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

Study Overview
=================
Brief Summary
-----------------
This phase I trial studies the side effects and best dose of CPI-613 when given together with combination chemotherapy in treating patients with metastatic pancreatic cancer. Drugs used in chemotherapy, CPI-613, leucovorin calcium, fluorouracil, irinotecan hydrochloride, and oxaliplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing.

Detailed Description
-----------------
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.

Official Title
-----------------
A Phase I Open-Label Dose-Escalation Clinical Trial of CPI-613 in Combination With Modified FOLFIRINOX in Patients With Metastatic Pancreatic Cancer and Good Performance Status

Conditions
-----------------
Acinar Cell Adenocarcinoma of the Pancreas, Duct Cell Adenocarcinoma of the Pancreas, Recurrent Pancreatic Cancer, Stage IV Pancreatic Cancer

Intervention / Treatment
-----------------
* Drug: 6,8-bis(benzylthio)octanoic acid
* Drug: oxaliplatin
* Drug: leucovorin calcium
* Drug: irinotecan hydrochloride
* Drug: fluorouracil
* Other: laboratory biomarker analysis


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (6,8-bis[benzylthio]octanoic acid, mFOLFIRINOX)<br>Patients receive 6,8-bis(benzylthio)octanoic acid 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. | Drug: 6,8-bis(benzylthio)octanoic acid<br>* Given IV<br>* Other names: CPI-613;Drug: oxaliplatin<br>* Given IV<br>* Other names: L-OHP;Drug: leucovorin calcium<br>* Given IV<br>* Other names: LV;Drug: irinotecan hydrochloride<br>* Given IV<br>* Other names: U-101440E;Drug: fluorouracil<br>* Given IV<br>* Other names: 5-FU;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose | of 6,8-bis(benzylthio)octanoic acid when used in combination with mFOLFIRINOX determined by dose-limiting toxicities graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0 | 2 weeks |