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

A Pharmacodynamic Study of Metformin in Patients With Resectable Pancreatic Cancer

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.

Study Overview

• Status: Withdrawn
• Conditions: Stage IIA Pancreatic Cancer; Stage IIB Pancreatic Cancer; Stage IA Pancreatic Cancer; Stage IB Pancreatic Cancer
• Intervention / Treatment: Other: pharmacological study; Drug: metformin hydrochloride

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.

• Study Type: Interventional
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

3

Arms and Interventions

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

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Case Comprehensive Cancer Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Jennifer Eads, MD, Case Comprehensive Cancer Center

Study record dates

Study Major Dates

• Study Start: January 1, 2014
• Primary Completion (Actual): March 1, 2015
• Study Completion (Actual): March 1, 2015

Study Registration Dates

• First Submitted: September 27, 2013
• First Submitted That Met QC Criteria: September 27, 2013
• First Posted (Estimate): October 7, 2013

Study Record Updates

• Last Update Posted (Estimate): July 15, 2015
• Last Update Submitted That Met QC Criteria: July 14, 2015
• Last Verified: July 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Endocrine System Diseases; Digestive System Neoplasms; Endocrine Gland Neoplasms; Pancreatic Diseases; Pancreatic Neoplasms; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: CASE1213; P30CA043703 (U.S. NIH Grant/Contract); NCI-2013-01836 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); CASE 1213 (Other Identifier: Case Comprehensive Cancer Center)