KR20210105923A - Methods and compositions for treating cancer using 6,8-bis-benzylthio-octanoic acid and an autophagy inhibitor - Google Patents

Abstract

The present invention provides a method and composition for treating cancer by implanting a therapeutically effective amount of 6,8-bis-benzylthio-octanoic acid and an autophagy inhibitor in a patient in need thereof.

Description

Methods and compositions for treating cancer using 6,8-bis-benzylthio-octanoic acid and an autophagy inhibitor

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is filed on December 20, 2018 in United States Provisional Patent Application Serial Nos. 62/782,928; U.S. Provisional Patent Application Serial No. 62/793,667, filed January 17, 2019; U.S. Provisional Patent Application Serial No. 62/834,475, filed April 16, 2019; and priority to U.S. Provisional Patent Application Serial No. 62/854,599, filed May 30, 2019; The contents of each of these documents are incorporated herein by reference in their entirety.

Technical Field of the Invention

The present invention provides methods and compositions for treating cancer by administering 6,8-bis-benzylthio-octanoic acid and an autophagy inhibitor. The present invention further provides a method and composition for treating cancer other than clear cell sarcoma by administering 6,8-bis-benzylthio-octanoic acid and an autophagy inhibitor.

CPI-613 (6,8-bis-benzylthio-octanoic acid) is a first-in-class investigational small-molecule (lipoate analog), a common energy in many cancer cells Targets metabolic changes. CPI-613 has been evaluated in Phase I, Phase I/II and Phase II multiphase clinical studies and has been evaluated in pancreatic cancer, acute myeloid leukemia (AML), peripheral T-cell lymphoma (PTCL), Burkitt's lymphoma and myelodysplastic syndrome (MDS). It has been approved as an orphan drug class for treatment.

There is a need to improve the safety and efficacy of cancer treatment by CPI-613. The present invention addresses this need and provides other related advantages.

Summary of the present invention

The present invention provides methods and compositions for treating cancer in a human patient in need thereof by administering to the patient a therapeutically effective amount of 6,8-bis-benzylthio-octanoic acid and an autophagy inhibitor. The cancer may be relapsed or refractory. The cancer may be lymphoma, leukemia, carcinoma, sarcoma, melanoma, myeloma, brain or spinal cancer, blastoma, germ cell tumor, cancer of the pancreas, colorectal cancer, myelodysplastic syndrome, or cancer of the prostate. In certain embodiments, the cancer is lymphoma, leukemia, carcinoma, sarcoma, melanoma, or myeloma. In certain embodiments, the cancer is relapsed or refractory Hodgkin's lymphoma, including relapsed or refractory Hodgkin's lymphoma in a patient who has failed with brentuximab vedotin and a PD-1 inhibitor, relapsed or refractory T-cell non-Hodgkin's lymphoma, relapsed or refractory Burkitt's lymphoma, or high-grade B-cell lymphoma with rearranged MYC and BCL2 and/or BCL6.

The present invention further includes methods and compositions for treating cancer other than clear cell sarcoma in a human patient in need thereof by administering to the patient a therapeutically effective amount of 6,8-bis-benzylthio-octanoic acid and an autophagy inhibitor. do. The cancer may be relapsed or refractory. The cancer may be lymphoma, leukemia, carcinoma, non-clear cell sarcoma, melanoma, myeloma, brain or spinal cancer, blastoma, germ cell tumor, cancer of the pancreas, colorectal cancer, myelodysplastic syndrome, or cancer of the prostate. In certain embodiments, the cancer is lymphoma, leukemia, carcinoma, non-clear cell sarcoma, melanoma, or myeloma.

This aspect of the invention is described in more detail in conjunction with further embodiments in the detailed description that follows.

1 shows the induction of autophagy by 6,8-bis-benzylthio-octanoic acid in K562 and MFL2 AML cells. HBSS=Hanks' balanced salt solution.
2 shows in vitro treatment of K562 and OCI-AML3 cells with the combination of chloroquine and CPI-613. All concentrations listed are in μM.
3 shows the treatment of MFL2 syngeneic tumors in C57Bl/6 mice by the combination of CPI-613 and chloroquine.
4 shows in vitro treatment of MFL2 cells with the combination of metformin and CPI-613. All concentrations listed are in μM. Met=Metformin, CPI=CPI-613
5 shows the treatment of MFL2 syngeneic tumors in C57Bl/6 mice by the combination of metformin and CPI-613 (Met+CPI).
6 shows in vitro treatment of MFL2 cells with the combination of 2-deoxyglucose and CPI-613. CPI=CPI-613 (μM), 2DG=2-deoxyglucose (mM).
7 shows in vitro treatment of OCI-AML3 cells and MFL2 cells with a combination of chloroquine, 2-deoxyglucose and CPI-613.
8 shows in vitro treatment of PANC-1 cells with chloroquine, hydroxychloroquine or CPI-613 alone or in combination.
9 shows in vitro treatment of AsPC-1 cells with chloroquine, hydroxychloroquine or CPI-613 alone or in combination.
10 shows in vitro treatment of BxPC-3 cells with chloroquine, hydroxychloroquine or CPI-613 alone or in combination.
11 shows in vitro treatment of MIA PaCa-2 cells with chloroquine or CPI-613 alone or in combination.
12 shows in vitro treatment of CoLo 205 and LoVo cells with the combination of chloroquine and CPI-613.
13 shows in vitro treatment of SW620 and HT-29 cells with the combination of chloroquine and CPI-613.
14 shows in vitro treatment of H460 cells with the combination of chloroquine and CPI-613.
15 shows the anti-tumor efficacy of oral 6,8-bis-benzylthio-octanoic acid in human non-small cell lung cancer xenografts in mice.
Figure 16 shows the anti-tumor efficacy of oral 6,8-bis-benzylthio-octanoic acid in human pancreatic cancer xenografts in mice.
17 is either Eudragit L100 or hydroxypropyl methylcellulose acetate succinate (HPMCAS-M) (top and middle diffraction patterns, respectively), and crystalline 6,8-bis-benzylthio-octanoic acid (bottom diffraction pattern). An X-ray powder diffraction pattern of a solid amorphous dispersion formulation of 6,8-bis-benzylthio-octanoic acid is shown.

The present invention provides methods and compositions for treating cancer in a human patient in need thereof by administering to the patient a therapeutically effective amount of 6,8-bis-benzylthio-octanoic acid and an autophagy inhibitor. The present invention further provides methods and compositions for treating cancer other than clear cell sarcoma in a human patient in need thereof by administering to the patient a therapeutically effective amount of 6,8-bis-benzylthio-octanoic acid and an autophagy inhibitor. .

In the practice of the present invention, unless otherwise specified, conventional techniques in medical chemistry, pharmacology and biochemistry are employed. Various aspects of the invention are set forth in the sections below; Aspects of the invention described in one specific section will not be limited to any specific section.

I. Definition

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

As used herein, the terms ["a," "an," and "the"] mean "one or more" and include the plural unless the context makes it inappropriate.

의 화학적 구조를 갖는, 데비미스타트(devimistat) 또는 CPI-613로 알려진 화합물을 말한다.The term "6,8-bis-benzylthio-octanoic acid" means:

It refers to a compound known as devimistat or CPI-613, having the chemical structure of

Certain compounds contained in the compositions of the present invention may exist in certain geometric or stereoisomeric forms. The present invention covers all such, including cis- and trans-isomers, R- and S -enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof. Compounds are contemplated and are within the scope of the present invention.

As used herein, the term "patient" refers to a human in need of cancer treatment.

As used herein, the term "treating" refers to, for example, alleviating, reducing, controlling, ameliorating or eliminating a condition, disease, disorder, etc., or symptoms thereof, thereby ameliorating, stabilizing, or , including any effect that slows its progression. For example, treatment may include alleviating the symptoms of the disorder, or completely eliminating the disorder. As another example, treatment may include slowing the progression of a disease, preventing or delaying its recurrence, such as maintenance treatment for preventing or delaying recurrence.

"Therapeutically effective amount" refers to an amount of a compound sufficient to inhibit, stop or ameliorate the disorder or condition being treated in a particular patient or population of patients. For example, a therapeutically effective amount may be an amount of a drug sufficient for maintenance treatment to slow the progression of a disease, prevent or delay its recurrence, eg, prevent or delay recurrence. The therapeutically effective amount may be determined empirically in an experimental or clinical setting, or may be an amount required by the guidelines of the US Food and Drug Administration or an equivalent foreign agency for a specific disease and patient being treated. It will be appreciated that the determination of formulations, dosages and routes of administration is within the level of those of ordinary skill in the pharmaceutical and medical arts.

As used herein, the term "pharmaceutical composition" refers to the combination of an active agent with an inert or active excipient that renders the composition suitable for administration to humans.

As used herein, the phrase "pharmaceutically acceptable" means, within the scope of sound judgment, human tissue with acceptable toxicity, irritation, allergic reaction and other problems or complications proportional to a reasonable benefit/risk ratio. used to refer to a compound, substance, composition and/or formulation suitable for use in contact with

As used herein, the term "pharmaceutically acceptable excipient" refers to any standard pharmaceutical excipient suitable for use in humans. For examples of excipients, see, eg, Martin, Remington's Pharmaceutical Sciences, 15th ed., Mack Publ. Co., Easton, PA [1975]].

As used herein, the term “pharmaceutically acceptable salt” refers to any salt ( eg , acid or base) of a compound of the invention suitable for administration to humans. As is known to those skilled in the art, "salts" of the compounds of the present invention may be derived from acids and bases, either inorganic or organic. Examples of acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, ethanesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, and the like. Examples of bases include alkali metal ( eg , sodium) hydroxide, alkaline earth metal ( eg , magnesium) hydroxide, ammonia, and of formula NW ₃ compounds, including but not limited to, wherein W is C _1-4 alkyl and the like.

Additional examples of salts include salts prepared using ion pairing agents described in US Pat. No. 8,263,653, the entire contents of which are incorporated herein by reference. Other additional ionic binders are described in Handbook of Pharmaceutical Salts Properties, Selection and Use, UIPAC, Wiley-VCH, P.H. Stahl, ed.], the entire contents of which are incorporated herein by reference.

For therapeutic use, salts of the compounds of the present invention are considered pharmaceutically acceptable. However, salts of acids and bases that are not pharmaceutically acceptable may also find use, for example, in the preparation or purification of pharmaceutically acceptable compounds.

Throughout this specification, when compositions are described as having, including, comprising, or when processes and methods are described as having or comprising specific steps, in addition, when they are described as having or comprising specific steps, they additionally include essentially the described components. It is contemplated that there are compositions of the present invention comprising, or consisting of, processes and methods according to the present invention comprising essentially of or consisting of the steps described.

In general, compositions specified in percentages are by weight unless otherwise specified. Additionally, if a variable is not accompanied by a definition, the previous definition of that variable is used.

II. therapeutic application

The present invention provides methods and compositions for treating cancer in a human patient in need thereof, comprising administering to the patient a therapeutically effective amount of 6,8-bis-benzylthio-octanoic acid and an autophagy inhibitor. include The present invention further provides methods and compositions for treating non-clear cell sarcoma in a human patient in need thereof, said method comprising administering to the patient a therapeutically effective amount of 6,8-bis-benzylthio-octanoic acid and autophagy administering an inhibitor.

We found that upon exposure to CPI-613, cancer cells exhibited an increase in autophagy. Without wishing to be bound by theory, the inventors show that when CPI-613 disrupts the altered metabolic pathways of cancer cells, the cells begin to starve and respond by using autophagy to help supply their metabolic needs. hypothesized that Inclusion of an autophagy inhibitor in the treatment regimen inhibits the use of autophagy by cancer cells, thereby counteracting the action of CPI-613 and significantly improving efficacy.

type of cancer

In certain embodiments, the cancer is associated with changes in energy metabolism. In certain embodiments, the cancer exhibits an increase in autophagy when contacted with CPI-613. As used herein, the term “cancer” is intended to include myelodysplastic syndromes, and in certain embodiments of the invention, the cancer is myelodysplastic syndromes. In certain embodiments, the cancer is high risk myelodysplastic syndrome (MDS). In certain embodiments, the cancer is high risk MDS in a patient who has progressed and relapsed due to failure to respond to hypomethylating treatment.

The method may be further characterized according to the severity or type of cancer. In certain embodiments, the cancer is stage I or early cancer, where the cancer is small and in only one area. In certain embodiments, the cancer is stage II or III, where 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 cancer, wherein the cancer has spread to other parts of the body.

In certain embodiments, the cancer is stage I lymphoma, wherein the cancer is found in an area of one lymph node, or the cancer has invaded an extralymphatic organ or site but not the lymph node area. In certain embodiments, the cancer is stage II lymphoma, wherein the cancer is found in a site of two or more lymph nodes on the same side of the diaphragm, or the cancer involves one organ and its regional lymph nodes, and in other lymph node sites on the same side of the diaphragm with or without cancer In certain embodiments, the cancer is stage III lymphoma, wherein the cancer is in lymph nodes on both sides of the diaphragm. In certain embodiments, the cancer is stage IV lymphoma, wherein the cancer has spread beyond the lymph nodes to one or more organs.

In certain embodiments, the cancer is advanced or refractory. In certain embodiments, the cancer is metastatic. In certain embodiments, the cancer is recurrent or relapsed. In certain embodiments, the cancer is relapsed or refractory. In certain embodiments, the cancer has not been previously treated. In certain embodiments, the cancer has not previously received systemic treatment. In certain embodiments, the cancer has not previously received systemic or topical treatment with chemoradiation. In certain embodiments, the patient has not received a hematopoietic cell transplant. In certain embodiments, the patient has received a hematopoietic cell transplant.

