This phase III trial studies how well vitamin D3 given with standard chemotherapy and bevacizumab works in treating patients with colorectal cancer that has spread to other parts of the body. Vitamin D3 helps the body use calcium and phosphorus to make strong bones and teeth. Drugs used in chemotherapy, such as leucovorin calcium, fluorouracil, oxaliplatin, and irinotecan hydrochloride, work in different ways to stop the growth of tumor cells by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as bevacizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving vitamin D3 with chemotherapy and bevacizumab may work better in shrinking or stabilizing colorectal cancer. It is not yet known whether giving high-dose vitamin D3 in addition to chemotherapy and bevacizumab would extend patients' time without disease compared to the usual approach (chemotherapy and bevacizumab).

PRIMARY OBJECTIVES:

I. 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:

I. 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.

II. 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.

III. To evaluate and compare the toxicity of adding high-dose vitamin D3 versus standard-dose vitamin D3 to chemotherapy + bevacizumab.

IV. 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.

V. To evaluate the incidence of vitamin D3 deficiency in participants with previously untreated metastatic colorectal cancer.

VI. 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.

VII. To evaluate the prognostic effect of highest-achieved 25(OH)D levels with PFS.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive bevacizumab intravenously (IV) over 30-90 minutes on day 1 and oxaliplatin IV over 2 hours on day 1, leucovorin calcium IV over 2 hours on day 1, and fluorouracil IV on days 1-3 or irinotecan hydrochloride IV on day 1, leucovorin calcium IV over 90 minutes on day 1, and fluorouracil IV on days 1-3. Patients also receive high-dose cholecalciferol orally (PO) once daily (QD) on days 1-14. Cycles repeat every 14 days for 5 years in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive bevacizumab and chemotherapy as in Arm I. Patients also receive standard-dose cholecalciferol PO QD on days 1-14. Cycles repeat every 14 days for 5 years in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed every 6 months for 5 years.

Inclusion Criteria:

• Histologically confirmed advanced/metastatic colorectal adenocarcinoma for which metastasectomy is not planned.

• No known mismatch repair deficiency (dMMR) or high-frequency microsatellite instability (MSI-H) disease.

• Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1.

• No prior systemic treatment for metastatic disease.

• 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.

• Patients may have received prior standard rectal cancer chemoradiation. Previous radiation therapy must have been completed >= 4 weeks prior to registration.

• 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.

• 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.

• 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.

• Eastern Cooperative Oncology Group (ECOG) performance status: 0-1.

• Absolute neutrophil count >= 1,500/mm^3.

• Platelet count >= 100,000/mm^3.

• Hemoglobin >= 9 g/dL.

• Creatinine =< 1.5 x upper limit of normal (ULN) OR calculated (Calc.) creatinine clearance (CrCl) > 30 mL/min.

• Calcium =< 1.0 x ULN.

  * Corrected for albumin level if albumin not within institutional limits of normal.

• Total bilirubin =< 1.5 x ULN.

  * 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).

• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x ULN.

  * AST/ALT < 5 x ULN if clearly attributable to liver metastases.

• Urine protein to creatinine (UPC) ratio =< 1 mg/dL OR urine protein =< 1+.

  * If urine protein is above 1, then 24-hour urine must be ≤ 1 g/24 hours.

• No resectable metastatic disease for which potentially curative metastasectomy is planned.

• No "currently active" second malignancy other than non-melanoma skin cancers or cervical carcinoma in situ. Patients are not considered to have a "currently active" malignancy if they have completed therapy and have been free of disease for >= 3 years.

• No significant history of bleeding events or bleeding diathesis =< 6 months of registration unless the source of bleeding has been resected.

• No history of arterial thrombotic events, including, but not limited to, transient ischemic attack, cerebrovascular accident, unstable angina, angina requiring surgical or medical intervention, or myocardial infarction =< 6 months of registration.

• No history of clinically significant peripheral artery disease =< 6 months of registration.

• No history of uncontrolled congestive heart failure defined as New York Heart Association (NYHA) class III or greater.

• No history of gastrointestinal (GI) perforation =< 12 months of registration except for GI perforation related to a primary colorectal tumor that has since been fully resected.

• No history of malabsorption, uncontrolled vomiting or diarrhea, or any other disease significantly affecting GI function that could interfere with the absorption of oral agents.

• No history of allergic reaction attributed to compounds of similar chemical or biological composition to the study agents.

• No uncontrolled hypertension (defined as blood pressure [BP] > 160/90).

• No serious or non-healing wound, ulcer, or bone fracture.

• No uncontrolled intercurrent illness, including, but not limited to, psychiatric illness/social situations that, in the opinion of the treating physician, may increase the risks associated with participation or treatment on the study or may interfere with the conduct of the study or interpretation of the study results.

• Patients positive for human immunodeficiency virus (HIV) are eligible only if they meet all of the following:

  • On effective anti-retroviral therapy
  • Undetectable HIV viral load by standard clinical assay =< 6 months of registration.

• No known pre-existing hypercalcemia =< 6 months of registration.

• No known active hyperparathyroid disease or other serious disturbance of calcium metabolism =< 5 years of registration.

• No predisposing colonic or small bowel disorders in which symptoms are uncontrolled as indicated by > 3 watery or soft stools daily in patients without a colostomy or ileostomy. Patients with a colostomy or ileostomy are allowed per treating physician discretion.

• No symptomatic genitourinary stones =< 12 months of registration.

• Patients with treated brain metastases are eligible if follow-up imaging after central nervous system (CNS)-directed therapy shows no evidence of progression >= 28 days prior to registration.

• Patients with new or progressive brain metastases (active brain metastases) or leptomeningeal disease are eligible if the treating physician determines that immediate CNS-specific treatment is not required and is unlikely to be required during the first cycle of protocol-specified therapy after registration.

• No uncontrolled seizure disorders.

• No grade >=2 peripheral neuropathy, neurosensory toxicity, or neuromotor toxicity per Common Terminology Criteria for Adverse Events (CTCAE) v5.0 regardless of causality.

• Patients must be able to swallow oral formulations of the agent.

• Concurrent use of supplemental calcium and/or vitamin D is not permitted. Patients must discontinue the supplement(s) at least 7 days prior to registration.

• Concurrent use of thiazide diuretics (e.g. hydrochlorothiazide) is not permitted. Patients must discontinue the drug(s) or switch to an alternative anti-hypertensive agent at least 7 days prior to registration.

• Chronic concomitant treatment with oral corticosteroids, lithium, phenytoin, quinidine, isoniazid, and/or rifampin are not permitted. Patients must discontinue the agent(s) at least 7 days prior to registration. Short-term use of corticosteroids as antiemetic therapy is acceptable.

• Concurrent use of other anti-cancer therapy including chemotherapy, targeted, and/or biological agents is not permitted.