JP2022515171A - Therapeutic methods and compositions for treating cancer with 6,8-bis-benzylthio-octanoic acid and autophagy inhibitors - Google Patents

Abstract

The present invention provides methods and compositions for treating cancer by administering therapeutically effective amounts of 6,8-bis-benzylthio-octanoic acid and an autophagy inhibitor to patients in need thereof. offer. [Selection diagram] Fig. 1

Description

Mutual reference to related applications This application is a US provisional patent application No. 62 / 782,928 filed on December 20, 2018, and a US provisional patent application No. 62/793 filed on January 17, 2019. Benefits of 667, US Provisional Patent Application No. 62 / 834,475 filed April 16, 2019, and US Provisional Patent Application No. 62 / 854,599 filed May 30, 2019. Priority is claimed and the content of each of these is incorporated herein by reference.

The present invention provides methods and compositions for treating cancer by administration of 6,8-bis-benzylthio-octanoic acid and an autophagy inhibitor. The present invention further provides methods and compositions for treating cancers other than clear cell non-epithelial malignancies by administration of 6,8-bis-benzylthio-octanoic acid and phagocytosis inhibitors.

CPI-613 (6,8-bis-benzylthio-octanoic acid) is a breakthrough test small molecule (lipoic acid analog) that targets modified energy metabolism common to many cancer cells. CPI-613 has been evaluated in multiple Phase I, I / II, and Phase II clinical trials, including pancreatic cancer, acute myeloid leukemia (AML), peripheral T-cell lymphoma (PTCL), and Berkitt lymphoma. And is designated as an orphan drug for the treatment of myelodysplastic syndrome (MDS).

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

The present invention is a method and composition for treating a cancer in a patient in need thereof by administering to the patient a therapeutically effective amount of 6,8-bis-benzylthio-octanoic acid and an autophagy inhibitor. Provide things. The cancer may be recurrent or refractory. Cancers include lymphoma, leukemia, epithelial malignancies, non-epithelial malignancies, melanoma, myeloma, brain or spinal cord cancer, blastoma, germ cell tumor, pancreatic cancer, colon cancer, myelodysplasia syndrome, Alternatively, it may be cancer of the prostate. In certain embodiments, the cancer is lymphoma, leukemia, epithelial malignancies, non-epithelial malignancies, melanoma, or myeloma. In certain embodiments, the cancer is relapsed or refractory Hodgkin lymphoma, relapsed or refractory T-cell non-Hodgkin's lymphoma, relapsed or Relapsed or refractory Hodgkin lymphoma, including refractory Burkitt lymphoma, or high-grade B-cell lymphoma with rearrangements of MYC and BCL2 and / or BCL6.

The present invention administers therapeutically effective doses of 6,8-bis-benzylthio-octanoic acid and phagocytosis inhibitors to patients in need of treatment for cancers other than clear cell non-epithelial malignancies. Further provided are methods and compositions for doing so. The cancer may be recurrent or refractory. Cancers include lymphoma, leukemia, epithelial malignant tumor, non-clear cell non-epithelial malignant tumor, melanoma, myeloma, brain or spinal cord cancer, blastoma, germ cell tumor, pancreatic cancer, colon cancer, myelodysplasia. It may be dysplastic syndrome or cancer of the prostate. In certain embodiments, the cancer is lymphoma, leukemia, epithelial malignancies, non-clear cell non-epithelial malignancies, melanomas, or myelomas.

The aforementioned embodiments of the present invention will be described in more detail in the following detailed description, along with additional embodiments.

Induction of phagocytosis by 6,8-bis-benzylthio-octanoic acid in K562 and MFL2 AML cells is shown. HBSS = Hanks equilibrium salt solution. In vitro treatment of K562 and OCI-AML3 cells with a combination of chloroquine and CPI-613 is shown. All concentrations listed are μM. The treatment of MFL2 syngeneic tumors in C57Bl / 6 mice with a combination of CPI-613 and chloroquine is shown. In vitro treatment of MFL2 cells with a combination of metformin and CPI-613 is shown. All concentrations listed are μM. Met = metformin, CPI = CPI-613 The treatment of MFL2 syngeneic tumors in C57Bl / 6 mice with a combination of metformin and CPI-613 (Met + CPI) is shown. In vitro treatment of MFL2 cells with a combination of 2-deoxyglucose and CPI-613 is shown. CPI = CPI-613 (μM), 2DG = 2-deoxyglucose (mM). In vitro treatment of OCI-AML3 cells and MFL2 cells with a combination of chloroquine, 2-deoxyglucose and CPI-613 is shown. In vitro treatment of PANC-1 cells with chloroquine, hydroxychloroquine, or CPI-613 alone or in combination is shown. In vitro treatment of AsPC-1 cells with chloroquine, hydroxychloroquine, or CPI-613 alone or in combination is shown. In vitro treatment of BxPC-3 cells with chloroquine, hydroxychloroquine, or CPI-613 alone or in combination is shown. In vitro treatment of MIA PaCa-2 cells with chloroquine or CPI-613 alone or in combination is shown. In vitro treatment of CoLo 205 and LoVo cells with a combination of chloroquine and CPI-613 is shown. In vitro treatment of SW620 and HT-29 cells with a combination of chloroquine and CPI-613 is shown. In vitro treatment of H460 cells with a combination of chloroquine and CPI-613 is shown. We show the antitumor efficacy of oral 6,8-bis-benzylthio-octanoic acid in human non-small cell lung cancer xenografts in mice. We show the antitumor efficacy of oral 6,8-bis-benzylthio-octanoic acid in human pancreatic cancer xenografts in mice. 6,8-bis-benzylthio-octanoic acid with either Amorphous L100 or hydroxypropylmethylcellulose acetate (HPMCAS-M) (upper and intermediate diffraction patterns, respectively), and crystalline 6,8-bis-benzylthio. -The X-ray powder diffraction pattern of the solid amorphous dispersion preparation of succinic acid (diffraction pattern below) is shown.

The present invention is a method and composition for treating a cancer in a patient in need thereof by administering to the patient a therapeutically effective amount of 6,8-bis-benzylthio-octanoic acid and an autophagy inhibitor. Provide things. The present invention administers therapeutically effective doses of 6,8-bis-benzylthio-octanoic acid and phagocytosis inhibitors to patients in need of treatment for cancers other than clear cell non-epithelial malignancies. Further provided are methods and compositions for doing so.

The practice of the present invention uses conventional techniques of pharmaceutical chemistry, pharmacology, and biochemistry unless otherwise indicated. The various aspects of the invention are described in the following sections, but the aspects of the invention described in one particular section should not be limited to any particular section.

I. Definitions To facilitate understanding of the invention, some terms and phrases are defined below.

The terms "a," "an," and "the," as used herein, mean "one or more," and include more than one, unless context is inappropriate.

The term "6,8-bis-benzylthio-octanoic acid" refers to a compound known as devimitat or CPI-613, which has the following chemical structure:

Certain compounds contained in the compositions of the present invention may be present in a particular geometric or stereoisomeric form. The present invention comprises all such compounds, including cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, racemic mixtures thereof, and other mixtures thereof. It is intended to fall within the scope of the present invention.

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

As used herein, the term "treating" refers to any condition, disease, disorder, or similar, or any effect that results in amelioration, stabilization, or delay in progression thereof, eg, Includes mitigation, reduction, adjustment, improvement, or elimination. For example, treatment may include diminishing the symptoms of the disease or completely eradicating the disorder. As another example, treatment may include delaying the progression of the disease, or preventing or delaying its reproduction, eg, maintenance treatment to prevent or delay recurrence.

"Therapeutically effective amount" refers to the amount of compound sufficient to inhibit, stop, or cause amelioration of the disorder or condition being treated in a particular patient or patient population. For example, a therapeutically effective amount can be an amount of drug sufficient for maintenance treatment to prevent or delay the progression of the disease, or its reappearance, eg, recurrence. A therapeutically effective amount can be determined experimentally in a laboratory or clinical environment, even if it is the amount required by the US Food and Drug Administration or equivalent foreign agency guidelines for the particular disease and patient being treated. good. It should be understood that the determination of suitable dosage forms, dosages and routes of administration is within the level of those skilled in the pharmaceutical and medical fields.

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

The phrase "pharmaceutically acceptable" means that, within sound judgment, toxicity, irritation, and allergic responses are acceptable and other problems or complications are commensurate with a reasonable benefit / risk ratio. As used herein, it refers to a compound, substance, composition, and / or dosage form suitable for use in contact with human tissue.

As used herein, the term "pharmaceutically acceptable excipient" refers to any of the standard pharmaceutical excipients suitable for use in humans. Examples of excipients include, for example, Martin, Remington's Pharmaceutical Sciences, 15th Ed. , MacPubl. 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, the "salt" of a compound of the invention may be derived from an inorganic or organic acid and an inorganic or organic base. Examples of acids are 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, tartrate acid, acetic acid. , Citric acid, methanesulfonic acid, ethanesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, and the like, but not limited to these. Examples of bases are alkali metal (eg, sodium) hydroxides, alkaline earth metals (eg, magnesium), hydroxides, ammonia, and compounds of formula NW ₃ (where W is C _1-4 alkyl). ), And similar, but not limited to these.

Further examples of salts include salts made using the ion adsorbents described in US Pat. No. 8,263,653, which is incorporated herein by reference in its entirety. Further ion combinations are described in Handbook of Pharmaceutical Salts Properties, Selection and Use, UIPAC, Wiley-VCH, P. et al., The entire disclosure of which is incorporated herein by reference. H. Stahl, ed. Can be selected using the guidelines from.

For therapeutic use, the salts of the compounds of the invention are contemplated as pharmaceutically acceptable. However, pharmaceutically acceptable acid and base salts may also be used, for example, in the preparation or purification of pharmaceutically acceptable compounds.

Throughout the description, if the composition is described as having, including, or compiling a particular component, or the process and method has a particular step, including. Or, where described as complicating, there is a composition of the invention consisting essentially of, or consisting of, the listed components, and essentially from the listed steps, or they. It is also contemplated that there is a process and method according to the invention comprising.

As a general rule, compositions that specify a percentage are by weight, unless otherwise specified. In addition, if the variable has no definition, the previous definition of the variable dominates.

II. Therapeutic Use The present invention relates to the treatment of cancer in a human patient in need thereof, comprising the step of administering to the patient a therapeutically effective amount of 6,8-bis-benzylthio-octanoic acid and an anti-phagocytosis agent. The method and composition of the above are provided. The present invention requires the treatment of cancers other than clear cell non-epithelial malignancies, comprising the step of administering to a patient a therapeutically effective amount of 6,8-bis-benzylthio-octanoic acid and a phagocytosis inhibitor. Further provided are methods and compositions for use in human patients.

The inventors have found that cancer cells exhibit increased phagocytosis when exposed to CPI-613. Not hoping to be bound by theory, we hope that when CPI-613 interferes with the modified metabolic pathways of cancer cells, the cells begin to starve and supply what they need for metabolism. Suppose you respond by using self-eating to help. The inclusion of an autophagy inhibitor in the treatment regimen inhibits the use of autophagy by cancer cells to counteract the effects of CPI-613 and significantly improves efficacy.

Types of Cancer In certain embodiments, cancer is associated with alterations in energy metabolism. In certain embodiments, the cancer exhibits increased phagocytosis when in contact with CPI-613. As used herein, the term "cancer" is intended to include myelodysplastic syndrome, and in certain embodiments of the invention the cancer is myelodysplastic syndrome. In certain embodiments, the cancer is high-risk myelodysplastic syndrome (MDS). In certain embodiments, the cancer is high-risk MDS in patients who have not responded, advanced, or relapsed during hypomethylation therapy.