In certain embodiments, the cancer is lymphoma. In certain embodiments, the cancer is T-cell lymphoma. In certain embodiments, the cancer is B-cell lymphoma. In certain embodiments, the cancer is mantle cell lymphoma. In certain embodiments, the cancer is leukemia. In certain embodiments, the cancer is 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 carcinoma. In certain embodiments, the cancer is a sarcoma. In certain embodiments, the cancer is not a sarcoma. In certain embodiments, the cancer is myeloma. In certain embodiments, the cancer is clear cell cancer. In certain embodiments, the cancer is not clear cell cancer. In certain embodiments, the cancer is clear cell sarcoma. In certain embodiments, the cancer is not clear cell sarcoma. In certain embodiments, the cancer is non-clear cell sarcoma. In certain embodiments, the cancer is clear cell carcinoma. In certain embodiments, the cancer is not a soft tissue cancer. In certain embodiments, the cancer is not clear cell carcinoma. In certain embodiments, the cancer is brain cancer or spinal cord cancer. In certain embodiments, the cancer is melanoma. In certain embodiments, the cancer is blastoma. In certain embodiments, the cancer is a germ cell tumor. In certain embodiments, the cancer is cancer of the pancreas. In certain embodiments, the cancer is metastatic pancreatic cancer. In certain embodiments, the cancer is locally advanced pancreatic cancer. In certain embodiments, the cancer is histologically or cytologically documented, measurable locally advanced pancreatic adenocarcinoma. In certain embodiments, the cancer is histologically or cytologically documented and measurable metastatic pancreatic adenocarcinoma. In certain embodiments, the cancer is histologically or cytologically documented, previously untreated, measurable locally advanced pancreatic adenocarcinoma. In certain embodiments, the cancer is histologically or cytologically documented, previously untreated, measurable metastatic pancreatic adenocarcinoma. In certain embodiments, the cancer is histologically or cytologically documented, measurable locally advanced pancreatic adenocarcinoma that has not previously received systemic treatment. In certain embodiments, the cancer is histologically or cytologically documented, measurable metastatic pancreatic adenocarcinoma that has not previously received systemic treatment. In certain embodiments, the cancer is measurable locally advanced pancreas, which has been documented histologically or cytologically and has not previously received systemic or local treatment with chemoradiation therapy. In certain embodiments, the cancer is measurable metastatic pancreatic adenocarcinoma, which has been documented histologically or cytologically and has not previously received systemic or topical treatment with chemoradiation. In certain embodiments, the cancer is locally advanced pancreatic adenocarcinoma. In certain embodiments, the cancer is metastatic pancreatic adenocarcinoma. In certain embodiments, the cancer is previously untreated, locally advanced pancreatic adenocarcinoma. In certain embodiments, the cancer is previously untreated metastatic pancreatic adenocarcinoma. In certain embodiments, the cancer is locally advanced pancreatic adenocarcinoma that has not previously received systemic treatment. In certain embodiments, the cancer is metastatic pancreatic adenocarcinoma, which has not previously received systemic treatment. In certain embodiments, the cancer is locally advanced pancreatic adenocarcinoma that has not previously received systemic or topical treatment with chemoradiation therapy. In certain embodiments, the cancer is pancreatic adenocarcinoma, which has not previously received systemic or topical treatment with chemoradiation therapy.

In certain embodiments, the cancer is cancer of the prostate. In certain embodiments, the cancer is castration resistant prostate cancer. In certain embodiments, the cancer is cancer of the lung. In certain embodiments, the cancer is non-small cell lung cancer. In certain embodiments, the cancer is cancer of the colon. In certain embodiments, the cancer is cancer of the rectum. In certain embodiments, the cancer is colorectal cancer. In certain embodiments, the cancer is cancer of the cervix. In certain embodiments, the cancer is a neuroendocrine tumor. In certain embodiments, the cancer is a gastrointestinal pancreatic neuroendocrine tumor. In certain embodiments, the cancer is cancer of the liver. In certain embodiments, the cancer is cancer of the uterus. In certain embodiments, the cancer is cancer of the cervix. In certain embodiments, the cancer is cancer of the bladder. In certain embodiments, the cancer is cancer of the kidney. In certain embodiments, the cancer is cancer of the breast. In certain embodiments, the cancer is cancer of the ovary.

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

General aspects of administering a therapeutic agent to a patient

Generally, a therapeutic agent—ie, 6,8-bis-benzylthio-octanoic acid and an autophagy inhibitor—is delivered to a patient in a therapeutically effective amount sufficient to treat the cancer. Treatment involves one or several administrations on the first or more days, and the dosage can be adjusted by the individual physician to achieve the desired effect. Preferably, the dosage of each agent should be sufficient to primarily interact with diseased cells, so that it should be relatively less detrimental to normal cells.

The dosage may be administered in the form of a single dose or in separate divided doses, such as once, twice, three times, or four times per day. In certain embodiments, the daily dosage is administered as a single dose. If the patient's response at a particular dose is insufficient, a higher or more frequent dose may be used depending on the degree of patient tolerance.

For the combination treatment of the present invention, each agent may be administered in a particular order and/or on the same or different days depending on the treatment cycle. For example, a dose of 6,8-bis-benzylthio-octanoic acid may be administered prior to administering an autophagy inhibitor, such as immediately prior to a treatment cycle, at the beginning of a specific day in a treatment cycle, or at an initial date in a treatment cycle, can be administered to the patient. In certain embodiments, the active agents may be administered on the same day as the treatment cycle, eg, co-administered simultaneously or immediately after each other. In certain embodiments, the dose of the autophagy inhibitor is administered prior to administering 6,8-bis-benzylthio-octanoic acid, such as immediately prior to a treatment cycle, at the beginning of a specific day in a treatment cycle, or on an initial day in a treatment cycle, administered to the patient. In certain embodiments, a treatment cycle may be repeated one or more times to maximize benefit to the patient.

6,8-bis-benzylthio-octanoic acid

6,8-Bis-benzylthio-octanoic acid may be administered in any suitable form, solid or liquid, including the free acid or salt. 6,8-Bis-benzylthio-octanoic acid may be crystalline, amorphous, or soluble in solution. In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered to the patient as a salt or ion pair. In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered to the patient as a salt or ion pair with triethanolamine. Exemplary ionic binders that may be used include, for example, tertiary amines (such as triethylamine or triethanolamine), other amines such as diethylamine, diethanolamine, monoethanolamine, mefenamic acid and tromethamine; and combinations thereof. In certain embodiments, the ionic binding agent is an organic Bronsted base. In another specific embodiment, the ionic binding agent is an amine compound. In another embodiment, the ionic binder is a monoalkylamine, dialkylamine, trialkylamine, amino-substituted aliphatic alcohol, hydroxymonoalkylamine, hydroxydialkylamine, hydroxytrialkylamine, amino-substituted heteroaliphatic alcohols, alkyldiamines, substituted alkyldiamines, or optionally substituted heteroaryl groups containing at least one ring nitrogen atom. In certain embodiments, the therapeutic agent is combined with 6,8-bis-benzylthio-octanoic acid as described in Berge et al., "Pharmaceutical salts," J. of Pharmaceutical Science , 1977; 66:1-19] or a salt of an ionic binder selected according to the guidelines of Handbook of Pharmaceutical salts Properties, Selection and Use, IUPAC, Wiley-VCH, PH Stahl, ed., the entire contents of which are herein incorporated by reference. incorporated by reference. Of particular note in the latter are ionic binders, without limitation, Table 5, p. 342 includes those listed.

Additional exemplary ionic binders include, for example, polyethyleneimine, polyglutamic acid, ammonia, L-arginine, benetamine benzathine, betaamine, calcium hydroxide, choline, theanol, diethanolamine (2,2'-iminobis). (ethanol)), diethylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylenediamine, N-methyl-glucamine, hydramine, 1H-imidazole, lysine, magnesium hydroxide, 4-(2- Hydroxyethyl)-morpholine, piperazine, potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidone, sodium hydroxide, triethanolamine (2,2',2"-nitrilotris (ethanol)), tromethamine, and zinc hydroxide.In another specific embodiment, the ionic binding agent is diisopropanolamine, 3-amino-1-propanol, meglumine, morpholine, pyridine, niacinamide, tris(hydroxymethyl) aminomethane, 2-((2-dimethylamino)ethoxy)ethanol, 2-(dimethylamino)ethanol, 1-(2-hydroxyethyl)pyrrolidone, or ammonium hydroxide. , the ionic binder is an alkali metal hydroxide or alkaline earth metal hydroxide, such as cesium hydroxide.

In certain embodiments, 6,8-bis-benzylthio-octanoic acid has a purity of at least about 50% (w/w). In certain embodiments, 6,8-bis-benzylthio-octanoic acid has a purity of at least about 60% (w/w). In certain embodiments, 6,8-bis-benzylthio-octanoic acid has a purity of at least about 70% (w/w). In certain embodiments, 6,8-bis-benzylthio-octanoic acid has a purity of at least about 80% (w/w). In certain embodiments, 6,8-bis-benzylthio-octanoic acid has a purity of at least about 90% (w/w). In certain embodiments, 6,8-bis-benzylthio-octanoic acid has a purity of at least about 95% (w/w). In certain embodiments, 6,8-bis-benzylthio-octanoic acid has a purity of at least about 96% (w/w). In certain embodiments, 6,8-bis-benzylthio-octanoic acid has a purity of at least about 97% (w/w). In certain embodiments, 6,8-bis-benzylthio-octanoic acid has a purity of at least about 98% (w/w). In certain embodiments, 6,8-bis-benzylthio-octanoic acid has a purity of at least about 99% (w/w).

autophagy inhibitors

The one or more autophagy inhibitors may be administered in any suitable form, including solid or liquid free acids or salts. Autophagy inhibitors may be crystalline, amorphous, or soluble in solution. In certain embodiments, the autophagy inhibitor is administered to the patient as a salt or ion pair. When the autophagy inhibitor is a basic compound such as chloroquine or hydroxychloroquine, it can be administered in ion-pairing with an inorganic or organic acid. Examples of acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, ethanesulfonic acid, formic acid , benzoic acid, malic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, and the like. In certain embodiments, the therapeutic agent is an autophagy inhibitor and is described in Berge et al., "Pharmaceutical salts," J. of Pharmaceutical Science , 1977; 66:1-19 or a salt with an ionic binder selected according to the guidelines of Handbook of Pharmaceutical salts Properties, Selection and Use, IUPAC, Wiley-VCH, PH Stahl, ed., the entire contents of which are herein incorporated by reference. Of particular note in the latter are ionic binders, without limitation Table 5, p. 342 includes those listed.

Any suitable autophagy inhibitor may be used. In certain embodiments, the autophagy inhibitor is 4-aminoquinoline, 3-methyladenine (3-MA, CAS#5142-23-4), MHY1485 (CAS#326914-06-1SP600125), 3-methyl-6-( 3-Methylpiperidin-1-yl)-3H-purine, 6-chloro-N-(1-ethylpiperidin-4-yl)-1,2,3,4-tetrahydroacridin-9 -amine, 4-(((1-(2-fluorophenyl)cyclopentyl)-amino)methyl)-2-((4-methylpiperazin-1-yl)methyl)phenol, 6-fluoro-N -[4-fluorobenzyl]quinazolin-4-amine, N-acetyl-L-cysteine, L-asparagine, N2,N4-dibenzylquinazoline-2,4-diamine, (2S,3S)-trans- Epoxysuccinyl-L-leucylamido-3-methylbutane ethyl ester, N-[6-(4-chlorophenoxy)hexyl]-N'-cyano-N"-piperidinyl-guanidine, leupeptin, 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one, 4,6-di-4-morpholinyl-N-(4-nitrophenyl)-1,3 ,5-triazin-2-amine, pepstatin A, 2-((5-bromo-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)oxy)- N-methylbenzamide, 6-fluoro-N-[(4-fluorophenyl)methyl]-4-quinazolinamine, thapsigargin, amodiaquine, artemisinin , mefloquine, primaquine, piperaquine, quinacrine, U0126, 3-methyladenine, bafilomycin A1, chloroquine, hydroxychloroquine, verteporfin ( verteporfin), LY294002, SB202190, SB203580, SC79 and wortmannin.In certain embodiments, the autophagy inhibitor is selected from chloroquine, hydroxychloroquine and verteporfin. In , the autophagy inhibitor is selected from hydroxychloroquine and verteporfin.In certain embodiments, the autophagy inhibitor is 4-aminoquinoline.In certain embodiments, The autophagy inhibitor is chloroquine. In certain embodiments, the autophagy inhibitor is chloroquine phosphate. In certain embodiments, the autophagy inhibitor is chloroquine sulfate. In certain embodiments, the autophagy inhibitor is chloroquine hydrochloride. In certain embodiments, the autophagy inhibitor is hydroxychloroquine. In certain embodiments, the autophagy inhibitor is hydroxychloroquine sulfate. In certain embodiments, the autophagy inhibitor is verteporfin.

The autophagy inhibitor may be any suitable type of autophagy (e.g., macroautophagy, microautophagy, chaperone-mediated autophagy, mitophagy or lipophagy). ), which can be achieved by any suitable mechanism (eg, by influencing the formation of autophagosomes or their contents). In certain embodiments, the autophagy inhibitor inhibits macroautophagy or mitophagy. In certain embodiments, the autophagy inhibitor inhibits macroautophagy. In certain embodiments, the autophagy inhibitor inhibits mitophagy. In certain embodiments, the mitophagy inhibitor is Mdivi-1. In certain embodiments, the mitophagy inhibitor is cyclosporine A. In certain embodiments, the autophagy inhibitor inhibits microautophagy. In certain embodiments, the autophagy inhibitor inhibits chaperone-mediated autophagy. In certain embodiments, the autophagy inhibitor inhibits lipophagy.

route of administration

The 6,8-bis-benzylthio-octanoic acid and the autophagy inhibitor may be administered to the patient by any suitable route. For example, in certain embodiments, 6,8-bis-benzylthio-silver octanoate and/or an autophagy inhibitor is administered orally to the patient. In certain embodiments, 6,8-bis-benzylthio-octanoic acid and an autophagy inhibitor are administered orally to the patient. In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered orally to the patient. In certain embodiments, the autophagy inhibitor is administered orally to the patient. In certain embodiments, 6,8-bis-benzylthio-octanoic acid and/or an autophagy inhibitor is administered subcutaneously to the patient. In certain embodiments, 6,8-bis-benzylthio-silver octanoate and/or an autophagy inhibitor is administered to the patient intravenously. In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered as an IV infusion for 2 hours. In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered as an IV infusion for 2 hours via a central venous catheter.

An advantage of oral administration of 6,8-bis-benzylthio-octanoic acid is that administration flexibility is substantially increased compared to IV. In the prior art, 6,8-bis-benzylthio-octanoic acid is formulated as a solution of 50 mg/mL in 1 M (150 mg/mL) aqueous triethanolamine, which is IV through a central venous catheter for 30-120 minutes. Prior to administration by infusion, it is diluted from 50 mg/mL to as little as 4 mg/mL (eg, 12.5 mg/mL) with sterile 5% dextrose for injection (D5W). Such infusions are inconvenient to the patient and effectively interfere with therapy associated with frequent and/or prolonged dosing. Since the half-life of 6,8-bis-benzylthio-octanoic acid after IV is only about 1-2 hours (Pardee, TS et al., Clin Cancer Res. 2014, 20, 5255-64), the patient is exposed to more drug. For this reason, it may be advantageous to use more frequent and/or prolonged administration.

