Study of Vitamin D in Untreated Metastatic Colorectal Cancer

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Randomized, Double-Blind, Phase II Trial of Vitamin D Supplementation in Patients With Previously Untreated Metastatic Colorectal Cancer

Conditions
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Metastatic Colorectal Cancer

Intervention / Treatment
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* Drug: FOLFOX + bevacizumab
* Dietary Supplement: Vitamin D


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Chemotherapy + Standard Dose Vitamin D<br>FOLFOX-bevacizumab: intravenously on Day 1 (+/- 7 days) of every two-week cycle per institutional standards + 400 IU vitamin D3 orally once daily Participants were treated until disease progression, unacceptable toxicity or withdrawal for other reasons. | Drug: FOLFOX + bevacizumab<br> <br> * Other names: Bevacizumab (Avastin);Dietary Supplement: Vitamin D<br> <br> |
| Active Comparator: Chemotherapy + Higher Dose<br>FOLFOX-bevacizumab: intravenously on Day 1 (+/- 7 days) of every two-week cycle per institutional standards + 8000 IU daily x 2 weeks as loading dose, followed by 4000 IU daily as maintenance dose. Participants were treated until disease progression, unacceptable toxicity or withdrawal for other reasons. | Drug: FOLFOX + bevacizumab<br> <br> * Other names: Bevacizumab (Avastin);Dietary Supplement: Vitamin D<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | Disease was evaluated every 4 cycles on treatment. Median (maximum) treatment duration was 7.3 (28.5) months. | 
| Grade 3-5 Treatment-Related Neutropenia Toxicity Rate | The percentage of treated participants experiencing grade 3-5 neutropenia with treatment attribution of possible, probable or definite based on Common Toxicity Criteria for Adverse Events version 4 (CTCAEv4) as reported on case report forms were counted. | AEs were evaluated at day 1 of each cycle on treatment and up to 30 days after the last dose. Maximum treatment duration is 28.5 months with median 7.3 months. | 
| Number of Participants With Vitamin D Deficiency at Baseline | Vitamin D deficiency was defined as plasma 25-hydroxyvitamin D [25(OH)D] level <20 ng/mL as measured in one batch per established methods by an independent laboratory. | Baseline | 
| Vitamin D Sufficiency Rate | Percentage of participants that achieve Vitamin D sufficiency defined as plasma 25(OH)D >=30 ng/mL on treatment as measured in one batch per established methods by an independent laboratory. | Plasma samples were collected at 3 timepoints on treatment: first restaging (cycle 5, day 1), second restaging (cycle 9, day 1) and at treatment discontinuation. Median (maximum) treatment duration was 7.3 (28.5) months. | 
| Plasma 25-hydroxyvitamin D Levels | Plasma 25-hydroxyvitamin D [25(OH)D] levels as measured in one batch per established methods by an independent laboratory. | Plasma samples were collected at 4 timepoints on study: baseline, first restaging (cycle 5, day 1), second restaging (cycle 9, day 1) and at treatment discontinuation. Median (maximum) treatment duration was 7.3 (28.5) months. | 
| Hazard Ratio Between Baseline Plasma 25(OH)D Level and PFS | Plasma 25-hydroxyvitamin D [25(OH)D] levels as measured in one batch per established methods by an independent laboratory. Plasma 25(OH)D Level is used as continuous data. PFS is estimated based on Kaplan-Meier method (see outcome measure 1). The PFS hazard ratio associated with one unit increase of 25()H)D. | Baseline Plasma 25(OH)D Level and up to 28.5m for evaluation of PFS. | 
| Hazard Ratio Between Baseline Plasma 25(OH)D Levels and OS | Plasma 25-hydroxyvitamin D [25(OH)D] levels as measured in one batch per established methods by an independent laboratory. Plasma 25(OH)D Level is used as continuous data. OS is estimated based on Kaplan-Meier method (see outcome measure 2). The OS hazard ratio associated with one unit increase of 25()H)D. | Baseline Plasma 25(OH)D Level and up to maximum 56.7 months for evaluation of OS. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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previously untreated