Metformin Hydrochloride in Treating Patients With Pancreatic Cancer That Can be Removed by Surgery

Phase 1

Withdrawn

Conditions: Stage IA Pancreatic Cancer
Stage IIB Pancreatic Cancer
Stage IB Pancreatic Cancer
Stage IIA Pancreatic Cancer

Brief Summary: This randomized clinical trial studies metformin hydrochloride in treating patients with pancreatic cancer that can be removed by surgery. Metformin hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description: PRIMARY OBJECTIVES:

I. To determine the effect of escalating doses of metformin (metformin hydrochloride) given pre-operatively on pancreatic cancer cell proliferation and apoptosis.

SECONDARY OBJECTIVES:

I. To assess toxicity of escalating doses of metformin given pre-operatively in patients with resectable pancreatic carcinoma.

II. To measure the effect of metformin on the expression of phosphorylated acetyl-CoA carboxylase alpha (ACC), phosphorylated mechanistic target of rapamycin (serine/threonine kinase) (mTOR), and pancreatic cancer stem cells.

OUTLINE: Patients are randomized to 1 of 3 treatment groups.

GROUP I: Patients undergo observation.

GROUP II: Patients receive metformin hydrochloride orally (PO) twice daily (BID) for at least 7 days in the absence of disease progression or unacceptable toxicity.

GROUP III: Patients receive metformin hydrochloride as in Group II.

After completion of study treatment, patients are followed up 30 days.

Recruitment & Eligibility

Inclusion Criteria

Patients must have histologically or cytologically confirmed resectable pancreatic carcinoma; patients with pancreatic neuroendocrine tumors are not eligible
Patients must be previously untreated with chemotherapy or radiation therapy
Eastern Cooperative Oncology Group (ECOG) performance status =< 2
Patients must have surgical resection of the pancreas planned, with enrollment at least 7 days prior to surgery; patients with surgery scheduled > 15 days will not be excluded
Hemoglobin (Hg)A1C must be below 7%
Total bilirubin less than 1.5 X institutional upper limit of normal
Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) =< 2.5 X institutional upper limit of normal
Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X institutional upper limit of normal
Serum creatinine within normal institutional limits
Alkaline phosphatase < 1.5 X institutional upper limit of normal
Subjects must have the ability to understand and be willing to provide written informed consent

Exclusion Criteria

History of metformin use in the previous 3 months
Treatment with neoadjuvant chemotherapy or radiation therapy
History of allergic reactions attributed to metformin
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
Metabolic acidosis, acute or chronic, including ketoacidosis
Metastatic disease

Arm && Interventions

Group	Intervention	Description
Group III (metformin hydrochloride)	pharmacological study	Patients receive metformin hydrochloride as in Group II.
Group II (metformin hydrochloride)	pharmacological study	Patients receive metformin hydrochloride PO BID for at least 7 days in the absence of disease progression or unacceptable toxicity.
Group III (metformin hydrochloride)	metformin hydrochloride	Patients receive metformin hydrochloride as in Group II.
Group II (metformin hydrochloride)	metformin hydrochloride	Patients receive metformin hydrochloride PO BID for at least 7 days in the absence of disease progression or unacceptable toxicity.

Primary Outcome Measures

Name	Time	Method
Pancreatic tumor cell proliferation and apoptosis as measured by the percentage of cells Ki-67+, percentage of cells TUNEL+, and mitotic counts in tissue samples	At time of surgery (after 7 days of treatment)	The difference between treatment groups will be compared using analysis of variance (ANOVA) (3 groups) followed by Tukey's pair-wise comparison procedure. Transformation may be applied (e.g. natural log) prior to analysis to better approximate normality.

Secondary Outcome Measures

Name	Time	Method
Expression of pACC and pMTOR quantified by the mean fluorescence intensity (MFI) in tissue samples	At time of surgery (after 7 days of treatment)	The difference between treatment groups will be compared using ANOVA followed by Tukey's pair-wise comparison procedure. Laser scanning cytometry and iCyte software used to quantify the MFI of pACC and pMTOR.
Percentage of pancreatic cancer stem cells in tissue samples	At time of surgery (after 7 days of treatment)	For each of biologic biomarkers (pACC, pMTOR, CD44+CD24+ESA+ cells), the difference between treatment groups will be compared using ANOVA (3 groups) followed by Tukey's pair-wise comparison procedure. Transformation may be applied (e.g. natural log) prior to analysis to better approximate normality.
Occurrence of grade 3 and 4 toxicities according to National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE; version 4.0)	Baseline to 30 days after treatment has been discontinued or after the date of surgery, whichever occurs first	Will be summarized as the percentage of patients by type and grade according to treatment group.