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

In certain embodiments, the cancer is found in only one lymph node region, or the cancer invades one extralymph node organ or site, but invades any lymph node region. Not stage I lymphoma. In certain embodiments, the cancer is cancer, whether or not the cancer is found in two or more lymph node areas on the same side of the diaphragm or in other lymph node areas on the same side of the diaphragm. Is a stage II lymphoma that involves one organ and its regional lymph nodes. In certain embodiments, the cancer is stage III lymphoma with cancer in the lymph nodes on either side of the septum. In certain embodiments, the cancer is a stage IV lymphoma in which 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 reproducible or relapsed. In certain embodiments, the cancer is recurrent or refractory. In certain embodiments, the cancer has not been previously treated. In certain embodiments, the cancer has not previously been treated with systemic therapy. In certain embodiments, the cancer has not previously been treated with topical treatment with systemic therapy or chemoradiation therapy. In certain embodiments, the patient has not received a hematopoietic cell transplant. In certain embodiments, the patient is undergoing 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 myelogenous leukemia. In certain embodiments, the cancer is acute lymphoblastic leukemia. In certain embodiments, the cancer is an epithelial malignancies. In certain embodiments, the cancer is a non-epithelial malignancies. In certain embodiments, the cancer is not a non-epithelial malignancies. 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 a clear cell non-epithelial malignancies. In certain embodiments, the cancer is not a clear cell non-epithelial malignancies. In certain embodiments, the cancer is a non-clear cell non-epithelial malignancies. In certain embodiments, the cancer is a clear cell epithelial malignancies. In certain embodiments, the cancer is not a soft tissue cancer. In certain embodiments, the cancer is not a clear cell epithelial malignancies. In certain embodiments, the cancer is cancer of the brain or spinal cord. In certain embodiments, the cancer is melanoma. In certain embodiments, the cancer is a neuroblastoma. In certain embodiments, the cancer is a germ cell tumor. In certain embodiments, the cancer is pancreatic cancer. 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 a histologically or cytologically supported measurable locally advanced pancreatic adenocarcinoma. In certain embodiments, the cancer is a histologically or cytologically supported measurable metastatic pancreatic adenocarcinoma. In certain embodiments, the cancer is a histologically or cytologically-supported, measurable, locally advanced pancreatic adenocarcinoma that has not been previously treated. In certain embodiments, the cancer is a histologically or cytologically supported measurable metastatic pancreatic adenocarcinoma that has not been previously treated. In certain embodiments, the cancer is a histologically or cytologically supported measurable locally advanced pancreatic adenocarcinoma that has not previously been treated with systemic therapy. In certain embodiments, the cancer is a histologically or cytologically supported measurable metastatic pancreatic adenocarcinoma that has not previously been treated with systemic therapy. In certain embodiments, the cancer is histologically or cytologically supported measurable locally advanced pancreatic adenocarcinoma that has not previously been treated with topical treatment with systemic or chemoradiotherapy. Is. In certain embodiments, the cancer is a histologically or cytologically supported measurable metastatic pancreatic adenocarcinoma that has not previously been treated with topical treatment with systemic or chemoradiotherapy. be. 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 locally advanced pancreatic adenocarcinoma that has not been previously treated. In certain embodiments, the cancer is metastatic pancreatic adenocarcinoma that has not been previously treated. In certain embodiments, the cancer is locally advanced pancreatic adenocarcinoma that has not previously been treated with systemic therapy. In certain embodiments, the cancer is metastatic pancreatic adenocarcinoma that has not previously been treated with systemic therapy. In certain embodiments, the cancer is locally advanced pancreatic adenocarcinoma that has not previously been treated with topical treatment with systemic therapy or chemoradiation therapy. In certain embodiments, the cancer is pancreatic adenocarcinoma that has not previously been treated with topical treatment with systemic therapy or chemoradiation therapy.

In certain embodiments, the cancer is prostate cancer. In certain embodiments, the cancer is castration-resistant prostate cancer. In certain embodiments, the cancer is lung cancer. In certain embodiments, the cancer is non-small cell lung cancer. In certain embodiments, the cancer is a cancer of the colon. In certain embodiments, the cancer is rectal cancer. 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 liver cancer. 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 kidney cancer. In certain embodiments, the cancer is breast cancer. In certain embodiments, the cancer is cancer of the ovary.

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

General Modes of Administering Therapeutic Agents to Patients In general, therapeutic agents, namely 6,8-bis-benzylthio-octanoic acid and phagocytosis inhibitors, are given to patients in therapeutically effective amounts sufficient to treat cancer. Will be delivered. Treatment may be accompanied by one or more doses per day or more, and the dosage may be adjusted by the individual healthcare professional to achieve the desired effect. Preferably, the dosage of each drug should be sufficient to interact primarily with diseased cells and keep normal cells relatively intact.

The dosage may be administered in a single dose or in the form of individual divided doses such as once, twice, three times or four times daily. In certain embodiments, the daily dose is administered as a single dose. If a response in a patient is inadequate at a particular dose, higher or more frequent doses may be used within the patient's tolerable range.

For this combination therapy, the agents may be administered in a particular order and / or on the same or different days according to the treatment cycle. For example, doses of 6,8-bis-benzylthio-octanoic acid may be administered to the patient prior to administration of the autophagy inhibitor, such as immediately before the treatment cycle, early in the day, or early in the day. In certain embodiments, the active agent may be administered on the same day of the treatment cycle, eg, co-administered simultaneously or sequentially. In certain embodiments, the dose of the autophagy inhibitor is administered to the patient prior to administration of 6,8-bis-benzylthio-octanoic acid, such as immediately before the treatment cycle, early in the day, or early in the day. May be done. In certain embodiments, the treatment cycle may be repeated one or more times to maximize the benefit to the patient.

6,8-Bis-benzylthio-octanoic acid 6,8-bis-benzylthio-octanoic acid may be administered in any suitable form, including as a solid or liquid, as a free acid or salt. The 6,8-bis-benzylthio-octanoic acid may be crystalline, amorphous, or dissolved 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 ion admixtures that may be used include, for example, tertiary amines (such as triethylamine or triethanolamine), diethylamine, diethanolamine, monoethanolamine, mephenamic acid, and other amines such as tromethamine, and combinations thereof. Can be mentioned. In certain embodiments, the ion pairing agent is an organic Bronsted base. In certain other embodiments, the ion combination agent is an amine compound. In yet another embodiment, the ion admixture is a monoalkylamine, dialkylamine, trialkylamine, amino-substituted aliphatic alcohol, hydroxymonoalkylamine, hydroxydialkylamine, hydroxytrialkylamine, amino-substituted heteroaliphatic alcohol. , Alkyldiamine, substituted alkyldiamine, or an optionally substituted heteroaryl group containing at least one ring nitrogen atom. In certain embodiments, the therapeutic agent is incorporated herein by reference in its entirety. , "Pharmaceutical Salts," J. Mol. of Pharmaceutical Science, 1977; 66: 1-19, or Handbook of Pharmaceutical Salts Properties, Selection and Use, IUPAC, Wiley-VCH, P.I. H. Stahl, ed. A salt of 6,8-bis-benzylthio-octanoic acid with an ion pairing agent selected using the guidelines from. Particularly noteworthy ion combinations in the latter include, but are not limited to, those listed in Table 5 on page 342.

Additional exemplary ion admixtures include, for example, polyethyleneimine, polyglutamic acid, ammonia, L-arginine, venetaminebenzatin, betaine, calcium hydroxide, choline, deanol, diethanolamine (2,2'-iminobis (2,2'-iminobis). Ethanol))), diethylamine, 2- (diethylamino) -ethanol, ethanolamine, ethylenediamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, lysine, magnesium hydroxide, 4- (2-hydroxyethyl) -morpholine, piperazine, Included are potassium hydroxide, 1- (2-hydroxyethyl) -pyrrolidine, sodium hydroxide, triethanolamine (2,2', 2'-nitrilotris (ethanol)), tromethamine, and zinc hydroxide. In certain other embodiments, the ion admixture is diisopropanolamine, 3-amino-1-propanol, meglumin, morpholine, pyridine, niacinamide, tris (hydroxymethyl) aminomethane, 2-((2-). Dimethylamino) ethoxy) ethanol, 2- (dimethylamino) ethanol, 1- (2-hydroxyethyl) pyrrolidine, or ammonium hydroxide. In certain other embodiments, the ion admixture is an alkali metal hydroxide or an alkaline earth metal hydroxide, for example 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 One or more autophagy inhibitors may be administered in any suitable form, including as solids or liquids, as free acids or salts. The autophagy inhibitor may be crystalline, amorphous, or dissolved in solution. In certain embodiments, the autophagy inhibitor is administered to the patient as a salt or ion pair. If the autophagy inhibitor is a basic compound such as chloroquine or hydroxychloroquine, it may be administered as an ion pair with an inorganic or organic acid. Examples of acids are 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, tartrate acid, acetic acid. , Citric acid, methanesulfonic acid, ethanesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, and the like, but not limited to these. In certain embodiments, the therapeutic agent is incorporated herein by reference in its entirety. , "Pharmaceutical Salts," J. Mol. of Pharmaceutical Science, 1977; 66: 1-19, or Handbook of Pharmaceutical Salts Properties, Selection and Use, IUPAC, Wiley-VCH, P.I. H. Stahl, ed. It is a salt of an autophagy inhibitor with an ion pairing agent selected using the guidelines from. Particularly noteworthy ion combinations in the latter include, but are not limited to, those listed in Table 5 on page 342.

Any suitable autophagy inhibitor can be used. In certain embodiments, the self-eating inhibitors are 4-aminoquinoline, 3-methyladenine (3-MA, CAS # 512-23-4), 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 ] Kinazoline-4-amine, N-acetyl-L-cysteine, L-asparagine, N2, N4-dibenzylkinazoline-2,4-diamine, (2S, 3S) -trans-epoxysuccinyl-L-leucylamide-3-3 Methylbutaneethyl ester, N- [6- (4-chlorophenoxy) hexyl] -N'-cyano-N''-4-pyridinyl-guanidine, leupeptin, 2- (4-morpholinyl) -8-phenyl-1 ( 4H) -benzopyran-4-one, 4,6-di-4-morpholinyl-N- (4-nitrophenyl) -1,3,5-triazine-2-amine, peptatin A, 2-((5-bromo) -2-((3,4,5-trimethoxyphenyl) amino) pyrimidin-4-yl) oxy) -N-methylbenzamide, 6-fluoro-N-[(4-fluorophenyl) methyl] -4-quinazoline Select from amines, tapcigargins, amodiakins, artemicinins, meflokins, primaquins, piperakins, quinacrines, U0126, 3-methyladenine, bafilomycin A1, chlorokins, hydroxychloroquines, verteporfins, LY294002, SB202190, SB203580, SC79, and Waltmannins. Will be done. In certain embodiments, the autophagy inhibitor is selected from chloroquine, hydroxychloroquine, and verteporfin. In certain embodiments, 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 inhibit any suitable type of autophagy (eg, macroautophagy, microautophagy, chaperone-mediated autophagy, mitophagy, or lipophagy). , By any suitable mechanism (eg, by influencing the formation of autophagosomes or their cargoes). In certain embodiments, the autophagy inhibitor inhibits macroautophagy or mitophagy. In certain embodiments, the phagocytosis 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 cyclosporin A. In certain embodiments, the phagocytosis inhibitor inhibits microautophagy. In certain embodiments, the autophagy inhibitor inhibits chaperone-mediated autophagy. In certain embodiments, the autophagy inhibitor inhibits lipophagy.

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

The advantage of oral dosing of 6,8-bis-benzylthio-octanoic acid is that it allows for substantially increased dosing flexibility compared to IV. In prior art, 6,8-bis-benzylthio-octanoic acid was formulated as a 50 mg / mL solution (150 mg / mL) in 1 M aqueous triethanolamine, which was 30-120 via a central venous catheter. Before being administered as an IV infusion over a minute, it is diluted with sterile 5% dextrose (D5W) for injection from 50 mg / mL to 4 mg / mL (eg, 12.5 mg / mL). Such infusions are inconvenient for the patient and effectively eliminate regimens with frequent and / or long-term dosing. Since the half-life of 6,8-bis-benzylthio-octanoic acid after IV dosing is only about 1-2 hours (Pardee, TS et al., Clin Cancer Res. 2014, 20, 5255-64). , More frequent and / or long-term dosing can be advantageously used to increase a patient's exposure to the drug.

