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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01312467
First received: March 7, 2011
Last updated: July 7, 2014
Last verified: June 2014
  Purpose

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.


Condition Intervention Phase
Adenomatous Polyp
Colorectal Cancer
Obesity
Drug: metformin hydrochloride
Other: pharmacological study
Other: laboratory biomarker analysis
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Prevention
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

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Change in activated S6serine235 (i.e., the ratio of pS6serine235/S6serine235) [ Time Frame: From baseline to 12 weeks ] [ Designated as safety issue: No ]
    A paired t-test will be used to examine the effect of oral metformin on activated S6serine235. The distribution of the difference between post- and pre-treatment values will be examined. Measures of central tendency and variability will be computed.


Secondary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • Safety and tolerability of metformin hydrochloride treatment [ Time Frame: Up to 16 weeks ] [ Designated as safety issue: No ]
    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.


Enrollment: 50
Study Start Date: March 2011
Study Completion Date: March 2014
Primary Completion Date: March 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Prevention (metformin hydrochloride)
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
Given PO
Other Name: Glucophage
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies
Other: laboratory biomarker analysis
Correlative studies

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.

  Eligibility

Ages Eligible for Study:   35 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01312467

Locations
United States, California
Veterans Administration Long Beach Medical Center
Long Beach, California, United States, 90822
University of California Medical Center At Irvine-Orange Campus
Orange, California, United States, 92868
Kaiser Permanente - Sacramento
Sacramento, California, United States, 95825
Canada, Quebec
Jewish General Hospital
Montreal, Quebec, Canada, H3T 1E2
Sponsors and Collaborators
Investigators
Principal Investigator: Jason Zell University of California Medical Center At Irvine-Orange Campus
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01312467     History of Changes
Other Study ID Numbers: NCI-2011-01744, NCI-2011-01744, UCI 10-31, 2010-7705, UCI09-13-01, 2010-7705, UCI09-13-01, P30CA062203, N01CN35160
Study First Received: March 7, 2011
Last Updated: July 7, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Adenoma
Colorectal Neoplasms
Obesity
Adenomatous Polyps
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
Overnutrition
Nutrition Disorders
Overweight
Body Weight
Signs and Symptoms
Metformin
Hypoglycemic Agents
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on August 19, 2014