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

NCT01312467 | Completed Phase 2 Results DMC

• 6 other identifiers: NCI-2011-01744UCI 10-312010-7705UCI09-13-01P30CA062203N01CN35160
• Study Type: interventional
• Target: 45
• Locations: 2 countries
• Sites: 4

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.

Conditions

Adenomatous Polyp; Colorectal Cancer; Obesity

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (3)

• 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)

  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)

  Up to 16 weeks

• Safety and Tolerability of Metformin Hydrochloride Treatment

  Up to 16 weeks

Study Arms (1)

Prevention (metformin hydrochloride)

EXPERIMENTAL

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

Interventions

metformin hydrochloride DRUG

Also known as: Glucophage

Prevention (metformin hydrochloride)

Eligibility Criteria

• Age: 35 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (4)

Veterans Administration Long Beach Medical Center

Long Beach, California, 90822, United States

Location

University of California Medical Center At Irvine-Orange Campus

Orange, California, 92868, United States

Location

Kaiser Permanente - Sacramento

Sacramento, California, 95825, United States

Location

Jewish General Hospital

Montreal, Quebec, H3T 1E2, Canada

Location

MeSH Terms

Conditions

Adenomatous Polyps; Colorectal Neoplasms; Obesity

Interventions

Metformin

Condition Hierarchy (Ancestors)

Adenoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Overweight; Overnutrition; Nutrition Disorders; Nutritional and Metabolic Diseases; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals

Results Point of Contact

• Title: Dr. Frank L. Meyskens, Jr.
• Organization: University of California, Irvine

flmeyske@uci.edu

714-456-6310

Study Officials

• Jason Zell

  University of California Medical Center At Irvine-Orange Campus

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 7, 2011
• First Posted: March 10, 2011
• Study Start: March 1, 2011
• Primary Completion: March 1, 2014
• Study Completion: December 1, 2014
• Last Updated: March 5, 2019
• Results First Posted: June 25, 2015

Record last verified: 2019-02

Locations

US (3); CA (1)