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 the 28-day cycle, followed by 6,8- each day. Accompanied by IV administration of bis-benzylthio-octanoic acid (2,000 mg / m ² ). For oral administration, healthcare professionals may have more flexibility regarding the dose and schedule of 6,8-bis-benzylthio-octanoic acid. 6,8-bis-benzylthio-octanoic acid can be orally administered in single daily doses on days 1-5 of the 28-day cycle, as in the IV schedule. Alternatively, 6,8-bis-benzylthio-octanoic acid can be administered in two or more (eg, 3 times, 4 times, or 5 times) divided doses. Single or divided doses may be administered on days 1-5 of the cycle, or on fewer and / or additional days of the cycle, up to daily.

Another advantage of oral dosing is that it makes maintenance therapy feasible. For example, patients who have been successfully treated with first-line therapy with or without 6,8-bis-benzylthio-octanoic acid and whose cancer is in partial or complete remission may have 6 to delay or prevent recurrence. , 8-Bis-benzylthio-octanoic acid and phagocytosis inhibitors (eg, hydroxychloroquine) may be treated orally for a long period of time. Maintenance treatment is a daily or weekly regular dose of 6,8-bis-benzylthio-octanoic acid and an autophagy inhibitor once, twice, three times, four times, or five times. May be accompanied by. In certain embodiments, maintenance therapy is for the treatment of pancreatic cancer.

Pharmaceutical Compositions Any suitable pharmaceutical composition can be used to administer 6,8-bis-benzylthio-octanoic acid and an autophagy inhibitor to a patient. Therapeutic agents may be administered together in the same pharmaceutical composition (eg, a multidrug mixture) or separately in different pharmaceutical compositions. There are a wide variety of suitable formulations of the pharmaceutical compositions of the present invention (eg, Remington: The Science and Practice of Pharmacy, 20th ed., Gennaro et al. Eds., Lippincott Williams and Williams, see Williams and 2000. ). In certain embodiments, one or more of the therapeutic agents are administered in a pharmaceutical composition in dry oral dosage form. In certain embodiments, the pharmaceutical composition is an oral dosage form selected from tablets, pills, capsules, caplets, powders, granules, liquids, suspensions, and gels. Oral dosage forms include pharmaceutically acceptable excipients such as carriers, diluents, stabilizers, plasticizers, binders, flow promoters, disintegrants, bulking agents, lubricants, plasticizers, colorants. Agents, film-forming agents, flavoring agents, preservatives, medication vehicles, and any combination of any of the aforementioned may be included.

The pharmaceutical composition will generally include at least one inert excipient. Excipients include pharmaceutically compatible binders, lubricants, wetting agents, disintegrants, and the like. Tablets, pills, capsules, troches, and the like may contain any of the following excipients, or compounds of similar nature: bindings such as microcrystalline cellulose, tragacant rubber, or gelatin. Agents, excipients such as starch or lactose, dispersants such as alginic acid, Primogel, or corn starch, lubricants such as magnesium stearate, flow promoters such as colloidal silicon dioxide, sweeteners such as sucrose or saccharin, or Flavoring agents such as peppermint, methyl salicylate, or orange fragrances. If the unit dosage form is a capsule, it may contain a liquid excipient such as fatty oil. In addition, the unit dosage form may contain a coating of various other materials, such as sugar, shellac, or enteric solvent, that alter the physical form of the dosage form. In addition, the syrup may contain sucrose as a sweetener, as well as certain preservatives, pigments, colorants, and flavors, in addition to the active compound. In certain embodiments, the pharmaceutical composition comprises an excipient in an amount of about 5% to about 99% by weight, eg, about 10% to about 85% by weight, of the composition, the rest being a therapeutic agent. It is composed. In certain embodiments, pharmaceutically acceptable excipients make up about 20% to about 80% of the total weight of the composition. In certain embodiments, the pharmaceutical composition comprises a therapeutic agent in an amount of at least about 40% by weight of the composition, the rest consisting of one or more excipients. 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.

Diluting agents for solid (eg, oral) compositions include microcrystalline cellulose (eg, AVICEL®), fine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, deki. Straight, Dextrin, Dextrose, Dibasic Calcium Phosphate Dihydrate, Tribasic Calcium Phosphate, Kaolin, Magnesium Carbonate, Magnesium Oxide, Maltodextrin, Mannitol, Polymethacrylate (eg Eudragit), Potassium Chloride, Powdered Cellulose, Sodium Chloride, Examples include, but are not limited to, sorbitol and talc.

Binders for solid (eg, oral) pharmaceutical compositions include acacia, tragacant, sucrose, glucose, alginic acid, carbomer (eg, Carbopol), sodium carboxymethyl cellulose, dextrin, ethyl cellulose, gelatin, guar gum, hardened vegetable oil, etc. Hydroxyethyl cellulose, hydroxypropyl cellulose (eg, KLUCEL®), hydroxypropylmethyl cellulose (eg, METHOCEL®), liquid glucose, aluminum magnesium silicate, maltdextrin, methylcellulose, polymethacrylate, povidone (eg, KOLLIDON). (Registered Trademark), PLASSONE®), pregelatinized starch, sodium alginate, and starch, but are not limited thereto. In certain embodiments, the pharmaceutical composition comprises a binder in an amount of about 0.5% to about 25% by weight, for example about 0.75% to about 15% by weight, of the composition. In certain embodiments, the pharmaceutical composition comprises an amount of about 1% to about 10% by weight of the binder of the binder.

The dissolution rate of the compressed solid pharmaceutical composition in the patient's stomach may be increased by adding a disintegrant to the composition. Disintegrants include alginate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose (eg AC-DI-SOL®, PRIMELLOSE®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (eg KOLLIDON). (Registered Trademark), POLYPLASSONE®, Guar Gum, Magnesium Aluminum Phosphate, Methyl Cellulose, Microcrystalline Cellulose, Powdered Cellulose, Pregelatinized Steel, Sodium Alginate, Sodium Stuff Glycolate (eg, EXPLOTAB®), And starch, but not limited to these. In certain embodiments, the pharmaceutical composition comprises a disintegrant in an amount of about 0.2% to about 30% by weight, eg, about 0.2% to about 10% by weight, of the composition. In certain embodiments, the pharmaceutical composition comprises an amount of about 0.2% by weight to about 5% by weight of the disintegrant.

The pharmaceutical composition optionally comprises one or more pharmaceutically acceptable wetting agents. Such wetting agents are preferably selected to maintain an API that is closely associated with water, a condition that is believed to improve the bioavailability of the composition. 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, sodium dioctyl sulfosuccinate, polyoxyethylene alkyl phenyl ethers, etc. , Nonoxynol 9, Nonoxynol 10, and Octoxinol 9, Poroxamar (polyoxyethylene and polyoxypropylene block copolymers), polyoxyethylene fatty acid glycerides and oils such as polyoxyethylene, capryl / capric acid mono and diglycerides (eg, eg, polyoxyethylene, capryl / capric acid mono and diglycerides). Gattefose Labrasol ™, polyoxyethylene glycol oil and polyoxyethylene hydrogenated castor oil; polyoxyethylene alkyl ethers such as polyoxyethylene cetostearyl ethers, polyoxyethylene fatty acid esters such as polyoxyethylene stearate, Polyoxyethylene sorbitan esters such as polysorbate 20 and polysorbate 80 (eg, ICI Tween ™ 80), propylene glycol fatty acid esters such as propylene glycol laurate (eg Gattefose Lauroglycol ™), sodium lauryl sulfate. , Its fatty acids and salts such as oleic acid, sodium oleate, and triethanolamine oleate, glyceryl fatty acid esters such as glyceryl monostearate, sorbitan esters such as sorbitan monolaurate, sorbitan monooleate, monoparticic acid. Includes sorbitan, and sorbitan monostearate, tyloxapol, and mixtures thereof. In certain embodiments, the pharmaceutical composition comprises a wetting agent in an amount of about 0.25% to about 15% by weight, eg, about 0.4% to about 10% by weight, of the composition. In certain embodiments, the pharmaceutical composition comprises a wetting agent in an amount of about 0.5% to about 5% by weight of the composition. In certain embodiments, the pharmaceutical composition comprises a wetting agent, which is an anionic surfactant. In certain embodiments, the pharmaceutical composition comprises sodium lauryl sulfate as a wetting agent. In certain embodiments, the pharmaceutical composition comprises sodium lauryl sulfate in an amount of about 0.25% to about 7% by weight, eg, about 0.4% to about 4% by weight, of the composition. In certain embodiments, the pharmaceutical composition comprises sodium lauryl sulfate in an amount of about 0.5% to about 2% by weight of the composition.

Lubricants (eg, anti-adhesives or flow promoters) are added to improve the flow properties of the solid composition and / or to reduce friction between the composition and the device during compression of the tablet formulation. Can be done. Excipients that can function as lubricants include, but are not limited to, colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate. Suitable lubricants include behapate (eg, Gattefose's Composite ™ 888), stearic acid and salts thereof, including magnesium, calcium and sodium stearate, zinc stearate, glyceryl monostearate, Glyceryl palmitostearate, hardened castor oil, hardened vegetable oil (eg, Abitec's Starotex ™), wax, boric acid, sodium benzoate, sodium acetate, sodium stearyl fumarate, sodium fumarate, sodium chloride, DL-leucine , PEG (eg, Carbowax ™ 4000 and Carbowax ™ 6000 of Dow Chemical Company), sodium oleate, sodium lauryl sulfate, and magnesium lauryl sulfate. In certain embodiments, the pharmaceutical composition comprises a lubricant in an amount of about 0.1% to about 10% by weight, for example about 0.2% to about 8% of the composition. In certain embodiments, the pharmaceutical composition comprises an amount of about 0.25% to about 5% by weight of the lubricant. In certain embodiments, the pharmaceutical composition comprises magnesium stearate as a lubricant. In certain embodiments, the pharmaceutical composition comprises colloidal silicon dioxide. In certain embodiments, the pharmaceutical composition comprises talc. In certain embodiments, the composition comprises magnesium stearate or talc in an amount of about 0.5% to about 2% by weight of the composition.

Flavors and flavor enhancers make the dosage form more palatable to the patient. Common flavoring agents and flavor enhancers for pharmaceuticals that may be included in the compositions of the present invention include maltol, vanillin, ethylvanillin, menthol, citric acid, ethylmaltol fumarate, and tartaric acid.

The compositions may be colored using any pharmaceutically acceptable colorant to improve their appearance and / or facilitate identification by the patient at the product and unit dose level. The pharmaceutical product of the present invention may be buffered by the addition of a suitable buffer.

In certain embodiments of the invention, the therapeutic agent may be formulated as a pharmaceutically acceptable oil, liposome, oil-water or lipid-oil-water emulsion or nanoemulsion, or liquid. To facilitate such formulation, the therapeutic agent may be combined with a pharmaceutically acceptable excipient for that purpose.

As described in detail below, the pharmaceutical composition is adapted for parenteral or sustained release formulations by, for example, subcutaneous, intramuscular, intravenous, or epidural injection as sterile solutions or suspensions. It may be specially formulated for administration in solid or liquid form, including those.

Further examples of pharmaceutical formulations of 6,8-bis-benzylthio-octanoic acid are described in US Pat. No. 8,263,653, which is incorporated herein by reference in its entirety.

The method of preparing a pharmaceutical formulation or composition comprises associating the compound of the invention with a carrier and optionally one or more co-ingredients. Generally, the pharmaceutical product is prepared by uniformly and intimately associating the compound of the present invention with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, molding the product. ..

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

Suitable pharmaceutical compositions for parenteral administration are sugars, alcohols, antioxidants, buffers, bacteriostatic agents, solutes or suspensions that make the formulation isotonic with the intended recipient's blood. One or more pharmaceutically acceptable sterile isotonic aqueous solution or non-aqueous solution, dispersion, suspension, or emulsion, which may contain an agent or thickener, or a sterile injectable solution immediately before use or Contains one or more compounds of the invention in combination with a sterile powder that can be reconstituted into a dispersion.

