TWI815933B - Use of a first therapeutic agent comprising 6,8-bis(benzylsulfanyl)octanoic acid or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating pancreatic cancer - Google Patents

Abstract

The invention provides methods, compositions, and medical kits for treating pancreatic cancer using (i) 6,8-bis-benzylthio-octanoic acid or a pharmaceutically acceptable salt thereof in combination with (ii) gemcitabine or a pharmaceutically acceptable salt thereof, and (iii) nab-paclitaxel.

Description

Use of a first therapeutic agent containing 6,8-bis-benzylthio-octanoic acid or a pharmaceutically acceptable salt thereof in preparing a drug for treating pancreatic cancer

The present invention provides a method for using (i) 6,8-bis-benzylthio-octanoic acid or a pharmaceutically acceptable salt thereof with (ii) gemcitabine or a pharmaceutically acceptable salt thereof and (iii) albumin-bound form Methods, compositions, and pharmaceutical kits for treating pancreatic cancer in combination with paclitaxel.

Cancer is the leading cause of death in many industrialized countries. Remarkable progress has been made in improving the diagnosis and treatment of cancer. However, current treatment options often suffer from serious adverse side effects and/or treatments are not effective for all patients. For example, many clinically accepted chemotherapeutic agents induce severe damage to normal, proliferating host cells. Another problem associated with many chemotherapy treatments is that in many tumor types there is innate or acquired resistance to treatment.

Pancreatic cancer affects a significant proportion of patients with cancer. Exemplary treatments currently used to help treat patients with pancreatic cancer include surgery, radiation therapy, and chemotherapy. The surgery involves the surgical removal of pancreatic tissue that has cancer. Radiation therapy involves applying ionizing radiation to diseased areas of the pancreas. However, not all patients achieve adequate remission from pancreatic cancer using existing treatments, and/or they experience adverse side effects when subjected to existing treatments.

Accordingly, there is a need for new treatments that provide improved efficacy and/or reduced side effects in treating pancreatic cancer. The present invention addresses this need and provides other related advantages.

The present invention provides a method for using (i) 6,8-bis-benzylthio-octanoic acid or a pharmaceutically acceptable salt thereof with (ii) gemcitabine or a pharmaceutically acceptable salt thereof and (iii) albumin-bound form Methods, compositions, and pharmaceutical sets for treating pancreatic cancer in combination with paclitaxel. For example, pancreatic cancer may be characterized as metastatic. 6,8-Bis-benzylthio-octanoic acid or a pharmaceutically acceptable salt thereof can be formulated as a pharmaceutical composition, for example, a pharmaceutical composition containing an ion pairing agent. 6,8-Bis-benzylthio-octanoic acid or a pharmaceutically acceptable salt thereof may be formulated as a pharmaceutical composition for use with one or more other agents (such as gemcitabine or its Pharmaceutical compositions (pharmaceutically acceptable salts) are administered separately to the patient.

Accordingly, one aspect of the invention provides methods for treating pancreatic cancer. The method includes administering to a patient in need thereof a therapeutically effective amount of (i) a first therapeutic agent comprising 6,8-bis-benzylthio-octanoic acid or a pharmaceutically acceptable salt thereof, (ii) gemcitabine or a pharmaceutically acceptable salt thereof, and (iii) a third therapeutic agent comprising nab-paclitaxel, thereby treating pancreatic cancer. The first therapeutic agent, the second therapeutic agent, and/or the third therapeutic agent can be administered, for example, by intravenous administration. Ideally, the first therapeutic agent, the second therapeutic agent, and the third therapeutic agent can all be administered to the patient on the same day.

Another aspect of the invention provides a pharmaceutical set for treating pancreatic cancer. The pharmaceutical set may comprise (i) a first therapeutic agent comprising 6,8-bis-benzylthio-octanoic acid or a pharmaceutically acceptable salt thereof, and (ii) using the first therapeutic agent with (a) comprising gemcitabine Instructions for treating pancreatic cancer in a patient in combination with a second therapeutic agent, or a pharmaceutically acceptable salt thereof, and (b) a third therapeutic agent comprising nab-paclitaxel. For example, the instructions may specify a route of administration of the first therapeutic agent, the second therapeutic agent, and/or the third therapeutic agent, such as intravenous administration.

In the following detailed description, together with additional embodiments, the above aspects of the invention are explained in more detail.

without

[Figure 1] depicts the antitumor efficacy of oral 6,8-bis-benzylthio-octanoic acid in human non-small cell lung cancer xenografts in mice.

[Figure 2] depicts the antitumor efficacy of oral administration of 6,8-bis-benzylthio-octanoic acid in human pancreatic cancer xenografts in mice.

[Figure 3] shows 6,8-bis-benzylthio- X-ray powder diffraction pattern of a solid amorphous dispersion formulation of octanoic acid, and crystalline 6,8-bis-benzylthio-octanoic acid (bottom diffraction pattern).

The present invention provides a method for using (i) 6,8-bis-benzylthio-octanoic acid or a pharmaceutically acceptable salt thereof with (ii) gemcitabine or a pharmaceutically acceptable salt thereof and (iii) albumin-bound form Methods, compositions, and pharmaceutical sets for treating pancreatic cancer in combination with paclitaxel. For example, pancreatic cancer may be characterized as metastatic. 6,8-Bis-benzylthio-octanoic acid or a pharmaceutically acceptable salt thereof can be formulated as a pharmaceutical composition, for example, a pharmaceutical composition containing an ion pairing agent. 6,8-Bis-benzylthio-octanoic acid or a pharmaceutically acceptable salt thereof may be formulated as a pharmaceutical composition for use with one or more other agents (such as gemcitabine or a pharmaceutically acceptable salt thereof) used in combination therapy. The pharmaceutical composition of the accepted salt) is administered to the patient separately. Unless otherwise indicated, the practice of this invention employs conventional techniques of organic chemistry, pharmacology, and biochemistry. Such techniques are explained in, for example, Comprehensive Organic Synthesis (B.M. Trost & I. Fleming, editors, 1991-1992), which is incorporated herein by reference. The following subsections list different aspects of the invention; however, aspects of the invention described in specific parts are not limited to any specific part.

I.Definition

To assist in understanding the present invention, various terms and phrases are defined below.

As used herein, the terms "a/an" and "the" mean "one or more" and include the plural unless the context is inappropriate.

的化合物。 The term "6,8-bis-benzylthio-octanoic acid" refers to CPI-613, which has the chemical structure

compound of.

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

As used herein, the term "patient" refers to an organism to be treated using the methods of the invention. Such organisms preferably include, but are not limited to, mammals (eg, mice, monkeys, equids (horses), bovines (cows), pigs, dogs, cats, etc.), and most preferably include humans.

As used herein, the term "treatment" includes any action, such as alleviation, reduction, regulation, amelioration, or elimination, resulting in amelioration of a condition, disease, disorder, etc., or amelioration of symptoms thereof. For example, treatment may include reduction of symptoms of the disorder, or complete eradication of the disorder. As another example, treatment may include slowing the progression of the disease, or preventing or delaying its recurrence, such as maintenance therapy to prevent or delay recurrence.

As used herein, the term "pharmaceutical composition" refers to a combination of an active agent and a carrier (inert or active) such that the composition is particularly suitable for diagnostic or therapeutic use in vivo or ex vivo.

The phrase "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for contact with human and animal tissue without undue toxicity, irritation sexual, allergic reactions, or other problems or complications, commensurate with a reasonable benefit/risk ratio.

As used herein, the term "pharmaceutically acceptable carrier" refers to any standard pharmaceutical carrier. The composition may also include stabilizers and preservatives. For examples of carriers, stabilizers, and adjuvants, see, for example, Martin. Remington's Pharmaceutical Sciences, 15th ed., Mack Publ. Co., Easton, Pa. State (PA) [1975].

As used herein, the term "pharmaceutically acceptable salt" refers to any pharmaceutically acceptable salt (eg, acid or base) of a compound of the invention that, when administered to a subject, provides a compound of the invention. As is known to those skilled in the art, "salts" of the compounds of the present invention may be derived from inorganic or organic acids and bases. Examples of acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, p-toluenesulfonic acid, Tartaric acid, acetic acid, citric acid, methanesulfonic acid, ethanesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, etc. Other acids, such as oxalic acid, when not themselves pharmaceutically acceptable, can be used to prepare salts that serve as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts. Examples of bases include, but are not limited to, alkali metal (eg, sodium) hydroxides, alkaline earth metal (eg, magnesium) hydroxides, ammonia, and compounds of formula NW ₃ , where W is C _{1 -4} alkyl, and the like.

Additional examples of salts include salts prepared using the ion pairing agents described in US Pat. No. 8,263,653, the entire disclosure of which is incorporated herein by reference. Additional ion pairing agents may be selected using guidance from Handbook of Pharmaceutical Salts Properties, Selection and Use, UIPAC, Wiley-VCH, edited by P.H. Stahl, whose entire disclosure is provided by This reference is incorporated herein.

Additional examples of salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate , camphor sulfonate, cyclopentane propionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, fluoroheptanoate, glycerophosphate, hemisulfate, heptane Acid, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, tobacco Acid, oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate , tartrate, thiocyanate, toluenesulfonate, undecanoate, etc. Still other examples of salts include the anions of the compounds of the invention complexed with suitable cations such as Na ⁺ , NH ₄ ⁺ , and NW ₄ ⁺ (where W is a C _{1 -4} alkyl group) and the like. The term "alkyl" is art-recognized and includes saturated aliphatic hydrocarbon groups, including straight chain alkyl groups and branched chain alkyl groups.

In certain embodiments, pharmaceutically acceptable salts are those prepared from the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, maleic acid, acetic acid, salicylic acid, p-toluenesulfonic acid, alcohol Stone acid, citric acid, methylsulfonic acid, formic acid, malonic acid, succinic acid, naphthalene-2-sulfonic acid, and benzenesulfonic acid. In certain other embodiments, pharmaceutically acceptable salts are alkali metal or alkaline earth metal salts, such as sodium, potassium, or calcium salts of the carboxylic acid group.

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

Throughout the specification, where compositions and pharmaceutical kits are described as having, comprising, or containing specific compounds, or where processes and methods are described as having, comprising, or comprising specific steps, it is contemplated that otherwise , there are compositions and pharmaceutical sets of the invention, which consist essentially of or consist of the recited compounds, and there are processes and methods according to the invention, which consist essentially of or consist of the recited processing steps.

Generally, compositions are specified as percentages by weight unless otherwise stated. Additionally, if a variable does not come with a definition, the previous definition of the variable is compared.

II. Therapeutic applications

The present invention provides for the use of (i) 6,8-bis-benzylthio-octanoic acid or a pharmaceutically acceptable salt thereof in combination with (ii) gemcitabine or a pharmaceutically acceptable salt thereof, and (iii) albumin-bound paclitaxel. Acceptable Salt Treatment for Pancreatic Cancer. These methods are described in more detail below.

One aspect of the invention provides methods for treating pancreatic cancer. The method includes administering to a patient in need thereof a therapeutically effective amount of (i) a first therapeutic agent comprising 6,8-bis-benzylthio-octanoic acid or a pharmaceutically acceptable salt thereof, (ii) gemcitabine or a pharmaceutically acceptable salt thereof, and (iii) a third therapeutic agent comprising nab-paclitaxel, thereby treating pancreatic cancer. The method may be further characterized according to one or more of the features described herein below.

Types of pancreatic cancer

This approach can be further characterized based on the type of pancreatic cancer. In certain embodiments, the pancreatic cancer is metastatic pancreatic cancer. In certain embodiments, the pancreatic cancer is locally advanced. In certain other embodiments, the pancreatic cancer is histologically or cytologically documented and measurable locally advanced pancreatic adenocarcinoma. In certain other embodiments, the pancreatic cancer is histologically or cytologically documented and measurable metastatic pancreatic adenocarcinoma. In certain embodiments, the pancreatic cancer is previously untreated. In certain embodiments, the pancreatic cancer has not been previously treated with systemic therapy. In certain embodiments, the pancreatic cancer has not been previously treated with systemic or local therapy with chemoradiotherapy. In certain other embodiments, the pancreatic cancer is previously untreated histologically or cytologically documented and measurable locally advanced pancreatic adenocarcinoma. In certain other embodiments, the pancreatic cancer is previously untreated histologically or cytologically documented and measurable metastatic pancreatic adenocarcinoma. In certain other embodiments, the pancreatic cancer is histologically or cytologically documented and measurable locally advanced pancreatic adenocarcinoma that has not been previously treated with systemic therapy. In certain other embodiments, the pancreatic cancer is histologically or cytologically documented and measurable metastatic pancreatic adenocarcinoma that has not been previously treated with systemic therapy. In certain other embodiments, the pancreatic cancer is a histologically or cytologically documented and measurable locally advanced pancreatic adenocarcinoma that has not been previously treated with systemic therapy or local therapy with chemoradiotherapy. In certain other embodiments, the pancreatic cancer is a histologically or cytologically documented and measurable metastatic pancreatic adenocarcinoma that has not been previously treated with systemic or local therapy with chemoradiotherapy.

