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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles
  • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

• the invention provides methods, compositions, and medical kits for treating lymphoma using 6,8-bis-benzylthio-octanoic acid or a pharmaceutically acceptable salt thereof.
• pharmaceutically acceptable salt thereof may be formulated as a pharmaceutical composition, such as a pharmaceutical composition containing an ion pairing agent.
• the 6,8-bis-benzylthio- octanoic acid or a pharmaceutically acceptable salt thereof may be formulated as a
• salts are alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts of a carboxylic acid group.
• the lymphoma is Burkitt’s Lymphoma. In certain embodiments, the lymphoma is relapsed or refractory Burkitt’s Lymphoma. In certain embodiments, the lymphoma is relapsed or refractory Burkitt’s Lymphoma in which the patient has failed at least one previous line of therapy. In certain embodiments, the lymphoma is relapsed or refractory Burkitt’s Lymphoma in which the patient has failed prior bone marrow transplant. In certain embodiments, the lymphoma is double hit diffuse large B cell lymphoma.
• the lymphoma is high-grade B cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6 (DHL/THL).
• the lymphoma is Hodgkin lymphoma.
• the lymphoma is non-Hodgkin lymphoma.
• the lymphoma is T-cell non-Hodgkin lymphoma.
• the lymphoma is relapsed or refractory Hodgkin lymphoma.
• the lymphoma is relapsed or refractory non-Hodgkin lymphoma.
• components in a combination therapy may be administered in a particular order and/or on the same or different days according to a treatment cycle.
• at least one dose of the 6,8-bis-benzylthio-octanoic acid or a pharmaceutically acceptable salt thereof is administered to the patient prior to administering the second therapeutic agent, such as on an earlier day in a treatment cycle.
• active components of the combination therapy may be administered on the same day of a treatment cycle, for example being co-administered simultaneously.
• treatment cycles may be repeated one or more times in order to maximize benefit to the patient.
• the 6,8-bis-benzylthio-octanoic acid or pharmaceutically acceptable salt thereof may be formulated in a pharmaceutical composition comprising a pharmaceutically acceptable carrier.
• the pharmaceutical composition comprises 6,8-bis-benzylthio- octanoic acid and a pharmaceutically acceptable carrier.
• the pharmaceutical composition comprises an ion pair of 6,8-bis-benzylthio-octanoic acid and a pharmaceutically acceptable carrier.
• the pharmaceutical composition comprises a pharmaceutically acceptable salt of 6,8-bis-benzylthio-octanoic acid and a pharmaceutically acceptable carrier.
• Exemplary ion pairing agents that may be used include, for example, a tertiary amine (such as triethanolamine), other amines such as diethanolamine, monoethanol amine, mefenamic acid and tromethamine, and combinations thereof.
• the ion pairing agent is an organic Bronsted base.
• the ion pairing agent is an amine compound.
• the ion pairing agent is diisopropanolamine, 3 -amino- 1 -propanol, meglumine, morpholine, pyridine, niacinamide, tris(hydroxymethyl)aminomethane, 2-((2-dimethylammo)ethoxy)ethanol, 2- (dimethylamino)ethanol, l-(2-hydroxyethyl)pyrrolidine, or ammonium hydroxide.
• the ion pairing agent is an alkali metal hydroxide or alkaline earth metal hydroxide, such as, for example, cesium hydroxide.
• the 6,8-bis-benzylthio-octanoic acid or pharmaceutically acceptable salt thereof is administered at a dosage of about 3,000 mg/'m 2 on any day it is administered to the patient. In certain embodiments, the 6,8-bis-benzylthio-octanoic acid or pharmaceutically acceptable salt thereof is administered at a dosage of about 2,750 mg/'m 2 or less on any day it is administered to the patient. In certain embodiments, the 6,8-bis-benzylthio-octanoic acid or pharmaceutically acceptable salt thereof is administered at a dosage of about 2,750 mg/m 2 on any day it is administered to the patient.
• 6,8-bis-benzylthio-octanoic acid or pharmaceutically acceptable salt thereof is administered at a dosage of about 2,250 mg/m 2 or less on any day it is administered to the patient.