In certain embodiments, one or more of the therapeutic agents are administered by parenteral administration. In certain other embodiments, one or more of the therapeutic agents are inhaled, oral, topical, transdermal, nasal, ocular, transpulmonary, transrectal, transmucosal, intravenous, intramuscular, subcutaneous. Aerosols, sprays, powders, gels, lotions, creams, suppositories, ointments, and for intraperitoneal, intrathoracic, intrathoracic, intrauterine, intratumoral, or injection methods or administrations, or any combination thereof. It is formulated in the form of a similar one. As indicated above, if such a formulation is desired, the formulation may be imparted with the desired consistency and other properties, including other additives known in the art.

In certain embodiments, the pharmaceutical composition of the invention is a unit dose composition. In certain embodiments, the pharmaceutical composition comprises from about 1 mg to about 5000 mg of therapeutic agent. In certain embodiments, the pharmaceutical composition comprises from about 100 mg to about 3000 mg of therapeutic agent. In certain embodiments, the pharmaceutical composition comprises 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, It contains 1800 mg, 1900 mg, 2000 mg, 2500 mg, or 3000 mg of therapeutic agent. In certain embodiments, the pharmaceutical composition comprises about 300 mg, 500 mg, 700 mg, or 1000 mg of therapeutic agent.

In certain embodiments, the pharmaceutical composition of the invention comprises the emulsion, particles, or gel described in US Pat. No. 7,220,428. In certain embodiments, the pharmaceutical composition is a solid or liquid formulation with a lipid or fatty acid component of about 0.1% to about 75% w / w. In certain embodiments, the pharmaceutical product contains 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 its analogs.

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

Pharmaceutical compositions of several autophagy inhibitors are commercially available. In certain embodiments, the pharmaceutical composition of the phagocytosis inhibitor is an oral tablet containing an amount of chloroquine phosphate corresponding to 150 mg of free base. In certain embodiments, the pharmaceutical composition of the phagocytosis inhibitor is an oral tablet containing an amount of chloroquine phosphate corresponding to 300 mg of free base. In certain embodiments, the pharmaceutical composition of the autophagy inhibitor is an oral tablet containing 200 mg hydroxychloroquine sulfate, which corresponds to 155 mg free base. In certain embodiments, the pharmaceutical composition of the autophagy inhibitor is an injectable solution containing chloroquine hydrochloride in an amount equivalent to 40 mg / mL free base.

Dosing and Schedule 6,8-bis-benzylthio-octanoic acid and the autophagy inhibitor may be administered to the patient at any suitable dose according to any suitable schedule. Dosages and schedules will vary based on the cancer being treated and will be used in the prior art when administered alone or in combination with other agents 6,8-bis-benzylthio-octanoic acid and self. It can be readily determined by one of ordinary skill in the art in view of the dose and schedule of the phagocytosis inhibitor, as well as the guidelines provided herein. In certain embodiments, the dose is the maximum tolerated dose.

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

The daily dose of 6,8-bis-benzylthio-octanoic acid may be administered as a single dose but may be given in two or more doses, eg b. i. d. (Twice a day), t. i. d. (3 times a day), or q. i. d. It may be divided into (4 times a day). In certain embodiments, the daily dose may be divided into 5 doses administered at regular intervals during the day. At higher daily doses and / or when administered orally or subcutaneously, daily doses of 6,8-bis-benzylthio-octanoic acid, b. i. d. , T. i. d. , Or q. i. d. It is often beneficial to administer in. Since 6,8-bis-benzylthio-octanoic acid has a relatively short half-life in blood, the efficacy may be improved by extending the exposure time by dividing the daily dose, and the peak plasma concentration may be improved. Safety may be improved by reducing the amount of blood plasma. 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 or twice daily. It is administered 3 times, 4 times, or 5 times. 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 and is administered once daily. 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 and is administered twice daily. 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 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 from about 0.5 g to 1.5 g and is administered four times daily. 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 and is administered 5 times daily. In certain embodiments, each dose of 6,8-bis-benzylthio-octanoic acid or a pharmaceutically acceptable salt thereof is about 1 g, once, twice, three times, four times daily. Or it is administered 5 times. 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 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 5 times daily.

6,8-bis-benzylthio-octanoic acid includes days when the dose of 6,8-bis-benzylthio-octanoic acid is administered and days when the dose of 6,8-bis-benzylthio-octanoic acid is not administered. It may be administered according to the treatment schedule. For example, 6,8-bis-benzylthio-octanoic acid is according to a schedule in which 6,8-bis-benzylthio-octanoic acid is administered during the first day of the cycle and not during the second half of the cycle. It may be administered. In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered on days 1-5 of the 28-day cycle. In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered on days 1, 8 and 15 of the 4-week cycle. In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered on days 1 and 3 of the 2-week cycle. In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered on days 1-5 of the 3-week cycle. In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered on days 1-5 of the 2-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 the 2-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 3 days a week. In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered 2 days a week. In certain embodiments, 6,8-bis-benzylthio-octanoic acid is administered once a week.

In certain embodiments, hydroxychloroquine sulphate is administered at a daily dose of about 50 mg to about 1500 mg. In certain embodiments, hydroxychloroquine sulfate is administered at a daily dose of about 100 mg to about 1500 mg. In certain embodiments, hydroxychloroquine sulfate is administered at a daily dose of about 200 mg to about 1200 mg. In certain embodiments, hydroxychloroquine sulfate is administered at a daily dose of about 300 mg to about 1200 mg. In certain embodiments, hydroxychloroquine sulfate is administered at a daily dose of about 400 mg to about 1200 mg. In certain embodiments, hydroxychloroquine sulfate is administered at a daily dose of about 600 mg to about 1200 mg. In certain embodiments, hydroxychloroquine sulfate is administered at a daily dose of about 600 mg to about 1000 mg. In certain embodiments, hydroxychloroquine sulfate is administered at a daily dose of about 100 mg. In certain embodiments, hydroxychloroquine sulfate is administered at a daily dose of about 200 mg. In certain embodiments, hydroxychloroquine sulfate is administered at a daily dose of about 300 mg. In certain embodiments, hydroxychloroquine sulfate is administered at a daily dose of about 400 mg. In certain embodiments, hydroxychloroquine sulfate is administered at a daily dose of about 500 mg. In certain embodiments, hydroxychloroquine sulfate is administered at a daily dose of about 600 mg. In certain embodiments, hydroxychloroquine sulfate is administered at a daily dose of about 700 mg. In certain embodiments, hydroxychloroquine sulfate is administered at a daily dose of about 800 mg. In certain embodiments, hydroxychloroquine sulfate is administered at a daily dose of about 900 mg. In certain embodiments, hydroxychloroquine sulphate is administered at a daily dose of about 1,000 mg. In certain embodiments, hydroxychloroquine sulphate is administered at a daily dose of about 1,100 mg. In certain embodiments, hydroxychloroquine sulphate is administered at a daily dose of about 1,200 mg. In certain embodiments, hydroxychloroquine sulphate is administered at a daily dose of about 1,300 mg. In certain embodiments, hydroxychloroquine sulfate is administered at a daily dose of about 1400 mg. In certain embodiments, hydroxychloroquine sulphate is administered at 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 approximately 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 approximately 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 approximately 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 approximately 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, but may be administered in two or more doses, such as b. i. d. It may be divided into. 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, b. i. d. Be administered.

In certain embodiments, chloroquine phosphate is administered at 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 at a daily dose of about 150 mg to about 1800 mg. In certain embodiments, chloroquine phosphate is administered at a daily dose of about 250 mg to about 1500 mg. In certain embodiments, chloroquine phosphate is administered at a daily dose of about 500 mg to about 1500 mg. In certain embodiments, chloroquine phosphate is administered at a daily dose of about 500 mg to about 1000 mg. In certain embodiments, chloroquine phosphate is administered at a daily dose of about 1000 mg to about 1500 mg. In certain embodiments, chloroquine phosphate is administered at a daily dose of about 250 mg. In certain embodiments, chloroquine phosphate is administered at 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 at a daily dose of about 1000 mg. In certain embodiments, chloroquine phosphate is administered at a daily dose of approximately 1,250 mg. In certain embodiments, chloroquine phosphate is administered at a daily dose of about 1,500 mg. In certain embodiments, chloroquine phosphate is administered at a daily dose of approximately 1750 mg. In certain embodiments, chloroquine phosphate is administered at 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 at 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 approximately 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 approximately 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 approximately 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 approximately 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 approximately 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 approximately 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, even when administered as a single dose, is two or more doses, eg b. i. d. It may be divided into. 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, b. i. d. Be administered.

For simplicity, the autophagy inhibitor typically has a treatment cycle of the same length as each treatment cycle of 6,8-bis-benzylthio-octanoic acid (eg, 2 weeks, 3 weeks, 4 weeks). Etc.). Similar to the 6,8-bis-benzylthio-octanoic acid cycle, the autophagy inhibitor cycle includes days when the dose of the autophagy inhibitor is administered and days when the dose of the autophagy inhibitor is not administered. And may be included. For example, an autophagy inhibitor is administered on the same day that the autophagy inhibitor is administered 6,8-bis-benzylthio-octanoic acid and 6,8-bis-benzylthio-octanoic acid. It may be administered according to a non-administered schedule on non-administered days. Alternatively, the autophagy inhibitor may be administered several days instead of all days when 6,8-bis-benzylthio-octanoic acid is administered and / or 6,8-bis-benzylthio-octanoic acid. May be administered on several days instead of all days when is not administered. In certain embodiments, the autophagy inhibitor may be administered each day of the cycle.

In certain embodiments, the dosing cycle is repeated at least once. In certain embodiments, the methods of the invention include two or more cycles of treatment. In certain embodiments, the methods of the invention include three or more cycles of treatment. In certain embodiments, the methods of the invention include four or more cycles of treatment. In certain embodiments, the methods of the invention include 5 or more cycles of treatment. In certain embodiments, the methods of the invention include 6 or more cycles of treatment. In certain embodiments, the methods of the invention include 7 or more cycles of treatment. In certain embodiments, the methods of the invention include 8 or more cycles of treatment. In certain embodiments, the methods of the invention include 9 or more cycles of treatment. In certain embodiments, the methods of the invention include 10 or more cycles of treatment. In certain embodiments, the methods of the invention include daily or weekly, such as at least 1 month, 6 months, 1 year, 2 years, 3 years, or more, 6,8-. Includes regular treatment with bis-benzylthio-octanoic acid and phagocytosis inhibitors.

Patients to be treated Treatment methods can be further characterized according to the patient being 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.

