Metformin Plus Modified FOLFOX 6 in Metastatic Pancreatic Cancer

PRIMARY OBJECTIVES:

I. To determine if metformin (metformin hydrochloride) when added to FOLFOX ( leucovorin
calcium, fluorouracil, oxaliplatin) improves overall survival in patients with metastatic
pancreatic cancer.

SECONDARY OBJECTIVES:

I. To assess response rate (RR). II. To assess progression free survival (PFS). III. To
assess toxicity in patients with metastatic pancreatic cancer receiving FOLFOX and metformin.
IV. To identify tumor/serum correlative markers.

OUTLINE: Patients receive metformin hydrochloride orally (PO) twice daily (BID) on days 1-7
for an introductory period before the addition of FOLFOX. After the introductory period,
patients will continue metformin twice daily and FOLFOX therapy comprising leucovorin calcium
intravenously (IV) over 120 minutes, fluorouracil IV continuously over 46 hours, and
oxaliplatin IV over 120 minutes on day 1. Courses repeat every 14 days in the absence of
disease progression or unacceptable toxicity. After completion of study treatment, patients
are followed up for periodically.

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed metastatic pancreatic
adenocarcinoma (or any mixed pathology if adenocarcinoma is predominant)

- Patients must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded) as >
20 mm with conventional techniques or as > 10 mm with spiral computed tomography (CT)
scan

- Patient must have not received systemic chemotherapy for metastatic disease; prior
chemotherapy, radiation therapy, concurrent chemoradiation are allowed if used for
treatment of non-metastatic disease; prior palliative radiation for symptom management
is allowed; any chemotherapy must have been completed 4 weeks prior to enrollment; any
radiotherapy must have been completed 2 weeks prior to enrollment

- Eastern Cooperative Oncology Group (ECOG) performance status 0-2

- Absolute neutrophil count ≥ 1,500/L

- Platelets ≥ 100,000/L

- Hemoglobin ≥ 9 g/dL

- Total bilirubin ≤ 2 mg/dL

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT]/alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT]) ≤
2.5 x institutional upper limit of normal

- Creatinine ≤ 1.5

- Women of childbearing potential and men must agree to use adequate contraception
(double barrier method of birth control or abstinence) prior to study entry and for
the duration of study participation; should a woman become pregnant or suspect that
she is pregnant while she or her partner is participating in this study, she should
inform the treating physician immediately

- Subjects must have the ability to understand and the willingness to sign a written
informed consent document

- Patients with diabetes are eligible for this trial; all diabetic patients who are
enrolled on this study should discuss the need to change their diabetes management
regimen with their primary care physician or endocrinologist prior to enrollment

- Diabetic patients who are on metformin are eligible as long as they have been on
metformin for less than 6 months (estimated 6 months or less duration of metformin
therapy from start of metformin to enrollment on study)

Exclusion Criteria:

- Chemotherapy within 4 weeks prior to entering the study, radiotherapy within 2 weeks
prior to entering the study or failure to recover from adverse events due to agents
administered more than 4 weeks earlier

- Prior treatment toxicities must be resolved to ≤ grade 1 according to National Cancer
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0

- Current use of metformin for more than 6 months prior to enrollment on study

- Use of any other investigational agents

- Patients with untreated brain metastases should be excluded from this clinical trial

- History of allergic reactions attributed to compounds of similar chemical or
biological composition to metformin or oxaliplatin or fluorouracil (5-FU)

- Active second primary malignancy or history of second primary malignancy within the
last 3 years, with the exception of basal cell skin cancers or carcinoma in situ that
have been adequately treated

- Patients with uncontrolled intercurrent illness including, but not limited to ongoing
or active infection, symptomatic congestive heart failure, unstable angina pectoris,
cardiac arrhythmia, or psychiatric illness/social situations that would limit
compliance with study requirements

- Pregnant or nursing women

- Human immunodeficiency virus (HIV)-positive patients

- Chronic or planned acute alcohol use of three or more drinks per day

- Metabolic acidosis, acute or chronic, including ketoacidosis