General form of administering therapeutic agents to patients

Typically, a therapeutic agent, such as 6,8-bis-benzylthio-octanoic acid or a pharmaceutically acceptable salt thereof, is delivered to the patient in a therapeutically effective amount. The therapeutically effective amount of a therapeutic agent can vary depending on: the activity of the specific agent employed; the metabolic stability and length of action of the agent; the species, age, weight, general health, dietary status, sex and diet of the subject; administration mode and time of administration; rate of excretion; combination of drugs, if any; and the degree and/or severity of the specific condition being treated. The precise dosage can be determined, which will involve administration once or several times a day, in whatever sequence is necessary or desired, thereby producing the desired results, and the dosage can be adjusted by the individual practitioner, thereby achieving the desired effect. Treatment may involve one or several administrations over one or more days, and the dosage may be adjusted by the individual practitioner to achieve the desired effect. Preferably, the dose of the agent or agents used is sufficient to interact primarily with diseased cells (eg, tumor cells) while leaving normal cells relatively unharmed (eg, substantially unharmed).

Doses may be administered as a single dose or in individually divided doses, for example from one to four or more times per day. In certain embodiments, the daily dose is administered as a single dose. In the event of insufficient response in a subject at certain doses, even higher doses (or effectively higher doses via different, more local delivery routes) may be used to the extent tolerated by the patient.

For combination therapy, the components of the combination therapy may be administered in a specific order, and/or according to the treatment cycle, for example, on the same day or on different days. For example, in certain embodiments, at least one dose of the first therapeutic agent is administered to the patient prior to the administration of the second therapeutic agent, eg, on an earlier day in the treatment cycle. In certain embodiments, the active components of the combination therapy may be administered on the same day of the treatment cycle, eg, simultaneously co-administered. In certain embodiments, at least one dose of the second therapeutic agent is administered prior to administration of 6,8-bis-benzylthio-octanoic acid or a pharmaceutically acceptable salt thereof, such as on an earlier day in the treatment cycle. Administer to patient. In certain embodiments, the active components of a combination therapy may be co-administered in a predetermined manner, ratio, and/or order of addition, thereby encompassing a treatment cycle. In certain embodiments, treatment cycles may be repeated, thereby maximizing patient benefit.

In certain embodiments, the first therapeutic agent and the second therapeutic agent can be administered to the patient on the same day. In certain embodiments, the first therapeutic agent and the third therapeutic agent can be administered to the patient on the same day. In certain embodiments, the first therapeutic agent, the second therapeutic agent, and the third therapeutic agent can all be administered to the patient on the same day of each treatment cycle. In certain embodiments, the first therapeutic agent, the second therapeutic agent, and the third therapeutic agent can all be administered to the patient on the same day of each treatment cycle, with the first therapeutic agent administered first and the third therapeutic agent administered first. The third therapeutic agent is administered simultaneously with or subsequent to the first therapeutic agent, and the second therapeutic agent is administered after the third therapeutic agent.

Properties of the first therapeutic agent

The treatment method can be further characterized based on the characteristics of the first therapeutic agent. For example, in certain embodiments, the first therapeutic agent is 6,8-bis-benzylthio-octanoic acid or a pharmaceutically acceptable salt thereof. In certain embodiments, the first therapeutic agent is 6,8-bis-benzylthio-octanoic acid. In certain embodiments, the first therapeutic agent is a salt of 6,8-bis-benzylthio-octanoic acid. In certain other embodiments, the first therapeutic agent is 6,8-bis-benzylthio-octanoic acid in an ion pair with triethanolamine. In certain embodiments, the first therapeutic agent is the triethanolamine salt of 6,8-bis-benzylthio-octanoic acid.

The first therapeutic agent can be formulated in a pharmaceutical composition. In certain embodiments, the first therapeutic agent can be administered to the patient in the form of a pharmaceutical composition comprising 6,8-bis-benzylthio-octanoic acid and a pharmaceutically acceptable carrier. In certain other embodiments, the first therapeutic agent can be administered to the patient in the form of a pharmaceutical composition comprising 6,8-bis-benzylthio-octanoic acid and an ion-pairing agent. In certain embodiments, the first therapeutic agent can be administered to the patient in the form of a pharmaceutical composition comprising 6,8-bis-benzylthio-octanoic acid and triethanolamine. In certain other embodiments, the pharmaceutical composition further comprises dextrose and water. In certain embodiments, the first therapeutic agent is 6,8-bis-benzylthio-octanoic acid in an ion pair with triethanolamine.

For example, exemplary ion pairing agents may include tertiary amines such as triethanolamine, other amines such as diethanolamine, monoethanolamine, mefenamic acid, and tromethamine, and combinations thereof. In certain embodiments, the ion pairing agent is an organic Bronsted base. In certain other embodiments, the ion pairing agent is an amine compound. In still other embodiments, the ion pairing agent is a monoalkylamine, a dialkylamine, a trialkylamine, an amine-substituted fatty alcohol, a hydroxymonoalkylamine, a hydroxydialkylamine, a hydroxytrialkylamine , amine-substituted heteroaliphatic alcohols, alkyldiamines, substituted alkyldiamines, or optionally substituted heteroaryl groups containing at least one ring nitrogen atom.

啉、哌

、氫氧化鉀、1-(2-羥乙基)-吡咯啶、氫氧化鈉、三乙醇胺(2,2’,2”-次氮基三(乙醇))、胺丁三醇、和氧化鋅。在某些其他實施方式中，離子配對劑係二異丙醇胺、3-胺基-1-丙醇、葡甲胺、

啉、吡啶、煙醯胺、三(羥甲基)胺基甲烷、2-((2-二甲胺基)乙氧基)乙醇、2-(二甲胺基)乙醇、1-(2-羥乙基)吡咯啶、或氫氧化銨。在某些其他實施方式中，離子配對劑係鹼金屬氫氧化物或鹼土金屬氫氧化物，例如像氫氧化銫。 For example, additional exemplary ion-pairing agents include polyethylenimine, polyglutamic acid, ammonia, L-arginine, benzylbenzylamine, betaine, calcium hydroxide, choline, dianosine, Diethanolamine (2,2'-iminobis(ethanol)), diethylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylenediamine, N-methyl-glucosamine, halamine ( hydrabamine), 1H-imidazole, lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-

Phenoline, pipera

, potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, sodium hydroxide, triethanolamine (2,2',2”-nitrilotris(ethanol)), tromethamine, and zinc oxide .In certain other embodiments, the ion pairing agent is diisopropanolamine, 3-amino-1-propanol, meglumine,

Phenoline, pyridine, nicotinamide, tris(hydroxymethyl)aminomethane, 2-((2-dimethylamino)ethoxy)ethanol, 2-(dimethylamino)ethanol, 1-(2- Hydroxyethyl)pyrrolidine, or ammonium hydroxide. In certain other embodiments, the ion pairing agent is an alkali metal hydroxide or an alkaline earth metal hydroxide, such as, for example, cesium hydroxide.

In certain embodiments, the first therapeutic agent has a purity of at least about 50% (w/w). In certain embodiments, the first therapeutic agent has a purity of at least about 60% (w/w). In certain embodiments, the first therapeutic agent has a purity of at least about 70% (w/w). In certain embodiments, the first therapeutic agent has a purity of at least about 80% (w/w). In certain embodiments, the first therapeutic agent has a purity of at least about 90% (w/w). In certain embodiments, the first therapeutic agent has a purity of at least about 95% (w/w). In certain embodiments, the first therapeutic agent has a purity of at least about 96% (w/w). In certain embodiments, the first therapeutic agent has a purity of at least about 97% (w/w). In certain embodiments, the first therapeutic agent has a purity of at least about 98% (w/w). In certain embodiments, the first therapeutic agent has a purity of at least about 99% (w/w).

In certain more specific embodiments, the first therapeutic agent is administered in the form of a pharmaceutical composition comprising 6,8-bis-benzylthio-octanoic acid and triethanolamine. Such pharmaceutical compositions can be further characterized based on the 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 1:10, from about 10:1 to about 5:1, or about Within the range of 8:1. In certain embodiments, the molar ratio of triethanolamine to 6,8-bis-benzylthio-octanoic acid is about 8:1.

Exemplary Routes of Administration for the First Therapeutic Agent

The treatment method can be further characterized based on the route of administration of the first therapeutic agent. For example, in certain embodiments, the first therapeutic agent can be administered intravenously to the patient. In certain embodiments, the first therapeutic agent can be administered orally to the patient.

Exemplary dosage and regimen of first therapeutic agent

The treatment method can be further characterized based on the dose of the first therapeutic agent administered to the patient. Accordingly, in certain embodiments, the first therapeutic agent is administered to the patient at a dose ranging from about 250 mg/ ^m to about 1500 mg/ ^m on any day the first therapeutic agent is administered to the patient. In certain embodiments, the first therapeutic agent is administered to the patient at a dose ranging from about 250 mg/ ^m to about 500 mg/ ^m on any day the first therapeutic agent is administered to the patient. In certain embodiments, the first therapeutic agent is administered to the patient at a dose ranging from about 500 mg/ ^m to about 1000 mg/ ^m on any day the first therapeutic agent is administered to the patient. In certain embodiments, the first therapeutic agent is administered to the patient at a dose ranging from about 1000 mg/ ^m to about 1500 mg/ ^m on any day the first therapeutic agent is administered to the patient. In certain embodiments, the first therapeutic agent is administered to the patient at a dose of about 250 mg/m on ^any day the first therapeutic agent is administered to the patient. In certain embodiments, the first therapeutic agent is administered to the patient at a dose of about 500 mg/m on ^any day the first therapeutic agent is administered to the patient. In certain embodiments, the first therapeutic agent is administered to the patient at a dose of about 1000 mg/m on ^any day the first therapeutic agent is administered to the patient. In certain embodiments, the first therapeutic agent is administered to the patient at a dose of about 1500 mg/ ^m on any day the first therapeutic agent is administered to the patient.

In certain embodiments, a method of treatment may be characterized in terms of a dosing regimen for administering the first therapeutic agent to the patient. Thus, in certain embodiments, the first therapeutic agent is administered less frequently than once every seven-day period. In certain embodiments, the first therapeutic agent is administered once every seven days for a period of at least 3 weeks. In certain embodiments, at least seven days exist between any subsequent administration of the first therapeutic agent to the patient.

In certain embodiments, the first therapeutic agent is administered to the patient on days 1 and 15 of the twenty-eight day cycle. In certain embodiments, the first therapeutic agent is administered to the patient on days 1, 8, and 15 of a twenty-eight day cycle.

In certain embodiments, the first therapeutic agent is administered at a dose of about 250 mg/m ^to about 1500 mg/ ^m on Days 1 and 15 of the twenty-eight day cycle. In certain embodiments, the first therapeutic agent is administered at a dose of about 250 mg/m ^to about 1500 mg/m on days 1, 8, and ¹⁵ of the twenty-eight day cycle. In certain embodiments, the first therapeutic agent is administered at a dose of about 250 mg/m on Days 1 and ¹⁵ of a twenty-eight day cycle. In certain embodiments, the first therapeutic agent is administered at a dose of about 250 mg/m on days 1, 8, and ¹⁵ of a twenty-eight day cycle. In certain embodiments, the first therapeutic agent is administered at a dose of about 500 mg/m on Days 1 and ¹⁵ of a twenty-eight day cycle. In certain embodiments, the first therapeutic agent is administered at a dose of about 500 mg/m on days 1, 8, and ¹⁵ of a twenty-eight day cycle. In certain embodiments, the first therapeutic agent is administered at a dose of about 1000 mg/m on days 1, 8, and ¹⁵ of a twenty-eight day cycle. In certain embodiments, the first therapeutic agent is administered at a dose of about 1500 mg/m on days 1, 8, and ¹⁵ of a twenty-eight day cycle. In certain embodiments, each more than one dose of the first therapeutic agent is administered as a two-hour IV infusion. In certain embodiments, the dosing cycle is repeated at least once. In certain embodiments, methods of the invention include treatment with at least 6 cycles. In certain embodiments, methods of the invention include treatment with at least 7 cycles. In certain embodiments, methods of the invention include treatment with at least 10 cycles.

