A Trial of Metformin for Colorectal Cancer Risk Reduction Among Patients With a History of Colorectal Adenomas and Elevated Body Mass Index
The purpose of this study is to find out whether METFORMIN decreases protein markers in colorectal tissue. This is a phase IIA study of the pharmacodynamics, safety and tolerability of Metformin in decreasing colorectal mucosa in patients with a history of colorectal adenomas in the past 3 years and a BMI >= 30, with decimals rounded to the nearest whole integer. Metformin as a potential chemopreventive agent for inhibition of the relevant molecular pathways involved in human colorectal carcinogenesis.
Drug: metformin hydrochloride
Other: pharmacological study
Other: laboratory biomarker analysis
|Study Design:||Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Prevention
|Official Title:||A Phase IIa Trial of Metformin for Colorectal Cancer Risk Reduction Among Patients With a History of Colorectal Adenomas and Elevated Body Mass Index|
- Change in activated S6serine235 (i.e., the ratio of pS6serine235/S6serine235) [ Time Frame: From baseline to 12 weeks ] [ Designated as safety issue: No ]A paired t-test will be used to examine the effect of oral metformin on activated S6serine235. The distribution of the difference between post- and pre-treatment values will be examined. Measures of central tendency and variability will be computed.
- Effects of metformin hydrochloride on colorectal mucosa proliferation (Ki-67, phosphorylated IGF-1 receptor, phosphorylated insulin receptor, phosphorylated AKT, phosphorylated mTOR, and phosphorylated AMP kinase) [ Time Frame: Up to 16 weeks ] [ Designated as safety issue: No ]
- Effects of metformin hydrochloride on serum (fasting and 2 hour postprandial insulin and glucose, fasting IGF-1, IGFBP-1, IGFBP-3, leptin, adiponectin and metformin levels) [ Time Frame: Up to 16 weeks ] [ Designated as safety issue: No ]
- Safety and tolerability of metformin hydrochloride treatment [ Time Frame: Up to 16 weeks ] [ Designated as safety issue: No ]All participants will be evaluable for toxicity from the time of their first dose of metformin. Since toxicities in this study are measured as categorical data, primary analysis shall be by tests of binomial proportions (e.g., Mantel-Haenszel chi-squared statistic). This study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse Events) Version 4.0 for toxicity and Serious Adverse Event reporting.
|Study Start Date:||March 2011|
|Study Completion Date:||March 2014|
|Primary Completion Date:||March 2014 (Final data collection date for primary outcome measure)|
Experimental: Prevention (metformin hydrochloride)
Patients receive metformin hydrochloride PO QD during week 1 and then BID during weeks 2-12. Treatment continues for 12 weeks in the absence of disease progression or unacceptable toxicity.
Drug: metformin hydrochloride
Other Name: GlucophageOther: pharmacological study
Other Name: pharmacological studiesOther: laboratory biomarker analysis
I. To determine if a 12-week intervention of oral metformin (metformin hydrochloride) treatment among obese patients with a history of colorectal adenomas results in at least a 35% decrease in colorectal mucosa activated pS6serine235 from baseline as assessed via immunostaining.
I. To assess the effect of metformin on additional relevant biomarkers in serum: metformin levels; fasting insulin-like growth factor (IGF)-1, insulin-like growth factor binding protein (IGFBP)-1, IGFBP-3; fasting leptin; fasting Adiponectin; fasting and 2 hour post-prandial insulin and glucose.
II. To examine the correlation among biomarkers (serum, tissue). III. To assess the independent effects of treatment on each biomarker, using multivariate regression models to account for clinical and biomarker data.
IV. To document the safety and tolerability of metformin in the study population.
I. To assess the effect of metformin on additional relevant biomarkers in tissue via immunostaining. This will include the effects on levels of colorectal mucosa proliferation estimated by: phosphorylated AMPK (pAMPK), phosphorylated AKTserine 473 (pAKT), phosphorylated mTOR, phosphorylated insulin receptor (pIR), phosphorylated IGF-1 (pIGF-1) receptor, and Ki-67.
II. To cross-validate immunostaining results with Western blotting experiments in a subset of consecutive patients for the following endpoints: phosphorylated S6serine235 (pS6serine235), phosphorylated AMPK (pAMPK), phosphorylated AKTserine 473 (pAKT), phosphorylated mTOR, phosphorylated insulin receptor (pIR), phosphorylated IGF-1 (pIGF-1) receptor, and Ki-67.
Patients receive metformin hydrochloride orally (PO) once daily (QD) during week 1 and then twice daily (BID) during weeks 2-12. Treatment continues for 12 weeks in the absence of disease progression or unacceptable toxicity.
After completion of study therapy, patients are followed up for 4 weeks.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01312467
|United States, California|
|Veterans Administration Long Beach Medical Center|
|Long Beach, California, United States, 90822|
|University of California Medical Center At Irvine-Orange Campus|
|Orange, California, United States, 92868|
|Kaiser Permanente - Sacramento|
|Sacramento, California, United States, 95825|
|Jewish General Hospital|
|Montreal, Quebec, Canada, H3T 1E2|
|Principal Investigator:||Jason Zell||University of California Medical Center At Irvine-Orange Campus|