Colorectal Neoplasms
Conditions
Keywords
colorectal tumor, colorectal cancer, colorectal carcinoma, neoplasms, colorectal, Metformin
Brief summary
The purpose of this study is to investigate the effects of short term oral Metformin therapy on biomarkers for tumor growth in subjects with newly diagnosed colon or rectal adenocarcinoma. It is hypothesized that there are independent actions of Metformin on the outcome of subjects with colorectal cancer (CRC). Also hypothesized is that metformin effects on CRC cell growth will correlate with this drug's effects on markers mentioned above, because the markers are closely related to tumor growth and metastases.
Detailed description
This is a randomized, double-blinded placebo controlled clinical investigation of the effects of short term oral Metformin therapy on biomarkers for tumor growth in subjects with newly diagnosed colon or rectal adenocarcinoma. Metformin is a well-tolerated drug widely prescribed for treatment of Type 2 diabetes mellitus. Preliminary studies have generated the hypothesis that metformin may have positive effects on both prevention and survival of colon cancer subjects. Clinical trials are ongoing to explore this possibility in breast cancer (NCT01101438). This investigation is the first study of Metformin in colorectal cancer (CRC) patients, and is designed to understand the mechanism of its anti-cancer actions, if any, and its interactions with biomarkers in colorectal cancer patients. Based upon epidemiological studies, it is hypothesized that there are independent actions of Metformin on the outcome of subjects with CRC. Also hypothesized is that metformin effects on CRC cell growth will correlate with this drug's effects on markers mentioned above, because the markers are closely related to tumor growth and metastases.
Interventions
DRUGPlacebo
2 capsules by mouth twice daily; minimum of 10 days, maximum of 21 days
DRUGMetformin
850 mg (2 capsules) by mouth twice daily; minimum of 10 days, maximum of 21 days
Sponsors
University of Arkansas
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female, all races and ethnicities are eligible * Age equal to or greater than 18 years of age * All subjects should have a pathological/histological diagnosis of colorectal cancer. * Clinical diagnosis of stage I, II, III or IV colon cancer or stage I, II, III or IV rectal cancer; cancer may be primary including a secondary primary * Candidate for elective surgery(for removal of primary) or endoscopic biopsy * ECOG Performance status of 0 - 2 * Adequate renal, liver, and bone marrow function * Hb: (adequate for surgical intervention, with transfusion if necessary) * WBC: (normal range) * Platelets: (180K/cmm) * LFTs: Normal bilirubin (\< 2.0mg/dL), AST/ALT (2xULN) * Renal function: normal creatinine * Subjects must have signed informed consent * Female subjects must either not be of child-bearing potential or must have a negative urine pregnancy test within 7 days of beginning the drug or placebo treatment. Subjects are considered not of child-bearing potential if they are surgically sterile or they are postmenopausal for greater than 12 months.
Exclusion criteria
* Previously diagnosed with diabetes mellitus Type 1 or Type 2. * Currently taking biguanides, sulfonylurea drugs, thiazolidinediones, insulin, or mTOR inhibitors or having taken any of these medications during the 12 weeks prior to study participation. * Currently taking any non-steroidal anti-inflammatory drugs (NSAIDs) or aspirin and unable to stop such medications due to a present medical condition. * Clinical symptoms of gastrointestinal obstruction or bleeding and consideration for immediate surgery or immediate neoadjuvant chemoradiation. * Familial Adenomatous Polyposis (FAP), hereditary non-polyposis colorectal cancer (HNPCC), Putz-Jeghers disease, ulcerative colitis, or Crohn's disease. * Pregnant or lactating. * History of lactic or other metabolic acidosis. * Known hypersensitivity to Metformin. * Uncontrolled infectious disease. * History of Positivity for human immunodeficiency virus (HIV). * History of congestive heart failure requiring pharmacologic treatment. * History of excessive alcohol abuse, defined by a habitual intake of more than three drinks daily. * Previous or concurrent malignancies, except non-melanoma skin cancers, unless curatively treated and with no evidence of recurrence for \> 5 years, with the exception of prior CRC which has been treated and the patient has been in remission and the current primary tumor is a second CRC. * Unable to swallow and retain oral medication. * Mal-absorption syndrome, disease affecting gastrointestinal function, or previous resection of the stomach or small bowel. * Current use of medications for weight loss. * Currently taking cimetidine, thiazide diuretics or cephalexin. If a patient needs some of these agents, alternative agents should be substituted. * If the physician feels that the candidate is not suitable for the study, he/she will be excluded.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Proliferation Status of CRC Tumor and Adjacent Normal Tissue Following Metformin Therapy | 10-21 days |
| Mucosal Apoptotic Status of CRC Tumor and Adjacent Normal Tissue Following Metformin Therapy | 10-21 days |
Countries
United States
Participant flow
Recruitment details
Study was open for enrollment between 7/13/2012 and 3/5/2014. Subjects were recruited from medical clinics at the University of Arkansas for Medical Sciences (UAMS) and the Central Arkansas Veterans Healthcare System (CAVHS).
Pre-assignment details
There were no significant events following participant enrollment, prior to group assignment.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo: 2 capsules by mouth twice daily; minimum of 10 days, maximum of 21 days | 2 |
| Metformin Metformin: 850 mg (2 capsules) by mouth twice daily; minimum of 10 days, maximum of 21 days | 3 |
| Total | 5 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo | Total | Metformin |
|---|---|---|---|
| Age, Continuous | 57 years | 49 years | 44 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 5 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 1 Participants | 3 Participants | 2 Participants |
| Region of Enrollment United States | 2 participants | 5 participants | 3 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 2 Participants | 5 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 2 / 4 | 1 / 3 |
| serious Total, serious adverse events | 0 / 4 | 0 / 3 |
Outcome results
Primary
Mucosal Apoptotic Status of CRC Tumor and Adjacent Normal Tissue Following Metformin Therapy
Time frame: 10-21 days
Population: Data not collected due to inadequate subject accrual. Analysis not completed.
Primary
Proliferation Status of CRC Tumor and Adjacent Normal Tissue Following Metformin Therapy
Time frame: 10-21 days
Population: Data not collected due to inadequate subject accrual. Analysis not completed.