In still other embodiments, the first therapeutic agent is administered in a four-week cycle, wherein the first therapeutic agent is administered once a week for the first three weeks, followed by one week off. In certain embodiments, the first therapeutic agent is administered on days 1, 8, and 15 of a four-week cycle. In certain embodiments, the first therapeutic agent is administered at a dose of about 250 mg/ ^m to about 1500 mg/m ^once weekly for the first three weeks, followed by one week off. In certain embodiments, the first therapeutic agent is administered at a dose of about 250 mg/m ^to about 1500 mg/m on days 1, 8, and ¹⁵ of a four-week cycle. In certain embodiments, the first therapeutic agent is administered at a dose of about 500 mg/ ^m to about 1000 mg/m ^once weekly for the first three weeks, followed by one week off. In certain embodiments, the first therapeutic agent is administered at a dose of about 500 mg/m ^to about 1000 mg/m on days 1, 8, and ¹⁵ of a four-week cycle. In certain embodiments, the first therapeutic agent is administered at a dose of about 1000 mg/ ^m to about 1500 mg/m ^once weekly for the first three weeks, followed by one week off. In certain embodiments, the first therapeutic agent is administered at a dose of about 1000 mg/m ^to about 1500 mg/m on days 1, 8, and ¹⁵ of a four-week cycle. In certain embodiments, each more than one dose of the first therapeutic agent is administered as a two-hour IV infusion. In some embodiments, the predetermined period repeats at least once. In certain embodiments, the predetermined period repeats at least 2, 3, 4, or 5 times. In certain embodiments, methods of the present invention include treatment with at least 6 predetermined cycles.

The first therapeutic agent can be administered orally to the patient. Dosages and regimens will vary based, for example, on the characteristics of the patient's cancer and can be readily determined by one skilled in the art in view of the guidance provided herein. In certain embodiments, the dosage and regimen are modified based on those used intravenously with 6,8-bis-benzylthio-octanoic acid or a pharmaceutically acceptable salt thereof, such as those listed herein. In certain embodiments, the dose is the maximum tolerated dose.

An advantage of oral administration of the first therapeutic agent is that it allows substantially increased dosing flexibility compared to IV. In the prior art, 6,8-bis-benzylthio-octanoic acid was formulated as a 50 mg/mL solution of 1 M (150 mg/mL) aqueous triethanolamine with sterile 5% dextrose for injection (D5W) from 50 mg/mL is diluted to as low as 4 mg/mL (e.g., 12.5 mg/mL) and administered as an IV infusion via a central venous catheter over 30-120 minutes. Such an infusion is inconvenient for the patient and effectively precludes regimens involving frequent and/or long-term dosing. Because the half-life of the first therapeutic agent is only about 1-2 hours after IV administration (Pardee, T.S. et al., Clin Cancer Res. 2014, 20, 5255-64), more frequent and/or Chronic administration may advantageously be used to increase the patient's exposure to the first therapeutic agent.

For example, a possible IV regimen for treating pancreatic cancer involves administering a first, second, and third therapeutic agent on days 1, 8, and 15 of a 28-day cycle. If the first therapeutic agent is administered orally, administration of the second and third therapeutic agents may continue on Days 1, 8, and 15 of the 28-day cycle, but at a dosage and schedule relative to the first therapeutic agent , practitioners can be more flexible. The first therapeutic agent is administered orally in single daily doses on days 1, 8, and 15 of the 28-day cycle. Alternatively, the first treatment may be administered in two or more (eg, three, four, or five) divided doses on days 1, 8, and 15 of a 28-day cycle agent, and/or the first therapeutic agent may be administered on a different day in the cycle than and/or except for Day 1, Day 8, and Day 15 up to and including every day.

Another advantage of oral administration is that it makes maintenance therapy more feasible. For example, patients who are successfully treated with first-line therapy - with or without the first therapeutic agent - and whose cancer has gone into partial or complete remission can be treated with first, second, and third oral therapeutic agents chronically, thereby delaying or preventing recurrence. For example, maintenance therapy may involve one, two, three, four, or five doses of the first therapeutic agent per day on a regular basis, such as daily or weekly.

In certain embodiments, the first therapeutic agent is administered orally in a dosage of from about 1 mg to about 10,000 mg for each day it is administered. The daily dose may be administered as one dose, or divided into two or more doses, such as three, four, or five doses. In certain embodiments, the daily dosage ranges from about 10 mg to about 7,500 mg. In certain embodiments, the daily dosage ranges from about 100 mg to about 5,000 mg. In certain embodiments, the daily dosage is from about 200 mg to about 4,000 mg. In certain embodiments, the daily dosage is from about 300 mg to about 3,000 mg. In certain embodiments, the daily dosage is about 400 mg to about 2,500 mg. In certain embodiments, the daily dosage ranges from about 500 mg to about 2,000 mg. In certain embodiments, the daily dosage is about 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1,000 mg, 1,250 mg, 1,500 mg, 1,750 mg, 2,000 mg, 2,500 mg, 3,000 mg , 3,500mg, 4,000mg, 4,500mg, 5,000mg, 6,000mg, 7,000mg, 8,000mg, 9,000mg, or 10,000mg.

In certain embodiments, the dosing cycle is repeated at least once. In certain embodiments, methods of the present invention include treatment with two or more cycles. In certain embodiments, methods of the invention include treatment with three or more cycles. In certain embodiments, methods of the invention include treatment with four or more cycles. In certain embodiments, methods of the present invention include treatment with five or more cycles. In certain embodiments, methods of the present invention include treatment with six or more cycles. In certain embodiments, methods of the present invention include treatment with seven or more cycles. In certain embodiments, methods of the present invention include treatment with eight or more cycles. In certain embodiments, methods of the present invention include treatment with nine or more cycles. In certain embodiments, methods of the present invention include treatment with ten or more cycles. In certain embodiments, methods of the present invention include conventional treatment (including on a daily or weekly basis) with a first therapeutic agent for an extended period of time, such as one, two, three, or longer .

Characteristics of the Second Therapeutic Agent

The treatment method can be further characterized based on the properties of the second therapeutic agent. For example, in certain embodiments, the second therapeutic agent is a pharmaceutically acceptable salt of gemcitabine. In certain embodiments, the second therapeutic agent is gemcitabine hydrochloride.

Exemplary Routes of Administration for Second Therapeutic Agents

Treatment methods can be further characterized based on the route of administration of the second therapeutic agent. For example, in certain embodiments, the second therapeutic agent can be administered intravenously to the patient.

Exemplary Dosage Dosages and Regimen for Second Therapeutic Agents

The treatment method can be further characterized based on the dose of the second therapeutic agent administered to the patient. Accordingly, in certain embodiments, the second therapeutic agent is administered to the patient at a dose ranging from about 650 mg/ ^m to about 1000 mg/ ^m on any day the second therapeutic agent is administered to the patient. In certain embodiments, the second therapeutic agent is administered to the patient at a dose ranging from about 650 mg/ ^m to about 800 mg/ ^m on any day the second therapeutic agent is administered to the patient. In certain embodiments, the second therapeutic agent is administered to the patient at a dose ranging from about 800 mg/ ^m to about 1000 mg/ ^m on any day the second therapeutic agent is administered to the patient. In certain embodiments, the second therapeutic agent is administered to the patient at a dose of about 650 mg/m on ^any day the second therapeutic agent is administered to the patient. In certain embodiments, the second therapeutic agent is administered to the patient at a dose of about 800 mg/m on ^any day the second therapeutic agent is administered to the patient. In certain embodiments, the second therapeutic agent is administered to the patient at a dose of about 1000 mg/ ^m on any day the second therapeutic agent is administered to the patient.

The treatment methods are further characterized in terms of the dosing regimen used to administer the second therapeutic agent to the patient. Thus, in certain embodiments, the second therapeutic agent is administered to the patient less frequently than once every seven-day period. In certain embodiments, the second therapeutic agent is administered to the patient once every seven days for a period of at least 3 weeks. In certain embodiments, at least seven days exist between any subsequent administration of the second therapeutic agent to the patient.

In certain embodiments, the second therapeutic agent is administered to the patient on Days 1 and 15 of the twenty-eight day cycle. In certain embodiments, the second therapeutic agent is administered to the patient on days 1, 8, and 15 of the twenty-eight day cycle.

In certain embodiments, the second therapeutic agent is administered at a dose of about 650 mg/m ^to about 1000 mg/ ^m on Days 1 and 15 of the twenty-eight day cycle. In certain embodiments, the second therapeutic agent is administered at a dose of about 650 mg/m ^to about 1000 mg/m on Days 1, 8, and ¹⁵ of the twenty-eight day cycle. In certain embodiments, the second therapeutic agent is administered at a dose of about 650 mg/m on Days 1 and ¹⁵ of the twenty-eight day cycle. In certain embodiments, the second therapeutic agent is administered at a dose of about 650 mg/m on Days 1, 8, and ¹⁵ of the twenty-eight day cycle. In certain embodiments, the second therapeutic agent is administered at a dose of about 800 mg/m on Days 1 and ¹⁵ of the twenty-eight day cycle. In certain embodiments, the second therapeutic agent is administered at a dose of about 800 mg/m on Days 1, 8, and ¹⁵ of the twenty-eight day cycle. In certain embodiments, the second therapeutic agent is administered at a dose of about 1000 mg/m on Days 1 and ¹⁵ of the twenty-eight day cycle. In certain embodiments, the second therapeutic agent is administered at a dose of about 1000 on days 1, 8, and 15 of the twenty-eight day cycle. In certain embodiments, each more than one dose of the second therapeutic agent is administered as a 30-minute IV infusion. In certain embodiments, the dosing cycle is repeated at least once. In certain embodiments, methods of the invention include treatment with at least 6 cycles. In certain embodiments, methods of the invention include treatment with at least 7 cycles. In certain embodiments, methods of the invention include treatment with at least 10 cycles.

In still other embodiments, the second therapeutic agent is administered in a four-week cycle, wherein the second therapeutic agent is administered once a week for the first three weeks, followed by one week off. In certain embodiments, the second therapeutic agent is administered on days 1, 8, and 15 of a four-week cycle. In certain embodiments, the second therapeutic agent is administered at a dose of about 650 mg/ ^m to about 1000 mg/m ^once weekly for the first three weeks, followed by one week off. In certain embodiments, the second therapeutic agent is administered at a dose of about 650 mg/m ^to about 1000 mg/m on days 1, 8, and ¹⁵ of a four-week cycle. In certain embodiments, the second therapeutic agent is administered at a dose of about 650 mg/ ^m to about 800 mg/m ^once weekly for the first three weeks, followed by one week off. In certain embodiments, the second therapeutic agent is administered at a dose of about 650 mg/m ^to about 800 mg/m on days 1, 8, and ¹⁵ of a four-week cycle. In certain embodiments, each of the more than one dose of the second therapeutic agent is administered as an intravenous infusion. In some embodiments, the predetermined period repeats at least once. In certain embodiments, the predetermined period repeats at least 2, 3, 4, or 5 times. In certain embodiments, methods of the present invention include treatment with at least 6 predetermined cycles.

Characteristics of the third therapeutic agent

The treatment method can be further characterized based on the properties of the third therapeutic agent. For example, in certain embodiments, the third therapeutic agent is albumin-bound paclitaxel.

Exemplary Routes of Administration for Third Therapeutic Agents

The treatment method can be further characterized based on the route of administration of the third therapeutic agent. For example, in certain embodiments, the third therapeutic agent can be administered intravenously to the patient.

Exemplary dosage and regimen of third therapeutic agent

The treatment method can be further characterized based on the dose of the third therapeutic agent administered to the patient. Accordingly, in certain embodiments, the third therapeutic agent is administered to the patient at a dose ranging from about 80 mg/ ^m to about 125 mg/ ^m on any day the third therapeutic agent is administered to the patient. In certain embodiments, the third therapeutic agent is administered to the patient at a dose ranging from about 80 mg/ ^m to about 100 mg/ ^m on any day the third therapeutic agent is administered to the patient. In certain embodiments, the third therapeutic agent is administered to the patient at a dose ranging from about 100 mg/ ^m to about 125 mg/ ^m on any day the third therapeutic agent is administered to the patient. In certain embodiments, the third therapeutic agent is administered to the patient at a dose of about 80 mg/ ^m on any day the third therapeutic agent is administered to the patient. In certain embodiments, the third therapeutic agent is administered to the patient at a dose of about 100 mg/m on ^any day the third therapeutic agent is administered to the patient. In certain embodiments, the third therapeutic agent is administered to the patient at a dose of about 125 mg/m on ^any day the third therapeutic agent is administered to the patient.

