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

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT01312467
• Collaborator: (none)
• Enrollment: 45
• Locations: 4
• Arm: 1
• Duration (Months): 45
• Patients Per Site: 11.3
• Patients Per Site Per Month: 0.2

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Adenomatous Polyp; Colorectal Cancer; Obesity	Drug: metformin hydrochloride	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. 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:

1. 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.

2. 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.

3. To document the safety and tolerability of metformin in the study population.

TERTIARY OBJECTIVES:

1. 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.

2. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 45 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (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
• Study Start Date: Mar 1, 2011
• Actual Primary Completion Date: Mar 1, 2014
• Actual Study Completion Date: Dec 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
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; Other Names: Glucophage

Outcome Measures

Primary Outcome Measures

1. Change in Activated S6serine235 (i.e., the Ratio of pS6serine235/S6serine235) [From baseline to 12 weeks]

   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.

Secondary Outcome Measures

1. 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]

   Data not collected.

2. 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]

   Data not collected.

3. Safety and Tolerability of Metformin Hydrochloride Treatment [Up to 16 weeks]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 35 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Locations

	Site	City	State	Country	Postal Code
1	Veterans Administration Long Beach Medical Center	Long Beach	California	United States	90822
2	University of California Medical Center At Irvine-Orange Campus	Orange	California	United States	92868
3	Kaiser Permanente - Sacramento	Sacramento	California	United States	95825
4	Jewish General Hospital	Montreal	Quebec	Canada	H3T 1E2

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Jason Zell, University of California Medical Center At Irvine-Orange Campus

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT01312467
• Other Study ID Numbers: NCI-2011-01744; NCI-2011-01744; UCI 10-31; 2010-7705; UCI09-13-01; P30CA062203; N01CN35160
• First Posted: Mar 10, 2011
• Last Update Posted: Mar 5, 2019
• Last Verified: Feb 1, 2019

• Additional relevant MeSH terms: Colorectal Neoplasms; Adenoma; Adenomatous Polyps; Metformin

Study Results

Participant Flow

Recruitment Details	Between 2011 and 2013, 45 obese colorectal adenoma (CRA) patients were enrolled at three study sites: UC Irvine, Long Beach VAMC, and Kaiser Permanente, Sacramento).

Arm/Group Title	Prevention (Metformin Hydrochloride)
Arm/Group Description	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. metformin hydrochloride: Given PO pharmacological study: Correlative studies laboratory biomarker analysis: Correlative studies
Period Title: Overall Study
STARTED	45
COMPLETED	32
NOT COMPLETED	13

Baseline Characteristics

Arm/Group Title	Prevention (Metformin Hydrochloride)
Arm/Group Description	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. metformin hydrochloride: Given PO pharmacological study: Correlative studies laboratory biomarker analysis: Correlative studies
Overall Participants	45
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	59.6 (6.83)
Sex: Female, Male (Count of Participants)
Female	15 33.3%
Male	30 66.7%
Region of Enrollment (participants) [Number]
United States	45 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

The analysis is based on 32 participants who have evaluable data.

Arm/Group Title	Prevention (Metformin Hydrochloride)
Arm/Group Description	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. metformin hydrochloride: Given PO pharmacological study: Correlative studies laboratory biomarker analysis: Correlative studies
Measure Participants	32
Mean (Standard Deviation) [weighted ratio of staining cells]	0.0228 (0.444)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Prevention (Metformin Hydrochloride)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	> 0.773
	Comments
	Method	A paired t-test
	Comments

2. Secondary Outcome

Title	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)
Description	Data not collected.
Time Frame	Up to 16 weeks

Outcome Measure Data

Analysis Population Description

Funding was not secured to complete the secondary and tertiary endpoints.

Arm/Group Title	Prevention (Metformin Hydrochloride)
Arm/Group Description	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. metformin hydrochloride
Measure Participants	0

3. Secondary Outcome

Title	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)
Description	Data not collected.
Time Frame	Up to 16 weeks

Outcome Measure Data

Analysis Population Description

Funding was not secured to complete the secondary and tertiary endpoints.

Arm/Group Title	Prevention (Metformin Hydrochloride)
Arm/Group Description	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. metformin hydrochloride
Measure Participants	0

4. Secondary Outcome

Title	Safety and Tolerability of Metformin Hydrochloride Treatment
Description	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.
Time Frame	Up to 16 weeks

Outcome Measure Data

Analysis Population Description

45 participants were enrolled and 45 participants were analyzed for toxicity.

Arm/Group Title	Prevention (Metformin Hydrochloride)
Arm/Group Description	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. metformin hydrochloride
Measure Participants	45
Grade 1	186
Grade 2	23
Grade 3 or higher	1