Efficacy and Safety of Treatment The therapeutic methods of the present invention may be further characterized by the efficacy and safety of treatment. Preferably, the method provides an acceptable safety profile in which the benefits of treatment outweigh the risks. When tested in a phase II or phase III clinical trial of at least 10 cancer patients, the methods of the invention preferably have an overall response rate of at least about 10%, a response period of at least about 1 month, at least. It provides progression-free survival (PFS) of about 1 month and / or overall survival (OS) of at least about 1 month. Preferably, the phase II or phase III clinical trial comprises at least 15 patients. More preferably, a phase II or phase III clinical trial comprises at least 20 patients. More preferably, a phase II or phase III clinical trial comprises at least 25 patients. More preferably, a phase II or phase III clinical trial comprises at least 50 patients. More preferably, a phase II or phase III clinical trial comprises at least 100 patients. More preferably, a phase II or phase III clinical trial involves at least 200 patients. More preferably, a phase II or phase III clinical trial comprises at least 300 patients. More preferably, a phase II or phase III clinical trial comprises at least 400 patients. More preferably, a phase II or phase III clinical trial comprises at least 500 patients. Preferably, the method of the invention provides an overall response rate of at least about 20% in the patient. More preferably, the method of the invention provides an overall response rate of at least about 30%. More preferably, the method of the invention provides an overall response rate of at least about 40%. More preferably, the method of the invention provides an overall response rate of at least about 50%. More preferably, the method of the invention provides an overall response rate of at least about 60%. More preferably, the method of the invention provides an overall response rate of at least about 70%. More preferably, the method of the invention provides an overall response rate of at least about 80%. More preferably, the method of the invention provides an overall response rate of at least about 90%. Preferably, the methods of the invention provide a duration of at least about 2 months, PFS, and / or OS. Preferably, the methods of the invention provide a duration of at least about 3 months, PFS, and / or OS. Preferably, the methods of the invention provide a duration of at least about 4 months, PFS, and / or OS. Preferably, the methods of the invention provide a duration of at least about 5 months, PFS, and / or OS. Preferably, the methods of the invention provide a duration of at least about 6 months, PFS, and / or OS. Preferably, the methods of the invention provide a duration of at least about 7 months, PFS, and / or OS. Preferably, the methods of the invention provide a duration of at least about 8 months, PFS, and / or OS. Preferably, the methods of the invention provide a duration of at least about 9 months, PFS, and / or OS. Preferably, the methods of the invention provide a duration of at least about 10 months, PFS, and / or OS. Preferably, the methods of the invention provide a duration of at least about 11 months, PFS, and / or OS. Preferably, the methods of the invention provide a duration of at least about 12 months, PFS, and / or OS. Preferably, the methods of the invention provide a duration of at least about 14 months, PFS, and / or OS. Preferably, the methods of the invention provide a duration of at least about 16 months, PFS, and / or OS. Preferably, the methods of the invention provide a duration of at least about 18 months, PFS, and / or OS. Preferably, the methods of the invention provide a duration of at least about 20 months, PFS, and / or OS. Preferably, the methods of the invention provide a duration of at least about 24 months, PFS, and / or OS. In certain embodiments, the overall response rate, duration of response, and progression-free survival described above are measured in Phase II clinical trials. In certain embodiments, the overall response rate, duration of response, and progression-free survival described above are measured in Phase III clinical trials.

Equivalents The above description describes a plurality of embodiments and embodiments of the invention, including therapeutic uses, methods of treatment, and pharmaceutical compositions. This patent application specifically contemplates all combinations and variations of embodiments and embodiments.

III. Examples The invention broadly described herein will be more easily understood by reference to the following examples. These examples are included only for the purpose of exemplifying certain aspects and embodiments of the invention and are not intended to limit the invention.

Example 1-CPI-613 K562 cells (100,000 cells / mL) in Roswell Park Memorial Laboratory Medium (RPMI) medium with 10% bovine fetal serum (FBS) that induces autophagy in AML cells. ), Or 45% Iskov modified Dalveco medium (IMDM) / 45% Dalvecco modified Eagle's medium (DMEM) / MFL2 cells in 10% FBS (Pardee, TS et al., Experimental Hematology, 2011, 39, 473- 485) (50,000 cells / mL) with CPI-613 (200 μM) at 37 ° C. under 5% CO ₂ for 4 hours, alone or as an early and late self-eating inhibitor 3 respectively. -After incubation in the presence of methyladenine (3MA) or Bafilomycin A (BafA), it was produced during self-eating (production reduced by 3MA) and consumed upon completion (degradation reduced by BafA). Blotted for LC3-II. Complete medium (“full”) and Hanks Equilibrium Salt Solution Medium (HBSS) were used as negative and positive controls for autophagy, respectively.

The results are shown in FIG. This example demonstrates that 6,8-bis-benzylthio-octanoic acid induces phagocytosis 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), or a combination of CPI-613 (100 μM) and chloroquine (25 μM or 50 μM), incubated at 37 ° C. under 5% CO ₂ for 72 hours, then using the Promega CellTiter-Glo assay. The survival rate was evaluated.

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

Example 3-Chloroquine injects 1 million MFL2 cells into the tail vein of a C57Bl / 6 mouse that sensitizes AML cells to CPI-613 in vivo on day 0 and bioluminescent images from day 7. After confirming engraftment by the method, a 50 mg / mL solution of 0.05 N NaOH in 5% dextrose adjusted to pH 7.5-8 with 4% glacial acetic acid daily except weekends until death. Forced feeding (300 mg / kg, 1 animal), daily intraperitoneal (IP) chloroquine (200 μL (about 100 mg / kg), Chlr, 3 animals in 10 mg / mL solution in PBS), or CPI- Treatment was performed with a combination of 613 (daily forced feeding of 300 mg / kg as described above) and chloroquine (200 μL daily IP as described above) (4 animals) and survival was followed. The control animal (1) was given both an oral vehicle and an IP vehicle. The p-value was determined by a logrank test.

The results are shown in FIG. By this example, the combination of 6,8-bis-benzylthio-octanoic acid and chloroquine significantly prolongs the survival of AML tumor-bearing mice in vivo compared to any drug of the same concentration alone. Is demonstrated.

Example 4-Metformin sensitizes AML cells to CPI-613 in vitro MFL2 cells in 45% IMDM / 45% DMEM / 10% FBS (Pardee, TS et al., Experimental Hematology, 2011. 39,473-485) (50,000 cells / mL), CPI-613 (50 μM), metformin (1 μM, 2.5 μM, or 5 μM), or CPI-613 (50 μM) and metformin (1 μM, 2.5 μM). , Or in combination with 5 μM), was incubated at 37 ° C. under 5% CO ₂ for 72 hours, and then survival was assessed using the Promega CellTiter-Glo assay.

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

Example 5-Metformin injects 1 million MFL2 cells into the tail vein of a C57Bl / 6 mouse that sensitizes AML cells to CPI-613 in vivo on day 0 and bioluminescent images from day 7. After confirming engraftment by the method, CPI-613 administered by forced feeding every day except weekends until death (pH adjusted to pH 7.5-8 with 4% glacial acetic acid, 0.05 N NaOH in 5% dextrose) 50 mg / mL solution of CPI-613 in 300 mg / kg), metformin (1 mg / mL in drinking water with constant feeding), or metformin (1 mg / mL in drinking water as described above) and CPI-613 (1 mg / mL in drinking water as described above) and CPI-613 ( Treatment was performed in combination (Met + CPI) with (daily forced feeding of 300 mg / kg) as described above and survival was followed. The p-value was determined by a logrank test.

The results are shown in FIG. 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 in 45% IMDM / 45% DMEM / 10% FBS (Pardee, TS et al., Experimental Hematology). , 2011, 39,473-485) (50,000 cells / mL), CPI-613 (50 μM), 2-deoxyglucose (0.25 mM or 0.5 mM), or CPI-613 (50 μM) and 2- Survival was assessed using the Promega CellTiter-Glo assay after incubation in combination with deoxy glucose (0.25 mM or 0.5 mM) at 37 ° C. under 5% CO ₂ for 72 hours.

The results are shown in FIG. This example demonstrates that the combination of 6,8-bis-benzylthio-octanoic acid and 2-deoxyglucose kills AML cells in vitro significantly better than any drug of the same concentration alone. To.

Example 7-The combination of chlorokin and 2-deoxyglucose is OCI-AML3 cells (100,000 cells / mL) or 45 in RPMI medium containing 10% FBS that 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% IMDM / 45% DMEM / 10% FBS were added to CPI-613 (50,000 cells / mL). 50 μM), chlorokin (25 μM for OCI, 10 μM for MFL2), 2-deoxyglucose (10 mM for OCI, 0.25 mM for MFL2), or CPI-613 (50 μM) and chlorokin (25 μM for OCI, 25 μM, Promega CellTiter-Glo assay after incubation with a combination of 2-deoxyglucose (10 mM for OCI, 0.25 mM for MFL2) at 37 ° C. under 5% CO ₂ for 72 hours (10 μM for MFL2). Was used to assess survival.

The results are shown in FIG. According to this example, the combination of 6,8-bis-benzylthio-octanoic acid, chloroquine and 2-deoxyglucose significantly better in vitro AML cells than any of the three single agents at the same concentration. Demonstrated to kill.

Example 8-Chloroquine contains 96 wells of pancreatic ductal adenocarcinoma cell (PDAC) strains, AsPC-1, PANC-1, BxPC-3, or MIA Paca-2 cells that sensitize PDAC cells to CPI-613 in vitro. In plates, 30,000 cells per well were seeded in complete RPMI medium and incubated for 18 hours. The cells were then incubated in serum-free RPMI for 20 hours, followed by modified Earl Equilibrium Salt Solution (EBSS) (CBS2 medium) for 3 hours to accommodate nutrient depletion conditions similar to tumor nutrient conditions. I let you. The drug was administered to CBS2 medium and incubated for 20 hours. The drug-containing medium was replaced with serum-free RPMI and incubated overnight. All incubations were performed in a humidified incubator at 37 ° C. and 5% CO ₂ . Cell viability was evaluated by the Promega CellTiter-Glo assay, where the luminescence unit is proportional to the number of living cells. Zero (0) luminescent units indicate that all cells have died.

Drug treatment of PANC-1 and ASPC-1 cells is 12.5 μM, 25 μM, 50 μM, 100 μM, or 200 μM chloroquine or hydroxychloroquine, 10 μM, 20 μM, or 40 μM CPI-613, or chloroquine or hydroxy at these concentrations. It was a combination of chloroquine and CPI-613. Drug treatment of BxPC-3 cells with 12.5 μM, 25 μM, 50 μM, 100 μM, or 200 μM chloroquine or hydroxychloroquine, 7.5 μM, 15 μM, or 30 μM CPI-613, or chloroquine or hydroxychloroquine at these concentrations. It was a combination with CPI-613. Drug treatment of MIA PaCa-2 cells is 12.5 μM, 25 μM, 50 μM, 100 μM, or 200 μM chloroquine, 10 μM, 20 μM, or 40 μM CPI-613, or a combination of these concentrations of chloroquine and CPI-613. there were.

The results are shown in FIGS. 8 to 11. This example demonstrates that the combination of 6,8-bis-benzylthio-octanoic acid and chloroquine or hydroxychloroquine kills PDAC cells in vitro better than either drug alone.

Example 9-Chlorokin inoculates CoLo 205 cells sensitizing colon cancer cells to CPI-613 in complete RPMI medium with 60,000 cells per well and LoVo cells complete F12 with 60,000 cells per well. -Seeded in K medium, SW620 and HT29 cells were seeded in complete McCoy medium with 60,000 cells per well in 96-well plates and incubated for 18 hours. The cells were then incubated for 20 hours in each serum-free medium followed by 3 hours in modified EBSS (CBS2 medium) to adapt to nutrient depletion conditions similar to tumor nutrient conditions. The drug was administered to CBS2 medium and incubated for 20 hours. The drug-containing medium was replaced with serum-free RPMI and incubated overnight. All incubations were performed in a humidified incubator at 37 ° C. and 5% CO ₂ . Cell viability was evaluated by the Promega CellTiter-Glo assay.

Drug treatment was 12.5 μM, 25 μM, 50 μM, or 100 μM chloroquine, 12.5 μM, 25 μM, or 50 μM CPI-613, alone or in combination.

The results are shown in FIGS. 12 and 13. This example demonstrates that at higher CPI-613 concentrations, the combination of 6,8-bis-benzylthio-octanoic acid and chloroquine kills colorectal cancer cells in vitro better than either drug alone. Will be done.

Example 10-Chloroquine seeded H460 cells, which sensitize non-small cell lung cancer cells to CPI-613 in vitro, in complete RPMI medium at 30,000 cells per well in a 96-well plate and incubated for 18 hours. The cells were then adapted to nutrient depletion conditions similar to tumor nutrient conditions by incubation in serum-free RPMI for 20 hours followed by modified EBSS (CBS2 medium) for 3 hours. The drug was administered to CBS2 medium and incubated for 5 hours. The drug-containing medium was replaced with serum-free RPMI and incubated overnight. All incubations were performed in a humidified incubator at 37 ° C. and 5% CO ₂ . Cell viability was evaluated by the Promega CellTiter-Glo assay.

