Study of Vitamin D in Untreated Metastatic Colorectal Cancer

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

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.

Study Overview

• Status: Completed
• Conditions: Metastatic Colorectal Cancer
• Intervention / Treatment: Dietary supplement: Vitamin D; Drug: FOLFOX + bevacizumab

Detailed Description

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
• Enrollment (Actual): 139
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Idaho
    • Boise, Idaho, United States, 83712
      • Mountain States Tumor Institute at St. Luke's Regional Medical Center
    • Fruitland, Idaho, United States, 83619
      • Mountain States Tumor Institute- Fruitland
    • Meridian, Idaho, United States, 83642
      • Mountain States Tumor Institute - Meridian
    • Nampa, Idaho, United States, 83686
      • Mountain States Tumor Institute- Nampa
    • Twin Falls, Idaho, United States, 83301
      • Mountain States Tumor Institute- Twin Falls
  • Illinois
    • Chicago, Illinois, United States
      • The Robert H. Lurie Comprehensive Cancer Center of Northwestern University
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute
    • Boston, Massachusetts, United States, 02115
      • Massachusetts General Hospital
    • Lowell, Massachusetts, United States
      • Lowell General Hospital
    • Milford, Massachusetts, United States
      • Dana-Farber/Brigham and Women's Cancer Center at Milford Regional Medical Center
    • Newton, Massachusetts, United States
      • Newton-Wellesley Hospital
    • South Weymouth, Massachusetts, United States
      • Dana-Farber/Brigham and Women's Cancer Center in Clinical Affiliation with South Shore Hospital
  • New Hampshire
    • Concord, New Hampshire, United States
      • New Hampshire Oncology Hematology-P.A.
    • Hooksett, New Hampshire, United States
      • New Hampshire Oncology Hematology-P.A.
    • Laconia, New Hampshire, United States
      • New Hampshire Oncology Hematology-P.A.
    • Londonderry, New Hampshire, United States
      • Dana-Farber/New Hampshire Oncology-Hematology
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt-Ingram Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Chemotherapy + Standard Dose Vitamin D; 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.	Dietary supplement: Vitamin D; Drug: FOLFOX + bevacizumab; Other Names: Leucovorin; Bevacizumab (Avastin); Oxaliplatin (Eloxatin); 5-FU (5-fluorouracil)
ACTIVE_COMPARATOR: Chemotherapy + Higher Dose; 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.	Dietary supplement: Vitamin D; Drug: FOLFOX + bevacizumab; Other Names: Leucovorin; Bevacizumab (Avastin); Oxaliplatin (Eloxatin); 5-FU (5-fluorouracil)

What is the study measuring?

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.

Collaborators and Investigators

• Sponsor: Dana-Farber Cancer Institute

Publications and helpful links

General Publications

• Ng K, Nimeiri HS, McCleary NJ, Abrams TA, Yurgelun MB, Cleary JM, Rubinson DA, Schrag D, Miksad R, Bullock AJ, Allen J, Zuckerman D, Chan E, Chan JA, Wolpin BM, Constantine M, Weckstein DJ, Faggen MA, Thomas CA, Kournioti C, Yuan C, Ganser C, Wilkinson B, Mackintosh C, Zheng H, Hollis BW, Meyerhardt JA, Fuchs CS. Effect of High-Dose vs Standard-Dose Vitamin D3 Supplementation on Progression-Free Survival Among Patients With Advanced or Metastatic Colorectal Cancer: The SUNSHINE Randomized Clinical Trial. JAMA. 2019 Apr 9;321(14):1370-1379. doi: 10.1001/jama.2019.2402.

Study record dates

Study Major Dates

• Study Start (ACTUAL): April 13, 2012
• Primary Completion (ACTUAL): November 9, 2019
• Study Completion (ACTUAL): November 9, 2019

Study Registration Dates

• First Submitted: January 13, 2012
• First Submitted That Met QC Criteria: January 23, 2012
• First Posted (ESTIMATE): January 24, 2012

Study Record Updates

• Last Update Posted (ACTUAL): April 26, 2022
• Last Update Submitted That Met QC Criteria: April 5, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: previously untreated
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Micronutrients; Vitamins; Bone Density Conservation Agents; Antidotes; Vitamin B Complex; Fluorouracil; Oxaliplatin; Vitamin D; Bevacizumab; Leucovorin
• Other Study ID Numbers: 11-436