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

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase IIa Trial of Metformin for Colorectal Cancer Risk Reduction Among Patients With a History of Colorectal Adenomas and Elevated Body Mass Index

Conditions
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Adenomatous Polyp, Colorectal Cancer, Obesity

Intervention / Treatment
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* Drug: metformin hydrochloride


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 35 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Prevention (metformin hydrochloride)<br>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<br> <br> * Other names: Glucophage;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Activated S6serine235 (i.e., the Ratio of pS6serine235/S6serine235) | 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. | From baseline to 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | Data not collected. | Up to 16 weeks | 
| 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) | Data not collected. | Up to 16 weeks | 
| Safety and Tolerability of Metformin Hydrochloride Treatment | 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. | Up to 16 weeks |