Drug treatment was 12.5 μM, 25 μM, 50 μM, 100 μM, or 200 μM chloroquine, 10 μM, 20 μM, or 40 μM CPI-613, alone or in combination.

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

Treatment of high-risk MDS in human patients who failed hypomethylation therapy using the combination of Example 11-CPI-613 with hydroxychloroquine This is a single-group open-label study. Treatment is not blinded to the investigator and the study subject. Also, patient allocation is not randomized because there is only a single group in this study.

The primary objective of this study was overall response rate (complete remission (CR)) in high-risk MDS patients who failed hypomethylating agents and were treated with a combination of CPI-613 and the maximum tolerated dose of hydroxychloroquine (HCQ). , Bone marrow CR, partial remission (PR), hematological improvement (HI)). Secondary objectives are assessing the safety of combination therapy, progression-free survival (PFS), overall survival (OS) defined as the time from trial enrollment to death from any cause, and changes in transfusion frequency. It is to be.

The dose of study design CPI-613 will be 2,000 mg / m ² . The maximum test dose for HCQ is 1,200 mg. The sample size will be a total of 17 patients treated with HCQ MTD for this Phase 1/2 study. This figure is based on Simon's two-stage design, in which nine patients are enrolled in Stage 1. If none of the 9 patients respond, the study will be discontinued due to lack of efficacy. If one or more patients respond, the study will continue until a total of 17 patients are treated with the combination therapy of HCQ with MTD. If 2 or more of the 17 patients respond, the combination therapy is considered to be sufficiently active for additional studies.

The initial phase of the study is a dose escalation of a constant dose of PO hydroxychloroquine from 600 mg to 1200 mg on days 1-5 every 28 days, 2 hours prior to CPI-613 infusion. The dose of CPI-613 is 2,000 mg / m ² and does not increase gradually. A cohort of 3 patients each is treated with 600, then 800, then 1,200 mg of HCQ in a 3 + 3 dose escalation design, as described below.

If patients in a given cohort do not develop dose-limiting toxicity (see DLT definition below), dose escalation continues in a cohort of 3 patients. However, if DLT is observed in a patient (whether the first, second, or third of the three intended patients) at any dose level, that dose. The level cohort will be expanded to up to 6 patients. If DLT is not observed in another of up to 6 patients, the dose escalation procedure is continued in 3 patients in each of the following cohorts until the final dose of 1,200 mg is reached. However, if DLT is observed in a total of 2 patients at any dose level, then HCQ dosing in patients at that dose level is immediate, even if the total number of patients in the last cohort was only 2. Stop. Dose escalation is considered complete. In two or more patients, the dose level that induces DLT is considered to be above MTD, and in two or more patients, the dose level immediately below the dose level that induces DLT is considered MTD. If the initial dose of 600 mg is found to exceed MTD, the HCQ dose drops to dose level -1 (400 mg). Once that dose (400 mg) yields two DLTs, the study is terminated and toxicity data are reviewed prior to any additional enrollment. When the 1,200 mg cohort is completed without DLT in the first 3 patients or without a second DLT in the first 6 patients, the HCQ dose escalation is complete. All subsequent patients will be treated at this dose level. The HCQ dose levels are summarized in Table 1.

Definition of DLT: Dose-limiting toxicity is defined as the occurrence of any clinically significant grade 3 or higher toxicity that is probably or arguably associated with the combination of HCQ and CPI-613. The following toxicity is excluded from the definition of DLT: grade 3 nausea and vomiting in response to antiemetics, grade 3 diarrhea in response to antidiarrheal therapy, grade 3 tumor lysis syndrome, oral or IV supplementation. Grade 3 or 4 metabolic abnormalities due to tumor lysis syndrome or antibacterial agents. Hematological toxicity can only function as DLT if it represents a significant (≥50%) reduction from baseline values. Infectious toxicity, in the opinion of the treating investigator, is the result of a 20% or greater reduction in ANC from baseline and is not the result of a natural history of relapsed or refractory MDS. Can function as.

Inclusion Criteria Patients must meet all of the following inclusion criteria prior to enrollment:
1) Histologically supported MDS in which the disease failed, progressed, or recurred while using hypomethylating agents.
1) Moderate, advanced, or ultra-high Revised International Programming System (IPSS-R) scores at the time of enrollment.
2) ECOG general condition of 3 or less.
3) Men and women over the age of 18.
4) Predicted survival time of more than 2 months.
5) Pregnant women (ie, premenopausal or surgically incapable of pregnancy) are allowed contraceptive methods during the study (abstinence, intrauterine device [IUD], oral contraceptives, or double barrier devices). Must be used and a negative serum or urinary pregnancy test within 1 week of the start of treatment.
6) Fertility men should practice effective contraceptive methods during the study unless evidenced by infertility.
7) The patient has fully recovered from the acute, non-hematological, non-infectious toxicity of any previous treatment with cytotoxic drugs, radiation therapy, or other anti-cancer modality. Patients with grade 2 or lower persistent, non-hematological, non-infectious toxicity from previous treatments are eligible, but this should be supported.
8) Test values obtained less than 2 weeks prior to enrollment demonstrate appropriate liver function, renal function, and coagulation as defined below.
a. Aspartate aminotransferase [AST / SGOT] 3 times or less of the normal upper limit [UNL]
b. Alanine aminotransferase [ALT / SGPT] 3 times or less of UNL
c. Bilirubin less than twice UNL d. Serum creatinine of 1.5 mg / dL or 133 μmol / L or less e. Albumin> 2.0 g / dL or> 20 g / L.
9) Responsible, understanding and willingness to sign IRB-approved written informed consent.
10) Have access via a central line (eg portacath).

Exclusion Criteria Exclude patients with the following characteristics.
1) Serious heart disease (eg, symptomatic congestive heart failure, unstable angina, symptomatic coronary artery disease, myocardial infarction within the last 3 months, controlled) that may increase the risk of toxicity to the patient No cardiac arrhythmia, cardiovascular disease, or serious medical disease such as New York Heart Association Class III or IV), or severe debilitating lung disease.
2) Patients with an active central nervous system (CNS) or epidural tumor.
3) Any active uncontrolled bleeding or bleeding diathesis (eg, active gastric ulcer).
4) In the opinion of the investigator, any condition or abnormality that may compromise the safety of the investigator.
5) Pregnant women, or fertile women who do not use reliable contraceptives.
6) Fertility men who are not willing to practice contraceptive methods during the study period.
7) Lactating women.
8) Lifespan less than 2 months.
9) Not willing or unable to comply with the requirements of the test protocol.
10) Evidence that a serious uncontrolled infection is underway.
11) The need for all types of emergency palliative treatment, including surgery.
12) Patients with uncontrolled HIV infection.
13) Within 2 weeks prior to the start of CPI-613 treatment, radiation therapy, surgery, treatment with cytotoxic agents (excluding hypomethylating agents, ie azacitidine or decitabine), treatment with biological agents, immunotherapy, or any Patients who have received any other anti-cancer therapy of any kind, or any other standard or investigational treatment for cancer, or any other investigational drug for any indication.
14) Patients who have received a chemotherapy regimen with stem cell support in the last 6 months.

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

Treatment with CPI-613 and Hydroxychloroquine CPI-613 is administered to the patient as shown in Table 3. Briefly, CPI-613 is given orally on days 1-5 of the 28-day cycle, 2 hours prior to each dose. Patients receive pretreatment antiemetics and symptomatic measures determined by the treating physician. The default premedication is ondansetron 16 mg either by IV infusion 15 minutes before therapy or orally 30 minutes before therapy and loperamide 2 mg orally 30 minutes before therapy (patients in the last 48 hours). (Except when not defecation).

Baseline transfusion frequency shall be recorded as the number of transfusions received during the 8 weeks prior to enrollment. After the patient initiates protocol treatment, the frequency of transfusions shall be assessed at the end of each of the two treatment cycles.

Safety Assessment The safety of CPI-613 is assessed from the first dose of CPI-613 to one month after the last dose. The assessment is based on the assessment of symptoms, vital signs, ECOG general status and survival, clinical chemistry (and renal function utilizing the Cockcroft-Gault formula), and hematology. All safety assessment studies are performed during screening (within 2 weeks prior to treatment with CPI-613). In addition, signs, vital signs, ECOG, and survival assessments will be assessed on each treatment day and results will be confirmed for review within 24 hours prior to CPI-613 administration. Clinical chemistry (renal function utilizing Cockcroft-Gault's formula), hematology, and coagulation are performed on day 1 of each treatment cycle, and results can be confirmed for review within 24 hours prior to administration of CPI-613.

At a minimum, the toxicity that may be associated with dose adjustment of CPI-613 is outlined in Table 4 below.

Once the toxicity has resolved below grade 1 (or returned to baseline), the patient's CPI-613 dose may be re-escalated at the discretion of the treating investigator. Patients with recurrent original toxicity are then not eligible for dose re-escalation.

Response evaluation Tumor responses include RR, PFS, and OS (Cheon BD et al., Clinical application and proposal for modifixation of the International Working Group: International Working Group (IWG) review. As described by 2006), as well as changes in transfusion frequency from baseline. RRs and PFSs derived from hematology and bone marrow examination are assessed every 6 treatment cycles for the 4th week of baseline, cycles 3, 6, and 12, followed by disease progression thereafter.

Baseline transfusion frequency shall be recorded as the number of transfusions received during the 8 weeks prior to enrollment. After the patient initiates protocol treatment, the frequency of transfusions shall be assessed at the end of each of the two treatment cycles.

Survival is assessed during the study and monitored by contact with the treating physician after the patient is removed from the study. ECOG General Condition Scale (Oken MM et al., Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5: 649-655, 1982) Evaluate what you are doing and how the disease affects your ability to live. ECOG grade 0 = normal activity. It is active enough to maintain all pre-illness abilities without limitation. ECOG grade 1 = I have symptoms, but I can walk. Physically burdensome activities are limited, but they are walkable and capable of performing light or sitting tasks (eg, light household chores, clerical work). ECOG grade 2 = less than 50% of the time lying on the floor. It is walkable and can manage all self-management, but cannot perform work activities. You can get up and move around for more than 50% of the time you are awake. ECOG grade 3 = spend more than 50% of the time in bed. He has limited self-management and stays in bed or chair for more than 50% of his waking hours. ECOG grade 4 = 100% bedridden. Completely disabled. You cannot manage yourself. I can't get away from my bed or chair completely. ECOG grade 5 = death.

Record the following parameters from bone marrow examination: morphology, immune phenotype, cytogenetics, karyotype (cell genetics and FISH, if applicable), molecular markers,% of myeloblasts,% of dysplasia, WHO classification do.

ヘモグロビンをデシリットルあたりのグラムからリットルあたりグラムに変換するには、デシリットルあたりのグラムに１０を乗じる。
ＭＤＳは骨髄異形成症候群、Ｈｇｂはヘモグロビン、ＣＲは完全寛解、ＨＩは血液学的改善、ＰＲは部分寛解、ＦＡＢはＦｒｅｎｃｈ－Ａｍｅｒｉｃａｎ－Ｂｒｉｔｉｓｈ、ＡＭＬは急性骨髄性白血病、ＰＦＳは無増悪生存期間、ＤＦＳは無疾患生存期間を示す。
^＊異形成変化は、異形成変化の正常範囲を考慮に入れる必要がある（修正）。
^†ＩＷＧ応答基準の修正。
^‡いくつかの状況では、プロトコル療法には、４週期間の前にさらなる治療（例えば、地固め、維持）の開始が求められ得る。かかる患者は、療法開始時に当てはまる応答カテゴリーに含めることができる。度重なる化学療法コース中の一過性の血球減少は、前のコースの改善された数に回復する限り、応答の持続性を妨げるものと見なされるべきではない。
The Modified International Working Group (IWG) -2006 response criteria for altering the natural history of MDS are listed in Table 5 below.

