Effect of Metformin on Biomarkers of Colorectal Tumor Cell Growth

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.

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.