For example, a possible IV schedule for the treatment of high-risk MDS is oral administration of hydroxychloroquine (600 mg to 1,200 mg) on days 1-5 of a 28-day cycle, followed by 6,8-bis on each day thereafter. -Related to IV administration of benzylthio-octanoic acid (2,000 mg/m ^{2 ).} When administered orally, the experimenter will have more flexibility with respect to the dosage and schedule of silver 6,8-bis-benzylthio-octanoic acid. 6,8-Bis-benzylthio-octanoic acid may be administered orally as a single daily dose on days 1-5 of a 28 day cycle as an IV schedule. Alternatively, 6,8-bis-benzylthio-octanoic acid may be administered in two or more divided doses (eg, 3, 4 or 5). Single or divided doses may be administered on Days 1-5 of the cycle, or on additional days including fewer and/or up to daily days of the cycle.

Another advantage of oral administration is that it enables maintenance treatment. For example, patients who have been successfully treated with first-line therapy with or without 6,8-bis-benzylthio-octanoic acid and whose cancer has shown partial or complete remission may be treated to delay or prevent recurrence. , chronically treated orally with 6,8-bis-benzylthio-octanoic acid and an autophagy inhibitor (eg, hydroxychloroquine). Maintenance treatment may involve periodic, eg daily or weekly, eg 1, 2, 3, 4 or 5 doses of 6,8-bis-benzylthio-octanoic acid and an autophagy inhibitor per day. can In certain embodiments, the maintenance treatment is for the treatment of pancreatic cancer.

pharmaceutical composition

Any suitable pharmaceutical composition may be used to administer 6,8-bis-benzylthio-octanoic acid and an autophagy inhibitor to a patient. The therapeutic agents may be administered together in the same pharmaceutical composition (eg, a fixed dose combination) or separately in different pharmaceutical compositions. There are a wide variety of suitable formulations of the pharmaceutical compositions of the present invention (see, eg, Remington: The Science and Practice of Pharmacy , 20th Edition, Gennaro et al. Eds., Lippincott Williams and Wilkins, 2000 ). In certain embodiments, one or more therapeutic agents are administered in a pharmaceutical composition that is a dry oral dosage form. In certain embodiments, the pharmaceutical composition is an oral dosage form selected from tablets, pills, capsules, dragees, powders, granules, solutions, suspensions and gels. Formulations for oral use may contain pharmaceutically acceptable excipients such as carriers, diluents, stabilizers, plasticizers, binders, glidants, disintegrants, bulking agents, lubricants, plasticizers, colorants, film formers, flavoring agents, preservatives, administration vehicles, and any combination of the above.

Pharmaceutical compositions will generally include at least one inert excipient. Excipients include pharmaceutically compatible binders, lubricants, wetting agents, disintegrating agents, and the like. Tablets, pills, capsules, troches and the like may contain any of the following excipients, or compounds having similar properties: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; excipients such as starch or lactose, dispersants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate; glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; or flavoring agents such as peppermint, methyl salicylate, or orange flavoring. When the unit dosage form is a capsule, it may contain liquid excipients such as fatty oils. In addition, unit dosage forms may contain coatings of various other substances that modify the physical form of the dosage unit, for example, sugars, shellac, or enteric agents. Additionally, syrups may contain, in addition to the active compound, sucrose as a sweetening agent, and certain preservatives, dyes, colorants and flavors. In certain embodiments, the pharmaceutical composition comprises an excipient in an amount from about 5% to about 99% by weight of the composition, such as from about 10% to about 85% by weight, and the therapeutic agent includes the balance. In certain embodiments, pharmaceutically acceptable excipients comprise from 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, and the one or more excipients include the balance. In certain embodiments, the pharmaceutical composition comprises a therapeutic agent in an amount of at least about 50% by weight of the composition. In certain embodiments, the pharmaceutical composition comprises a therapeutic agent in an amount of at least about 60% by weight of the composition. In certain embodiments, the pharmaceutical composition comprises a therapeutic agent in an amount of at least about 70% by weight of the composition. In certain embodiments, the pharmaceutical composition comprises a therapeutic agent in an amount of at least about 80% by weight of the composition. In certain embodiments, the pharmaceutical composition comprises a therapeutic agent in an amount of at least about 90% by weight of the composition.

Diluents for solid (eg oral) compositions include microcrystalline cellulose (eg AVICEL®), ultrafine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrate, dextrin, Dextrose, dicalcium phosphate dihydrate, tricalcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylate (eg Eudragit), potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc including, but not limited to.

Binders for solid (eg oral) pharmaceutical compositions include acacia, tragacanth, sucrose, glucose, alginic acid, carbomer (eg Carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, Gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (eg KLUCEL®), hydroxypropyl methyl cellulose (eg METHOCEL®), liquid glucose, magnesium aluminum silicate, maltodextrin , methylcellulose, polymethacrylate, povidone (eg KOLLIDON®, PLASDONE®), pregelatinized starch, sodium alginate and starch. In certain embodiments, the pharmaceutical composition comprises a binder in an amount from about 0.5% to about 25% by weight of the composition, such as from about 0.75% to about 15% by weight. In certain embodiments, the pharmaceutical composition comprises a binder in an amount from about 1% to about 10% by weight of the composition.

The rate at which the compressed solid pharmaceutical composition dissolves in the patient's stomach can be increased by adding a disintegrant to the composition. Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (eg AC-DI-SOL®, PRIMELLOSE®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (eg KOLLIDON®, POLYPLASDONE®), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (eg EXPLOTAB®) and starch. doesn't happen In certain embodiments, the pharmaceutical composition comprises a disintegrant in an amount of from about 0.2% to about 30% by weight of the composition, such as from about 0.2% to about 10% by weight. In certain embodiments, the pharmaceutical composition comprises a disintegrant in an amount from about 0.2% to about 5% by weight of the composition.

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

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

Flavors and flavor enhancers make the formulation more palatable to the patient. Common flavors and flavor enhancers for pharmaceutical products that may be included in the compositions of the present invention include maltol, vanillin, ethyl vanillin, menthol, citric acid, ethyl maltol fumarate and tartaric acid.

The composition may also be colored using any pharmaceutically acceptable colorant to improve its appearance and/or facilitate patient identification of the product and dosage level. The formulations of the present invention may be buffered by the addition of a suitable buffer.

In certain embodiments of the invention, the therapeutic agent is a pharmaceutically-acceptable oil; liposomes; oil-water or lipid-oil-water emulsions or nanoemulsions; Or it may be formulated as a liquid. To facilitate such preparation, the therapeutic agent may be combined with a pharmaceutically-acceptable excipient therefor.

As described in detail below, the pharmaceutical compositions may be especially formulated for administration in solid or liquid form, which may be administered parenterally, e.g. subcutaneously, e.g., as a sterile solution or suspension, or as a sustained release formulation. including those intended for intramuscular, intravenous or epidural injection.

Additional examples of pharmaceutical formulations of 6,8-bis-benzylthio-octanoic acid are described in US Pat. No. 8,263,653, the entire disclosure of which is incorporated herein by reference.

A method of preparing a pharmaceutical preparation or pharmaceutical composition comprises the step of bringing into association a compound of the invention with a carrier and, optionally, one or more accessory ingredients. In general, formulations are prepared by uniformly and intimately bringing into association a compound of the invention with liquid carriers, or finely divided solid carriers, or both, and, if necessary, shaping the product.

In certain embodiments, the pharmaceutical composition comprising the first therapeutic agent is a spray-dried dispersion. In certain embodiments, a pharmaceutical composition comprising a first therapeutic agent is a polyacrylate, polymethacrylate, poly(vinylpyrrolidone), hydroxypropyl methyl cellulose (HPMC), cellulose acetate phthalate (CAP), and a spray-dried dispersion comprising at least one polymer selected from hydroxypropyl methylcellulose acetate succinate (HPMCAS-M). In certain embodiments, the pharmaceutical composition comprising the first therapeutic agent is Eudragit L100, poly(vinylpyrrolidone), hydroxypropyl methyl cellulose (HPMC), cellulose acetate phthalate (CAP), and hydroxypropyl methylcellulose acetate. a spray-dried dispersion comprising at least one polymer selected from succinate (HPMCAS-M). In certain embodiments, the pharmaceutical composition comprising the first therapeutic agent comprises Eudragit L100, poly(vinylpyrrolidone) viscosity grade K30 (PVP K30), hydroxypropyl methyl cellulose (HPMC), cellulose acetate phthalate (CAP), and at least one polymer selected from hydroxypropyl methylcellulose acetate succinate (HPMCAS-M). In certain embodiments, the pharmaceutical composition comprising the first therapeutic agent is a spray-dried dispersion comprising Eudragit L100 and at least one polymer selected from hydroxypropyl methylcellulose acetate succinate (HPMCAS-M). In certain embodiments, the pharmaceutical composition comprising the first therapeutic agent is a spray-dried dispersion comprising Eudragit L100. In certain embodiments, the pharmaceutical composition comprising the first therapeutic agent is a spray-dried dispersion comprising hydroxypropyl methylcellulose acetate succinate (HPMCAS-M).

A pharmaceutical composition of the invention suitable for parenteral administration comprises a combination of one or more compounds of the invention with one or more pharmaceutically-acceptable isotonic or non-aqueous aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders. sugars, alcohols, antioxidants, buffers, bacteriostats, which can be reconstituted prior to use into a sterile injectable solution or dispersion, and which render the formulation isotonic with the blood of the intended recipient or with a suspension or thickening agent. ), may contain a solute.

In certain embodiments, the one or more therapeutic agents are administered by intraparenteral administration. In certain other embodiments, the one or more therapeutic agents are inhaled, oral, topical, transdermal, nasal, ophthalmic, pulmonary, rectal, transmucosal, intravenous, in the form of an aerosol, spray, powder, gel, lotion, cream, suppository, ointment, etc. It is formulated for intra, intramuscular, subcutaneous, intraperitoneal, intrathoracic, intrapleural, intrauterine, intratumoral, or method or administration of infusion, or any combination thereof. As indicated above, if such a formulation is desired, other additives known in the art may also be added to impart the formulation with the desired consistency and other properties.

In certain embodiments, the pharmaceutical compositions of the present invention are unit dose compositions. In certain embodiments, the pharmaceutical composition contains from about 1 mg to about 5000 mg of therapeutic agent. In certain embodiments, the pharmaceutical composition contains from about 100 mg to about 3000 mg of therapeutic agent. In certain embodiments, the pharmaceutical composition contains from about 200 mg to about 2000 mg of therapeutic agent. In certain embodiments, the pharmaceutical composition is 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 therapeutic agent. In certain embodiments, the pharmaceutical composition contains about 300 mg, 500 mg, 700 mg, or 1000 mg of the therapeutic agent.

In certain embodiments, the pharmaceutical composition comprises an emulsion, particle or gel described in US Pat. 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 of a lipid or fatty acid component. In certain embodiments, the formulation contains from about 0.1% to about 15% w/v of lipid and fatty acid components. In certain embodiments, the fatty acid component comprises saturated or unsaturated C4, C5, C6, C7, C8, C9, C10, C11, or C12 fatty acids and/or salts of such fatty acids. Lipids may include cholesterol and analogs thereof.

In certain embodiments, the pharmaceutical composition of 6,8-bis-benzylthio-octanoic acid comprises triethanolamine and 6,8-bis-benzylthio-octanoic acid, triethanolamine to 6,8-bis-benzylthio The molar ratio of -octanoic acid is from about 10:1 to about 1:10. In certain embodiments, the molar ratio of triethanolamine to 6,8-bis-benzylthio-octanoic acid is from about 10:1 to about 5:1. In certain embodiments, the molar ratio of triethanolamine to 6,8-bis-benzylthio-octanoic acid is about 8:1. In certain embodiments, the pharmaceutical composition comprises a 50 mg/mL solution of 6,8-bis-benzylthio-octanoic acid in 1M aqueous triethanolamine. In certain embodiments, the pharmaceutical composition comprises 6,8-bis-benzylthio- in 1M aqueous triethanolamine diluted from 50 mg/mL to as little as 12.5 mg/mL with sterile aqueous 5% dextrose for injection (D5W). Contains a solution of octanoic acid. In certain embodiments, the pharmaceutical composition is 6,8-bis-benzylthio-oxide in 1M aqueous triethanolamine, diluted from 50 mg/mL to about 12.5 mg/mL with sterile aqueous 5% dextrose (D5W) for injection. Contains a solution of carbonic acid.

Several pharmaceutical compositions of autophagy inhibitors are commercially available. In certain embodiments, the pharmaceutical composition of an autophagy inhibitor is an oral tablet comprising chloroquine phosphate in an amount equivalent to 150 mg of free base. In certain embodiments, the pharmaceutical composition of an autophagy inhibitor is an oral tablet comprising chloroquine phosphate in an amount equivalent to 300 mg of free base. In certain embodiments, the pharmaceutical composition of an autophagy inhibitor is an oral tablet comprising 200 mg hydroxychloroquine sulfate equivalent to 155 mg free base. In certain embodiments, the pharmaceutical composition of an autophagy inhibitor is an injectable liquid comprising chloroquine hydrochloride in an amount equivalent to 40 mg/mL of free base.

Dosage & Schedule

The 6,8-bis-benzylthio-octanoic acid and the autophagy inhibitor may be administered to the patient at any suitable dose on any suitable schedule. Dosages and schedules will vary based on the cancer being treated, and include doses of 6,8-bis-benzylthio-octanoic acid and an autophagy inhibitor, and schedules used in the prior art when administered alone or in combination with other agents; Rather, one of ordinary skill in the art can readily determine, taking into account the guidance provided herein. In certain embodiments, the dose is a dose that is a maximum number.