To convert hemoglobin from grams per deciliter to grams per liter, multiply gram per deciliter by 10.
MDS is myelodysplastic syndrome, Hgb is hemoglobin, CR is complete remission, HI is hematological improvement, PR is partial remission, FAB is French-American-British, AML is acute myeloid leukemia, PFS is progression-free survival, DFS indicates disease-free survival.
^* Dysplastic changes need to take into account the normal range of dysplastic changes (correction).
^† Revised IWG response criteria.
^‡ In some situations, protocol therapy may require the initiation of further treatment (eg, consolidation, maintenance) prior to the 4-week period. Such patients can be included in the response categories that apply at the start of therapy. Transient cytopenia during repeated chemotherapy courses should not be considered to impede the sustainability of the response as long as it recovers to an improved number of previous courses.

ＩＷＧ応答基準への削除は示されていない。
Ｈｇｂはヘモグロビン、ＲＢＣは赤血球、ＨＩは血液学的改善を示す。
^＊１週間以上間隔をあけた少なくとも２回の測定（輸血の影響を受けない）の処置前の数の平均（修正）。
^†ＩＷＧ応答基準の修正。
^‡急性感染症、度重なる化学療法コース（修正）、消化管出血、溶血などといった、別の解釈がない場合。２種類の赤血球および血小板応答を、全体として、および個々の応答パターン別に報告することが推奨される。
The Modified International Working Group (IWG) -2006 response criteria for hematological improvement are listed in Table 6 below.

No deletion into the IWG response criteria has been shown.
Hgb indicates hemoglobin, RBC indicates red blood cells, and HI indicates hematological improvement.
^* Average (corrected) pretreatment number of at least two measurements (unaffected by blood transfusion) at least one week apart.
^† Revised IWG response criteria.
^‡ If there is no other interpretation such as acute infection, repeated chemotherapy course (correction), gastrointestinal bleeding, hemolysis, etc. It is recommended to report the two red blood cell and platelet responses as a whole and by individual response pattern.

Treatment with CPI-613 and HCQ should be continued except in the following cases, or until the following occurs, as long as the treating physician considers it to be of clinical benefit: the patient exhibits disease progression; also dose reduction. Regardless of unacceptable toxicity from CPI-613 and HCQ; withdrawal of patient consent; investigator's discretion to withdraw patient from study because continuing study participation is not in the patient's best interests; undercurrent Some illnesses (conditions, injuries, or illnesses that are not related to the illness being studied by the study, which jeopardize the continuation of treatment or make regular follow-up impossible); ineligible for further study treatment , General or specific changes in the patient's condition; non-compliance with the evaluation or follow-up visit required by the study treatment, protocol; or termination of the clinical trial. Upon exiting the trial, patient survival and post-trial cancer treatment will be monitored by follow-up visits after the patient is excluded from the trial. All patients will be followed up for 5 years after treatment or until death (unless consent to follow-up is withdrawn).

CPI-613
CPI-613 is provided in a 10 mL amber glass vial. Each vial contains 10 mL of CPI-613 at a concentration of 50 mg / mL, which corresponds 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 injection via an IV catheter, flowing D5W at a rate of approximately 125-150 mL / hour. CPI-613 should be administered via a central venous catheter to avoid local reactions at and around the site of administration.

CPI-613 can cause leaching of DEHP from IV infusion sets and IV bags. For this reason, DEHP-containing IV infusion sets, IV bags, or syringes should not be used for mixing or administering CPI-613. Examples of IV sets, IV bags, and syringes that can be used to administer CPI-613 because they do not contain DEHP are:
-Expansion set when using a syringe pump: All expansion sets of MED-RX do not contain DEHP.
Syringe: All Monoject syringes do not contain DEHP.
IV infusion set: The IV infusion set that can be used to administer CPI-613 is:
○ PVC Material-ADDit IV® Primery IV Set, General Purpose Spike, Check Valve, Two Injection Sites, DEHP Free and Latex Free, 15 Drops / mL, Reference Number V14453, B Braun Medical Inc.
○ Latex material-Interlink (registered trademark) System System Measurement Set, 10 drops / mL, 2C7451, Baxter Healthcare Corporation
○ PVC Material-Surfetti Winged Information Set, 0.19 mL Volume, Latex Free, DEHP Free, SV * S25BLS, Terumo Medical Products Hangzhou Co., Ltd. Ltd.
○ Polyethylene material-Interlink (registered trademark) System Paclitaxel Set by Baxter HealthCare, non-DEHP-free: Polyethylene tube with 0.22 microfilter, product number 2C7558, 10 drops / mL
Syringe: CPI-613 drug product (50 mg / mL), and drug product diluted to various concentrations with D5W (1.6-25 mg / mL) are compatible with various types of syringes, as listed below. It is sex. Therefore, any of these types of syringes, and syringes made of the same material, can be used for administration of CPI-613. Also, since the glass (glass container, etc.) is compatible with the CPI-613 drug product, a glass syringe can also be used.
○ Norm-Ject, polyethylene barrel, polyethylene plunger, latex-free (Henke Sass Wolf GMBH) syringe ○ Becton Syringe syringe ○ Terumo syringe ○ Monoject syringe ○ Glass syringe.

CPI-613 needs to be diluted from 50 mg / mL to 12.5 mg / mL with 5% dextrose water (D5W) prior to administration (ie, 1 portion of CPI-613 diluted with 3 parts of D5W). Diluted drug products should be visually inspected for transparency. Do not use diluted drug products for administration if turbidity, precipitation, or discoloration (except colorless) is observed. After diluting with sterile D5W, the solution is clear and has a pH of 8.4-8.8. Diluted CPI-613 drug products have been found to be stable at room temperature and refrigeration temperatures for 24 hours.

CPI-613 is free-flowing, via an IV catheter that does not contain air in the dead space of the IV catheter, to minimize irritation, inflammation, and acute toxicity of CPI-613. Need to be administered. Animal studies have shown that accidental co-administration of excess air in the dead space of an IV catheter during administration of CPI-613 can induce acute toxicity of CPI-613. .. Also, according to animal studies, accidental leakage of CPI-613 into the perivascular space during IV administration can prolong exposure of perivascular tissue to CPI-613 and induce significant local inflammation. CPI-613 should be administered via a central venous catheter to avoid local reactions at and around the site of administration.

CPI-613 should be administered not as a bolus, but by injection at a rate of about 0.5 mL / min via a central venous catheter, flowing D5W at a rate of about 125-150 mL / hour. This is to minimize the possible acute toxicity of CPI-613 according to animal studies.

The following measures should be taken when administering CPI-613.
-Check the placement of the IV line to ensure that CPI-613 does not leak into the perivascular space.
-Confirm that the IV line is free liquidity.
-Check that there is no dead space with air in the IV line.
• Dilute the CPI-613 drug product with D5W according to the instructions in the protocol.
• Administer CPI-613 by infusion rather than bolus.
• After administration of CPI-613, rinse the IV line with approximately 10 mL D5W to remove residual CPI-613.
CPI-613 should be administered via a central venous catheter to avoid local reactions at and around the site of administration.

The amount of CPI-613 at each dose level is based on the patient's BSA. The BSA value is calculated based on the height and weight taken during the screening, and this BSA value is used throughout the study. This excludes cases where there is a weight change of> 10% from baseline during the test. At that point, the BSA needs to be corrected based on the new weight and height. The new BSA value will be used from that point on for the rest of the study unless there is an additional 10% or more weight change requiring further correction of BSA.

Other Drugs Patients will receive any standard or study drug (except CPI-613 and hydroxychloroquine) for MDS during this study, or any other study for any non-cancer indication. You can't take medicine either. All other permitted concomitant medications (including trade name, generic name, dosage, and dosing schedule) must be recorded. Treatment of disease-related symptoms (such as nausea) is permitted. The drug administered in such cases should be considered a concomitant drug and should be appropriately documented. Supportive treatments may include antiemetics, antidiarrheals, antipyretics, antiallergic agents, antihypertensive agents, analgesics, antibiotics, alloprinols, and other medications such as blood products. Patients may use growth factors in accordance with ASCO guidelines at the discretion of the investigator in treatment.

Adverse Events CTP Active Version of the NCI Common Terminology Criteria for Adverse Events (CTCAE 4.0) are used to report adverse events. This is the CTEP website http: // ctep. cancer. gov / protocolDevelopment / electronic_applications / ctc. It is identified and searched in http. All suitable therapeutic areas need to have access to a copy of the CTEP Active Version of CTCAE.

Characteristics of adverse events (AEs):
Confirmation-AE is clearly associated with study drug.
• High likelihood-AE is likely to be associated with study drug.
• Possibly-AE may be associated with study drug.
-Low probability-It is doubtful that AE is associated with study drug.
Not relevant-AE is clearly not associated with study drug.

List of adverse events reported: abdominal pain; alkaline phosphatase; ALT (SGPT); loss of appetite; AST (SGOT); bilirubin; (hyperbilirubinemia); calcium (hypercalcemia, hypocalcemia); creatinine; Diarrhea; Facial red tide; Hemoglobin (anemia); Injection site reaction; White blood cells; Lymphopenia; Nausea; Neutrophils (neutropenia); Platelets (platelet hypoplasia); Potassium; Sodium; Vomiting. All Grade 3, 4, 5 adverse events must be reported on the flow sheet and ORIS, regardless of whether they are on this list. All unexpected Grade 4 and All Grade 5 SAEs in these tests need to be reported for review.

Any unexpected problems with risks and adverse events to the subject or others must be reported promptly to the IRB. Reporting to the IRB is required regardless of whether the investigator, over-the-counter drug, biopharmacy, or device is involved in the funder, sponsor, or event. Reportable events are not limited to physical injuries, but include psychological, economic, and social harm. Reportable events may occur as a result of drugs, biological agents, devices, procedures, or other interventions, or as a result of questionnaires, surveys, observations, or other interactions with the subject of study.

All members of the research team are responsible for properly reporting to the IRB and other relevant parties any unexpected problems that may pose a risk to the subject or others. However, the Principal Investigator has the ultimate responsibility to ensure that the IRB is promptly informed of any unexpected problems that may pose a risk to the subject or others. The Principal Investigator also ensures that all reported unexpected risks to the subject and others received are reviewed and does the report indicate changes in the risks and / or interests of study participants? It is responsible for determining whether informed consent, the protocol, or any other study-related document needs to be modified.

Any unexpected problem (internal event) with risk to the subject or others that occurs in a facility where the trial is approved by the IRB must be reported to the IRB. It is justified to modify the risk to the potential benefits of the study and, as a result, substantially modify the protocol or informed consent process / document to ensure the safety, rights, or welfare of the study subject. Any event, incident, experience, or consequence of becoming an event must be reported to the IRB.

Statistical study The sample size will be a total of 17 patients treated with HCQ MTD for this Phase 1/2 study. This figure is based on Simon's two-stage design (Simon R., Controlled Clinical Trials, 1989, 10: 1-10), in which nine patients are enrolled in Stage 1. If none of the 9 patients respond, the study will be discontinued due to lack of efficacy. If one or more patients respond, the study will continue until a total of 17 patients are treated with the combination therapy of HCQ with MTD. If 2 or more of the 17 patients respond, the combination therapy is considered to be sufficiently active for additional studies. These parameters impart a power of 0.0466 α and 0.8122 to detect differences from no intervention (set to a response rate of 5%).

Data management and reporting schedules Disease responses include RR, PFS, and OS (Chon BD et al., Clinical application and proposal for modifixation of the International Working Group: IWG) (As described by 425, 2006), as well as changes in transfusion frequency from baseline. RRs and PFSs derived from hematology and bone marrow examination are evaluated at the following designated points of time:
-Baseline-Fourth week of every two treatment cycles up to cycle 6-After that, every three treatment cycles (ie, cycle 9, cycle 12, cycle 15, etc.) until evidence of disease progression.
Bone marrow examination results must be documented at each designation.