In certain embodiments, a method of treatment may be characterized in terms of a dosing regimen for administering the third therapeutic agent to the patient. Thus, in certain embodiments, the third therapeutic agent is administered to the patient less frequently than once every seven-day period. In certain embodiments, the third therapeutic agent is administered to the patient once every seven days for at least 3 weeks. In certain embodiments, at least seven days exist between any subsequent administration of the third therapeutic agent to the patient.

In certain embodiments, the third therapeutic agent is administered to the patient on Days 1 and 15 of the twenty-eight day cycle. In certain embodiments, the third therapeutic agent is administered to the patient on days 1, 8, and 15 of the twenty-eight day cycle.

In certain embodiments, the third therapeutic agent is administered at a dose of about 80 mg/m ^to about 125 mg/m on Days 1 and ¹⁵ of the twenty-eight day cycle. In certain embodiments, the third therapeutic agent is administered at a dose of about 80 mg/m ^to about 125 mg/m on Days 1, 8, and ¹⁵ of the twenty-eight day cycle. In certain embodiments, the third therapeutic agent is administered at a dose of about 80 mg/m on Days 1 and ¹⁵ of the twenty-eight day cycle. In certain embodiments, the third therapeutic agent is administered at a dose of about 80 mg/m on Days 1, 8, and ¹⁵ of the twenty-eight day cycle. In certain embodiments, the third therapeutic agent is administered at a dose of about 100 mg/m on Days 1 and ¹⁵ of the twenty-eight day cycle. In certain embodiments, the third therapeutic agent is administered at a dose of about 100 mg/m on days 1, 8, and ¹⁵ of the twenty-eight day cycle. In certain embodiments, the third therapeutic agent is administered at a dose of about 125 mg/m on Days 1 and ¹⁵ of the twenty-eight day cycle. In certain embodiments, the third therapeutic agent is administered at a dose of about 125 mg/m on Days 1, 8, and ¹⁵ of the twenty-eight day cycle. In certain embodiments, each more than one dose of the third therapeutic agent is administered as a 30-minute IV infusion. In certain embodiments, the dosing cycle is repeated at least once. In certain embodiments, methods of the invention include treatment with at least 6 cycles. In certain embodiments, methods of the invention include treatment with at least 7 cycles. In certain embodiments, methods of the invention include treatment with at least 10 cycles.

In still other embodiments, the third therapeutic agent is administered in a four-week cycle, wherein the third therapeutic agent is administered once a week for the first three weeks, followed by one week off. In certain embodiments, the third therapeutic agent is administered on days 1, 8, and 15 of a four-week cycle. In certain embodiments, the third therapeutic agent is administered at a dose of about 80 mg/ ^m to about 125 mg/m ^once weekly for the first three weeks, followed by one week off. In certain embodiments, the third therapeutic agent is administered at a dose of about 80 mg/m ^to about ¹²⁵ mg/m on Days 1, 8, and 15 of the four-week cycle. In certain embodiments, the third therapeutic agent is administered at a dose of about 80 mg/ ^m to about 100 mg/m ^once weekly for the first three weeks, followed by one week off. In certain embodiments, the third therapeutic agent is administered at a dose of about 80 mg/m ^to about 100 mg/m on days 1, 8, and ¹⁵ of the four-week cycle. In certain embodiments, the third therapeutic agent is administered at a dose of about 100 mg/ ^m to about 125 mg/m ^once weekly for the first three weeks, followed by one week off. In certain embodiments, the third therapeutic agent is administered at a dose of about 100 mg/m ^to about 125 mg/m on days 1, 8, and ¹⁵ of the four-week cycle. In certain embodiments, each of the more than one dose of the third therapeutic agent is administered as an intravenous infusion. In some embodiments, the predetermined period repeats at least once. In certain embodiments, the predetermined period repeats at least 2, 3, 4, or 5 times. In certain embodiments, methods of the present invention include treatment with at least 6 predetermined cycles.

patients for treatment

Treatment methods can be further characterized based on the patient to be treated. Preferably, the patient is human. In certain embodiments, the patient is an adult. In certain embodiments, the patient is at least partially refractory to the first therapeutic agent. In certain embodiments, the patient is at least partially refractory to the second therapeutic agent. In certain embodiments, the patient is at least partially refractory to the third therapeutic agent.

IV.Therapeutic Efficacy and Safety

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

Such methods ideally administer a therapeutically effective amount of one or more indicated compounds to the patient. A therapeutically effective amount can be determined based on the guidance herein, and, for example, can be an amount of a compound sufficient to inhibit, cease, or cause amelioration of the disorder or condition being treated in a particular subject or population of subjects. For example, a therapeutically effective amount may be an amount of drug sufficient to slow the progression of a disease, or an amount of drug sufficient to prevent or delay its recurrence, such as maintenance therapy to prevent or delay recurrence. in person species or other mammals, the therapeutically effective amount may be determined experimentally in a laboratory or clinical setting for the particular disease and subject being treated, or may be determined by the United States Food and Drug Administration ), or the amount required by the guidance of an equivalent foreign agency. It is to be understood that one of ordinary skill in the pharmaceutical and medical arts is well within his/her ability to determine appropriate dosage forms, dosages, and routes of administration.

V. Medical Kit

Another aspect of the invention provides pharmaceutical kits comprising therapeutic agents and/or pharmaceutical compositions described herein together with instructions for use of the pharmaceutical kits to treat disorders described herein. In certain embodiments, the pharmaceutical composition can comprise (i) a first therapeutic agent comprising 6,8-bis-benzylthio-octanoic acid or a pharmaceutically acceptable salt thereof, and (ii) using the first therapeutic agent Instructions for treating pancreatic cancer in a patient in combination with (a) a second therapeutic agent comprising gemcitabine or a pharmaceutically acceptable salt thereof and (b) a third therapeutic agent comprising nab-paclitaxel. The pharmaceutical set may be further characterized according to one or more of the features described herein in connection with the therapeutic use herein.

VI.Drug composition

The therapeutic agents described herein may be formulated as pharmaceutical compositions containing one or more therapeutic agents and a pharmaceutically acceptable carrier. For example, the first therapeutic agent can be formulated as a pharmaceutical composition, eg, the composition further contains an additional anti-cancer agent if desired. A pharmaceutical composition containing both a first therapeutic agent and a second therapeutic agent may be referred to as a co-formulated composition.

In certain embodiments of the invention, the therapeutic agent may be formulated as a pharmaceutically acceptable oil; a liposome; an oil-water or lipid-oil-water emulsion or nanoemulsion; a liquid; or a salt, crystalline form, or Other solid forms delivered as tablets or capsules. To facilitate such formulation, the therapeutic agent may be combined with its pharmaceutically acceptable carrier or excipient. Examples of pharmaceutically acceptable carriers are well known in the art and include those conventionally used in pharmaceutical compositions, such as salts, lipids, buffers, chelating agents, Flavoring agents, coloring agents, preservatives, absorption enhancers to enhance bioavailability, antimicrobial agents, and combinations thereof, optionally in combination with other therapeutic ingredients.

As described in detail below, pharmaceutical compositions may be specially formulated for administration in solid or liquid forms, including those suitable for parenteral administration, such as, for example, as sterile solutions or suspensions, or sustained release formulations, e.g., by By subcutaneous, intramuscular, intravenous or epidural injection.

U.S. Patent No. 8,263,653, the entire disclosure of which is incorporated herein by reference, describes additional embodiments of pharmaceutical formulations of CPI-613 or a pharmaceutically acceptable salt thereof.

Methods of preparing pharmaceutical formulations or compositions include the steps of bringing into association a compound of the invention with the carrier and, optionally, one or more accessory ingredients. In general, such formulations are prepared by uniformly and thoroughly bringing into association a compound of the invention with liquid carriers or fine solid carriers, or both, and then, if necessary, shaping the product.

Pharmaceutical compositions of the invention suitable for parenteral administration include one or more compounds of the invention in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or Sterile powder (before use, the sterile powder can be coated with water to form a sterile injectable solution or dispersion), which can contain sugar, alcohol, antioxidants, buffers, bacteriostatic agents, lysates (the lysates make the formulation and isotonic) or suspending or thickening agent in the blood of the intended recipient.

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 formulated for inhalation, oral administration, topical use, etc., in the form of aerosols, sprays, powders, gels, lotions, creams, suppositories, ointments, etc. , transdermal, intranasal, ocular, pulmonary, rectal, transmucosal, intravenous, intramuscular, subcutaneous, intraperitoneal, intrathoracic, intrapleural, intrauterine, intratumoral, or infusion method, or any combination thereof. As noted above, if such a formulation is desired, other additives known in the art may be included, thereby imparting the desired compatibility and other characteristics to the formulation.

In certain embodiments, the pharmaceutical composition comprising the first therapeutic agent is in an oral dosage form, such as a dry oral dosage form. In certain embodiments, the pharmaceutical composition comprising the first therapeutic agent is an oral dosage form selected from the group consisting of tablets, pills, capsules, caplets, powders, granules, solutions, suspensions, and gels. Oral dosage forms may include pharmaceutically acceptable excipients, such as carriers, diluents, stabilizers, plasticizers, binders, glidants, disintegrants, swelling agents, lubricants, plasticizers, colorants, Film-forming agents, flavoring agents, preservatives, delivery vehicles, and any combination of any of the above. Pharmaceutically acceptable excipients can be determined in part by the specific composition to be administered, as well as by the specific dosage regimen. Accordingly, there are a wide variety of suitable formulations of the pharmaceutical compositions of the invention (see, e.g. , Remington: The Science and Practice of Pharmacy , 20th ed., Gennaro et al., editors, Lippink Lippincott, Williams and Wilkins, 2000 ).

Oral pharmaceutical compositions containing the first therapeutic agent will generally include at least one inert excipient. Excipients include pharmaceutically compatible binders, lubricants, wetting agents, disintegrating agents, etc. Tablets, pills, capsules, dragees, etc. may contain any of the following excipients or compounds of similar properties: binders, such as microcrystalline cellulose, tragacanth or gelatin; excipients, such as starch or lactose; dispersing agents agents, such as alginic acid, Primogel, or cornstarch; lubricants, such as magnesium stearate; glidants, such as colloidal silica; sweeteners, such as sucrose or saccharin; or flavoring agents, such as peppermint, salicylate Ester or orange flavor. When the unit dosage form is a capsule, it may contain liquid excipients such as fatty oils. In addition, dosage unit forms may contain various other materials that modify the physical form of the dosage unit, such as sugar, shellac, or enteric coatings. In addition, the syrup may contain, in addition to the active compounds, sucrose as a sweetening agent, and certain preservatives, dyes, colorants, and flavoring agents. In certain embodiments, an oral pharmaceutical composition comprising a first therapeutic agent includes an excipient in an amount from about 5% to about 99%, such as from about 10% to about 85%, by weight of the composition, wherein the first Therapeutics make up the remainder. In certain embodiments, pharmaceutically acceptable excipients comprise from about 20% to about 80% of the total weight of the composition. In certain embodiments, the drug The compositions comprise the first therapeutic agent in an amount of at least about 40% by weight of the composition, with one or more excipients constituting the remainder. In certain embodiments, the pharmaceutical composition includes the first therapeutic agent in an amount of at least about 50% by weight of the composition. In certain embodiments, the pharmaceutical composition includes the first therapeutic agent in an amount of at least about 60% by weight of the composition. In certain embodiments, the pharmaceutical composition includes the first therapeutic agent in an amount of at least about 70% by weight of the composition. In certain embodiments, the pharmaceutical composition includes the first therapeutic agent in an amount of at least about 80% by weight of the composition. In certain embodiments, the pharmaceutical composition includes the first therapeutic agent in an amount of at least about 90% by weight of the composition.

Diluents for solid oral pharmaceutical compositions containing the first therapeutic agent include, but are not limited to, microcrystalline cellulose (e.g., AVICEL®), microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar , glucose binding agent, dextrin, dextrose, dicalcium phosphate dihydrate, tricalcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylate (such as Eudragit), chloride Potassium, powdered cellulose, sodium chloride, sorbitol and talc.

Binders for solid oral pharmaceutical compositions containing the first therapeutic agent include, but are not limited to, gum arabic, tragacanth, sucrose, glucose, alginic acid, carbomer (e.g., polycarboethylene), sodium carboxymethylcellulose , dextrin, ethylcellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethylcellulose, hydroxypropylcellulose (e.g. KLUCEL®), hydroxypropyl methylcellulose (e.g. METHOCEL®), liquid glucose , magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylate, polyvinylpyrrolidone (e.g. KOLLIDON®, PLASDONE®), pregelatinized starch, sodium alginate and starch. In certain embodiments, pharmaceutical compositions include a binder in an amount from about 0.5% to about 25%, such as from about 0.75% to about 15%, by weight of the composition. In certain embodiments, pharmaceutical compositions include a binder in an amount from about 1% to about 10% by weight of the composition.