In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered at a daily dose of ^{about 150 mg/m 2} to about 3000 mg/m ^{2 .} In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered at a daily dose of ^{about 250 mg/m 2} to about 2500 mg/m ^{2 .} In certain embodiments, the first 6,8-bis-benzylthio-octanoic acid is administered at a daily dose of ^{about 500 mg/m 2} to about 2000 mg/m ^{2 .} In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered at a daily dose of ^{about 150 mg/m 2 .} In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered at a daily dose of ^{about 200 mg/m 2 .} In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered at a daily dose of ^{about 250 mg/m 2 .} In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered at a daily dose of ^{about 300 mg/m 2 .} In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered at a daily dose of ^{about 350 mg/m 2 .} In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered at a daily dose of ^{about 400 mg/m 2 .} In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered at a daily dose of ^{about 450 mg/m 2 .} In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered at a daily dose of ^{about 500 mg/m 2 .} In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered at a daily dose of ^{about 600 mg/m 2 .} In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered at a daily dose of ^{about 700 mg/m 2 .} In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered at a daily dose of ^{about 800 mg/m 2 .} In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered at a daily dose of ^{about 900 mg/m 2 .} In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered at a daily dose of ^{about 1000 mg/m 2 .} In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered at a daily dose of ^{about 1100 mg/m 2 .} In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered at a daily dose of ^{about 1200 mg/m 2 .} In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered at a daily dose of ^{about 1300 mg/m 2 .} In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered at a daily dose of ^{about 1400 mg/m 2 .} In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered at a daily dose of ^{about 1500 mg/m 2 .} In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered at a daily dose of ^{about 1600 mg/m 2 .} In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered at a daily dose of ^{about 1700 mg/m 2 .} In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered at a daily dose of ^{about 1800 mg/m 2 .} In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered at a daily dose of ^{about 1900 mg/m 2 .} In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered at a daily dose of ^{about 2000 mg/m 2 .} In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered at a daily dose of ^{about 2500 mg/m 2 .} In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered at a daily dose of ^{about 3000 mg/m 2 .}

In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered in a daily dose of about 1 mg to about 10,000 mg. In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered in a daily dose of about 10 mg to about 7,500 mg. In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered in a daily dose of about 100 mg to about 5,000 mg. In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered in a daily dose of about 200 mg to about 4,000 mg. In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered in a daily dose of about 300 mg to about 3,000 mg. In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered in a daily dose of about 400 mg to about 2,500 mg. In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered in a daily dose of about 500 mg to about 2,000 mg. In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered in a daily dose of about 100 mg. In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered in a daily dose of about 200 mg. In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered in a daily dose of about 300 mg. In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered in a daily dose of about 400 mg. In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered in a daily dose of about 500 mg. In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered in a daily dose of about 600 mg. In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered in a daily dose of about 700 mg. In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered in a daily dose of about 800 mg. In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered in a daily dose of about 900 mg. In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered in a daily dose of about 1,000 mg. In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered in a daily dose of about 1,250 mg. In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered in a daily dose of about 1,500 mg. In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered at a daily dose of about 1,750 mg. In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered in a daily dose of about 2,000 mg. In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered in a daily dose of about 2,500 mg. In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered at a daily dose of about 3,000 mg. In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered at a daily dose of about 3,500 mg. In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered at a daily dose of about 4,000 mg. In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered at a daily dose of about 4,500 mg. In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered in a daily dose of about 5,000 mg. In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered at a daily dose of about 6,000 mg. In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered at a daily dose of about 7,000 mg. In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered at a daily dose of about 8,000 mg. In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered in a daily dose of about 9,000 mg. In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered in a daily dose of about 10,000 mg.

The daily dose of 6,8-bis-benzylthio-octanoic acid can be administered as a single dose or divided into two or more doses - eg, bid (twice daily), tid (daily) 3 times), or qid (4 times a day). In certain embodiments, the daily dose may be divided into 5 doses, administered at periodic intervals throughout the day. At higher daily doses, and/or when administered orally or subcutaneously, it will often be beneficial for the daily dose of 6,8-bis-benzylthio-octanoic acid to be administered as b.i.d., t.i.d., or q.i.d. Since 6,8-bis-benzylthio-octanoic acid has a relatively short blood half-life, dividing the daily dose may improve efficacy by prolonging exposure time, and may also improve safety by reducing peak plasma concentrations. In certain embodiments, each dose of 6,8-bis-benzylthio-octanoic acid or a pharmaceutically acceptable salt thereof is from about 0.5 g to 1.5 g, once, twice, three times, four or five times a day. is administered twice. In certain embodiments, each dose of 6,8-bis-benzylthio-octanoic acid or a pharmaceutically acceptable salt thereof is between about 0.5 g and 1.5 g and is administered once daily. In certain embodiments, each dose of 6,8-bis-benzylthio-octanoic acid or a pharmaceutically acceptable salt thereof is between about 0.5 g and 1.5 g, administered twice daily. In certain embodiments, each dose of 6,8-bis-benzylthio-octanoic acid or a pharmaceutically acceptable salt thereof is between about 0.5 g and 1.5 g, administered three times daily. In certain embodiments, each dose of 6,8-bis-benzylthio-octanoic acid or a pharmaceutically acceptable salt thereof is between about 0.5 g and 1.5 g, administered four times a day. In certain embodiments, each dose of 6,8-bis-benzylthio-octanoic acid or a pharmaceutically acceptable salt thereof is between about 0.5 g and 1.5 g, administered five times a day. In certain embodiments, each dose of 6,8-bis-benzylthio-octanoic acid or a pharmaceutically acceptable salt thereof is about 1 g and is administered once, twice, three times, four times or five times a day. . In certain embodiments, each dose of 6,8-bis-benzylthio-octanoic acid or a pharmaceutically acceptable salt thereof is about 1 g and is administered once daily. In certain embodiments, each dose of 6,8-bis-benzylthio-octanoic acid or a pharmaceutically acceptable salt thereof is about 1 g and is administered twice daily. In certain embodiments, each dose of 6,8-bis-benzylthio-octanoic acid or a pharmaceutically acceptable salt thereof is about 1 g and is administered three times daily. In certain embodiments, each dose of 6,8-bis-benzylthio-octanoic acid or a pharmaceutically acceptable salt thereof is about 1 g and is administered four times a day. In certain embodiments, each dose of 6,8-bis-benzylthio-octanoic acid or a pharmaceutically acceptable salt thereof is about 1 g and is administered 5 times a day.

6,8-Bis-benzylthio-octanoic acid is a treatment that includes days when a dose of 6,8-bis-benzylthio-octanoic acid is administered and days when 6,8-bis-benzylthio-octanoic acid is not administered. It may be administered according to a schedule. For example, 6,8-bis-benzylthio-octanoic acid may be administered on a schedule in which 6,8-bis-benzylthio-octanoic acid is administered during the initial days of the cycle and then not administered during the later days of the cycle. have. In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered on days 1-5 of a 28 day cycle. In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered on days 1, 8 and 15 of a 4-week cycle. In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered on days 1 and 3 of a two-week cycle. In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered on days 1-5 of a 3-week cycle. In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered on days 1-5 of a two-week cycle. In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered on days 1-3 of a 3-week cycle. In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered on days 1-3 of a two-week cycle. In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered daily. In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered every other day. In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered for 3 days per week. In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered for 2 days per week. In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered for 1 day per week.

In certain embodiments, hydroxychloroquine sulfate is administered in a daily dose of about 50 mg to about 1500 mg. In certain embodiments, hydroxychloroquine sulfate is administered in a daily dose of about 100 mg to about 1500 mg. In certain embodiments, hydroxychloroquine sulfate is administered in a daily dose of about 200 mg to about 1200 mg. In certain embodiments, hydroxychloroquine sulfate is administered in a daily dose of about 300 mg to about 1200 mg. In certain embodiments, hydroxychloroquine sulfate is administered in a daily dose of about 400 mg to about 1200 mg. In certain embodiments, hydroxychloroquine sulfate is administered in a daily dose of about 600 mg to about 1200 mg. In certain embodiments, hydroxychloroquine sulfate is administered in a daily dose of about 600 mg to about 1000 mg. In certain embodiments, hydroxychloroquine sulfate is administered in a daily dose of about 100 mg. In certain embodiments, hydroxychloroquine sulfate is administered in a daily dose of about 200 mg. In certain embodiments, hydroxychloroquine sulfate is administered in a daily dose of about 300 mg. In certain embodiments, hydroxychloroquine sulfate is administered in a daily dose of about 400 mg. In certain embodiments, hydroxychloroquine sulfate is administered in a daily dose of about 500 mg. In certain embodiments, hydroxychloroquine sulfate is administered in a daily dose of about 600 mg. In certain embodiments, hydroxychloroquine sulfate is administered in a daily dose of about 700 mg. In certain embodiments, hydroxychloroquine sulfate is administered in a daily dose of about 800 mg. In certain embodiments, hydroxychloroquine sulfate is administered in a daily dose of about 900 mg. In certain embodiments, hydroxychloroquine sulfate is administered in a daily dose of about 1,000 mg. In certain embodiments, hydroxychloroquine sulfate is administered in a daily dose of about 1,100 mg. In certain embodiments, hydroxychloroquine sulfate is administered in a daily dose of about 1,200 mg. In certain embodiments, hydroxychloroquine sulfate is administered in a daily dose of about 1,300 mg. In certain embodiments, hydroxychloroquine sulfate is administered in a daily dose of about 1400 mg. In certain embodiments, hydroxychloroquine sulfate is administered in a daily dose of about 1,500 mg.

In certain embodiments, hydroxychloroquine sulfate is administered at a daily dose of about 2 mg/kg to about 25 mg/kg. In certain embodiments, hydroxychloroquine sulfate is administered at a daily dose of about 5 mg/kg to about 20 mg/kg. In certain embodiments, hydroxychloroquine sulfate is administered at a daily dose of about 6.5 mg/kg to about 19.5 mg/kg. In certain embodiments, hydroxychloroquine sulfate is administered at a daily dose of about 2.5 mg/kg. In certain embodiments, hydroxychloroquine sulfate is administered at a daily dose of about 3 mg/kg. In certain embodiments, hydroxychloroquine sulfate is administered at a daily dose of about 3.5 mg/kg. In certain embodiments, hydroxychloroquine sulfate is administered at a daily dose of about 4 mg/kg. In certain embodiments, hydroxychloroquine sulfate is administered at a daily dose of about 4.5 mg/kg. In certain embodiments, hydroxychloroquine sulfate is administered at a daily dose of about 5 mg/kg. In certain embodiments, hydroxychloroquine sulfate is administered at a daily dose of about 5.5 mg/kg. In certain embodiments, hydroxychloroquine sulfate is administered at a daily dose of about 6 mg/kg. In certain embodiments, hydroxychloroquine sulfate is administered at a daily dose of about 6.5 mg/kg. In certain embodiments, hydroxychloroquine sulfate is administered at a daily dose of about 7 mg/kg. In certain embodiments, hydroxychloroquine sulfate is administered at a daily dose of about 7.5 mg/kg. In certain embodiments, hydroxychloroquine sulfate is administered at a daily dose of about 8 mg/kg. In certain embodiments, hydroxychloroquine sulfate is administered at a daily dose of about 8.5 mg/kg. In certain embodiments, hydroxychloroquine sulfate is administered at a daily dose of about 9 mg/kg. In certain embodiments, hydroxychloroquine sulfate is administered at a daily dose of about 9.5 mg/kg. In certain embodiments, hydroxychloroquine sulfate is administered at a daily dose of about 10 mg/kg. In certain embodiments, hydroxychloroquine sulfate is administered at a daily dose of about 10.5 mg/kg. In certain embodiments, hydroxychloroquine sulfate is administered at a daily dose of about 11 mg/kg. In certain embodiments, hydroxychloroquine sulfate is administered at a daily dose of about 11.5 mg/kg. In certain embodiments, hydroxychloroquine sulfate is administered at a daily dose of about 12 mg/kg. In certain embodiments, hydroxychloroquine sulfate is administered at a daily dose of about 12.5 mg/kg. In certain embodiments, hydroxychloroquine sulfate is administered at a daily dose of about 13 mg/kg. In certain embodiments, hydroxychloroquine sulfate is administered at a daily dose of about 13.5 mg/kg. In certain embodiments, hydroxychloroquine sulfate is administered at a daily dose of about 14 mg/kg. In certain embodiments, hydroxychloroquine sulfate is administered at a daily dose of about 14.5 mg/kg. In certain embodiments, hydroxychloroquine sulfate is administered at a daily dose of about 15 mg/kg. In certain embodiments, hydroxychloroquine sulfate is administered at a daily dose of about 15.5 mg/kg. In certain embodiments, hydroxychloroquine sulfate is administered at a daily dose of about 16 mg/kg. In certain embodiments, hydroxychloroquine sulfate is administered at a daily dose of about 16.5 mg/kg. In certain embodiments, hydroxychloroquine sulfate is administered at a daily dose of about 17 mg/kg. In certain embodiments, hydroxychloroquine sulfate is administered at a daily dose of about 17.5 mg/kg. In certain embodiments, hydroxychloroquine sulfate is administered at a daily dose of about 18 mg/kg. In certain embodiments, hydroxychloroquine sulfate is administered at a daily dose of about 18.5 mg/kg. In certain embodiments, hydroxychloroquine sulfate is administered at a daily dose of about 19 mg/kg. In certain embodiments, hydroxychloroquine sulfate is administered at a daily dose of about 19.5 mg/kg. In certain embodiments, hydroxychloroquine sulfate is administered at a daily dose of about 20 mg/kg.

The daily dose of hydroxychloroquine sulfate may be administered as a single dose, or divided into two or more doses - eg b.i.d. In certain embodiments, the daily dose of hydroxychloroquine sulfate is administered as a single dose. In certain embodiments, the daily dose of hydroxychloroquine sulfate is divided into two doses and administered b.i.d.

In certain embodiments, chloroquine phosphate is administered in a daily dose of about 50 mg to about 2000 mg, which is equivalent to about 30 mg to about 1200 mg of chloroquine base. In certain embodiments, chloroquine phosphate is administered in a daily dose of about 150 mg to about 1800 mg. In certain embodiments, chloroquine phosphate is administered in a daily dose of about 250 mg to about 1500 mg. Certain chloroquine phosphates are administered in a daily dose of about 500 mg to about 1500 mg. In certain embodiments, chloroquine phosphate is administered in a daily dose of about 500 mg to about 1000 mg. In certain embodiments, chloroquine phosphate is administered in a daily dose of about 1000 mg to about 1500 mg. In certain embodiments, chloroquine phosphate is administered in a daily dose of about 250 mg. In certain embodiments, chloroquine phosphate is administered in a daily dose of about 500 mg. In certain embodiments, chloroquine phosphate is administered at a daily dose of about 750 mg. In certain embodiments, chloroquine phosphate is administered in a daily dose of about 1000 mg. In certain embodiments, chloroquine phosphate is administered at a daily dose of about 1,250 mg. In certain embodiments, chloroquine phosphate is administered in a daily dose of about 1,500 mg. In certain embodiments, chloroquine phosphate is administered at a daily dose of about 1750 mg. In certain embodiments, chloroquine phosphate is administered in a daily dose of about 2000 mg. In certain embodiments, chloroquine phosphate is administered at a daily dose of about 2250 mg. In certain embodiments, chloroquine phosphate is administered in a daily dose of about 2500 mg.

