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

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Pharmacodynamic Study of Metformin in Patients With Resectable Pancreatic Cancer

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

Intervention / Treatment
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* Drug: metformin hydrochloride
* Other: pharmacological study


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Group I (observation)<br>Patients undergo observation. | |
| Experimental: Group II (metformin hydrochloride)<br>Patients receive metformin hydrochloride PO BID for at least 7 days in the absence of disease progression or unacceptable toxicity. | Drug: metformin hydrochloride<br>* Given PO<br>* Other names: Glucophage;Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;|
| Experimental: Group III (metformin hydrochloride)<br>Patients receive metformin hydrochloride as in Group II. | Drug: metformin hydrochloride<br>* Given PO<br>* Other names: Glucophage;Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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. | At time of surgery (after 7 days of treatment) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of grade 3 and 4 toxicities according to National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE; version 4.0) | Will be summarized as the percentage of patients by type and grade according to treatment group. | Baseline to 30 days after treatment has been discontinued or after the date of surgery, whichever occurs first | 
| Expression of pACC and pMTOR quantified by the mean fluorescence intensity (MFI) in tissue samples | 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. | At time of surgery (after 7 days of treatment) | 
| Percentage of pancreatic cancer stem cells in tissue samples | 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. | At time of surgery (after 7 days of treatment) |