By adding a disintegrant to the composition containing the first therapeutic agent, the rate of dissolution of the compacted solid pharmaceutical composition in the patient's stomach can be increased. Disintegrants include, but are not limited to, alginic acid, calcium carboxymethylcellulose, sodium carboxymethylcellulose (e.g., AC-DI-SOL®, PRIMELLOSE®), colloidal silica, Croscarmellose sodium, crospovidone (e.g. KOLLIDON®, POLYPLASDONE®), guar gum, magnesium aluminum silicate, methylcellulose, microcrystalline cellulose, powdered cellulose, pregelatinized starch , sodium alginate, sodium starch glycolate (e.g. EXPLOTAB®) and starch. In certain embodiments, pharmaceutical compositions include a disintegrant in an amount from about 0.2% to about 30%, such as from about 0.2% to about 10%, by weight of the composition. In certain embodiments, pharmaceutical compositions include a disintegrant in an amount from about 0.2% to about 5% by weight of the composition.

The oral pharmaceutical composition containing the first therapeutic agent optionally contains one or more pharmaceutically acceptable wetting agents. Preferably, such wetting agents are selected to maintain the API in close association with water, a condition thought 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, bensonine chloride and cetylpyridinium chloride, dioctyl sulfonate succinate Sodium phosphate, polyoxyethylene alkylphenyl ethers such as nonoxynol ether 9, nonoxynol ether 10, and octoxynol 9, poloxamer (polyoxyethylene and polyoxypropylene block copolymer ), polyoxyethylene fatty acid glycerides and oils, such as polyoxyethylene, caprylic/capric mono- and diglycerides (e.g. Labrasol ^™ from Gattefosse), polyoxyethylene castor oil and polyoxyethylene Hydrogenated castor oil; polyoxyethylene alkyl ethers, such as polyoxyethylene cetearyl ether, polyoxyethylene fatty acid esters, such as polyoxyethylene stearate, polyoxyethylene sorbitan esters, such as polysorbate Alcohol esters 20 and polysorbate 80 (e.g., Tween ^™ 80 from ICI), propylene glycol fatty acid esters, such as propylene glycol laurate (e.g., Lauroglycol ^™ from Gettyfors), 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 monooil acid esters, sorbitan monopalmitate and sorbitan monostearate, tyloxapol, and mixtures thereof. In certain embodiments, pharmaceutical compositions comprising the first therapeutic agent include a wetting agent in an amount from about 0.25% to about 15%, such as from about 0.4% to about 10%, by weight of the composition. In certain embodiments, pharmaceutical compositions include a wetting agent in an amount from about 0.5% to about 5% by weight of the composition. In certain embodiments, pharmaceutical compositions include a wetting agent that is an anionic surfactant. In certain embodiments, pharmaceutical compositions include sodium lauryl sulfate as a wetting agent. In certain embodiments, pharmaceutical compositions comprise sodium lauryl sulfate in an amount from about 0.25% to about 7%, such as from about 0.4% to about 4%, by weight of the composition. In certain embodiments, pharmaceutical compositions include sodium lauryl sulfate in an amount from about 0.5% to about 2% by weight of the composition.

Lubricants (e.g., anti-adhesive agents or glidants) may be added to improve the flow characteristics of the solid oral pharmaceutical composition containing the first therapeutic agent, and/or to reduce the weight of the composition and equipment during compression of the tablet formulation. friction between. Excipients that can act as lubricants include, but are not limited to, colloidal silica, magnesium trisilicate, powdered cellulose, starch, talc, and tricalcium phosphate. Suitable lubricants further include glyceryl behapate (eg Compritol ^™ 888 from Gettyforth); stearic acid and its salts, including magnesium stearate, calcium stearate and sodium stearate ; Zinc stearate; Glyceryl monostearate; Palm stearyl glyceryl ester; Hydrogenated castor oil; Hydrogenated vegetable oil (such as Abitex's Sterotex ^TM ); Wax; Boric acid; Sodium benzoate; Sodium acetate; Stearyl glyceryl Sodium alcohol fumarate; sodium fumarate; sodium chloride; DL-leucine; PEG (eg, Carbowax ^™ 4000 and Carbowax ^™ 6000 from The Dow Chemical Company); sodium oleate; lauryl sulfate Sodium; and magnesium lauryl sulfate. In certain embodiments, oral pharmaceutical compositions comprising the first therapeutic agent include a lubricant in an amount from about 0.1% to about 10%, such as from about 0.2% to about 8%, by weight of the composition. In certain embodiments, pharmaceutical compositions include lubricant in an amount from about 0.25% to about 5% by weight of the composition. In certain embodiments, pharmaceutical compositions include magnesium stearate as a lubricant. In certain embodiments, the pharmaceutical composition includes colloidal silica. In another embodiment, the pharmaceutical composition includes talc. In certain embodiments, the compositions include magnesium stearate or talc in an amount of about 0.5% to about 2% by weight of the composition.

Flavoring agents and flavor enhancers make the oral dosage form containing the first therapeutic agent more palatable to the patient. Common flavoring agents and flavor enhancers for pharmaceutical products that may be included in the compositions of the present invention include maltol, vanillin, ethovanillin, menthol, citric acid, ethyl maltol fumarate, and tartaric acid.

Pharmaceutically acceptable colorants may also be used to color the compositions, thereby improving their appearance and/or assisting patients in identifying the product and unit dosage levels.

The selection of excipients and the amounts used can be readily determined by the formulation scientist based on experience in the art and taking into account standard procedures, as well as reference work. Solid oral compositions containing the first therapeutic agent include powders, granules, aggregates, and compacted compositions. Such dosages may conveniently be presented in unit dosage form and may be prepared by any method well known in the pharmaceutical art. Dosage forms include solid dosage forms like tablets, pills, powders, caplets, granules, capsules, sachets, lozenges and lozenges. In certain embodiments, the pharmaceutical composition comprising the first therapeutic agent is a tablet. 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 is a spray-dried dispersion comprising at least one polymer selected from the group consisting of polyacrylates, polymethacrylates, poly(vinylpyrrole) hydroxypropyl methyl cellulose (HPMC), cellulose acetate phthalate (CAP), and hydroxypropyl methylcellulose acetate succinate (hydroxypropyl methylcellulose) acetate succinate,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, poly(vinylpyrrolidone), hydroxypropyl Methylcellulose (hydroxypropyl methyl cellulose, HPMC), cellulose acetate phthalate (CAP), and hydroxypropyl methylcellulose acetate succinate (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, poly(vinylpyrrolidone) viscosity grade K30 ( PVP K30), hydroxypropyl methylcellulose (HPMC), cellulose acetate phthalate (CAP), and hydroxypropyl methylcellulose acetate succinate (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 the group consisting of Eudragit L100 and hydroxypropyl methylcellulose acetate succinate. ester (HPMCAS-M). In certain embodiments, the pharmaceutical composition comprising the first therapeutic agent is a spray-dried dispersion comprising Eudragit L100. In certain embodiments, the pharmaceutical composition comprising the first therapeutic agent is a spray-dried dispersion comprising hydroxypropyl methylcellulose acetate succinate (HPMCAS-M).

The formulations of the present invention can be buffered by adding suitable buffering agents.

In certain embodiments, the oral pharmaceutical compositions of the present invention comprising a first therapeutic agent are unit dose compositions. In certain embodiments, pharmaceutical compositions contain from about 1 mg to about 5000 mg of the first therapeutic agent. In certain embodiments, the pharmaceutical composition contains from about 100 mg to about 3000 mg of the first therapeutic agent. In certain embodiments, the pharmaceutical composition contains from about 200 mg to about 2000 mg of the first therapeutic agent. In certain embodiments, the pharmaceutical composition contains about 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg, 2000 mg, 2500 mg, or 3000 mg of first therapeutic agent. In certain embodiments, the pharmaceutical composition contains about 300 mg, 500 mg, 700 mg, or 1000 mg of the first therapeutic agent.

In certain embodiments, pharmaceutical compositions of the invention comprise emulsions, particles, or gels as described in U.S. Patent No. 7,220,428. In certain embodiments, pharmaceutical compositions are solid or liquid formulations having from about 0.1% to about 75% w/w lipid or fatty acid component. In certain embodiments, formulations contain from about 0.1% to about 15% w/v lipid and fatty acid components. In certain embodiments, the fatty acid component includes 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.

The above specification describes various aspects and embodiments of the invention, including methods of treatment, pharmaceutical compositions, and pharmaceutical sets. This application specifically contemplates all combinations and permutations of such aspects and embodiments.

Example

The invention being generally described will now be more readily understood by reference to the following examples, which are included solely for the purpose of illustrating certain aspects and embodiments of the invention and are not intended to be limiting of the invention.

Example 1 - Treatment of pancreatic cancer in human patients using 6,8-bis-benzylthio-octanoic acid triethanolamine ion pair combination with gemcitabine hydrochloride and nab-paclitaxel

The 6,8-bis-benzylthio-octanoic acid triethanolamine ion pair in combination with gemcitabine hydrochloride and nab-paclitaxel is administered to human patients with locally advanced or metastatic pancreatic cancer. The experimental procedures are described below.

research design

This was a single-arm, open-label study, and investigators and subjects were not blinded to treatment.

Treatment options and follow-up

Subjects will be followed for survival until death, loss of follow-up, or study completion. Study completion was 1 year after the last subject began treatment with study medication. For subjects with remission, at least six months of treatment is recommended unless or until the following occurs:

- In the opinion of the principal investigator, the patient exhibits disease progression

- Unacceptable treatment toxicity

- The patient withdraws from the protocol

- It is the investigator's discretion for patients to withdraw from the study because continued participation in the study is not the best option for the patient.

- Underlying disease: a condition, injury, or disease unrelated to the disease for which the study is being conducted, making continued treatment unsafe or impossible to follow regularly

- General or specific changes in the patient's condition that render the patient ineligible for further investigational treatment

- Assessment or follow-up that does not meet investigational treatment or protocol requirements

- Termination of clinical trial by sponsor.

When treatment is discontinued during this trial, investigators should make every effort to communicate with the patient and conduct a final evaluation. Furthermore, the reason or reasons for withdrawing from the study must be documented. After patients complete their participation in this trial, survival and post-study treatment will be recorded every two months.

Filter

It is expected that at least two patients will be screened each month.

Patient inclusion criteria

1. Histologically or cytologically documented and measurable locally advanced and metastatic pancreatic adenocarcinoma.

2. Eastern Cooperative Oncology Group (ECOG) behavioral status 0-2.

3. First-line treatment for patients diagnosed with metastatic disease.

4. First-line treatment for patients with locally advanced pancreatic cancer who have not been treated with systemic therapy or local therapy with chemoradiotherapy.

5. Expected survival >3 months.

6. Women of potential pregnancy must receive a contraceptive method (abstinence, intrauterine device, oral contraceptive pill, or double barrier device) during the study and must have a negative test result within 1 week before the start of treatment Serum or urine pregnancy test.

7. Men of childbearing age must use effective contraceptive methods during the study period, unless there is documentation proving infertility.

2週的化驗值必須是： 8.

Laboratory values for 2 weeks must be:

100,000個細胞/mm³或

100bil/L；絕對中性粒細胞計數[ANC]

1500個細胞/mm3或

1.5bil/L；以及血紅蛋白

9g/dL或

90g/L)。 A. Adequate blood values (platelet count

100,000 cells/mm ³ or

100bil/L; absolute neutrophil count [ANC]

1500 cells/mm3 or

1.5bil/L; and hemoglobin

9g/dL or

90g/L).

