Trial of Metformin for Colorectal Cancer Risk Reduction for History of Colorectal Adenomas and Elevated BMI
Condition: Adenomatous Polyp; Colorectal Cancer; Obesity
MeSH terms: Colorectal Neoplasms; Adenoma; Adenomatous Polyps
Study type: Interventional
Phase: Phase 2

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 description: 
      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 (pAKT), phosphorylated mTOR,
      phosphorylated insulin receptor (pIR), phosphorylated IGF-1 (pIGF-1) receptor, and Ki-67.

      OUTLINE:

      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.
    

Intervention name(s): metformin hydrochloride
Intervention type(s): Drug
Other intervention name(s): Glucophage
Intervention MeSH terms: Metformin
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Prevention