Study of Vitamin D in Untreated Metastatic Colorectal Cancer

Dana-Farber Cancer Institute139 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

139

Conditions

Metastatic Colorectal Cancer

Interventions

FOLFOX + bevacizumabDRUG

Vitamin DDIETARY_SUPPLEMENT

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (18)

Mountain States Tumor Institute at St. Luke's Regional Medical Center

Boise, Idaho, United States

Outcomes

Primary Outcomes

Median Progression-free Survival (PFS)

Progression-free survival based on the Kaplan-Meier method is defined as the duration of time from study entry to documented disease progression (PD) or death. Per RECIST 1.1 criteria: progressive disease (PD) is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions. Patients who discontinued treatment to pursue potentially curative resection were censored for progression-free survival at the time of surgery. Patients who had not experienced cancer progression or died were censored at their last known follow-up date.

Time frame: Disease was evaluated every 4 cycles on treatment and off treatment every 8-16 weeks until PD or non-protocol therapy start if discontinued for reason other than PD. Participants were observed up to 28.5 months with maximum follow-up of 56.7 months.

Secondary Outcomes

Median Overall Survival (OS)

OS based on the Kaplan-Meier method is defined as the time from study entry to death or censored at date last known alive. Patients who discontinued treatment to pursue potentially curative resection were censored for progression-free survival at the time of surgery. Patients who had not experienced cancer progression or died were censored at their last known follow-up date.

Time frame: Participants were followed for survival by clinic visit or telephone every 3 months post-treatment discontinuation up to 36 months from the date that the last participant was enrolled. Median follow-up was 22.9 months with maximum 56.7 months.

Objective Response Rate

The objective response rate (ORR) was defined as the percentage of participants achieving complete response (CR) or partial response (PR) based on RECIST 1.1 criteria on treatment. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PR or better overall response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions.

Data from ClinicalTrials.gov

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