B. Adequate liver function (aspartate aminotransferase [AST/SGOT] ≤ 3x upper normal limit [UNL], alanine aminotransferase [ALT/SGPT] ≤ 3x UNL (≤ 5x UNL if liver metastases are present), total bilirubin ≤ 1.5x UNL. C. Adequate renal function (serum creatinine ≤ 2.0 mg/dL or 177 μmol/L). D. Adequate coagulation ( International Normalized Ratio or INR must be ≤ 1.5), unless the patient is receiving anticoagulant therapy, in which case the INR should be within therapeutic levels and not higher than 3.5. E. Albumin > 2.5 g/dL. 9. No evidence of clinically significant active infection. 10. Intellectually sound, capable of understanding, and willing to sign informed consent. Patient Exclusion Criteria 1. Unwilling or unable to comply with protocol requirements. Endocrine or acinar pancreas 2. Known metastases to the brain, central nervous system (CNS), or epidural tumors. 3. Metastatic adenocarcinoma of the pancreas, or stage III (locally advanced) adenocarcinoma treated with any systemic chemotherapy Prior treatment. 4. Presence of clinically significant ascites. 5. The patient has received any other standard or investigational treatment for their cancer, or for any indication, within the past 2 weeks prior to initiating treatment with CPI-613 Any other investigational agent. 6. Serious medical illness that would potentially increase the patient's risk of toxicity. 7. Any active uncontrolled bleeding, and any patient with an etiology of bleeding (such as active peptic ulcer disease). 8 . Pregnant women, or women of potential pregnancy who are not using reliable contraceptive methods (because the teratogenic potential of CPI-613 is unknown). 9. Breastfeeding women. 10. Men of childbearing age who are unwilling to use contraceptive methods during the study period. 11. Life expectancy less than 3 months. 12. Any condition or abnormality that the investigator believes will compromise the safety of the patient. 13. Unwillingness or inability to comply with protocol requirements. 14. Active heart disease, including but not limited to symptomatic congestive heart disease Heart failure (NYHA class 3 or 4), symptomatic coronary artery disease, symptomatic angina, or symptomatic myocardial infarction. 15. Patient has a history of myocardial infarction within > 3 months prior to enrollment. 16. Evidence of clinically significant active infection. 17. Patient is known to have HIV infection. 18. Patient has received any type of cancer immunotherapy within the past 2 weeks prior to initiating treatment with CPI-613 Compound. For contrast agent-induced allergy The use of steroids is permitted if the patient has a disease or other indication for supportive therapy. 19. For the need for immediate palliative care of any kind (including surgery). 20. Any other malignant tumor within the last 3 years. 21. History of interstitial lung disease, idiopathic pulmonary fibrosis or pulmonary sensitivity pneumonitis. 22. Peripheral neuropathy grade 2 or higher. Research steps

CPI-613 drug was administered on Days 1, 8, and 15 in combination with gemcitabine hydrochloride and nab-paclitaxel administered on Days 1, 8, and 15 in a 28-day cycle compound. CPI-613 pharmaceutical compound is a 6,8-bis-benzylthio-octanoic acid triethanolamine ion pair.

Key research steps are summarized in the table below.

The primary endpoints of this pilot study were to establish the MTD, characterize the safety profile, and determine clinical activity, as measured by the RR of the CPI-613 drug compound in combination with gemcitabine hydrochloride and nab-paclitaxel.

The dose-limiting toxicity (DLT) assessment period will be defined as consisting of 1 cycle (4 weeks).

A modified 3+3 design will be implemented during the dose-escalation portion of the study. Initially, at dose level 1, 3 patients will participate: • If 2 of 3 patients experience a dose-limiting toxicity (DLT) during the DLT evaluation period, dose escalation will be stopped and dose level 1 will be considered above the MTD and 3 patients will be treated at dose level -1 patient. If at dose level -1, more than 1 patient experiences a DLT, then 3 patients will be treated at dose level -2. If at dose level -2, more than 1 patient experiences a DLT, on days 1 and 15, the study will return to the original treatment regimen and 3 more patients will participate in dose level 1, and only D1 and D15 regimens continue with dose escalation. • If 0 out of 3 patients experience DLT during the DLT assessment period, the dose will be escalated to dose level 2 in the next cohort. • If 1 of 3 patients experiences a DLT during the DLT evaluation period, the other 3 patients will participate in dose level 1. • If during the DLT assessment period, up to 1 of 6 patients experience a DLT, the dose will be escalated to dose level 2 within the next cohort. • If during the DLT assessment period more than 1 of 6 patients experience a DLT, dose escalation will be stopped and dose level 1 will be considered above the MTD and 3 patients will be treated at dose level -1. If at dose level -1, more than 1 patient experiences a DLT, then 3 patients will be treated at dose level -2. If at dose level -2, more than 1 patient experiences a DLT, on days 1 and 15, the study will return to the original treatment regimen and 3 more patients will participate in dose level 1, and only D1 and D15 regimens continue with dose escalation.

If escalation continues to dose level 2, there will first be 3 patients participating in dose level 2: • If, during the DLT assessment period, 2 of 3 patients experience DLT, dose level 1 will be considered MTD. • If 0 of 3 patients experience DLT during the DLT assessment period, the dose will be escalated to dose level 3 within the next cohort. • If during the DLT evaluation period, 1 of 3 patients experiences a DLT, the other 3 patients will participate in dose level 2. • If during the DLT assessment period, up to 1 of 6 patients experience a DLT, the dose will be escalated to dose level 3 within the next cohort. • If more than 1 out of 6 patients experience a DLT during the DLT assessment period, dose level 1 will be considered an MTD.

If escalation continues to dose level 3, there will first be 3 patients participating in dose level 3: • If, during the DLT assessment period, 2 of 3 patients experience a DLT, dose level 2 will be considered an MTD. • If, during the DLT assessment period, 0 of 3 patients experience a DLT, dose escalation will be discontinued and dose level 3 will be considered MTD. Doses above dose level 3 will not be evaluated. • If during the DLT evaluation period, 1 of 3 patients experiences a DLT, the other 3 patients will participate in dose level 3. • If during the DLT assessment period, up to 1 of 6 patients experience a DLT, dose escalation will be stopped and dose level 3 will be considered MTD. Doses above dose level 3 will not be evaluated. • If more than 1 out of 6 patients experience a DLT during the DLT assessment period, dose level 2 will be considered an MTD.

An additional cohort of 6 patients will participate in the MTD for further toxicity assessment and assessment of preliminary clinical activity.

Patients participating in MTD will be included in the initial assessment of the clinical activity of the combination, as measured by RR. If preliminary assessment of clinical activity (as assessed by the principal investigator) demonstrates a response rate of 40% or greater, the current study may be modified to include an expanded cohort of patients treated in the open-label Phase II portion.

Based on the excellent tolerability of a modified chemotherapy regimen in combination with 500 mg/ ^m2 (vs.) CPI-613 drug compound and gemcitabine + nab-paclitaxel on Days 1 and 15, the trial has been modified to Tolerability of the standard of care approved regimen (with gemcitabine + nab-paclitaxel given on days 1, 8, and 15) was explored. The following dose level escalations are presented below. CPI 613 will be administered only when chemotherapy is administered based on standard parameters for chemotherapy.

This article describes dose modifications for chemotherapy-induced hematologic toxicity.

If dose level "-2" is intolerable (> 1 patient with DLT), in which a new chemotherapy architecture of gemcitabine hydrochloride + nab-paclitaxel is used on days 1, 8, and 15, then day 8 The sky will be abandoned, as proposed below.

Toxicity and Safety Assessment: Toxicity will be assessed at each visit using the National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0. Safety assessments will be conducted on the day of each treatment. Safety assessment will include vital signs, ECOG performance status, medical history, physical examination, review of concomitant medications, complete blood count (CBC), concomitant chemistry liver function tests, and CA 19-9. Symptom management and supportive care will be provided as clinically indicated to ensure optimal patient care. Subject safety assessments will be conducted after a break in study treatment, 30 days after the last dose of study drug.

Clinical chemistry to be evaluated includes:

Hematology includes: Blood clotting includes:

Efficacy: Response Evaluation Criteria in Solid Tumors version 1.1 will be performed using a protocol CT scan of the chest, abdomen, and pelvis with iv contrast every 2 cycles and as clinically indicated. (RECIST 1.1) standards to evaluate efficacy. Patients determined by the principal investigator to have progressed will be removed from the study, while those determined to have stable disease or favorable response will continue, with subsequent re-imaging every 2 cycles until unacceptable toxicity or progression.

After treatment is terminated, OS will be monitored via telephone communication every two months. OS and PFS will be calculated from the first day of treatment. The duration of OS will be measured until the day of death or when the follow-up is censored. The duration of response will be measured from the day the first objective response is recorded (assessed by PFS) until the first sign of progression as assessed by MRI. RR is defined as the % of patients who experience complete response (CR) or partial response (PR). CR and PR are based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Best response documented from the start of treatment until disease progression (DP) will be considered. Related Articles: Sample collection for this study will include the following: 1. Plasma and serum at baseline, day 1 of each 28-day cycle, and at disease progression. 2. For 3 patients treated at each different dose level, Cycle 1 Day 1 before dose, 15', 30', 60', 90', 120', 150', 180', and 240' from infusion ', and draw PK samples before dose on Day 1 of Cycle 2. 3. If the patient is able to provide a sample, an initial urine sample (10-15 ml) after CPI-613 infusion on Day 1 of Cycle 1. Dosing Delays and Dose Modifications CPI - 613 Dose Adjustments for Drug Compound-Related Toxicity

For adverse events that are not related to an increase in serum creatinine or a decrease in renal function, but are potentially related to the CPI-613 drug compound, the occurrence of grade 1 toxicities does not generally require dose modification of subsequent doses in that patient. However, if grade 2 toxicities (other than alopecia and nausea) that may be associated with the CPI-613 drug compound develop, treatment is to be discontinued and restarted only when the grade 2 toxicities have declined to grade 1 or less, and with The dose level for subsequent doses in this patient will be reduced by 25% of the dose at which such Grade 2 toxicity occurred. Grade 2 alopecia and nausea do not require discontinuation of treatment or dose reduction. If grade 3 or 4 toxicities that may be associated with the CPI-613 drug compound develop, the patient's administration of the CPI-613 drug compound will be discontinued and should be monitored for recovery from such grade 3 or 4 toxicities, and their reversibility patient. In order to restart treatment with a CPI-613 drug compound for a patient who has had grade 3 or 4 toxicity associated with the CPI-613 drug compound, the grade 3 or 4 toxicity must decrease to grade 1 or less and be used for the patient's subsequent The dose level will be reduced to 50% of the dose at which such grade 3 or 4 toxicity occurs.

For adverse events related to increased creatinine or decreased renal function that may be related to the CPI-613 drug compound, patient dosing will be discontinued, even if the severity level is Grade 2 or greater. Treatment should only be restarted after toxicity has decreased to level 1. If the severity level is Grade 1, the dose level for subsequent doses to that patient will be reduced by 15%, for Grade 2 toxicity, by 25%, and for Grade 3 or 4 toxicity, by 50%.

The CPI-613 drug compound is not expected to cause hematologic toxicity, and therefore hematologic toxicity will be attributable to the chemotherapeutic agents (gemcitabine and nab-paclitaxel), and dose modifications are described below. Dose adjustment for blood-related toxicities of gemcitabine hydrochloride and / or nab-paclitaxel Neutropenia:

For grade 2 or greater neutropenia, withhold treatment for up to 2 weeks until recovery to at least grade 1. If the patient does not recover to grade 1 or less within 2 weeks, interrupt treatment. Follow the drug-specific modifications below for subsequent cycles. It is recommended that 6 mg of pegfilgrastim be administered subcutaneously with each subsequent Day 15 dose of gemcitabine hydrochloride and/or nab-paclitaxel. Thrombocytopenia:

For grade 2 or greater thrombocytopenia, discontinue treatment for up to 2 weeks until recovery to at least grade 1. If the patient does not recover to grade 1 or less within 2 weeks, interrupt treatment. Follow the drug-specific modifications below for subsequent cycles. Peripheral Sensory Neuropathy - Dose modification for nab-paclitaxel only:

Permanently discontinue gemcitabine hydrochloride for any of the following: • Unexplained dyspnea or other evidence of severe pulmonary toxicity. • Severe liver toxicity. • Hemolytic-uremic syndrome. • Capillary leak syndrome. • Reversible posterior encephalopathy syndrome.

For other serious (Grade 3 or 4) non-hematological toxicities, discontinue gemcitabine hydrochloride or reduce the dose by 50%. No dosage modification is recommended for alopecia, nausea, or vomiting. For nab-paclitaxel dosage to adjust liver function: a. If AST is less than 10 times the upper limit of normal (ULN) and total bilirubin is 1.26 to 2 times ULN, reduce the dose by 25%. b. If AST is less than 10 times ULN and total bilirubin is 2.01 to 5 times ULN, reduce the dose by 50%. c. If AST is greater than or equal to 10 times ULN and/or total bilirubin is greater than 5 times ULN, use is not recommended. For each patient in each cohort, the duration of treatment

For subjects with remission, at least six months of treatment is recommended unless or until the following occurs: - The principal investigator believes the patient exhibits disease progression. - Unacceptable treatment toxicity. - The patient withdrew from the protocol. - The investigator uses the discretion of the patient to withdraw from the study because continuing to participate in the study is not the best option for the patient. - Underlying disease: A condition, injury, or disease unrelated to the disease for which the study is being conducted, making continued treatment unsafe or impossible to follow regularly. - General or specific changes in the patient's condition that make the patient ineligible for further investigational treatment. - Evaluation or tracking that does not meet the requirements of research treatments and protocols. - The clinical trial is terminated by the sponsor.