In certain embodiments, chloroquine phosphate is administered at a daily dose of about 2 mg/kg to about 25 mg/kg. In certain embodiments, chloroquine phosphate is administered at a daily dose of about 5 mg/kg to about 20 mg/kg. In certain embodiments, chloroquine phosphate is administered at a daily dose of about 6.5 mg/kg to about 19.5 mg/kg. In certain embodiments, chloroquine phosphate is administered at a daily dose of about 2.5 mg/kg. In certain embodiments, chloroquine phosphate is administered at a daily dose of about 3 mg/kg. In certain embodiments, chloroquine phosphate is administered at a daily dose of about 3.5 mg/kg. In certain embodiments, chloroquine phosphate is administered at a daily dose of about 4 mg/kg. In certain embodiments, chloroquine phosphate is administered at a daily dose of about 4.5 mg/kg. In certain embodiments, chloroquine phosphate is administered at a daily dose of about 5 mg/kg. In certain embodiments, chloroquine phosphate is administered at a daily dose of about 5.5 mg/kg. In certain embodiments, chloroquine phosphate is administered at a daily dose of about 6 mg/kg. In certain embodiments, chloroquine phosphate is administered at a daily dose of about 6.5 mg/kg. In certain embodiments, chloroquine phosphate is administered at a daily dose of about 7 mg/kg. In certain embodiments, chloroquine phosphate is administered at a daily dose of about 7.5 mg/kg. In certain embodiments, chloroquine phosphate is administered at a daily dose of about 8 mg/kg. In certain embodiments, chloroquine phosphate is administered at a daily dose of about 8.5 mg/kg. In certain embodiments, chloroquine phosphate is administered at a daily dose of about 9 mg/kg. In certain embodiments, chloroquine phosphate is administered at a daily dose of about 9.5 mg/kg. In certain embodiments, chloroquine phosphate is administered at a daily dose of about 10 mg/kg. In certain embodiments, chloroquine phosphate is administered at a daily dose of about 10.5 mg/kg. In certain embodiments, chloroquine phosphate is administered at a daily dose of about 11 mg/kg. In certain embodiments, chloroquine phosphate is administered at a daily dose of about 11.5 mg/kg. In certain embodiments, chloroquine phosphate is administered at a daily dose of about 12 mg/kg. In certain embodiments, chloroquine phosphate is administered at a daily dose of about 12.5 mg/kg. In certain embodiments, chloroquine phosphate is administered at a daily dose of about 13 mg/kg. In certain embodiments, chloroquine phosphate is administered at a daily dose of about 13.5 mg/kg. In certain embodiments, chloroquine phosphate is administered at a daily dose of about 14 mg/kg. In certain embodiments, chloroquine phosphate is administered at a daily dose of about 14.5 mg/kg. In certain embodiments, chloroquine phosphate is administered at a daily dose of about 15 mg/kg. In certain embodiments, chloroquine phosphate is administered at a daily dose of about 15.5 mg/kg. In certain embodiments, chloroquine phosphate is administered at a daily dose of about 16 mg/kg. In certain embodiments, chloroquine phosphate is administered at a daily dose of about 16.5 mg/kg. In certain embodiments, chloroquine phosphate is administered at a daily dose of about 17 mg/kg. In certain embodiments, chloroquine phosphate is administered at a daily dose of about 17.5 mg/kg. In certain embodiments, chloroquine phosphate is administered at a daily dose of about 18 mg/kg. In certain embodiments, chloroquine phosphate is administered at a daily dose of about 18.5 mg/kg. In certain embodiments, chloroquine phosphate is administered at a daily dose of about 19 mg/kg. In certain embodiments, chloroquine phosphate is administered at a daily dose of about 19.5 mg/kg. In certain embodiments, chloroquine phosphate is administered at a daily dose of about 20 mg/kg.

The daily dose of chloroquine phosphate may be administered in one dose or divided into two or more doses-eg, b.i.d. In certain embodiments, the daily dose of chloroquine phosphate is administered as a single dose. In certain embodiments, the daily dose of chloroquine phosphate is divided into two doses and administered b.i.d.

Simply, the autophagy inhibitor will typically be administered according to a treatment cycle of the same length as each treatment cycle for 6,8-bis-benzylthio-octanoic acid (eg, 2 weeks, 3 weeks, 4 weeks, etc.) . As with the cycle for 6,8-bis-benzylthio-octanoic acid, the autophagy inhibitor cycle can include days on which a dose of the autophagy inhibitor is administered and days on which no dose of the autophagy inhibitor is administered. For example, the autophagy inhibitor is administered on the same day that 6,8-bis-benzylthio-octanoic acid is administered, and 6,8-bis-benzylthio-octanoic acid is not administered. may be administered according to a schedule in which no autophagy inhibitor is also administered. Alternatively, the autophagy inhibitor may be administered on some but not all of the days 6,8-bis-benzylthio-octanoic acid is administered and/or 6,8-bis-benzylthio-octanoic acid is not administered. It may be administered on some but not all days. In certain embodiments, the autophagy inhibitor may be administered on each day of the cycle.

In certain embodiments, the dosing cycle is repeated at least once. In certain embodiments, the methods of the invention comprise two or more cycles of treatment. In certain embodiments, the methods of the invention comprise three or more cycles of treatment. In certain embodiments, the methods of the invention comprise 4 or more cycles of treatment. In certain embodiments, the methods of the invention comprise 5 or more cycles of treatment. In certain embodiments, the methods of the present invention comprise 6 or more cycles of treatment. In certain embodiments, the methods of the invention comprise at least 7 cycles of treatment. In certain embodiments, the methods of the invention comprise 8 or more cycles of treatment. In certain embodiments, the methods of the invention comprise at least 9 cycles of treatment. In certain embodiments, the methods of the invention comprise at least 10 cycles of treatment. In certain embodiments, the methods of the present invention comprise periodic treatment with 6,8-bis-benzylthio-octanoic acid and an autophagy inhibitor, which may be administered for an extended period of time, such as at least 1 month, 6 months, 1 year, Includes 1 day or 1 week basis for 2 years, 3 years, or more.

patient for treatment

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

Therapeutic efficacy and safety

The treatment methods of the present invention may be further characterized by the efficacy and safety of the treatment. Preferably, the method provides acceptable safety characteristics and has a therapeutic benefit that outweighs the risks. The method of the present invention, when tested in a phase II or phase III clinical trial with at least 10 cancer patients, preferably has a total response rate of at least about 10%, a response duration of at least about 1 month, and a response duration of at least about 1 month. progression-free survival (PFS), and/or total survival (OS) of at least about 1 month. Preferably, a phase II or III clinical trial includes at least 15 patients. More preferably, the Phase II or Phase III clinical trial includes at least 20 patients. More preferably, the Phase II or Phase III clinical trial includes at least 25 patients. More preferably, the Phase II or Phase III clinical trial includes at least 50 patients. More preferably, the Phase II or Phase III clinical trial includes at least 100 patients. More preferably, the Phase II or Phase III clinical trial includes at least 200 patients. More preferably, the Phase II or Phase III clinical trial includes at least 300 patients. More preferably, the phase II or phase III clinical trial includes at least 400 patients. More preferably, the Phase II or Phase III clinical trial includes at least 500 patients. Preferably, the methods of the present invention provide a total response rate in patients of at least about 20%. More preferably, the method of the present invention provides a total reaction rate of at least about 30%. More preferably, the method of the present invention provides a total reaction rate of at least about 40%. More preferably, the method of the present invention provides a total reaction rate of at least about 50%. More preferably, the method of the present invention provides a total reaction rate of at least about 60%. More preferably, the method of the present invention provides a total reaction rate of at least about 70%. More preferably, the method of the present invention provides a total reaction rate of at least about 80%. More preferably, the method of the present invention provides a total reaction rate of at least about 90%. Preferably, the methods of the present invention provide a response duration, PFS, and/or OS of at least about 2 months. Preferably, the methods of the present invention provide a response duration, PFS, and/or OS of at least about 3 months. Preferably, the methods of the present invention provide a response duration, PFS, and/or OS of at least about 4 months. Preferably, the methods of the present invention provide a response duration, PFS, and/or OS of at least about 5 months. Preferably, the methods of the present invention provide a response duration, PFS, and/or OS of at least about 6 months. Preferably, the methods of the present invention provide a response duration, PFS, and/or OS of at least about 7 months. Preferably, the methods of the present invention provide a response duration, PFS, and/or OS of at least about 8 months. Preferably, the methods of the present invention provide a response duration, PFS, and/or OS of at least about 9 months. Preferably, the methods of the present invention provide a response duration, PFS, and/or OS of at least about 10 months. Preferably, the methods of the present invention provide a response duration, PFS, and/or OS of at least about 11 months. Preferably, the methods of the present invention provide a response duration, PFS, and/or OS of at least about 12 months. Preferably, the methods of the present invention provide a response duration, PFS, and/or OS of at least about 14 months. Preferably, the methods of the present invention provide a response duration, PFS, and/or OS of at least about 16 months. Preferably, the methods of the present invention provide a response duration, PFS, and/or OS of at least about 18 months. Preferably, the methods of the present invention provide a response duration, PFS, and/or OS of at least about 20 months. Preferably, the methods of the present invention provide a response duration, PFS, and/or OS of at least about 24 months. In certain embodiments, the aforementioned total response rate, duration of response, and progression-free survival are determined in a phase II clinical trial. In certain embodiments, the aforementioned total response rate, duration of response, and progression-free survival are determined in a phase III clinical trial.

equality

The foregoing detailed description sets forth a number of aspects and embodiments of the invention, including therapeutic applications, methods of treatment and pharmaceutical compositions. This patent application specifically contemplates all combinations and permutations of the above aspects and embodiments.

III. Example

The invention, which has been generally described below, will be more readily understood by reference to the following examples, which are included solely for the purpose of illustrating specific aspects and embodiments of the invention, and serve to illustrate the invention It is not intended to be limiting.

Example One - CPI-613 induces autophagy in AML cells in vitro.

K562 cells (100,000 cells/mL) in Roswell Park Memorial Institute (RPMI) medium with 10% fetal bovine serum (FBS), or 45% Iscove's Modified Dulbeccos' Medium (IMDM)/45% MFL2 cells (Pardee, TS et al, Experimental Hematology, 2011, 39, 473-485) (50,000 cells/mL) in Dulbecco's Modified Eagle's Medium (DMEM)/10% FBS, either alone or in early and late autologous, respectively After incubation with CPI-613 (200 μM) for 4 hours at _{37° C. under 5% CO 2} in the presence of the phagocytic inhibitors 3-methyladenine (3MA) or bafilomycin A (BafA) for LC3-II Blotted, the LC3-II is produced during autophagy (reduced production by 3MA) and consumed upon completion (degraded degradation by BafA). Complete medium ("Full") and Hank's balanced salt solution medium (HBSS) were used as negative and positive controls for autophagy, respectively.

The results are presented in FIG. 1 . This example demonstrates that 6,8-bis-benzylthio-octanoic acid induces autophagy in AML cells.

Example 2 - Chloroquine sensitizes AML cells to CPI-613 in vitro.

K562 or OCI-AML3 cells (100,000 cells/mL) in RPMI medium with 10% FBS, CPI-613 (100 μM), chloroquine (25 μM or 50 μM) at 37° C. under _{5% CO 2 for 72 hours} , or after incubation with a combination of CPI-613 (100 μM) and chloroquine (25 μM or 50 μM), viability was assessed using the Promega CellTiter-Glo assay.

The results are presented in FIG. 2 . This example demonstrates that the combination of 6,8-bis-benzylthio-octanoic acid and chloroquine significantly better kills AML cells in vitro than either agent alone.

Example 3 - Chloroquine sensitizes AML cells to CPI-613 in vivo.

On day 0 and starting from day 7, 1 million MFL2 cells were injected into the tail vein of C57Bl/6 mice, and upon confirmation of engraftment by bioluminescence imaging, CPI-613 (4 300 mg/kg of a 50 mg/mL solution in 0.05 N NaOH in 5% dextrose, adjusted to pH 7.5-8 with % glacial acetic acid; 1 animal) by gavage daily except weekends until death, or Chloroquine (200 µL of a 10 mg/mL solution in PBS (ca. 100 mg/kg); Chlr; 3 animals) was treated intraperitoneally (IP) daily except weekends until death, or CPI-613 (as above After treatment with the same combination of gavage treatment at 300 mg/kg per day) and chloroquine (with 200 μL of daily IP treatment as above) (4 animals), survival was followed. Control animals (1) received both oral and IP vehicle. P values were determined by log rank test.

The results are presented in FIG. 3 . This example demonstrates that the combination of 6,8-bis-benzylthio-octanoic acid and chloroquine significantly prolongs the survival of AML tumor-bearing mice in vivo compared to when either agent is used alone at the same concentration. prove it

Example 4 - Metformin sensitizes AML cells to CPI-613 in vitro.

MFL2 cells (Pardee, TS et al., Experimental Hematology, 2011, 39, 473-485) (50,000 cells/mL) in 45% IMDM/45% DMEM/10% FBS at 37° C. under _{5% CO 2 for 72 hours} After incubation with CPI-613 (50 µM), metformin (1 µM, 2.5 µM, or 5 µM), or a combination of CPI-613 (50 µM) and metformin (1 µM, 2.5 µM, or 5 µM) during , viability was assessed using the Promega CellTiter-Glo assay.

The results are presented in FIG. 4 . This example demonstrates that the combination of 6,8-bis-benzylthio-octanoic acid and metformin kills AML cells significantly better in vitro than either agent alone at the same concentration. .

Example 5 - Metformin sensitizes AML cells to CPI-613 in vivo.