Oral Efficacy of 6,8-bis-benzylthio-octanoic Acid in Example 12-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 were negative for viral contamination using the Mouse Antibodies Production (MAP) test performed by the Charles River Laboratories Molecular Division when they received tumor cells from the ATCC. Tumor cells were humidified at 37 ° C. in a T225 tissue culture flask containing 50 mL RPMI 1640 solution containing 10% fetal bovine serum (FBS) and 2 mM L-glutamine. Maintained in a% CO ₂ atmosphere. Cells were divided by trypsinization at a ratio of 1:10 every 2-3 days and resuspended in fresh medium in fresh flasks. Cells were similarly harvested for experimentation with 70-90% confluency.

CD1-Nu / Nu female mice about 4-6 weeks old were obtained from Charles River Laboratories. Five mice were housed in cages in the Department of Animal Laboratory Research microisolator room at the State University of New York (SUNY) in Stony Brook. The light-dark cycle was 12 hours daily, with light from 7:00 am to 7:00 pm. Food (Purina Rodent Show) and water (distilled sterile filtered water, pH 7) were provided on an uninterrupted basis. The protocols and procedures were in accordance with the rules of the SUNY Instrumental Care and Use Committee (IACUC) and were approved by the Committee.

There was a 7-day acclimation period between the animal's arrival at the test facility and the experiment prior to tumor inoculation. On the right flank of a mouse, 2 x 10 ⁶ human H460 NSCLC or BxPC3 pancreatic cancer cells suspended in 0.1 mL of Dulbeccoline buffered saline (PBS) solution, 1 cc syringe with a 27-5 / 8 gauge needle. Was inoculated subcutaneously (SC) using. Tumor dimensions (length and width) were measured daily before, during, and after treatment (using calipers) and tumor volume was calculated using the oblate elliptic formula (length x width ² ) / 2. .. Treatment with test or control was initiated 8 days after tumor cell transplantation when the tumor was approximately 300 mm ³ .

Oral dosing 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 amount of 0.01-0.05 N NaOH in 5% dextrose and titrated to pH 7.0 and 50 mg / mL with 4% glacial acetic acid. did. Prior to administration, the suspension was diluted with 5% dextrose to 12.5 mg / mL, whereby the animal received 100 mg / kg in a dose volume of approximately 0.2 mL delivered by the gastric tube forced feeding cavity. rice field. Mice were treated on days 8, 15, 22, and 29 after tumor cell transplantation.

Similar tests were performed on CD-1 nude mice (n = 9) inoculated with 2 × 10 ⁶ BxPC-3 cells. The study started when the tumor reached an average size of 150 mm ³ (day 0) and CPI-613 was administered at an oral dose of 100 mg / week for 4 weeks. A comparative group (n = 9) was performed with IP treatment at a weekly dose of 25 mg / kg.

The results are shown in FIGS. 15 and 16. It is clear that tumor growth in mice treated with 6,8-bis-benzylthio-octanoic acid was much slower than in tumors treated with 5% dextrose or untreated mice. This effect was particularly pronounced in BxPC3 tumors. This example demonstrates that 6,8-bis-benzylthio-octanoic acid is effective in treating cancer when orally administered.

Example 13-6,8-Bis-benzylthio-octanoic acid spray dry dispersion oral preparation A solid amorphous dispersion preparation of 6,8-bis-benzylthio-octanoic acid (API) is prepared with API and the following polymers: One of Eudragit L100, poly (vinylpyrrolidone) viscosity throwing K30 (PVP K30), hydroxypropylmethylcellulose (HPMC), cellulose acetate phthalate (CAP), or hydroxypropylmethylcellulose acetate (HPMCAS-M) is 1 Prepared by mixing at 4: 4 and spray drying from methanol or acetone using a small-scale Bend Lab Dryer with a dry gas flow capacity of 35 kg / hour (BLD-35). The conditions, yields, and residual solvent levels of the 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 to study if any degree of fusion or crystallinity was visible. The particles exhibit a collapsed spherical morphology with no crystallization or fusion.

X-ray diffraction is typically sensitive to the presence of crystalline material with a LOD of about 1% of the sample mass. Crystallinity was not detected by PXRD for any of the SDD preparations. A differential gram compared to the crystalline 6,8-bis-benzylthio-octanoic acid API can be found in FIG. 17, the upper defractogram is the Eudragit L100 formulation and the intermediate defractogram is the HPMCAS-M formulation. And the diffractgram below is crystalline 6,8-bis-benzylthio-octanoic acid.

Examples 14-6,8-bis-benzylthio-octanoic acid emulsion oral preparation Monolaurin (131 mg) and 6,8-bis-benzylthio-octanoic acid (93 mg) are polysorbate in a round bottom flask equipped with a magnetic stirring rod. It was heated to 50 ° C. in -80 (2.5 mL). After the solution was completely dissolved until it became transparent, water (7.5 mL) was added at 50 ° C. with vigorous stirring to obtain an emulsion.

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

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

The suspended vehicle is (a) combined with Tris buffer (48 mg) and HPMCAS-HF (20 mg) in 14 mL of distilled water, (b) adjusted to 7.4 pH with sodium hydroxide solution and HPMCAS-. Steps to dissolve HF, (c) heat the resulting solution to about 90 ° C., (d) add Metothell A4M Premium (100 mg) to the hot solution, (e) vigorously stir and dissolve the mixture. The step of suspending the unresolved Methocel A4M, (f) the step of cooling and stirring the mixture in an ice bath until the Methocel A4M is dissolved (about 10 minutes), (g) diluting the solution with distilled / deionized water and totaling. It was prepared by the steps of making the volume 20 mL and (h) adjusting the pH to 7.4 with an acetate or sodium hydroxide diluent to provide a suspended vehicle.

For the suspension of the spray-dried preparation of Example 13, 400 mg of each SDD preparation is added to the mortar, and 4 mL of the suspended vehicle is slowly added (for uniform dispersion, each time a small amount is added, the mixture is completely mixed with a milk stick. After that, it was prepared by transferring to a flask and stirring for 1 minute before administration. The resulting suspension of the Eudragit L100 SDD formulation (20 mg / mL 6,8-bis-benzylthio-octanoic acid) is identified as "15B" in Example 16 below. The resulting suspension of the HPMCAS-M SDD formulation (20 mg / mL 6,8-bis-benzylthio-octanoic acid) is identified as "15C" in Example 16 below.

Similarly, a 20 mg / mL suspension of 6,8-bis-benzylthio-octanoic acid, 80 mg of 6,8-bis-benzylthio-octanoic acid added to the mortar, and 4 mL of the suspended vehicle slowly added ( (Mix thoroughly with a milk stick each time a small amount is added) for uniform dispersion), then transfer to flask and prepared by stirring for 1 minute prior to administration. The resulting suspension of 6,8-bis-benzylthio-octanoic acid is identified as "15D" in Example 16 below.

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

Examples 16-6,8-bis-benzylthio-octanoic acid oral bioavailability 6,8-bis-benzylthio in 6 groups of 16 BALB / c nude mice (8 males and 8 females) per group. -Octanoic acid was administered by the following six different methods: (1) 5 μL / g IV injection (tail vein) of the triethanolamine / dextrose solution of Example 15 (25 mg / kg, 5 mL / kg, Example 15A). , (2) 5 μL / g IP injection of the triethanolamine / dextrose solution of Example 15 (25 mg / kg, 5 mL / kg, 15A), (3) 5 μL / g of the Eudragit L100 SDD suspension of Example 15 orally. Administration (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) Example. 15 20 mg / mL 6,8-bis-benzylthio-octanoic acid suspension 5 μL / g orally (100 mg / kg, 5 mL / kg, 15D), or (6) 10 mg / mL SOLUTOL in Example 15. Oral administration of 10 μL / g of the solution (100 mg / kg, 10 mL / kg, 15E). In each experiment, 0.083 from one subgroup of 4 male and 4 female mice at 0.083, 1, 4, and 24 hours after dosing, and 4 at 0.5, 2, and 8 hours. Approximately 80 μL of blood was collected from the other subgroup of male and 4 female mice. Plasma from the collected blood samples was analyzed by LC-MS / MS for the presence of 6,8-bis-benzylthio-octanoic acid.

This example demonstrates that 6,8-bis-benzylthio-octanoic acid can be orally administered.

Incorporation by Reference The entire disclosure of each of the patent literature and scientific papers referred to herein is incorporated by reference for all purposes.

Equivalents The invention may be embodied in other particular form without departing from its spirit or essential features. Therefore, the aforementioned embodiments should be regarded as exemplary in all respects, rather than limiting the inventions described herein. Thus, the scope of the invention is indicated by the appended claims, rather than by the aforementioned description, and all modifications within the meaning and scope of the claims are included therein. Is intended.

Claims (38)

A method for treating cancer in a human patient in need thereof, the step of administering to the patient a therapeutically effective amount of 6,8-bis-benzylthio-octanoic acid and a phagocytosis inhibitor. Including, method. The method of claim 1, wherein the cancer exhibits an increased phagocytosis in response to contact with CPI-613. The method of claim 1, wherein the cancer is lymphoma. The method of claim 3, wherein the lymphoma is a relapsed or refractory Hodgkin lymphoma. The method of claim 4, wherein the brentuximab vedotin and PD-1 inhibitor to the patient has failed. The method of claim 3, wherein the lymphoma is a relapsed or refractory T-cell non-Hodgkin's lymphoma. The method of claim 6, further comprising the step of administering to the patient a therapeutically effective amount of bendamustine hydrochloride. The method of claim 3, wherein the lymphoma is recurrent or refractory Burkitt lymphoma. The method of claim 3, wherein the lymphoma is a high-grade B-cell lymphoma with a rearrangement of MYC and BCL2 and / or BCL6. The method according to claim 1, wherein the cancer is leukemia. The method according to claim 1, wherein the cancer is an epithelial malignant tumor. The method according to claim 1, wherein the cancer is a non-epithelial malignant tumor. The method of claim 1, wherein the cancer is myeloma. The method according to claim 1, wherein the cancer is clear cell cancer. The method according to claim 14, wherein the cancer is a clear cell non-epithelial malignant tumor. The method according to claim 14, wherein the cancer is a clear cell epithelial malignant tumor. 16. The method of claim 16, wherein the cancer is a clear cell renal epithelial malignancies. The method according to claim 1, wherein the cancer is a solid tumor. The method of claim 1, wherein the cancer is cancer of the brain or spinal cord. The method of claim 1, wherein the cancer is melanoma. The method according to claim 1, wherein the cancer is a blastoma. The method of claim 1, wherein the cancer is a germ cell tumor. The method according to claim 1, wherein the cancer is pancreatic cancer. The method according to claim 1, wherein the cancer is a cancer of the prostate. The method according to claim 1, wherein the cancer is myelodysplastic syndrome. 25. The method of claim 25, wherein the cancer is a high-risk myelodysplastic syndrome. 26. The method of claim 26, wherein the cancer is a high-risk myelodysplastic syndrome in a patient who has not responded, advanced or relapsed during hypomethylation therapy. The method according to claim 1 or 2, wherein the cancer is not a clear cell cancer. The method according to claim 1 or 2, wherein the cancer is not a clear cell non-epithelial malignant tumor. The method according to claim 1 or 2, wherein the cancer is a non-clear cell non-epithelial malignant tumor. The method according to claim 1 or 2, wherein the cancer is not a soft tissue cancer. The method according to claim 1 or 2, wherein the cancer is not a clear cell epithelial malignant tumor. The method according to any one of claims 1 to 32, wherein the autophagy inhibitor is 4-aminoquinoline. 33. The method of claim 33, wherein the autophagy inhibitor is hydroxychloroquine. 34. The method of claim 34, wherein the hydroxychloroquine is administered to the patient as hydroxychloroquine sulfate. 33. The method of claim 33, wherein the autophagy inhibitor is chloroquine. 36. The method of claim 36, wherein the chloroquine is administered to the patient as chloroquine phosphate. A method for treating cancers other than clear cell non-epithelial malignancies in human patients in need thereof, wherein therapeutically effective amounts of 6,8-bis-benzylthio-octanoic acid and autologous are given to the patients. A method comprising the step of administering a phagocytosis inhibitor.

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