• the 6,8-bis-benzylthio-octanoic acid or pharmaceutically acceptable salt thereof is administered at a dosage of about 2,250 mg/'m 2 on any day it is administered to the patient.
• the 6,8-bis-benzylthio-octanoic acid or pharmaceutically acceptable salt thereof is administered at a dosage of about 2,000 mg/'m 2 or less on any day it is administered to the patient.
• the 6,8-bis-benzylthio-octanoic acid or pharmaceutically acceptable salt thereof is administered at a dosage of about 2,000 mg/'m 2 or less on any day it is administered to the patient.
• the treatment cycle comprises an induction phase and a maintenance phase, wherein the dosing regimen in the induction phase is different from the dosing regimen in the maintenance phase.
• the maintenance phase treatment cycle is repeated at least once.
• the maintenance phase comprises at least 2 cycles. In certain embodiments, the maintenance phase comprises at least 3 cycles.
• the 6,8-bis- benzylthio-octanoic acid or pharmaceutically acceptable salt thereof is preferably administered pursuant to a treatment cycle comprising an induction phase followed by a maintenance phase, wherein the induction phase comprises two, two-week cycles and the maintenance phase comprises one or more three-week cycles, and the 6,8-bis-benzylthio-octanoic acid or pharmaceutically acceptable salt thereof is administered on days 1-5 of each cycle.
• the 6,8-bis-benzylthio- octanoic acid or pharmaceutically acceptable salt thereof is preferably administered pursuant to a treatment cycle comprising an induction phase followed by a maintenance phase, wherein the induction phase comprises two, two-week cycles and the maintenance phase comprises one or more three-week cycles, and the 6,8-bis-benzylthio-octanoic acid or pharmaceutically acceptable salt thereof is administered at a daily dosage of about 2,500 mg/m 2 on days 1-5 of each cycle.
• the 6,8-bis-benzylthio-octanoic acid or pharmaceutically acceptable salt thereof is preferably administered pursuant to a treatment cycle comprising an induction phase followed by a maintenance phase, wherein the induction phase comprises two, two-week cycles and the maintenance phase comprises one or more three-week cycles, and the 6,8-bis- benzylthio-octanoic acid or pharmaceutically acceptable salt thereof is administered at a daily dosage of about 2,500 mg/m 2 on days 1-5 of each cycle.
• the 6,8-bis-benzylthio-octanoic acid or pharmaceutically acceptable salt thereof is preferably administered pursuant to treatment cycles of four weeks, in which the 6,8-bis-benzylthio-octanoic acid or pharmaceutically acceptable salt thereof is administered on days 1-4 of each cycle.
• the 6,8-bis-benzylthio-octanoic acid or pharmaceutically acceptable salt thereof is administered on days 1-4 of each cycle.
• the method of the present invention further comprises administration of a therapeutically effective amount of a second therapeutic agent.
• the present invention provides a method for treating a lymphoma, comprising administering to a patient in need thereof a therapeutically effective amount of
• the therapeutic method may be further characterized according to the route of administration of the second therapeutic agent.
• the second therapeutic agent is administered intravenously to the patient.
• the second therapeutic agent is bendamustine hydrochloride and is administered by IV infusion over 10 minutes.
• the therapeutic method may be further characterized according to the dosing regimen used for administering the second therapeutic agent to the patient.
• the second therapeutic agent is preferably bendamustine or a pharmaceutically acceptable salt thereof.
• the second therapeutic agent is bendamustine hydrochloride.
• the bendamustine or pharmaceutically acceptable salt thereof is preferably administered pursuant to treatment cycles of four weeks, in which the bendamustine or pharmaceutically acceptable salt thereof is administered on days 4 and 5 of each cycle.
• pharmaceutically acceptable salt thereof is administered at a dose of about 2,500 mg/m 2 or less on each day that it is administered, and further comprising the step of administering to the patient bendamustine or a pharmaceutically acceptable salt thereof on days 4 and 5 of each cycle.
