Study of Vitamin D in Untreated Metastatic Colorectal Cancer

• Overall Survival [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  To compare the overall survival (OS) of participants with previously untreated metastatic colorectal cancer randomized to FOLFOX-bevacizumab plus higher-dose vitamin D versus FOLFOX-bevacizumab plus standard-dose vitamin D
• Objective tumor response rate [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  To compare the objective tumor response rate (RR) of participants with previously untreated metastatic colorectal cnacer randomized to FOLFOX-bevacizumab plus higher-dose vitamin D versus FOLFOX-bevacizumab plus standard-dose vitamin D
• Safety [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
  To evaluate and compare the toxicity of adding higher-dose vitamin D versus standard-dose vitamin D to FOLFOX-bevacizumab
• Incidence of vitamin D deficiency [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  To evaluate the incidence of vitamin D deficiency in participants with previously untreated metastatic colorectal cancer
• Proportion of participants able to achieve and maintain vitamin D sufficiency [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  To compare the proportion of participants who are able to achieve and maintain vitamin D sufficiency with higher-dose vitamin D versus standard-dose vitamin D
• Time course of change in plasma 25-hydroxyvitamin D3 levels [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  To compare the time course of change in plasma 25-hydroxyvitamin D3 [25(OH)D] levles in participants randomized to higher-dose vitamin D versus standard-dose vitamin D
• Association between plasma 25(OH)D levels and PFS and OS [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  To evaluate the association between plasma 25(OH)D levels and PFS and overall survival

The Vitamin D receptor is found in colon cancer cells. When Vitamin D binds to the receptor in the cancer cells, it may stop cancer cells from growing abnormally and may cause cell death. Vitamin D has been used in other research studies and information from those other research studies suggests that Vitamin D may help in the treatment of colorectal cancer.

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.

While on study, the following tests and procedures will be performed:

Cycle 1, Day 1

• Questions about your health, current medications and any allergies.
• Physical exam, including vital signs
• Performance status
• Routine blood tests to evaluate your health
• Urine test

Subsequent Cycles, Day 1

• Questions about your health, current medications, allergies and any side effects you may be having.
• Physical exam, including vital signs
• Performance status
• Routine blood tests to evaluate your health
• Urine test
• Review of your study drug diary (please bring with you every visit).

Every 4 cycles (approximately every 8 weeks): An assessment of your tumor by CT scan or MRI.

Additional blood samples for research: Samples will be drawn (a little more than 1 teaspoon of blood) after Cycle 4, Cycle 8 and then every 8 Cycles thereafter.

You will continue to receive treatment as long as your disease does not get worse and you are tolerating the treatment.

End of treatment

• Questions about your health, current medications and any allergies.
• Physical exam, including vital signs
• Performance status
• Blood tests (routine blood tests to evaluate your health and a blood sample for research)
• Urine test
• An assessment of your tumor by CT scan or MRI

After the final dose of the study drug:

You will be followed for safety reasons for 30 days after the last dose of study drug. If you are experiencing side effects, you may continue to be followed until the side effects resolve or until you start another treatment.

If you discontinue study treatment for reasons other than disease progression (for example, side effects), you will be asked to continue to get tumor assessments every 8 - 16 weeks until your disease worsens as demonstrated by a tumor assessment or until you start another therapy to treat your cancer. These assessments may coincide with your routine follow-up, in which case they would not need to be repeated.

We would like to keep track of your medical condition for the rest of your life. We would like to do this by reviewing your medical records and/or by calling you on the telephone every 3 months to see how you are doing. Keeping in touch with you and checking on your condition helps us look at the long-term effects of the research study.

• Drug: FOLFOX + bevacizumab
  Given intravenously on Day 1 of every cycle
  Other Names:

  • 5-FU (5-fluorouracil)
  • Leucovorin
  • Oxaliplatin (Eloxatin)
  • Bevacizumab (Avastin)
• Dietary Supplement: Vitamin D
  Standard Dose (400 IU once daily)
• Dietary Supplement: Vitamin D
  Higher Dose (8000 IU once daily for 2 weeks, followed by 4000 IU once daily)

• Active Comparator: Standard Dose Vitamin D
  Standard Dose Vitamin D with Bevacizumab and FOLFOX. FOLFOX contains: 5-FU (5-fluorouracil), Leucovorin and Oxaliplatin (Eloxatin).
  Interventions:

  • Drug: FOLFOX + bevacizumab
  • Dietary Supplement: Vitamin D
• Active Comparator: Higher Dose Vitamin D
  Higher Dose Vitamin D with Bevacizumab and FOLFOX. FOLFOX contains: 5-FU (5-fluorouracil), Leucovorin and Oxaliplatin (Eloxatin).
  Interventions:

  • Drug: FOLFOX + bevacizumab
  • Dietary Supplement: Vitamin D

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