This is a prospective, randomized, double-blind phase II trial to evaluate the efficacy and safety of two doses of vitamin D supplementation in combination with standard chemotherapy in participants with previously-untreated metastatic colorectal adenocarcinoma.

In this research study, the investigators are comparing standard and higher dose Vitamin D treatment when given in combination with standard treatment for metastatic colorectal cancer. Standard treatment includes the chemotherapy combination of 5-FU, Leucovorin and Oxaliplatin (FOLFOX) with bevacizumab.

Participants will be randomized into one of the study groups-Arm A: Vitamin D (standard dose of 400 IU/day), FOLFOX and Bevacizumab or Arm B: Vitamin D (higher dose of 8000 IU/day for 2 weeks followed by 4000 IU/day), FOLFOX and Bevacizumab.

Study Treatment (A cycle of treatment is 14 days):

Vitamin D

Cycle 1: You will take two capsules of Vitamin D orally, once a day (at the same time), every day. Participants randomized to Arm A will be taking one capsule with 400 IU of Vitamin D and one capsule with placebo (pills with no medicine) so that neither you nor your doctor will know what group you have been assigned to. Participants randomized to Arm B will be taking two capsules of 4000 IU each.

Subsequent Cycles: You will take one capsule orally, once a day (at the same time), every day. Participants randomized to Arm A will be taking one capsule with 400 IU of Vitamin D. Participants randomized to Arm B will be taking one capsule with 4000 IU of Vitamin D.

FOLFOX and bevacizumab

FOLFOX and bevacizumab will be given intravenously (IV, through a vein in your arm) on Day 1 of every cycle for all participants in both Arms A and B. The infusions will take several hours, in addition to your doctor's visit, so you should plan on being in clinic most of the day. Note that the 5-FU is given bolus on day 1 (given as one dose), and is then given as a continuous IV infusion over 2 days. You will need to have a port-a-cath placed. A port-a-cath is a medical device that is placed under the skin. The continuous infusion is delivered by a pump that is inserted into the port-a-cath. The pump will be carried in a pouch that you can hook around your waist. Arrangements will be made for you to have the pump disconnected after 2 days. You may need to return to clinic to have it disconnected.

Inclusion Criteria:

• Histologically confirmed adenocarcinoma of the colon or rectum that is metastatic or locally advanced (unresectable)
• Measurable disease
• KRAS wild-type and KRAS mutant patients are eligible
• No prior systemic treatment for advanced or metastatic colorectal cancer is allowed
• No prior radiotherapy to more than 25% of bone marrow
• No surgery or major biopsy within 4 weeks of randomization
• Paraffin-embedded and/or snap-frozen tumor tissue samples must be available

Exclusion Criteria:

• Not pregnant or breastfeeding
• No prior chemotherapy, systemic therapy or investigational agent
• No concurrent use of other anti-cancer therapy
• No known brain metastases
• No history of other malignancies except adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, curatively treated lobular or ductal carcinoma in situ of the breast or other cancer curatively treated with no evidence of disease for more than 3 years prior to randomization
• No regular use of vitamin D supplements greater than 2000 IU per day in the past year
• No history of allergic reactions attributed to compounds of similar chemical or biologic composition to 5-FU, capecitabine, oxaliplatin, leucovorin, bevacizumab and/or vitamin D3
• No significant history of bleeding events, pre-existing bleeding diathesis, coagulopathy or gastrointestinal perforation
• No arterial thrombotic events within 6 months of randomization
• No serious non-healing wound, ulcer or bone fracture
• No history of uncontrolled hypertension
• No clinically significant peripheral neuropathy
• No predisposing colonic or small bowel disorders in which the symptoms are uncontrolled
• No uncontrolled seizure disorder or active neurological disease
• No pre-existing hypercalcemia
• No known active hyperparathyroid disease
• No regular use of thiazide diuretics
• No malabsorption, uncontrolled vomiting or diarrhea
• No known co-morbid disease that would increase the risk of toxicity
• No use of chronic oral corticosteroid therapy or any other therapy that can cause vitamin D depletion
• No clinically significant cardiovascular disease
• No uncontrolled intercurrent illness
• No history of any medical or psychiatric condition or addictive disorder or laboratory abnormality that may increase the risks associated with study participation