• the bendamustine or pharmaceutically acceptable salt thereof is administered at a daily dosage of about 100 mg/m 2 or less on days 4 and 5 of each four week cycle. In certain embodiments, the bendamustine or pharmaceutically acceptable salt thereof is administered at a daily dosage of about 90 mg/m 2 or less on days 4 and 5 of each four week cycle. In certain embodiments, the bendamustine or pharmaceutically acceptable salt thereof is administered at a daily dosage of about 90 mg/m 2 on days 4 and 5 of each four week cycle. In certain embodiments, the bendamustine or pharmaceutically acceptable salt thereof is bendamustine hydrochloride and the bendamustine hydrochloride is administered at a daily- dosage of about 100 mg/m 2 or less on days 4 and 5 of each four week cycle.
• the method of the present invention preferably provides a response rate of at least about 10%, a disease control rate (DCR) of at least about 10%, progression-free survival of at least about 1 month, and/or overall survival of at least about 1 month.
• the patients in the clinical trial have failed brentuximab vedotin and a PD-1 inhibitor.
• the clinical trial comprises at least 5 patients. More preferably, the clinical trial comprises at least 7 patients. More preferably, the clinical trial comprises at least 10 patients. More preferably, the clinical trial comprises at least 12 patients. More preferably, the clinical trial comprises at least 15 patients.
• International Normalized Ratio must be ⁇ 1.5. Due to the occurrence of thrombocytopenia, patients with a coagulopathy should not participate. Patients on anticoagulants should be on short-acting therapy (e.g., low molecular weight heparin) rather than oral anticoagulants.
• short-acting therapy e.g., low molecular weight heparin
• Any active uncontrolled bleeding or bleeding diathesis e.g., active peptic ulcer disease.
• Bone marrow biopsy core biopsy, aspirate and cell markers. If a core biopsy has already been done within the 4-week window without an aspirate and cell markers, it does not need to be repeated. If a marrow is being done, the patient should sign consent first to allow for a research sample (5cc in EDTA).
• ⁇ CBC comprehensive metabolic panel (includes Na, K, Cl, CO2, Ca, Total Protein, Albumin, Creatinine, Glucose, BUN, Alkaline Phosphate, Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Total Bilirubin, uric acid, phosphorus, EGFR African American, EGFR Non-African American, Anion Gap
• CPI-613 administration of CPI-613 is described in the table below. Briefly, the first two treatment cycles are 14-days in duration, with all subsequent cycles being 21 -days in duration. CPI-613 (2,500 mg/m 2 /day) is given on Days 1 through 5 of each treatment cycle. Note that the CPI-613 dose may be modified if toxicity/side effects are observed as discussed below. Study treatment will be provided in outpatient chemotherapy units.
• AEs must be reported through the end-of-study visit. AEs which completely resolve and then recur should be recorded as a new AE. For subjects who complete the end of study visit less than 30 days following the last study intervention, a follow up of ongoing AEs should be attempted by telephone and documented in the subject’s source. AEs continuing at 30 days post-last treatment should have a comment in the source by the Investigator that the event has stabilized or is not expected to improve.
• CPI-613 Given the limited data for treating Burkitt lymphoma and other hematological malignancies with CPI-613, the following are the most frequent toxi cities seen in prior CPI-613 studies treating other types of cancers.
• Common side effects of CPI-613 in prior studies include nausea, leukocytopenia, neutrophils (neutropenia), fatigue, and elevated alkaline phosphatase (ALP).
• Occasional side effects of CPI-613 in prior studies include diarrhea, vomiting, hemoglobin (anemia), abnormal liver function tests (elevated bilirubin, alanine
• PET/CT scan will be performed at baseline only, and then as indicated by the treating physician.
• Patients with bone marrow involvement bone marrow biopsy performed at baseline, after Cycle 3 of CPI-613 and every 4 cycles of maintenance thereafter until the first year of study treatment.