Patients in response who have acceptable tolerance to treatment (with dose modifications for each regimen as needed) should continue treatment unless or until criteria for removal from the study as listed above occur.

When treatment is discontinued during this trial, investigators should make every effort to communicate with the patient and conduct a final evaluation. Furthermore, the reason or reasons for withdrawing from the study must be documented.

After patients complete their participation in this trial, survival and post-study treatment will be recorded every two months. All patients will be followed until death. statistical project

The safety analysis set (SAF) consists of all subjects participating in the study who received at least one dose of any study treatment.

MTD will be assessed using a 3+3 design during the dose escalation portion of the study. Configuration, demographics, and baseline characteristics

The number and percentage of participating patients for each dose level were tabulated. Demographic information and other baseline characteristics (e.g., disease characteristics, medical history, ECOG behavioral status) will be summarized by dose level. Concomitant drug therapy

The number and percentage of subjects treated with concomitant medications will be described by the summary table provided and the dose levels in the table. safety assessment

Patients in the safety analysis group will be included in the safety analysis. Study drug exposure will be summarized descriptively (e.g., number of CPI-316 cycles, duration of exposure). Definition of serious adverse event

An AE or suspected adverse reaction is considered "serious" if, in the opinion of the investigator or sponsor, it results in any of the following outcomes: death, life-threatening adverse event, hospitalization or extension of existing hospitalization; normal life Sustained or significant loss or severe impairment of the ability to function; or congenital abnormality/birth defect. Based on appropriate medical judgment, an important medical event that may not result in death, be life-threatening, or may require medical or surgical intervention to prevent one of the outcomes listed in this definition may or an important medical event requiring hospitalization is considered serious. Examples of such medical events include allergic bronchospasm requiring intensive treatment in the emergency room or at home, blood disorders or seizures that do not result in hospitalization, or the development of drug dependence or abuse. Severity of Event 1. Mild : The event requires minimal or no treatment and does not interfere with the participant's daily activities. 2. Moderate : The incident causes a low level of inconvenience or involves therapeutic measures. Moderate events can cause some interference with functioning. 3. Severe : The event interrupts the participant's usual daily activities and will require systemic medication or other treatment. Serious events are often potentially life-threatening or disabling.

Hematology, biochemistry, and CA 19-9 laboratory values as well as ECOG behavioral status will be summarized descriptively by dose level. Patients with laboratory values outside the normal range will have their laboratory values presented in the list. Preliminary efficacy assessment

Because patients are required to have measurable disease per inclusion criteria, a safety analysis panel will be used to assess preliminary efficacy. Patients who do not have an evaluable baseline or follow-up scan will have a Not Evaluable (NE) best overall response (per RECIST v1.1) indication and will be included in the denominator of the response rate calculation.

Efficacy will be assessed in a preliminary manner during the dose escalation phase of the study with the following endpoints: • Tumor Response Rate (RR): defined as the proportion of patients with complete or partial response (CR or PR) according to RECIST v1.1. • Progression-Free Survival (PFS): A PFS event is defined by investigator assessment as the date of death or the date of the first scan showing disease progression, whichever occurs first. PFS was defined by month as (date of PFS event - date of first dose of study treatment + 1)/30.4375 No patients with a PFS event were observed at the date of last disease assessment. • Overall Survival (OS): OS is defined by month as (date of death - date of first dose of study treatment + 1)/30.4375 will be at last known alive date, examination unknown Patients who have died.

Tumor response rates will be summarized by dose level, and accurate 95% confidence intervals will be calculated for response rates (using the Copper-Pearson method).

Median PFS and OS will be described in summary tables, and supportive Kaplan-Meier plots will be generated describing these endpoints. Sample size and power Dose escalation

For dose escalation, a 3+3 design will be implemented. During the dose escalation period, up to 18 patients (6 per dose level) are planned to participate. Once the MTD is determined, an additional 6 patients will participate in further assessment of toxicity and preliminary clinical activity under the MTD. Therefore, the dose-escalation portion of the study will involve a total enrollment of up to 24 patients. Participation numbers may be higher or lower depending on observed toxicities or the need to replace patients who do not complete the DLT evaluation period for reasons other than DLT.

If the observed initial tumor response rate (as assessed by the investigator) is at least 40% at the MTD among participating patients, the study can continue to the open-label Phase II portion. The design plan involves up to 12 patients under MTD. For 12 patients, 5 remissions will be needed to reach the 40% threshold. For this ratio of 0.417, the 95% accurate CI would be (0.152, 0.723).

With 12 patients, an adverse event with an overall frequency of 1% would be observed with a probability of 11.4%. For an adverse event with an overall frequency of 5%, the probability of observing at least one such event is 46%. Open label phase II

If the study proceeds to the open-label Phase II portion, Simon's two-stage design will be implemented to establish preliminary efficacy for further studies. The null hypothesis that the true confirmed tumor response rate is 23% will be tested against the one-sided alternative hypothesis of 40%. In the first phase, under MTD, 24 patients will be accumulated. If there are 5 or fewer confirmed responses, the study will stop. Otherwise, 22 additional patients will participate, for a total of 46 patients. If out of 46 patients, 16 or more responses are observed, the null hypothesis will be rejected. When the alternative hypothesis is 40% and one-sided α=0.05, the design has 80% power to reject the null hypothesis.

Therefore, if both parts of the study were completed, the total projected maximum sample size for the entire study would be 70 patients. Available Resources 1. In her opinion from her private practice, there is no issue between PI expectations and recruitment as they will be part of the standard patient population. 2. Subjects will be seen during regular diagnostic hours. In addition, the study coordinator and PI will meet regularly. They will meet every two weeks to discuss patient care. 3. The research coordinator is an RN trained according to AHS research needs. Additionally, we have data and compliance partners who enforce IRB and sponsor data management requirements along with oversight of submission requirements. 4. The participating investigator offices and oncology research offices at MMC and Overlook will be used to admit patients. Patients will be in the investigator's office for study-related physician visits. 5. PI and Sub-I departments can provide appropriate medical evaluation and confirmed MD. The oncology service chain provides social work support as needed. 6. The sponsor will provide training upon initial access to the website. Investigators and study coordinators will provide additional training as needed to participants who are unable to participate in SIV. Reportable Events Adverse Event Characteristics • CTCAE Terminology (AE Description) and Grades: Use the current version of CTEP (CTCAE 4.0) of the NCI Common Terminology Criteria for Adverse Events (CTCAE 4.0) for AE reporting. • All appropriate treatment areas should have access to a copy of the CTCAE's current version of the CTEP. • "Expected": For purposes of the rapid reporting system only, an AE may be "unexpected" or "anticipated." • Properties of the AE: - Unambiguously - The AE is clearly related to the CPI-613 drug compound. - Most likely - AEs may be related to the CPI-613 drug compound. - Possible - AEs may be related to CPI-613 drug compounds. - Unlikely - The AE is not conclusively related to the CPI-613 drug compound. - Unrelated- The AE was clearly unrelated to the CPI-613 drug compound.

The Red Cap Database will be used in this study to monitor natural increases in dose levels and toxicity-related data. All grade 3, 4, and 5 adverse events should be reported. List of adverse events for CPI - 613 drug compounds that may be related to: • Alkaline phosphatase • Anorexia • ALT (SGPT) • AST (SGOT) • Bilirubin (hyperbilirubinemia) • Calcium (hypercalcemia) anemia, hypocalcemia) • Flushing • Hemoglobin (anemia) • *Injection site reaction • White blood cells • Lymphopenia • Neutrophils (neutropenia) • Platelets (thrombocytopenia) • Potassium • Sodium Likely Related: • *Creatinine • *Vomiting • *Nausea • *Diarrhea An asterisk (*) indicates expected adverse events. List of Adverse Events of Gemcitabine • *Neutropenia- Definitely related• * Thrombocytopenia- Definitely related• * Anemia- Definitely related• * Interstitial pneumonitis- Definitely related• * Pulmonary fibrosis- Definitely related Related• Pulmonary edema - possibly related• *Adult respiratory distress syndrome-possibly related• *Hemolytic uremic syndrome-definitely related• Liver injury-possibly related•*Capillary leak syndrome-definitely related•* Posterior Reversible Encephalopathy Syndrome - A clearly relevant asterisk (*) indicates expected adverse events. List of adverse events for nab-paclitaxel • *Nausea - Definitely related • *Vomiting - Definitely related • * Dyspepsia - Likely • *Diarrhea - Likely • Mouth ulcers - Likely • Headache - Possibly • Muscle or joint pain - possibly • * Numbness/tingling/burning in the hands or feet - Definitely • Weakness - possibly • Dizziness - possibly • Dehydration - possibly • Hypokalemia - possibly • *Anemia - Definitely • *Temporary hair loss - Definitely • *Easy bruising or bleeding, skin rashes - Possibly • Fast/slow/irregular heartbeat - Most likely • Pain/redness/swelling/weakness in arms or legs • Touch Warm calf pain or swelling - possibly • Visual changes - probably • Infection: (mainly including oral candidiasis, respiratory tract infections, and pneumonia) - probably • Definition of DLT and DLT Assessment Period

Dose-limiting toxicity was defined as the occurrence of any clinically relevant grade ≥3 toxicity at least potentially related to CPI-613 drug compound. Exclude the following toxicities from any source from the definition of DLT: Grade 3 nausea and vomiting in response to antiemetics despite antiemetic treatment unless they are >7 consecutive days; Response to antidiarrhea despite antidiarrheal treatment Treatment-responsive to grade 3 diarrhea unless it lasts >7 days; Grade 3 or 4 neutropenia lasting >7 days; Grade 3 thrombocytopenia; Grade 3 or 4 metabolic derangement due to tumor lysis syndrome, unless Metabolic disorder >7 days; or treat with oral or IV supplemental administration of corrected antimicrobials.

For each patient, the DLT assessment period ran through Cycle 1 (4 weeks). Reconstitution and Administration of CPI-613 Drug Compounds

CPI-613 drug compound must be diluted from 50 mg/mL to 12.5 mg/mL with 5% dextrose water or D5W prior to administration (i.e., 1 part CPI-613 drug compound is diluted with 3 parts D5W). Diluted drug products should be checked visually for clarity. If turbidity, precipitate or staining (not colorless) is observed, do not administer the diluted drug product. After dilution with sterile D5W, the solution was clear and had a pH of 8.4-8.8. Diluted CPI-613 drug product has been found to be stable for 24 hr at room and freezing temperatures.

The CPI-613 drug compound must be administered IV via an IV catheter that is free-flowing and contains no air in the dead space of the IV catheter, thereby minimizing the vascular irritation, inflammation, and acute toxicity of the CPI-613 drug compound. To avoid local reactions at and around the site of administration, the CPI-613 drug compound must be administered via a central venous catheter.

The CPI-613 drug compound must be administered not as a single bolus but by infusion (at approximately 4 mL/min via a central venous catheter) with the D5W running at a rate of approximately 125-150 mL/hr for 500 mg/ ^m2 dose. At any dose above 500 mg/ ^m2 , the infusion will last 2 hours. This serves to minimize the potential acute toxicity of CPI-613 drug compounds.

When administering CPI-613 drug compound, the following precautions must be taken: A. Confirmation of IV tube placement to ensure no leakage of CPI-613 drug compound into the perivascular space. B. Confirm that the IV tubing is flowing freely. C. Confirm that the IV piping system does not contain dead air spaces. D. Dilute CPI-613 drug compound with D5W as directed in the study protocol. E. Administer CPI-613 drug compound by infusion rather than a single bolus injection. F. After administration of CPI-613 drug compound, flush the IV line with approximately 10 mL of D5W, thereby removing residual CPI-613 drug compound. G. To avoid local reactions at and around the site of administration, CPI-613 drug compounds should be administered via a central venous catheter. Example 2 - Oral efficacy of 6,8 - bis - benzylthio -octanoic acid in non-small cell lung cancer

Human H460 NSCLC cells (catalog number HTB-177, Manassas, VA) were obtained from the American Type Cell Culture Collection (ATCC). Upon receipt of tumor cells from ATCC, the cell lines were tested negative for vial contamination using the Mouse Antibody Production (MAP) test by Charles River Labs Molecular Division of. In a T225 tissue culture flask containing 50 mL of Roswell Park Memorial Institute (RPMI) 1640 solution with 10% fetal bovine serum (FBS) and 2 mM glutamine, at 37°C. , maintain tumor cells in a humidified 5% _CO2 atmosphere. Aliquot cells every 2-3 days by trypsinization and resuspended in fresh culture medium in new flasks at a ratio of 1:10. At 70%-90% confluency, cells were harvested for experiments in the same manner.