On day 0 and starting from day 7, 1 million MFL2 cells were injected into the tail vein of C57Bl/6 mice, and upon confirmation of engraftment by bioluminescence imaging, the mice were treated with CPI-613 (with 4% glacial acetic acid). 300 mg/kg of a 50 mg/mL solution of CPI-613 in 0.05 N NaOH in 5% dextrose, adjusted to pH 7.5-8, by gavage, daily except weekends, or metformin (in drinking water) until death 1 mg/mL, ad hoc), or a combination of metformin (1 mg/mL in drinking water, ad libitum as above) plus CPI-613 (300 mg/kg gavage per day as above) (Met). +CPI) and followed for survival. P values were determined by log-rank test.

The results are presented in FIG. 5 . This example demonstrates that the combination of 6,8-bis-benzylthio-octanoic acid and metformin significantly prolongs the survival of AML tumor-bearing mice in vivo.

Example 6 - 2-deoxyglucose sensitizes AML cells to CPI-613 in vitro.

MFL2 cells (Pardee, TS et al., Experimental Hematology, 2011, 39, 473-485) (50,000 cells/mL) in 45% IMDM/45% DMEM/10% FBS at 37° C. under _{5% CO 2 for 72 hours.} After incubation with CPI-613 (50 μM), 2-deoxyglucose (0.25 mM or 0.5 mM), or a combination of CPI-613 (50 μM) and 2-deoxyglucose (0.25 mM or 0.5 mM) in Viability was assessed using the Promega CellTiter-Glo assay.

The results are shown in FIG. 6 . This example shows that the combination of 6,8-bis-benzylthio-octanoic acid and 2-deoxyglucose kills AML cells significantly better in vitro than when either agent was used alone at the same concentration in vitro. prove the facts

Example 7 - Combination of chloroquine and 2-deoxyglucose sensitizes AML cells to CPI-613 in vitro.

OCI-AML3 cells (100,000 cells/mL) in RPMI medium with 10% FBS, or MFL2 cells in 45% IMDM/45% DMEM/10% FBS (Pardee, TS et al., Experimental Hematology, 2011, 39, 473- 485) (50,000 cells/mL) with CPI-613 (50 μM), chloroquine (25 μM for OCI; 10 μM for MFL2), 2-deoxyglucose (in OCI) at 37° C. under _{5% CO 2 for 72 hours.} 10 mM for MFL2), or CPI-613 (50 μM), chloroquine (25 μM for OCI; 10 μM for MFL2), and 2-deoxyglucose (10 mM for OCI; 0.25 mM for MFL2) After incubation with the combinations, viability was assessed using the Promega CellTiter-Glo assay.

The results are presented in FIG. 7 . This example shows that the combination of 6,8-bis-benzylthio-octanoic acid, chloroquine and 2-deoxyglucose significantly reduced AML cells in vitro than either of the three agents alone at the same concentration. It proves that it kills better.

Example 8 - Chloroquine sensitizes PDAC cells to CPI-613 in vitro.

Pancreatic ductal adenocarcinoma cell line (PDAC), AsPC-1, PANC-1, BxPC-3, or MIA Paca-2 cells were seeded in complete RPMI medium at 30,000 cells per well in 96-well plates and cultured for 18 hours. Cells were then acclimatized to nutrient depletion conditions resembling tumor trophic conditions by incubating in serum-free RPMI for 20 h, followed by incubation in modified Eagles Balanced Salt Solution (EBSS) (CBS2 medium) for 3 h. The drug was administered in CBS2 medium and incubated for 20 hours. The drug-containing medium was replaced with serum-free RPMI and incubated overnight. All incubations were done in a humidified incubator at 37° C. and 5% CO _{2 .} Cell viability was assessed by the Promega CellTiter-Glo assay, where luminescence units are proportional to the number of living cells. Zero (0) luminescence units indicate that all cells have been killed.

For PANC-1 and ASPC-1 cells, drug treatment is as follows: chloroquine or hydroxychloroquine at 12.5 μM, 25 μM, 50 μM, 100 μM or 200 μM, CPI-613 at 10 μM, 20 μM or 40 μM, or chloroquine at the above concentrations or a combination of hydroxychloroquine and CPI-613. For BxPC-3 cells, drug treatment was as follows: chloroquine or hydroxychloroquine at 12.5 μM, 25 μM, 50 μM, 100 μM, or 200 μM, CPI-613 at 7.5 μM, 15 μM or 30 μM, or chloroquine or hydroxychloroquine at the above concentrations Combination of hydroxychloroquine with CPI-613. For MIA PaCa-2 cells, drug treatment is as follows: chloroquine at 12.5 μM, 25 μM, 50 μM, 100 μM or 200 μM, CPI-613 at 10 μM, 20 μM or 40 μM or a combination of chloroquine and CPI-613 at the above concentrations.

The results are presented in Figures 8-11. This example demonstrates that the combination of 6,8-bis-benzylthio-octanoic acid with chloroquine or hydroxychloroquine kills PDAC cells better in vitro than either agent alone.

Example 9 - Chloroquine sensitizes colorectal cancer cells to CPI-613 in vitro.

CoLo 205 cells were seeded at 60,000 cells per well in complete RPMI medium; LoVo cells were seeded at 60,000 cells per well in complete F12-K medium, and SW620 and HT29 cells were seeded at 60,000 cells per well in complete McCoys medium in 96-well plates and cultured for 18 hours. Then, each of these serum-free medium was incubated for 20 hours, followed by incubation in modified EBSS (CBS2 medium) for 3 hours, to adapt the cells to nutrient depletion conditions resembling tumor trophic conditions. The drug was administered in CBS2 medium and incubated for 20 hours. The drug-containing medium was replaced with serum-free RPMI and incubated overnight. All cultures were carried out in a humidified incubator at 37° C. and 5% CO _{2 .} Cell viability was assessed by the Promega CellTiter-Glo assay.

Drug treatment is as follows: 12.5 μM, 25 μM, 50 μM or 100 μM of chloroquine, 12.5 μM, 25 μM or 50 μM of CPI-613 alone or in combination.

The results are presented in FIGS. 12 and 13 . This example shows that the higher the CPI-613 concentration, the better the combination of 6,8-bis-benzylthio-octanoic acid and chloroquine kills colorectal cancer cells in vitro than either one of the agents alone. prove the

Example 10 - Chloroquine sensitizes non-small cell lung cancer cells to CPI-613 in vitro.

H460 cells were seeded at 30,000 cells per well in complete RPMI medium in a 96-well plate, and cultured for 18 hours. Cells were then acclimatized to nutrient depletion conditions resembling tumor trophic conditions by culturing in serum-free RPMI for 20 hours, followed by incubation in modified EBSS (CBS2 medium) for 3 hours. The drug was administered in CBS2 medium and incubated for 5 hours. The drug-containing medium was replaced with serum-free RPMI and incubated overnight. All cultures were carried out in a humidified incubator at 37° C. and 5% CO _{2 .} Cell viability was assessed by the Promega CellTiter-Glo assay.

Drug treatment is as follows: 12.5 μM, 25 μM, 50 μM, 100 μM, or 200 μM of chloroquine, 10 μM, 20 μM or 40 μM of CPI-613 alone or in combination.

The results are presented in FIG. 14 . This example demonstrates that the combination of 6,8-bis-benzylthio-octanoic acid and chloroquine kills non-small cell lung cancer cells better in vitro than either agent alone.

Example 11 - Treatment of high-risk MDS in human patients who have failed hypomethylation treatment with the combination of CPI-613 and hydroxychloroquine.

This is a single-arm open-label study. Investigators and study subjects are not blinded to treatment. Also, since there is only one arm in this study, the allocation of patients will not be random.

The main objective of this study was to determine the total response rate (Cure (CR), bone marrow remission, partial remission (PR), blood improvement (HI)). The second objective was to evaluate the safety of the combination, progression-free survival (PFS), total survival (OS), defined as the time from enrollment in the study to death from any cause, and changes in blood transfusion frequency. .

study design

The dose of CPI-613 will be 2,000 mg/m ² . The maximum tested dose of HCQ will be 1,200 mg. The sample size will be a total of 17 patients, who will be treated with MTD's HCQ for this Phase 1/2 trial. This number is based on Simon's two-stage design, in which nine patients will be enrolled in stage 1. If none of the nine patients respond, the study will be discontinued for no efficacy. If more than one patient responds, the trial will continue until a total of 17 patients are treated with the above combination of HCQs in MTD. If 2 or more of 17 patients respond, the combination will be considered worthy of further study with sufficient activity.

At the beginning of the study, hydroxychloroquine will be escalated from 600 mg to 1200 mg PO flat doses 2 hours prior to the infusion of CPI-613 every day 1-5 of every 28-day cycle. The dose of CPI-613 will be 2,000 mg/m ² and will not be escalated. A cohort of 3 patients will each be treated with HCQ of 600 mg, then 800 mg, and then 1,200 mg in the design of 3+3 dose escalation described below.

Dose escalation will continue in the cohort of 3 patients if no dose-limiting toxicity (see definition of DLT below) occurs in a given cohort of patients. However, if a DLT at any dose level is observed in a patient (regardless of whether the first, second, or third of 3 intended patients), the cohort at that dose level will expand to a maximum of 6 patients. If no DLT is observed in another of up to 6 patients, the dose escalation process will continue in 3 patients for each subsequent cohort until a final dose of 1,200 mg is reached. However, once a DLT is observed in a total of 2 patients at any dose level, HCQ administration to the patient will be discontinued immediately, although the total number of patients in the last cohort may be as low as 2 patients. Dose escalation is considered complete. A dose level that induces a DLT in two or more patients is considered above the MTD, and a dose level immediately below a dose level that induces a DLT in two or more patients is considered an MTD. If the initial dose of 600 mg is found to be above the MTD, the HCQ dose will drop to dose level-1 (400 mg). If the dose (400 mg) results in two DLTs, the study will be closed and toxicity data will be reviewed until any further enrollment. If the 1,200 mg cohort is complete without a DLT in the first 3 patients, or a second DLT in the first 6 patients, the dose escalation of HCQ will be complete. All subsequent patients will be treated at this dose level. HCQ dose levels are summarized in Table 1.

Definition of DLT: Dose-limiting toxicity is defined as the occurrence of any clinically relevant grade 3 or greater toxicity, possibly or absolutely due to its association with the combination of HCQ and CPI-613. The following toxicities are excluded from the definition of DLT: Grade 3 nausea and vomiting in response to anti-emetics, Grade 3 diarrhea in response to antidiarrheal treatment, Grade 3 oncolytic syndrome, oral or IV Grade 3 or Grade 4 metabolic derangement due to supplementally treated oncolytic syndrome or antimicrobial agents. Hemotoxicity can only act as a DLT if they show a significant (>50%) decrease from baseline. Infectious toxicity could only serve as a DLT if they were, in the opinion of the treating investigators, a reduction of 20% or more from baseline in ANC and not as a result of a natural history of relapsed or refractory MDS.

inclusion criteria

Patients must satisfy all of the following inclusions prior to enrollment:

1) Histologically documented MDS that has failed, has progressed, or has relapsed in response to hypomethylation agents.

1) At the time of registration, the Revised International Prognostic Scoring System (IPSS-R) score is medium, high, or very high.

2) ECOG performance status of 3 or less.

3) Men and women over 18 years of age.

4) Survival of more than 2 months.

5) Women of childbearing potential (i.e., women who are premenopausal or not surgically infertile) must use an accepted method of contraception (abstinence, intrauterine device [IUD], oral contraceptives or double barrier device) during the study and initiate treatment Serum or urine pregnancy test should be negative within the previous week.

6) Reproductive males should practice effective contraception during the study, unless infertility is documented.

7) The patient must fully recover from the acute, non-hematologic, non-infectious toxicity of cytotoxic drugs, radiotherapy or any previous treatment with other anti-cancer modalities. Patients with persistent, non-hematologic, non-infectious toxicity ≤ Grade 2 due to prior treatment are eligible, but must be documented.

8) Experimental values obtained within 2 weeks or less prior to registration must demonstrate adequate liver function, renal function, and coagulation as defined below:

a. 3×aspartate aminotransferase [AST/SGOT] below the upper limit of normal [UNL].

b. Alanine aminotransferase [ALT/SGPT] of 3×UNL or less.

c. Bilirubin less than 2×UNL

d. Serum creatinine of 1.5 mg/dL or 133 μmol/L or less.

e. Albumin greater than 2.0 g/dL or greater than 20 g/L

9) Mentally stable, capable of understanding and willing to sign an IRB-approved written informed consent form.

10) Access via a centerline (eg portacath).

Exclusion Criteria

Patients with the following characteristics are excluded:

1) Serious medical conditions that potentially increase the patient's risk for toxicity, such as significant heart disease (e.g., symptomatic congestive heart failure, unstable angina, symptomatic coronary artery disease, myocardial infarction within the past 3 months, control unexplained cardiac arrhythmias, pericardial disease, or New York Heart Association type III or IV), or severe debilitating lung disease.

2) Patients with active central nervous system (CNS) or epidural tumors.

3) Any active uncontrolled bleeding or hemorrhagic constitution (eg, active peptic ulcer disease).

4) Any condition or abnormality that, in the opinion of the investigator, would compromise the safety of the person.

5) Pregnant women, or women of childbearing potential who are not using reliable contraceptives.

6) Fertility males who were unwilling to practice contraception during the study period.

7) lactating women.

8) Life expectancy of less than 2 months.

9) Unwillingness or inability to follow the protocol.

10) Evidence of persistent, uncontrolled, serious infection.

11) Need for immediate palliative treatment of any kind, including surgery.

12) Patients with uncontrolled HIV infection.

13) Within 2 weeks prior to initiation of CPI-613 treatment, radiotherapy, surgery, treatment with cytotoxic agents (excluding hypomethylating agents, i.e., azacytidine or decitabine), biologics treatment, immunotherapy, or any other anti-cancer treatment of any other type, or any other standard treatment or treatment under investigation for these cancers, or any other study agent for any indication.

14) Patients receiving chemotherapy including stem cell adjuvant within the past 6 months.

Research Procedures

Table 2 provides an overview of the pre-study screening and assessments and procedures performed during each treatment cycle.

Treatment with CPI-613 and hydroxychloroquine

CPI-613 will be administered to the patient as shown in Table 3. Briefly, CPI-613 is given on days 1-5 of a 28-day cycle, with hydroxychloroquine taken orally 2 hours before each dose. Patients will receive pre-therapeutic antiemetics and adjuvant measures, as determined by the treating physician. The default premedication is an IV infusion 15 minutes prior to treatment, 16 mg of ondansetron orally administered 30 minutes prior to treatment, and an oral infusion 30 minutes prior to treatment (unless the patient has defecated within the last 48 hours). It will consist of 2 mg of loperamide.