• FDG-PET [ 18 F]2-fluoro-d-deoxy-D-glucose positron emission tomography
• CT computerized tomography
• Participants will also be followed and analyzed for secondary outcomes of progression-free and overall survival. Participants will be monitored for survival through routine follow-up visits for up to six months after completion of CPI-613 therapy. Confidence intervals will be calculated around the estimates of the overall response rate (CR, PR, and SD) of CPI-613. We will use Kaplan-Meier method to analyze progression-free and overall survival.
• the primary objective of the study is to determine the overall response rate of CPI- 613 in patients with relapsed or refractory Burkitt Lymphoma/Leukemia and double hit diffuse large B cell lymphoma analyzed as two separate cohorts.
• the first assessment is after cycle 3. As per clinical research standard, only patients who reach the first assessment time point are assessable for response. Patients who are off study due to toxicity before the first response assessment will not be replaced, but will be considered non-responders for the purpose of determining the primary endpoint.
• PFS Progression Free Survival
• OS Overall Survival
• CPI-613 6,8- bis-benzylthio-octanoic acid
• the primary objectives are to determine the MTD of CPI-613, when used in combination with
• All CPI-613 dose escalations conducted in this Traditional Dose-Escalation stage will be with an increment of 250 mg/m 2 .
• the dose level for CPI-613 of the first cohort in the Traditional Dose-Escalation scheme is the same as that used in the last cohort in the Single- Patient Dose-Escalation scheme.
• the number of patients in each cohort at this stage will initially be 3, including the first patient in which a > Grade 1 toxicity is observed in the Single- Patient-Dose-Escalation scheme.
• the starting dose of the Traditional Dose-Escalation stage will be 2,500 mg/m 2 . If no patients in any cohort develop a dose-limiting toxicity (DLT, see definition below), dose escalation will continue in cohorts of 3 patients. However, if a DLT is observed in a patient (whether it is the first, second or third of the 3 intended patients) at any dose level, that cohort will be expanded to a maximum of 6 patients. If no DLT is observed in another patient out of a maximum of 6 patients, dose escalation procedure will continue in 3 patients for each subsequent cohort.
• DLT dose-limiting toxicity
• a DLT is defined as any toxicity, at least probably related to CPI-613, which meets the criteria outlined in this paragraph. Events that can clearly be determined to be unrelated to the drug are not considered DLT.
• the DLT evaluation period is through Cycle 1(4 weeks) for each patient.
• hepatic function Adequate hepatic function (aspartate aminotransferase [AST/SGOT] ⁇ 3x upper normal limit [UNL], alanine aminotransferase [ALT/SGPT] ⁇ 3x UNL ( ⁇ 5x UNL if liver metastases present), bilirubin ⁇ 1.5x UNL).
• a. Adequate hepatic function aspartate aminotransferase [AST/SGOT] ⁇ 3x upper normal limit [UNL], alanine aminotransferase [ALT/SGPT] ⁇ 3x UNL ( ⁇ 5x UNL if liver metastases present), bilirubin ⁇ 1.5x UNL).
• ALT/SGPT alanine aminotransferase
• Active heart disease including but not limited to symptomatic congestive heart failure, symptomatic coronary artery disease, symptomatic angina pectoris, symptomatic myocardial infarction or symptomatic congestive heart failure.
• Bendamustine is given immediately after CPI-613 administration.
• CPI-613 is to be given as 2-hr IV infusion via a central venous catheter.
• Mitochondrial Inhibition Syndrome This is a constellation of symptoms that may include high fevers, hypotension, lethargy pancytopenia, altered mental status and generalized weakness and lactic acidosis. If this occurs or is suspected the recommended treatment until symptoms resolve is:
• prophylactic treatment for drug-related symptoms can be given according to Package Inserts of the study drugs and clinical practice.
• Supportive treatment may include anti-emetic, anti-diarrhea, anti-pyretic, anti-allergic, anti-hypertensive, analgesics, antibiotics, allopurinol, and others such as blood products and bone marrow growth factors.
• Patients may use erythropoietin for chronic anemia.
• the investigator may utilize erythropoietic factors, or blood or platelet transfusions at their discretion.
• a DLT is defined as follows:
• the DLT evaluation period is through Cycle 1 (4 weeks) for each patient.

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