Adverse Events

Time Frame	Adverse Events that were occurred on and after the treatment began date to the end of the study (up to 16 weeks).
Arm/Group Title	Prevention (Metformin Hydrochloride)
Arm/Group Description	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. metformin hydrochloride: Given PO pharmacological study: Correlative studies laboratory biomarker analysis: Correlative studies
All Cause Mortality
	Prevention (Metformin Hydrochloride)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Prevention (Metformin Hydrochloride)
	Affected / at Risk (%)	# Events
Total	1/45 (2.2%)
Reproductive system and breast disorders
DUCTAL CARCINOMA IN SITU, HIGH GRADE, SOLID AND CRIBRIFORM TYPE WITH APOCRINE FEATURES AND FOCAL NEC	1/45 (2.2%)	1
Other (Not Including Serious) Adverse Events
	Prevention (Metformin Hydrochloride)
	Affected / at Risk (%)	# Events
Total	36/45 (80%)
Blood and lymphatic system disorders
HEMATOCRIT LAB RESULT BELOW THE NORMAL RANGE	1/45 (2.2%)	4
HEMOGLOBIN LAB RESULT BELOW THE NORMAL RANGE	1/45 (2.2%)	4
IRON LAB RESULT OUT OF RANGE	1/45 (2.2%)	1
TRANSFERRIN SATURATION OUT OF RANGE - LOW	1/45 (2.2%)	1
Ear and labyrinth disorders
DECREASED HEARING	1/45 (2.2%)	1
Eye disorders
EYE IRRITATION	1/45 (2.2%)	1
SCRATCHED LEFT EYE CORNEA	1/45 (2.2%)	1
Gastrointestinal disorders
ABDOMINAL CRAMPING	1/45 (2.2%)	1
ABDOMINAL PAIN	1/45 (2.2%)	1
BLOATING	1/45 (2.2%)	1
CONSTIPATION	5/45 (11.1%)	5
CRAMPING	3/45 (6.7%)	8
DIARRHEA	14/45 (31.1%)	25
DRY MOUTH	3/45 (6.7%)	3
FLATULENCE	8/45 (17.8%)	8
HEARTBURN	5/45 (11.1%)	6
HEMATOCHEZIA	1/45 (2.2%)	1
HEMORRHOIDS	1/45 (2.2%)	1
INCREASED GAS	1/45 (2.2%)	1
LOOSE STOOLS	4/45 (8.9%)	4
LOOSE STOOLS/DIARRHEA	1/45 (2.2%)	1
MILD CRAMPING	2/45 (4.4%)	5
MILD GERD	1/45 (2.2%)	1
NAUSEA	7/45 (15.6%)	8
STOMACH CRAMPS	1/45 (2.2%)	1
STOMACH DISCOMFORT	1/45 (2.2%)	1
STOMACH PAIN	6/45 (13.3%)	7
VERY LOOSE STOOLS	1/45 (2.2%)	1
VOMITING	2/45 (4.4%)	2
General disorders
ELEVATED TEMPERATURE	1/45 (2.2%)	2
FATIGUE	7/45 (15.6%)	7
FELT COLD	1/45 (2.2%)	1
FEVER	2/45 (4.4%)	3
SLIGHT COLD	1/45 (2.2%)	1
SWELLING LESS IN FEET	1/45 (2.2%)	1
Infections and infestations
COLD	1/45 (2.2%)	1
INFECTION IN SITE OF LUMPECTOMY	1/45 (2.2%)	1
NASAL CONGESTION	1/45 (2.2%)	1
Injury, poisoning and procedural complications
MORE BRUISING	1/45 (2.2%)	1
Metabolism and nutrition disorders
HYPOGLYCEMIA	1/45 (2.2%)	1
HYPOGLYCEMIC	1/45 (2.2%)	1
INCREASED APPETITE	1/45 (2.2%)	1
LOSS OF APPETITE	6/45 (13.3%)	6
LOSS OF APPETITE-EATING LESS	1/45 (2.2%)	1
SMALLER APPETITE	1/45 (2.2%)	1
SWEET CRAVINGS	1/45 (2.2%)	1
Musculoskeletal and connective tissue disorders
BACK PAIN	1/45 (2.2%)	1
CRAMPS IN LEGS	1/45 (2.2%)	2
HEEL PAIN	1/45 (2.2%)	1
KNEE PAIN	1/45 (2.2%)	1
LEG CRAMPS	2/45 (4.4%)	2
MUSCLE PAIN	1/45 (2.2%)	1
SCIATICA FLARE	1/45 (2.2%)	1
SORE RIGHT WRIST	1/45 (2.2%)	1
TWITCHING RIGHT THIGH	1/45 (2.2%)	1
Nervous system disorders
DIZZINESS	7/45 (15.6%)	7
HEADACHE	5/45 (11.1%)	5
JITTERS	1/45 (2.2%)	2
LIGHTHEADED	2/45 (4.4%)	2
LIGHTHEADED/DIZZINESS	1/45 (2.2%)	2
LIGHTHEADEDNESS	2/45 (4.4%)	2
Psychiatric disorders
FEELS AWAKE	1/45 (2.2%)	1
INSOMNIA	3/45 (6.7%)	3
Renal and urinary disorders
DIFFICULTY HOLDING BLADDER-URGENCY	1/45 (2.2%)	1
Respiratory, thoracic and mediastinal disorders
COUGH	1/45 (2.2%)	1
ITCHY THROAT	1/45 (2.2%)	2
SHORTNESS OF BREATH	2/45 (4.4%)	2
STUFFY NOSE	1/45 (2.2%)	1
Skin and subcutaneous tissue disorders
DRY SKIN	1/45 (2.2%)	1
HEAT RASH	1/45 (2.2%)	1
INCREASED SWEATING	1/45 (2.2%)	1
ITCHY SKIN	1/45 (2.2%)	1
SWEATING	2/45 (4.4%)	2
Vascular disorders
HYPERTENSION	1/45 (2.2%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.