CPI-613 and Combination Chemotherapy in Treating Patients With Metastatic Pancreatic Cancer

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of CPI-613 (6,8-bis[benzylthio]octanoic acid), when used in combination with modified leucovorin calcium, fluorouracil, irinotecan hydrochloride, and oxaliplatin (mFOLFIRINOX), in patients with metastatic pancreatic cancer.

SECONDARY OBJECTIVES:

I. To assess the safety of CPI-613/mFOLFIRINOX combination in patients with metastatic pancreatic cancer.

II. To collect tissue for future genomic analyses. III. To obtain preliminary data on efficacy of treatment with CPI-613/mFOLFIRINOX.

OUTLINE: This is a dose-escalation study of 6,8-bis(benzylthio)octanoic acid.

Patients receive 6,8-bis(benzylthio)octanoic acid intravenously (IV) over 2 hours on days 1 and 3. Patients also receive oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, irinotecan hydrochloride IV over 90 minutes, and fluorouracil IV continuously over 46 hours on day 1. Treatment repeats every 2 weeks for 6 months in the absence of disease progression or unacceptable toxicity.

Inclusion criteria

• Histologically and cytologically confirmed metastatic pancreatic adenocarcinoma
• Eastern Cooperative Oncology Group (ECOG) performance status being 0-1
• Expected survival > 2 months
• Women of child-bearing potential (i.e., women who are pre-menopausal or not surgically sterile) must use accepted contraceptive methods (abstinence, intrauterine device [IUD], oral contraceptive or double barrier device) during the study, and must have a negative serum or urine pregnancy test within 1 week prior to treatment initiation
• Fertile men must practice effective contraceptive methods during the study, unless documentation of infertility exists
• At least 2 weeks must have elapsed from any prior surgery or hormonal therapy
• Granulocyte count >= 1500/mm^3
• White blood cell (WBC) >= 3500 cells/mm^3 or >= 3.5 bil/L
• Platelet count >= 100,000 cells/mm^3 or >= 100 bil/L
• Absolute neutrophil count (ANC) >= 1500 cells/mm^3 or >= 1.5 bil/L
• Hemoglobin >= 9 g/dL or >= 90 g/L
• Aspartate aminotransferase (AST/serum glutamic oxalic transaminase [SGOT]) =< 3 x upper normal limit (UNL), alanine aminotransferase (ALT/serum glutamate pyruvate transaminase [SGPT]) =< 3 x UNL (=< 5 x UNL if liver metastases present)
• Bilirubin =< 1.5 x UNL
• Serum creatinine =< 2.0 mg/dL or 177 µmol/L
• International normalized ratio or INR must be =< 1.5 unless on therapeutic blood thinners
• No evidence of active infection and no serious infection within the past month
• Mentally competent, ability to understand and willingness to sign the informed consent form

Exclusion criteria

• Endocrine or acinar pancreatic carcinoma
• Previous radiotherapy for cerebral metastases, central nervous system (CNS) or epidural tumor
• Prior treatment with any chemotherapy for metastatic disease from pancreatic cancer
• Patients receiving any other standard or investigational treatment for their cancer, or any other investigational agent for any indication within the past 4 weeks prior to initiation of CPI-613 treatment
• Serious medical illness that would potentially increase patients' risk for toxicity
• Any active uncontrolled bleeding, and any patients with a bleeding diathesis (e.g., active peptic ulcer disease)
• Pregnant women, or women of child-bearing potential not using reliable means of contraception (because the teratogenic potential of CPI-613 is unknown)
• Lactating females
• Fertile men unwilling to practice contraceptive methods during the study period
• Life expectancy less than 2 months
• Any condition or abnormality which may, in the opinion of the investigator, compromise the safety of patients
• Unwilling or unable to follow protocol requirements
• 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
• Patients with a history of myocardial infarction that is < 3 months prior to registration
• Evidence of active infection, or serious infection within the past month
• Patients with known human immunodeficiency virus (HIV) infection
• Patients who have received immunotherapy of any type within the past 4 weeks prior to initiation of CPI-613 treatment
• Requirement for immediate palliative treatment of any kind including surgery
• Patients that have received a chemotherapy regimen with stem cell support in the previous 6 months
• Any condition or abnormality which may, in the opinion of the investigator, compromise the safety of the patient