Clinical Trial: A Trial of Metformin for Colorectal Cancer Risk Reduction Among Patients With a History of Colorectal Adenomas and Elevated Body Mass Index

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

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

Brief Summary: 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.

Detailed Summary:

PRIMARY OBJECTIVES:

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.

SECONDARY OBJECTIVES:

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.

TERTIARY OBJECTIVES:

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 (pA
Sponsor: National Cancer Institute (NCI)

Current Primary Outcome: Change in Activated S6serine235 (i.e., the Ratio of pS6serine235/S6serine235) [ Time Frame: From baseline to 12 weeks ]

Tissue S6Ser235 immunostaining was analyzed by the study pathologist using Histo Score (HScore) analysis at baseline and post- metformin (Week 12). The Hscore is determined by estimation of the percentage of cells positively stained with mild, moderate, or strong staining intensity. The final score is determined by weighted estimate, as follows: Hscore = (# cell stained with High intensity/total # cells)x3 + (# cells stained with median intensity/total # cells)x2 + (# cells stained with low intensity/total # cells)x1. Mean and standard deviation of the change in the histo score (H score) of pS6serine235 from baseline were calcuated.


Original Primary Outcome: Reduction in pS6serine235 [ Time Frame: 12 weeks ]

To determine if a 12-week intervention of oral metformin 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.


Current Secondary Outcome:

  • 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 ]
    We are in the process of identifying and securing funding to complete the secondary and tertiary endpoints. Once the information is available, we will provide those results with any relevant post-hoc analyses.
  • 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 ]
    We are in the process of identifying and securing funding to complete the secondary and tertiary endpoints. Once the information is available, we will provide those results with any relevant post-hoc analyses.
  • Safety and Tolerability of Metformin Hydrochloride Treatment [ Time Frame: Up to 16 weeks ]

    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.

    We are in the process of identifying and securing funding to complete the secondary and tertiary endpoints. Once the information is available, we will provide those results with any relevant post-hoc analyses.



Original Secondary Outcome:

  • Assess the effect of Metformin on additional relevant biomarkers in serum [ Time Frame: 12 weeks ]
    • Metformin levels
    • Fasting IGF-1, IGFBP-1, IGFBP-3
    • Fasting Leptin
    • Fasting Adiponectin
    • Fasting and 2 hour post-prandial insulin and glucose
  • Assess effect of Metformin on additional relevant biomarkers in tissue via immunostaining and cross-validating with Western blot methods. [ Time Frame: 12 weeks ]

    The following are biomarkers used for this process:

    • phosphorylated AMPK (pAMPK)
    • phosphorylated AKTserine 473 (pAKT)
    • phophorylated mTOR
    • phosphorylated insulin receptor (pIR)
    • phosporylated IGF-1 (pIGF-1) receptor
    • Ki-67
  • To assess the effects of Metformin on biomarkers and patient safety [ Time Frame: 12 weeks ]
    • Examine the correlation among biomarkers (serum, tissue)
    • Assess the independent effects of treatment on each biomarker, using multivariate regression models to account for clinical and biomarker data
    • Document the safety and tolerability of metformin in the study population


Information By: National Cancer Institute (NCI)

Dates:
Date Received: March 7, 2011
Date Started: March 2011
Date Completion:
Last Updated: June 3, 2015
Last Verified: June 2014