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