Primary objective:
To compare the progression-free survival (PFS) of patients receiving high-dose cholecalciferol (vitamin D3) in combination with standard chemotherapy (leucovorin calcium, fluorouracil, and oxaliplatin [FOLFOX] or leucovorin calcium, fluorouracil, and irinotecan hydrochloride [FOLFIRI]) and bevacizumab versus those receiving standard-dose vitamin D3 in combination with standard chemotherapy and bevacizumab.

Secondary objectives:

  1. To compare the objective response rate (ORR) of patients receiving high-dose vitamin D3 in combination with standard chemotherapy + bevacizumab versus those receiving standard-dose vitamin D3 in combination with standard chemotherapy + bevacizumab.
  2. To compare the overall survival (OS) of patients receiving high-dose vitamin D3 in combination with standard chemotherapy + bevacizumab versus those receiving standard-dose vitamin D3 in combination with standard chemotherapy + bevacizumab.
  3. To evaluate and compare the toxicity of adding high-dose vitamin D3 versus standard-dose vitamin D3 to chemotherapy + bevacizumab.
  4. To assess the influence of diet, body mass index, physical activity, and other lifestyle habits on PFS among patients with locally advanced/metastatic colorectal cancer.
  5. To evaluate the incidence of vitamin D3 deficiency in participants with previously untreated metastatic colorectal cancer.
  6. To compare the efficacy of high-dose vitamin D3 versus standard-dose vitamin D3 in subgroups of patients defined by baseline plasma calcifediol (25[OH]D) levels.
  7. To evaluate the prognostic effect of highest-achieved 25(OH)D levels with PFS.

Inclusion Criteria:

  1. Histologically confirmed advanced/metastatic colorectal adenocarcinoma for which metastasectomy is not planned.
  2. No mismatch repair deficiency (dMMR) or high-frequency microsatellite instability (MSI-H) disease.
  3. Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1.
  4. No prior systemic treatment for metastatic disease.
  5. Patients may have received prior neoadjuvant or adjuvant chemotherapy and/or chemoradiation. The last course of adjuvant therapy must have been completed > 12 months prior to colorectal cancer recurrence.
  6. Patients may have received prior standard rectal cancer chemoradiation so long as prior radiotherapy was to =< 25% of bone marrow. Previous radiation therapy must have been completed >= 4 weeks prior to registration.
  7. No continuous daily use of vitamin D supplements >= 2,000 IU per day for the 12 months prior to registration. Patients may have had continuous daily use of vitamin D supplements >= 2,000 IU per day if total duration < 12 months in the 12 months prior to registration. Patients may have had continuous daily use of vitamin D supplements < 2,000 IU per day for any duration prior to registration.
  8. Patients must have completed any major surgery or open biopsy >= 4 weeks prior to registration and must have completed any minor surgery or core biopsy >= 1 week prior to registration. (Note: insertion of a vascular access device is not considered major or minor surgery.) Patients must have recovered from the effects of any surgery (e.g. wound is healed, no active infection, no drains, etc.) prior to registration.
  9. Not pregnant and not nursing. This study involves an agent that has known genotoxic, mutagenic, and teratogenic effects. Therefore, for women of childbearing potential only, a negative serum or urine pregnancy test done =< 14 days prior to registration is required.
  10. Eastern Cooperative Oncology Group (ECOG) performance status: 0-1.
  11. Absolute neutrophil count >= 1,500/mm^3.
  12. Platelet count >= 100,000/mm^3.
  13. Hemoglobin >= 9 g/dL.
  14. Creatinine =< 1.5 x upper limit of normal (ULN) OR calculated (Calc.) creatinine clearance (CrCl) > 30 mL/min.
  15. Calcium =< 1.0 x ULN.
  16. Corrected for albumin level if albumin not within institutional limits of normal.
  17. Total bilirubin =< 1.5 x ULN.
  18. If Gilbert's disease, use direct bilirubin instead of total bilirubin; direct bilirubin =< 1.5 x ULN if patient to receive FOLFIRI; direct bilirubin =< 3.0 x ULN if patient to receive leucovorin, infusional fluorouracil, and oxaliplatin (modified [m]FOLFOX6).
  19. Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x ULN.
  20. AST/ALT < 5 x ULN if clearly attributable to liver metastases.
  21. Urine protein to creatinine (UPC) ratio < 1 OR urine protein =< 1.
Clinical Program: Gastroinstestinal Cancer Program
Primary Sponsor: Alliance
Contact Info: 2029941161