CD1-Nu/Nu female mice (approximately 4-6 weeks old) were obtained from Charles River Laboratories. Five mice are housed in a cage in a microisolation chamber at Stony Brook, the Department of Animal Laboratory Research at the State University of New York (SUNY). . The light-dark cycle was 12 h per day, with light from 7 am to 7 pm, and food (Purina rodent chow) and water (distilled sterile filtered water, pH 7) were available ad libitum ( ad libitum ). supply. Experimental protocols and procedures were performed in accordance with rules approved by the SUNY Institutional Animal Care and Use Committee (IACUC).

An acclimation period of 7 days was allowed between the animals' arrival at the study site and the experiment prior to tumor inoculation. Using a 1 cc syringe with a 27-5/8 metered needle, inoculate the mouse right flank subcutaneously (SC) with 0.1 mL of Dulbeco's Phosphate Buffered Salt (PBS). ) 2 x ¹⁰ H460 NSCLC or BxPC3 pancreatic cancer cells in solution. Tumor dimensions (length and width) were measured (using vernier calipers) before, during and daily after treatment, and tumor volume was calculated using the prolate ellipsoid formula: (length x ^width2 )/2. Treatment with test or control was initiated 8 days ^after tumor cell implantation when the tumor was approximately 300 mm3.

6,8-bis-benzylthio-octanoic acid was administered orally at 100 mg/kg per group of 11 animals. Suspend 100 mg of 6,8-bis-benzylthio-octanoic acid in a small volume of 0.01-0.05 N NaOH in 5% dextrose and titrate to pH 7.0 with 4% glacial acetic acid to 50 mg/mL. Prior to administration, the suspension was diluted with 5% dextrose to 12.5 mg/mL so that a dose volume of approximately 0.2 mL was delivered by gastric gavage and the animal received 100 mg/kg. Mice were treated on days 8, 15, 22, and 29 after tumor cell implantation.

Similar studies were performed in CD-1 nude mice (n = 9) inoculated with 2 x 10 ⁶ BxPC-3 cells. The study began when tumors reached a mean size of ¹⁵⁰ mm (Day 0), and CPI-613 was administered at an oral dose of 100 mg/week for 4 weeks. A comparison group (n = 9) was treated with IP at a weekly dose of 25 mg/kg.

The results are presented in Figures 1 and 2. It was clear that tumors in mice treated with 6,8-bis-benzylthio-octanoic acid grew much slower than those in mice treated with 5% dextrose or untreated. In BxPC3 tumors, the effect was particularly dramatic. This example demonstrates that 6,8-bis-benzylthio-octanoic acid is effective in treating cancer when administered orally. Example 3 - Spray-dried dispersion oral formulation of 6,8 - bis - benzylthio-octanoic acid

A solid amorphous dispersion formulation of 6,8-bis-benzylthio-octanoic acid (API) was prepared by mixing API 1:4 with one of the following polymers: Eudragit L100, poly(vinylpyrrolidone) ) Viscosity grade K30 (PVP K30), hydroxypropyl methylcellulose (HPMC), cellulose acetate phthalate (CAP), or hydroxypropyl methylcellulose acetate succinate (HPMCAS-M), and spray drying from methanol or acetone using a small-scale Bend laboratory dryer (BLD-35) with a drying gas flow rate capability of 35 kg/hr. The conditions, yields, and residual solvent levels for 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 investigate whether melting or crystallinity was visually present. The particles display a collapsed spheroid morphology with no significant crystallization or melting.

X-ray diffraction is generally sensitive to the presence of crystalline materials with an LOD of about 1% of the sample mass. No crystallinity was detected by PXRD for either SDD formulation. Comparative diffraction patterns with crystalline 6,8-bis-benzylthio-octanoic acid API can be found in Figure 3, where the top diffraction pattern is for the Eudragit L100 formulation, the middle diffraction pattern is for the HPMCAS-M formulation, and the bottom The diffraction pattern is that of crystalline 6,8-bis-benzylthio-octanoic acid. Example 4 - Emulsion oral formulation of 6,8 - bis - benzylthio -octanoic acid

In a round-bottomed flask equipped with a magnetic stir bar, combine monolaurin (131 mg) and 6,8-bis-benzylthio-octanoic acid (93 mg) in Polysorbate-80 (2.5 mL). ) and heat to 50°C. After complete dissolution to a clear solution, water (7.5 mL) was added with vigorous stirring at 50°C, thereby providing an emulsion.

6,8-Bis-benzylthio-octanoic acid (312 mg) was combined with polysorbate 80 (6.25 g), soybean oil (1.25 g), and a lipid mixture (100 mg) containing: cholesterol (14 g), acetic acid Cholesteryl esters (14g), cholesteryl benzoate (14g), glyceryl monolaurate (25.4g), and glyceryl monopalmitate (32.6g), and the mixture was heated to 50°C until the solids dissolved (30 min). Dextrose (11.25g) was dissolved in 236 mL of water, and the resulting aqueous dextrose solution was added to the above oil solution. The resulting biphasic mixture was stirred at room temperature for 30 min and then vacuum filtered through a 0.22 um filter. Example 5 - Liquid formulation of 6,8 - bis - benzylthio -octanoic acid

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

Prepare suspension vehicle by (a) combining tris buffer (48 mg) and HPMCAS-HF (20 mg) in 14 mL of distilled water, (b) adjusting the pH to 7.4, thereby dissolving HPMCAS-HF, (c) heating the resulting solution to approximately 90°C, (d) adding Methocel A4M Premium (100 mg) to the hot solution, (e) stirring the mixture vigorously, thereby suspending the undissolved of Methocel A4M, (f) cool with an ice bath and stir the mixture until Methocel A4M dissolves (approximately 10 minutes), (g) dilute the solution with distilled/deionized water to reach a total volume of 20 mL, and (h) use Dilute acetic acid or dilute sodium hydroxide adjusts the pH to 7.4, thereby providing a suspension vehicle.

Suspensions of the spray-dried formulations of Example 3 were prepared by adding 400 mg of each SDD formulation to a mortar and slowly adding 4 mL of suspension vehicle (using a pestle after each small addition Mix well until uniformly dispersed) and then transfer to a flask and stir for one minute before dosing. In Example 6 below, the resulting suspension of Eudragit L100 SDD formulation (20 mg/mL 6,8-bis-benzylthio-octanoic acid) was identified as "5B". In Example 6 below, the resulting suspension of HPMCAS-M SDD formulation (20 mg/mL 6,8-bis-benzylthio-octanoic acid) was identified as "5C".

In the same manner, prepare a 20 mg/mL suspension of 6,8-bis-benzylthio-octanoic acid by adding 80 mg of 6,8-bis-benzylthio-octanoic acid to a mortar and slowly adding 4 mL of suspension vehicle (mix thoroughly with a pestle after each small addition until uniformly dispersed) and then transfer to a flask and stir for one minute before dosing. In Example 6 below, the resulting suspension of 6,8-bis-benzylthio-octanoic acid was identified as "5D".

Prepare a solution of 6,8-bis-benzylthio-octanoic acid by dissolving SOLUTOL® (polyethylene glycol 15-hydroxystearate; KOLLIPHOR® HS 15) (3 g) in distilled water (7 mL) and A 30% solution was formed, 6,8-bis-benzylthio-octanoic acid (50 mg) was added to 5 mL of the 30% solution, vortexed for 1 minute, and then sonicated for 45 minutes, thereby providing a clear colorless solution ( 10 mg/mL; pH 7). In Example 6 below, the resulting solution was identified as "5E". Example 6 - Oral bioavailability of 6,8 - bis - benzylthio -octanoic acid

Six groups of 16 BALB/c nude mice (8 males and 8 females) were administered 6,8-bis-benzylthio-octanoic acid in six different ways. (1) 5 μL/g IV injection (tail vein) of the triethanolamine/dextrose aqueous solution of Example 5 (25 mg/kg; 5 mL/kg; Example 5A); (2) Three of Example 5 5 µL/g IP injection of ethanolamine/dextrose aqueous solution (25 mg/kg; 5 mL/kg; 5A); (3) 5 µL/g oral administration of Eudragit L100 SDD suspension of Example 5 (100 mg /kg; 5 mL/kg; 5B); (4) Oral administration of 5 µL/g of the HPMCAS-M SDD suspension of Example 5 (100 mg/kg; 5 mL/kg; 5C); (5) Implementation Oral administration of 5 µL/g of the 20 mg/mL 6,8-bis-benzylthio-octanoic acid suspension of Example 5 (100 mg/kg; 5 mL/kg; 5D); or (6) 10 of Example 5 10 µL/g of mg/mL SOLUTOL solution is administered orally (100 mg/kg; 10 mL/kg; 5E). In each experiment, approximately 80 µL of blood was collected from a subgroup of 4 male and 4 female mice at 0.083, 1, 4, and 24 hours after dosing, and at 0.5, 2, and 8 hours after dosing. , blood was collected from another subgroup of 4 male and 4 female mice. Plasma from collected blood samples was analyzed for the presence of 6,8-bis-benzylthio-octanoic acid by LC-MS/MS.

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

The entire disclosure of each of such patent documents and scientific papers mentioned herein is incorporated by reference for all purposes. equals

The invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The foregoing embodiments should therefore be considered in all respects as illustrative and not limiting of the invention described herein. The scope of the invention is therefore indicated by the appended claims rather than the foregoing description, and all changes coming within the meaning and equivalence range of the claims are intended to be embraced therein.

Claims (18)

Use of a first therapeutic agent comprising 6,8-bis-benzylthio-octanoic acid or a pharmaceutically acceptable salt thereof for preparing a drug for treating pancreatic cancer, wherein the drug is administered on the first day of a twenty-eight-day cycle on days 1, 8, and 15, administered with a second therapeutic agent comprising gemcitabine or a pharmaceutically acceptable salt thereof, and a third therapeutic agent comprising nab-paclitaxel, and the first treatment The first therapeutic agent is administered to the patient at a dose of about 500 mg/m ² , about 1000 mg/m ² , or about 1500 mg/m ² on any day the patient is administered the first therapeutic agent. The use as described in claim 1, wherein the pancreatic cancer is metastatic pancreatic cancer. The use as claimed in claim 1, wherein the pancreatic cancer is locally advanced. The use of any one of claims 1-3, wherein the first therapeutic agent is administered less frequently than once per any seven-day period. The use of claim 4, wherein the second therapeutic agent is administered to the patient less frequently than once every seven-day period. The use of claim 5, wherein the third therapeutic agent is administered to the patient less frequently than once every seven-day period. The use of claim 6, wherein the second therapeutic agent is administered to the patient in a dosage range from about 650 mg/ ^m to about 800 mg/ ^m on any day on which the second therapeutic agent is administered to the patient . The use of claim 7, wherein the third therapeutic agent is administered to the patient in a dosage range from about 80 mg/ ^m to about 100 mg/ ^m on any day on which the third therapeutic agent is administered to the patient . The use of claim 6, wherein the third therapeutic agent is administered to the patient in a dosage range from about 80 mg/ ^m to about 100 mg/ ^m on any day on which the third therapeutic agent is administered to the patient . Use of a first therapeutic agent comprising 6,8-bis-benzylthio-octanoic acid or a pharmaceutically acceptable salt thereof for preparing a drug for treating pancreatic cancer, wherein the drug is administered on the first day of a twenty-eight-day cycle Days 1, 8, and 15, administered with a second therapeutic agent comprising gemcitabine or a pharmaceutically acceptable salt thereof, and a third therapeutic agent comprising nab-paclitaxel, wherein the first therapeutic agent is administered The first therapeutic agent is administered to the patient at a dosage ranging from about 500 mg/ ^m to about 1000 mg/ ^m on any day on which the therapeutic agent is administered. The use of claim 10, wherein the second therapeutic agent is administered to the patient in a dosage range from about 650 mg/ ^m to about 800 mg/ ^m on any day on which the second therapeutic agent is administered to the patient . The use of claim 11, wherein the third therapeutic agent is administered to the patient in a dosage range from about 80 mg/ ^m to about 100 mg/ ^m on any day on which the third therapeutic agent is administered to the patient . The use of claim 10, wherein the third therapeutic agent is administered to the patient in a dosage range from about 80 mg/ ^m to about 100 mg/ ^m on any day on which the third therapeutic agent is administered to the patient . The use of any one of claims 10-13, wherein the first therapeutic agent is administered less frequently than once every seven-day period. The use of claim 14, wherein the second therapeutic agent is administered to the patient less frequently than once every seven-day period. The use of claim 15, wherein the third therapeutic agent is administered to the patient less frequently than once every seven-day period. The use as claimed in claim 16, wherein the pancreatic cancer is metastatic pancreatic cancer. The use as claimed in claim 16, wherein the pancreatic cancer is locally advanced.