Trial of Metformin for Colorectal Cancer Risk Reduction for History of Colorectal Adenomas and Elevated BMI

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.

Inclusion Criteria:

- History of prior colorectal adenomas within the past 3 years; only patients who have
had adenomas endoscopically removed are eligible; documentation of colorectal adenomas
must be determined via review of pathology reports

- Body mass index (BMI) >= 30; rounded to the nearest whole integer

- Eastern Cooperative Oncology Group (ECOG) performance status 0-1

- Leukocytes ≥ 3,000/μL (>= 2,500/μL for African-American participants)

- Absolute neutrophil count >= 1,500/μL (>= 1,000/μL for African-American participants)

- Platelets >= 100,000/μL

- Total bilirubin within normal institutional limits

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 1.5 X institutional upper limit of normal (ULN)

- Creatinine within normal institutional limits

- Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry and for
the duration of study participation

- A serum pregnancy test must be performed and be negative in all women of childbearing
potential within 2 weeks prior to starting treatment

- Ability to understand and willingness to sign a written informed consent document

Exclusion Criteria:

- History of colorectal cancer or other cancer(s) (except for non-melanoma skin cancers)
within the last 3 years

- Family history of hereditary intestinal polyp disorder (e.g., familial adenomatous
polyposis [FAP], hereditary non-polyposis colorectal cancer [HNPCC], Putz-Jegher's
disease)

- Participants with diabetes

- History of vitamin B12 deficiency or megaloblastic anemia

- History of lactic acidosis

- Diet or other medications for weight loss

- Diseases associated with weight loss: anorexia, bulimia, or nausea

- Treatment with medications that may increase metformin levels: cationic drugs, e.g.,
digoxin, amiloride, procainamide, trimethoprim, vancomycin, triamterene, and morphine

- Treatment with other oral hypoglycemic agents

- Participants who have undergone full bowel resection, ablation or other local
therapies

- Participants may not be receiving any other investigational agents

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to metformin

- Participants with human immunodeficiency virus (HIV), cirrhosis of any cause, NASH
(nonalcoholic steatohepatitis), or hepatitis (auto-immune or infectious)

- Kidney disease or renal insufficiency (defined as serum creatinine > 1.4 mg/dL for
females or > 1.5 mg/dL for males)

- Metabolic acidosis, acute or chronic, including ketoacidosis

- Uncontrolled intercurrent illness including, but not limited to:

- Ongoing or active infection

- Symptomatic congestive heart failure

- Unstable angina pectoris

- Cardiac arrhythmia

- Psychiatric illness/social situations that would limit compliance with study
requirements

- Renal failure

- Hepatic failure

- Sepsis

- Hypoxia

- Pregnant or breastfeeding women are excluded

- Participants anticipating elective surgery during the study period

- Contraindication to colonoscopy/flexible sigmoidoscopy

- Participants may not be using metformin, cimetidine (Tagament) furosemide (Lasix),
nifedipine (Cardizem), Ranitidine (Zinetac or Zantac), digoxin (Lanoxin), Quinidine or
any other drug contraindicated for use with metformin

- Chronic alcohol use or a history of alcohol abuse

- Participants with any medical psychosocial condition that, in the opinion of the
investigator, could jeopardize participation in and compliance with the study criteria

- Participants that regularly use aspirin (ASA), nonsteroidal anti-inflammatory drugs
(NSAIDs), calcium, and cyclooxygenase (Cox)-2 inhibitors are not eligible for
enrollment; however, patients that use aspirin 81 mg daily, or aspirin 325 mg, NSAIDs,
calcium, or Cox-2 inhibitors at a frequency < 10 times per month are eligible