acid to estimate the amount of cells present after treatment. Results were calculated using the following equation: % growth = (mean luminescence of the test article) x 100 / (mean luminescence of the non-treated article). IC50 values were calculated with SigmaPlot 11 (BxPC-3, H460, SF539) or Graph pad prism (AsPC-1, HT-29, COLO 205, SW620) software.

Part II - Results

[00080] IC50 values for 4,6-bis(benzylthio)hexanoic acid against H460, BxPC-3, SF539, AsPC- 1, HT-29, COLO 205, and SW620 tumor cell lines are shown in the following table, where results are presented as mean ± standard of deviation from three independent experiments with n = 6 in each group (BxPC-3, H460, SF539) or mean from one independent experiment with n = 2 in each group (AsPC-1, HT-29, COLO 205, SW620).

Example 2 - Anti-cancer Activity of 4,6-Bis(benzylthio)hexanoic acid in CDl-Nu/Nu Mice with NCI-H460 Non-small Cell Lung Carcinoma (NSCLC) Human Xenograft

[00081] The anti-cancer activity of 4,6-bis(benzylthio)hexanoic acid was tested in CDl-Nu/Nu mice having aNCI-H460 non-small cell lung carcinoma (NSCLC) human xenograft. Experimental procedures and results are described below.

Part I - Experimental Procedures

[00082] CDl-Nu/Nu female mice were obtained from Charles River Laboratories, Wilmington, MA. Mice were housed at five per cage in a micro isolator room, with light-dark cycles of 12 hours each. Animals were provided food (Purina Rodent Chow) and distilled sterile-filtered water (pH 7) ad libitum. The mice (5-7 weeks) were inoculated subcutaneously in the right flank with 2xl0⁶ H460 NSCLC cells. Test compound 4,6-bis(benzylthio)hexanoic acid was constituted to a stock solution of 50 mg/mL in triethanolamine (1M in water), and stored at 2-8 degrees Celsius. The stock solution was further diluted with 5% dextrose for dosing.

[00083] Starting on the 12^th day after inoculation (tumor volume - 170 mm³), the test compound was administered at 25 mg/kg IP, once daily, 3 times per week for 3 consecutive weeks (n = 5). Another group of mice (5% dextrose only, n = 5) was used as the control. Dose volumes for both groups were 2.0 mL.

[00084] Anti-tumor efficacy was assessed based on body weight and tumor growth inhibition. Body weight was recorded once weekly and tumor size was assessed up to twice weekly. Animal care and euthanasia were performed according to Institutional Animal Care and Use Committee (IACUC) regulations. Results were analyzed with one-way Analysis of Variance (ANOVA), and graphed using Excel.

Part II - Results

[00085] Average tumor volumes in mice bearing a NCI-H460 NSCLC human xenograft treated with 4,6-bis(benzylthio)hexanoic acid at 25 mg/kg (IP) for three weeks are provided in the graph depicted in Figure 1. Mean body weight values of the mice during the course of the study for mice treated with 4,6-bis(benzylthio)hexanoic acid and for mice treated with dextrose solution are shown in the graph depicted in Figure 2. Sample size was 5 mice per group. Results are presented as mean ± standard deviation.

INCORPORATION BY REFERENCE

[00086] The entire disclosure of each of the patent documents and scientific articles referred to herein is incorporated by reference for all purposes.

EQUIVALENTS

[00087] The description above describes multiple aspects and embodiments of the invention, including therapeutic applications, treatment methods, and pharmaceutical compositions. The patent application specifically contemplates all combinations and permutations of the aspects and embodiments.

Claims

Claims:

1. A method of treating cancer in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and 4,6-bis(benzylthio)hexanoic acid or a pharmaceutically acceptable salt thereof to treat the cancer.

2. The method of claim 1, wherein the cancer is a carcinoma, sarcoma, or myeloma.

3. The method of claim 1, wherein the cancer is lymphoma.

4. The method of claim 1, wherein the cancer is leukemia.

5. The method of claim 1, wherein the cancer is a solid tumor.

6. The method of claim 1, wherein the cancer is bladder cancer, colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, esophagus cancer, lung cancer, stomach cancer, cervical cancer, testicular cancer, skin cancer, rectal cancer, thyroid cancer, kidney cancer, uterus cancer, or liver cancer.

7. The method of claim 1, wherein the cancer is an acoustic neuroma, oligodendroglioma, meningioma, neuroblastoma, or retinoblastoma.

8. The method of claim 1, wherein the cancer is Burkitf s lymphoma.

9. The method of claim 1, wherein the cancer is a T-cell lymphoma.

10. The method of claim 1, wherein the cancer is acute lymphocytic leukemia or acute myeloid leukemia.

11. The method of claim 1, wherein the cancer is chronic lymphocytic leukemia or chronic myeloid leukemia.

12. The method of claim 1, wherein the cancer is myelodysplastic syndrome or hairy cell leukemia.

13. The method of any one of claims 1-12, wherein the pharmaceutical composition is administered orally to the patient.

14. The method of any one of claims 1-12, wherein the pharmaceutical composition is administered by intravenous injection to the patient.

15. The method of any one of claims 1-14, wherein the patient is a human.

16. The method of any one of claims 1-15, wherein the patient is refractory to a standard of care anti-cancer medicine.

17. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and 4,6- bis(benzylthio)hexanoic acid or a pharmaceutically acceptable salt thereof.

18. The pharmaceutical composition of claim 17, wherein the pharmaceutical composition is in the form of a tablet or capsule.

19. The pharmaceutical composition of claim 17, wherein the pharmaceutical composition is in the form of an aqueous mixture.

20. The pharmaceutical composition of claim 17, wherein the pharmaceutical composition is in the form of an isotonic aqueous mixture for intravenous injection.