The baseline transfusion frequency should be recorded as the number of transfusions received during the 8 weeks prior to enrollment. Once the patient begins protocol treatment, the frequency of transfusions should be assessed at the end of every two treatment cycles.

safety assessment

The safety of CPI-613 will be assessed from the first dose to 1 month after the last dose of CPI-613. Assessment will be based on assessment of symptoms, vital signs, ECOG performance status and survival, clinical chemistry (and renal function using the Cockcroft-Gault formula), and hematology. All safety assessment studies are performed during screening (conducted within 2 weeks prior to treatment with CPI-613). Additionally, assessment of symptoms, vital signs, ECOG, and survival will be assessed on each treatment day, and results will be available for review within 24 hours prior to administration of CPI-613. Clinical chemistry (renal function using Cockcroft-Goldt formula) hematology, and coagulation will be performed on Day 1 of each treatment cycle, and the results will be available for review within 24 hours prior to administration of dosing CPI-613.

At least the toxicities considered likely to be related to CPI-613 dose adjustments will be outlined in Table 4 below.

Once toxicity resolves below Grade 1 (or returns to baseline), the patient may re-escalate the dose of CPI-613 at the discretion of the treating investigator. Patients whose original toxicity recurs are not subject to subsequent dose re-escalation.

evaluation of response

Tumor response was assessed for myelodysplasia (as described in Cheson BD et al., Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood. 108:419-425, 2006). RR, PFS and OS, as well as changes in transfusion frequency from baseline will be assessed. RR and PFS derived from hematology and bone marrow examination will be assessed at baseline, during Week 4 of Cycles 3, 6 and 12, and thereafter every 6 treatment cycles until disease progression.

Baseline transfusion frequency should be recorded as the number of transfusions received during the 8 weeks prior to enrollment. Once the patient initiates protocol treatment, the frequency of transfusions should be measured at the end of every two treatment cycles.

Survival will be assessed during the study and will be monitored by contacting the treating physician after the patient has withdrawn from the trial. Using the ECOG Performance Status Scale (Oken MM et al., Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982), assess how the patient is progressing with the disease, and how the disease progresses. We will evaluate whether it affects the patient's daily life. ECOG grade 0 = normal activity. Fully functional and capable of performing all pre-disease performance without restriction. ECOG grade 1 = symptomatic but ambulatory; Physically strenuous activities are limited, but ambulatory and able to perform tasks of a light or sedentary nature (eg , light housework, office work). ECOG grade 2 = in bed less than 50% of the time; Ambulatory, capable of all self-care, but no work activities; More than 50% of waking hours at most. ECOG grade 3 = in bed more than 50% of the time; Only limited self-management, and in bed or chair for more than 50% of waking hours. ECOG grade 4 = 100% bedridden; completely immobile; no self-management; Completely in bed or in a chair. ECOG grade 5 = death.

The following variables will be reported from bone marrow examination: morphology, immunophenotype, cytoplasm, karyotype (cytogenetic means and FISH as appropriate), molecular markers, % of myeloblasts, % of dysplasia, WHO classification.

The revised International Working Group (IWG)-2006 Response Criteria to Change the Natural History of MDS is presented in Table 5 below.

To convert hemoglobin from grams per deciliter to grams per liter, multiply grams per deciliter by 10.

MDS represents myelodysplastic syndrome; Hgb, hemoglobin; CR, complete remission; HI, hematologic improvement; PR, partial remission; FAB, France-US-UK; AML, Acute Myeloid Leukemia; PFS, progression-free survival; Shows DFS, disease-free survival.

^* Dysplastic changes should be considered as dysplastic changes in the normal range (Revised).

† Revisions to IWG Response Criteria.

• In some situations, protocol treatment may require initiating additional treatment (eg, consolidation, maintenance) prior to a 4-week cycle. Such patients may be included in the response category they were in at the time of initiation of treatment. Transient cytopenia occurring during repeated courses of chemotherapy should not be considered as interrupting the continuity of the response, as long as they return to the improved numbers of the previous course.

The revised International Working Group (IWG)-2006 Response Criteria for Improving Blood is presented in Table 6 below.

No deletions are shown for the IWG response criteria.

Hgb is hemoglobin; RBC: red blood cells; HI: indicates blood improvement.

^{* The} pretreatment count averages (revised) at least two measurements (not affected by transfusion) at intervals of at least 1 week.

† Revisions to IWG Response Criteria.

‡ Without further explanation, eg, acute infection, repeated course of chemotherapy (revision), gastrointestinal bleeding, hemolysis, etc. It is recommended that the two types of erythrocyte and platelet responses be reported as an overall response pattern as well as an individual response pattern.

Treatment with CPI-613 and HCQ should be continued as long as the treating physician deems there is no clinical benefit or until the following occurs: the patient exhibits disease progression; unacceptable toxicity resulting from CPI-613 and HCQ despite dose reduction; waiver of patient consent; the investigator's judgment to exclude a patient from the study because continued participation in the study is not in the patient's best interest; underlying medical conditions (conditions, injuries, or diseases not related to the intended disease for which the study is ongoing, which render continued treatment unsafe or prevent periodic follow-up); general or specific changes in the patient's condition that render the patient ineligible for further treatment under study; refusal to study treatment, protocol-requirement assessment, or follow-up visit; or termination of a clinical trial. Upon withdrawal from the trial, the patient's survival and post-study cancer treatment will be monitored through follow-up of physician visits after the patient is withdrawn from the clinical trial. All patients will be followed up for 5 years after treatment (unless informed consent is given to waive follow-up) or until death.

CPI-613

CPI-613 is provided in a 10-mL yellow glass vial. Each vial contains 10 mL of CPI-613 at a concentration of 50 mg/mL, equivalent to 500 mg of CPI-613. The drug product of CPI-613 is a clear, colorless solution that does not contain any particulate matter.

CPI-613 is administered IV by infusion, via an IV containing D5W running at a rate of about 125-150 mL/hr. To avoid local reactions at and near the site of administration, CPI-613 should be administered by a central venous catheter.

CPI-613 is capable of leaching DEHP from IV infusion sets and IV pouches. Therefore, DEHP-containing IV infusion sets, IV pouches or syringes should not be used for mixing or administering CPI-613. Examples of IV sets, IV pouches and syringes that do not contain DEHP and thus can be used for administration of CPI-613 include:

• Extension Sets for Syringe Pump Applications : All extension sets from MED-RX are DEHP-free.

● Syringe : All Monoject syringes do not contain DEHP.

● IV Infusion Sets : The IV infusion sets that can be used to administer CPI-613 include:

ㆍ PVC Material - Universal Spike, Backcheck Valve, ADDitIV™ Primary IV Set with 2 Injection Sites, DEHP-Free and Latex-Free, 15 Drops/mL, REF V14453, B Braun Medical Inc.

ㆍ Latex material - Interlink™ System Secondary Medication Set, 10 drops/mL, 2C7451, Baxter Healthcare Corporation

ㆍ PVC material - Surshield™ Safety Winged Infusion Set, 0.19mL volume, latex-free, DEHP-free, SV*S25BLS, Terumo Medical Products Hangzhou Co. Ltd.

Polyethylene material - Interlink® System Paclitaxel Set from Baxter HealthCare, non-DEHP-free: Polyethylene tube with 0.22 microfilter, Item # 2C7558, 10 drops/mL

● Syringe : CPI-613 drug product (50 mg/mL) and drug product diluted to various concentrations (1.6-25 mg/mL) by D5W are compatible with the various types of syringes listed below. Thus, any syringe of these types, and syringes made of the same material, can be used to administer CPI-613. In addition, since glass (eg, glass containers) is compatible with the CPI-613 drug product, glass syringes may also be used.

ㆍ Norm-Ject, polyethylene barrel, polyethylene plunger, latex-free (Henke Sass Wolf GMBH) syringe

ㆍ Becton Dickinson syringe

ㆍ Terumo syringe

ㆍ Monoject syringe

・Glass syringe.

CPI-613 should be diluted from 50 mg/mL to 12.5 mg/mL in 5% dextrose water (D5W) prior to dosing (ie, 1x CPI-613 diluted with 3x D5W). Diluted drug products should be visually inspected for transparency. If turbidity, sediment, or color (not colorless) is observed, the diluted drug product is not used for administration. After dilution with sterile D5W, the solution is clear and has a pH of 8.4-8.8. The diluted CPI-613 drug product was found to be stable at room temperature and refrigerated temperature for 24 hours.

CPI-613 should be administered IV through an IV catheter that does not contain air and flowing into the dead space of the IV catheter to minimize vascular irritation, inflammation, and acute toxicity of CPI-613. Animal studies demonstrate the potential to induce acute toxicity of CPI-613 if additional air is accidentally co-administered in the dead space of an IV catheter during administration of CPI-613. In addition, accidental leakage of CPI-613 into the perivascular space during IV administration prolongs the exposure of perivascular tissues to CPI-613, which can induce significant local inflammation according to animal studies. To avoid local reactions at or near the site of administration, CPI-613 should be administered via a central venous catheter.

CPI-613 should be administered via a central venous catheter with a D5W flowing at a rate of about 125-150 mL/hr, by infusion, not as a bolus, at a rate of 0.5 mL/min or less. This will minimize the potential acute toxicity of CPI-613 according to animal studies.

When administering CPI-613, the following precautions should be taken:

● Confirmation of IV line placement to ensure that CPI-613 does not leak into the perivascular space.

● Verify that there is no flow in the IV line.

● Ensure that the IV line does not contain dead air space.

● Dilute the CPI-613 drug product by D5W as described in the study protocol.

● Administer CPI-613 as an infusion, not as a bolus.

• After administration of CPI-613, flush the IV line with 10 mL or less of D5W to remove residual CPI-613.

● To avoid local reactions at and around the site of administration, CPI-3 should be administered via a central venous catheter.

The amount of CPI-613 at each dose level is based on the patient's BSA. BSA values will be calculated based on height and weight measured during screening, and these BSA values will be used throughout the study. This is done during the study until there is a change in body weight greater than 10% from baseline. At that point, the BSA should be corrected based on the new weight and height. The new BSA value will be used for the remainder of the study from that point until there is an additional >10% body weight change, and further correction of the BSA will be required if there is an additional >10% body weight change.

other agents

Patients cannot receive any standard of care or on-trial treatment (except CPI-613 and hydroxychloroquine) for their MDS during this study, or receive any other on- investigation drugs for any indication that is not cancer. none. All other permissible ancillary medications (including trade names and generic names, dosages and dosing schedules) should be reported. Treatment of disease-related symptoms (eg, nausea) is permitted. Medication administered in these cases is considered concomitant medication and should be documented. Adjuvant treatments may include anti-emetic agents, antidiarrheal agents, antipyretics, anti-allergic agents, anti-hypertensive medications, analgesics, antibiotics, allopurinol, and others, such as blood products. Patients may use growth factors in accordance with ASCO guidelines at the discretion of the treating investigator.

adverse event

For AE reporting, the CTEP active version (CTCAE 4.0) of the NCI Common Terminology Criteria for Abnormalities was used. This can be found and found on the website [http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm]. All appropriate therapeutic areas will be available in copies of the CTEP valid version.

Attributes of an anomaly (AE):

● Absolute -AE is clearly related to study treatment.

● Likely -AEs are likely to be related to study treatment.

● Possible -AE may be related to study treatment.

● Low probability -AE is uncertainly related to study treatment.

● Not relevant -AE Not explicitly related to study treatment.

List of Abnormalities to be Reported: Abdominal pain; alkaline phosphatase; ALT (SGPT); anorexia; AST (SGOT); bilirubin; (hyperbilirubin); calcium (hypercalcemia, hypocalcemia); creatinine; diarrhea; flushing; hemoglobin (anemia); injection site reactions; leukocyte; lymphopenia; sickness; neutrophils (neutropenia); thrombocytopenia (thrombocytopenia); potassium; salt; throw up. All Class 3, 4, and 5 anomalies, whether or not they are on this list, should be reported in the flow sheet and in ORIS. All unexpected grade 4 and all grade 5 SAEs in this study should be reported for review.

Any unforeseen issues related to risks and abnormalities to the subject or otherwise should be reported to the IRB immediately. Reporting to the IRB is required irrespective of funding sources, research sponsors, or whether the above anomalies relate to drugs, biologicals or devices being studied or marketed. Reportable events are not limited to physical injuries, but include physiological, economic and social harm. A reportable matter may arise as a result of a drug, biological, device, process, or other intervention, or as a result of an inquiry, investigation, observation, or other interaction with a subject of study.

All members of the research team are responsible for properly reporting any unforeseen issues related to risks to subjects, etc. to the IRB and other appropriate agencies. However, the study director is ultimately responsible for making sure and urgently reporting any unforeseen issues related to subjects or other risks to the IRB. The study director will also be responsible for determining whether the report presents a change in risks and/or benefits for study participants, and whether any changes in informed consent, protocols, or other study-related documents are necessary, including any other It is also responsible for ensuring that any unforeseen risks reported for the

Any unforeseen issues related to risks to subjects, etc., occurring in locations approved by the IRB (Internal Matters), must be reported to the IRB. Any matter, event, experience or outcome that justifies a substantial change in the research protocol or informed consent process/documentation to change the risks versus potential benefits of the research and, as a result, ensure the safety, rights or welfare of the research subjects , must be reported to the IRB.

Statistical Considerations

The sample size will be a total of 17 patients, who will be treated with MTD's HCQ for this Phase 1/2 trial. This number is based on Simon's two-stage design (Simon R., Controlled Clinical Trial, 1989, 10:1-10), in which nine patients will be enrolled in stage 1. If none of the 9 patients respond, the study will be discontinued as no efficacy. If more than one patient responds, the trial will continue until a total of 17 patients have been treated in combination with MTD's HCQ. If two or more of the 17 patients respond, the combination will be considered to have sufficient activity to warrant further study. These variables give an α of 0.0466 and a power of 0.8122 to detect differences from no publication (set at a response rate of 5%).

Data handling and reporting schedule

Disease response (as described in Cheson BD et al., Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood. 108:419-425, 2006) RR, PFS, and OS , as well as changes in transfusion frequency from baseline. RR and PFS from hematology and bone marrow examinations will be assessed at the following specific time points:

● Base time

● Up to cycle 6, every 4 weeks of every 2 treatment cycles.

● After that, every 3 treatment cycles (ie cycle 9, cycle 12, cycle 15, etc.) until evidence of disease progression appears.

Bone marrow examination results should be documented at each specific time point.

Example 12 -Oral efficacy of 6,8-bis-benzylthio-octanoic acid in non-small cell lung cancer

Human H460 NSCLC cells were obtained from American Type Cell Culture (ATCC) (Cat. No. HTB-177, Manassas, Va.). These cells tested were tested negative for viral contamination in a mouse antibody production (MAP) test conducted by the Charles River Labs Molecular Division when they received tumor cells from the ATCC. Tumor cells were cultured in a T225 tissue culture flask containing 50 mL of a Roswell Park Memorial Institute (RPMI)-1640 solution containing 10% fetal bovine serum (FBS) and 2 mM L-glutamine at 37 °C _{in a humidified 5% CO 2 atmosphere.} was maintained Cells were split at a ratio of 1:10 every 2-3 days by trypsinization and resuspended in fresh medium in fresh flasks. When 70-90% confluency was reached, cells were harvested for experiments in the same manner.

CD1-Nu/Nu female mice up to 4-6 weeks of age were obtained from Charles River Laboratories. Mice were housed 5 per cage in the micro-isolator of the Department of Animal Laboratory Research at the State University of New York (SUNY), Stony Brook. The light-dark cycle was 12 hours daily, and the light was exposed from 7 am to 7 pm. Feed (Purina Rodent Chow) and water (distilled sterile-filtered water, pH 7) were supplied ad libitum. Protocols and procedures followed the rules and were approved by the SUNY Commission on Animal Experiments (IACUC).

An acclimatization period of 7 days was allowed between the animals' arrival at the study site and the experiment prior to tumor inoculation. ^{In the right flank of mice, 2×10 6} human H460 NSCLC or BxPC3 pancreatic cancer cells suspended in 0.1 mL of Dulbecco’s phosphate buffered salt (PBS) solution were subcutaneously injected using a 1 cc syringe with a 27-5/8 gauge needle. (SC) inoculated. Tumor dimensions (length and width) were measured daily before, during, and after treatment (using Vernier calipers), and tumor volume was calculated using the ^{prolate ellipsoid formula: (length×width 2 )/2} did. Treatment with test article or control article was started 8 days after tumor cell transplantation when the ^{tumor was approximately 300 mm 3 .}

The oral dose of 6,8-bis-benzylthio-octanoic acid was 100 mg/kg for 11 animals per group. 100 mg of 6,8-bis-benzylthio-octanoic acid was suspended in a small volume of 0.01-0.05N NaOH in 5% dextrose and titrated to pH 7.0 with 4% glacial acetic acid to give 50 mg/mL. Prior to dosing, the suspension was diluted to 12.5 mg/mL with 5% dextrose, and 100 mg/kg was delivered to the animals by gavage in a dose volume of about 0.2 mL. After tumor cell transplantation, mice were treated on days 8, 15, 22 and 29.

A similar study was performed in CD-1 nude mice (n = 9) inoculated with ^{2×10 6 BxPC-3 cells.} The study was initiated when the tumors reached a mean size of 150 mm ³ (day 0) and CPI-613 was administered at an oral dose of 100 mg/week for 4 weeks. The comparator arm (n=9) was performed by IP treatment at a once-weekly dose of 25 mg/kg.

The results are presented in FIGS. 15 and 16 . It is evident that the tumors of mice treated with 6,8-bis-benzylthio-octanoic acid grew much more slowly than mice treated with or without 5% dextrose. The effect was particularly remarkable in BxPC3 tumors. This example demonstrates that 6,8-bis-benzylthio-octanoic acid, when administered orally, is effective in the treatment of cancer.

Example 13 Spray dried dispersion oral formulation of -6,8-bis-benzylthio-octanoic acid

A solid amorphous dispersion formulation of 6,8-bis-benzylthio-octanoic acid (API) is formulated with API and the following polymers: Eudragit L100, poly(vinylpyrrolidone) viscosity grade K30 (PVP K30), hydroxypropyl methyl cellulose (HPMC), cellulose acetate phthalate (CAP), or hydroxypropyl methylcellulose acetate succinate (HPMCAS-M) was mixed 1:4 and a small-scale Bend Lab dryer was installed at a dry gas flow rate of 35 kg/hr. It was prepared by spray drying from methanol or acetone using a dose (BLD-35). The conditions, yields and residual solvent levels of two representative spray dried dispersion (SDD) formulations (75 g each) are presented in the table below.

Scanning electron microscopy (SEM) was used to qualitatively determine the particle morphology of the two SDD formulations and study whether any degree of fusion or crystallization was visually present. The particles appeared in the form of crushed spheres, with no crystallization or noticeable fusion.

X-ray diffraction is sensitive to the presence of crystalline materials that typically have an LOD of about 1% of the sample mass. For either of the SDD formulations, no crystals were detected by PXRD. A diffractogram versus 6,8-bis-benzylthio-octanoic acid API can be found in Figure 17, where the upper diffractogram is the Eudragit L100 formulation and the middle diffractogram is HPMCAS-M formulation, lower diffractogram is crystalline form 6,8-bis-benzylthio-octanoic acid.

Example 14 -Oral emulsion formulation of -6,8-bis-benzylthio-octanoic acid

Monolaurin (131 mg) and 6,8-bis-benzylthio-octanoic acid (93 mg) were warmed to 50 °C in polysorbate-80 (2.5 mL) in a round bottom flask equipped with a magnetic stir bar. did it After complete dissolution into a clear solution, water (7.5 mL) was added with vigorous stirring at 50° C. to give an emulsion.

6,8-bis-benzylthio-octanoic acid (312 mg), polysorbate 80 (6.25 g), soybean oil (1.25 g), and cholesterol (14 g), cholesteryl acetate (14 g), cholesteryl benzoate ( 14 g), monolaurin (25.4 g) and monopalmitin (32.6 g) were combined with a lipid mix (100 mg) and the mixture was heated to 50° C. until the solids dissolved (30 min). Dextrose (11.25 g) was dissolved in 236 mL of water and the resulting aqueous dextrose solution was added to the oil solution. The resulting biphasic mixture was stirred at room temperature for 30 minutes and then vacuum filtered through a 0.22 um filter.

Example 15 Liquid formulation of -6,8-bis-benzylthio-octanoic acid

The 6,8-bis-benzylthio-octanoic acid solution was prepared by (a) providing a 50 mg/mL solution of 6,8-bis-benzylthio-octanoic acid in 1 M aqueous triethanolamine, and (b) 50 mg /mL solution was prepared by diluting with 5% aqueous dextrose to a concentration of 5 mg/mL. The resulting 5 mg/mL solution is identified as "15A" in Example 16 below.

A suspension vehicle was prepared by the following steps: (a) combining Tris buffer (48 mg) and HPMCAS-HF (20 mg) in 14 mL of distilled water, (b) adjusting the pH to 7.4 with dilute sodium hydroxide, Dissolving HPMCAS-HF, (c) heating the resulting solution to approximately 90° C., (d) adding Methocel A4M Premium (100 mg) to the hot solution, (e) stirring the mixture thoroughly, suspending the dissolved Methocel A4M, (f) cooling and stirring the mixture in an ice-water bath until Methocel A4M is dissolved (approximately 10 minutes), (g) diluting the solution with distilled/deionized water, bringing the total volume to 20 mL, and (h) adjusting the pH to 7.4 with dilute acetic acid or dilute sodium hydroxide to provide a suspension vehicle.

A suspension of the spray-dried formulation of Example 13 was prepared by adding 400 mg of each SDD formulation to a mortar, slowly adding 4 mL of the suspension vehicle (in small portions after each addition, then to the mortar) mixing thoroughly until uniformly dispersed), and then transferring to a flask and stirring for 1 minute prior to dosing. The resulting suspension of Eudragit L100 SDD formulation (6,8-bis-benzylthio-octanoic acid at 20 mg/mL) is identified as "15B" in Example 16 below. The resulting suspension of HPMCAS-M SDD formulation (6,8-bis-benzylthio-octanoic acid at 20 mg/mL) is identified as "15C" in Example 16 below.

In the same way, a 20 mg/mL suspension of 6,8-bis-benzylthio-octanoic acid is prepared by adding 80 mg of 6,8-bis-benzylthio-octanoic acid to a mortar, 4 mL of the suspension vehicle slowly adding (in small portions of each, mixing thoroughly until uniformly dispersed with a mortar), then transferring to a flask and stirring for 1 minute prior to dosing. The resulting suspension of 6,8-bis-benzylthio-octanoic acid is identified as "15D" in Example 16 below.

A solution of 6,8-bis-benzylthio-octanoic acid was prepared by dissolving SOLUTOL® (polyoxyl 15 hydroxystearate; KOLLIPHOR® HS 15) (3 grams) in distilled water (7 mL) to form a 30% solution. , 6,8-bis-benzylthio-octanoic acid (50 mg) was added to 5 mL of the 30% solution, vortexed for 1 minute, and then sonicated for 45 minutes, resulting in a clear colorless solution (10 mg/mL; pH 7). The resulting solution is identified as "15E" in Example 16 below.

Example 16 Oral bioavailability of -6,8-bis-benzylthio-octanoic acid

Six groups of 16 BALB/c nude mice (8 males and 8 females) per group were dosed with 6,8-bis-benzylthio-octanoic acid in 6 different ways: (1) 5 μL/g IV injection of triethanolamine/dextrose aqueous solution of Example 15 (tail vein) (25 mg/kg; 5 mL/kg; Ex. 15A); (2) 5 μL/g IP injection of triethanolamine/dextrose aqueous solution of Example 15 (25 mg/kg; 5 mL/kg; 15A); (3) oral administration of 5 μL/g of Eudragit L100 SDD suspension of Example 15 (100 mg/kg; 5 mL/kg; 15B); (4) 5 μL/g oral administration of the HPMCAS-M SDD suspension of Example 15 (100 mg/kg; 5 mL/kg; 15C); (5) 5 μL/g oral administration of the 20 mg/mL 6,8-bis-benzylthio-octanoic acid suspension of Example 15 (100 mg/kg; 5 mL/kg; 15D); or (6) 10 μL/g oral administration of the 10 mg/mL SOLUTOL solution of Example 15 (100 mg/kg; 10 mL/kg; 15E). In each experiment, subgroups of 4 male and 4 female mice were treated at 0.083 hours, 1 hour, 4 hours and 24 hours after dosing and 4 mice 0.5 hours, 2 hours and 8 hours after dosing. From different subgroups of males and four females, approximately 80 μL of blood was drawn. Plasma from the collected blood samples was analyzed by LC-MS/MS in the presence of 6,8-bis-benzylthio-octanoic acid.

This example demonstrates that 6,8-bis-benzylthio-octanoic acid is orally bioavailable.

Inclusion by reference

The patent literature and scientific papers mentioned herein are each incorporated by reference in their entirety for all purposes.

equality

The present invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. Accordingly, the above embodiments are to be considered in all respects illustrative rather than limiting of the invention described herein. Accordingly, the scope of the present invention is indicated by the appended claims rather than the above detailed description, and all changes within the meaning and scope of the doctrine of equivalents are intended to be embraced therein.

Claims (38)

A method of treating cancer in a human patient in need thereof, comprising administering to the patient a therapeutically effective amount of 6,8-bis-benzylthio-octanoic acid and an autophagy inhibitor. The method of claim 1 , wherein the cancer exhibits increased autophagy in response to contact with CPI-613. The method of claim 1 , wherein the cancer is lymphoma. 4. The method of claim 3, wherein the lymphoma is relapsed or refractory Hodgkin's lymphoma. 5. The method of claim 4, wherein the patient has failed brentuximab vedotin and a PD-1 inhibitor. 4. The method of claim 3, wherein the lymphoma is relapsed or refractory T-cell non-Hodgkin's lymphoma. 7. The method of claim 6, further comprising administering to the patient a therapeutically effective amount of bendamustine hydrochloride. 4. The method of claim 3, wherein the lymphoma is relapsed or refractory Burkitt's lymphoma. The method of claim 3 , wherein the lymphoma is a high-grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6. The method of claim 1 , wherein the cancer is leukemia. The method of claim 1 , wherein the cancer is carcinoma. The method of claim 1 , wherein the cancer is sarcoma. The method of claim 1 , wherein the cancer is myeloma. The method of claim 1 , wherein the cancer is clear cell cancer. The method of claim 14 , wherein the cancer is clear cell sarcoma. The method of claim 14 , wherein the cancer is clear cell carcinoma. The method of claim 16 , wherein the cancer is clear cell renal carcinoma. The method of claim 1 , wherein the cancer is a solid tumor. The method of claim 1 , wherein the cancer is brain cancer or spinal cord cancer. The method of claim 1 , wherein the cancer is melanoma. The method of claim 1 , wherein the cancer is blastoma. The method of claim 1 , wherein the cancer is a germ cell tumor. The method of claim 1 , wherein the cancer is cancer of the pancreas. The method of claim 1 , wherein the cancer is cancer of the prostate. The method of claim 1 , wherein the cancer is myelodysplastic syndrome. The method of claim 25 , wherein the cancer is high risk myelodysplastic syndrome. The method of claim 26 , wherein the cancer is a high-risk myelodysplastic syndrome in a patient who has failed, has progressed or relapsed to hypomethylation therapy. 3. The method of claim 1 or 2, wherein the cancer is not clear cell cancer. 3. The method of claim 1 or 2, wherein the cancer is not clear cell sarcoma. 3. The method of claim 1 or 2, wherein the cancer is non-clear cell sarcoma. 3. The method of claim 1 or 2, wherein the cancer is not a soft tissue cancer. 3. The method of claim 1 or 2, wherein the cancer is not clear cell carcinoma. 33. The method of any one of claims 1-32, wherein the autophagy inhibitor is 4-aminoquinoline. 34. The method of claim 33, wherein the autophagy inhibitor is hydroxychloroquine. 35. The method of claim 34, wherein the hydroxychloroquine is administered to the patient as hydroxychloroquine sulfate. 34. The method of claim 33, wherein the autophagy inhibitor is chloroquine. 37. The method of claim 36, wherein the chloroquine is administered to the patient as chloroquine phosphate. A method of treating cancer other than clear cell sarcoma in a human patient in need thereof, comprising administering to the patient a therapeutically effective amount of 6,8-bis-benzylthio-octanoic acid and an autophagy inhibitor.

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