Clinical trial NCT01516216: Study of Vitamin D in Untreated Metastatic Colorectal Cancer
Official title: Randomized, Double-Blind, Phase II Trial of Vitamin D Supplementation in Patients With Previously Untreated Metastatic Colorectal Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Metastatic Colorectal Cancer
Keywords: previously untreated
Lead sponsor: Dana-Farber Cancer Institute
Sponsor class: OTHER
First posted: 2012-01-24
Enrollment: 139
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Median Progression-free Survival (PFS)
timeFrame: 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:
measure: Median Overall Survival (OS)
timeFrame: 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.
measure: Objective Response Rate
timeFrame: Disease was evaluated every 4 cycles on treatment. Median (maximum) treatment duration was 7.3 (28.5) months.
measure: Grade 3-5 Treatment-Related Neutropenia Toxicity Rate
timeFrame: 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.
measure: Number of Participants With Vitamin D Deficiency at Baseline
timeFrame: Baseline
measure: Vitamin D Sufficiency Rate
timeFrame: 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.
measure: Plasma 25-hydroxyvitamin D Levels
timeFrame: 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.
measure: Hazard Ratio Between Baseline Plasma 25(OH)D Level and PFS
timeFrame: Baseline Plasma 25(OH)D Level and up to 28.5m for evaluation of PFS.
measure: Hazard Ratio Between Baseline Plasma 25(OH)D Levels and OS
timeFrame: Baseline Plasma 25(OH)D Level and up to maximum 56.7 months for evaluation of OS.
Other outcomes:
Locations:
city: Boise
country: United States
facility: Mountain States Tumor Institute at St. Luke's Regional Medical Center
state: Idaho
city: Fruitland
country: United States
facility: Mountain States Tumor Institute- Fruitland
state: Idaho
city: Meridian
country: United States
facility: Mountain States Tumor Institute - Meridian
state: Idaho
city: Nampa
country: United States
facility: Mountain States Tumor Institute- Nampa
state: Idaho
city: Twin Falls
country: United States
facility: Mountain States Tumor Institute- Twin Falls
state: Idaho
city: Chicago
country: United States
facility: The Robert H. Lurie Comprehensive Cancer Center of Northwestern University
state: Illinois
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Lowell
country: United States
facility: Lowell General Hospital
state: Massachusetts
city: Milford
country: United States
facility: Dana-Farber/Brigham and Women's Cancer Center at Milford Regional Medical Center
state: Massachusetts
city: Newton
country: United States
facility: Newton-Wellesley Hospital
state: Massachusetts
city: South Weymouth
country: United States
facility: Dana-Farber/Brigham and Women's Cancer Center in clinical affiliation with South Shore Hospital
state: Massachusetts
city: Concord
country: United States
facility: New Hampshire Oncology Hematology-P.A.
state: New Hampshire
city: Hooksett
country: United States
facility: New Hampshire Oncology Hematology-P.A.
state: New Hampshire
city: Laconia
country: United States
facility: New Hampshire Oncology Hematology-P.A.
state: New Hampshire
city: Londonderry
country: United States
facility: Dana-Farber/New Hampshire Oncology-Hematology
state: New Hampshire
city: Nashville
country: United States
facility: Vanderbilt-Ingram Cancer Center
state: Tennessee
Study officials:
affiliation: Dana-Farber Cancer Institute
name: Kimmie Ng, MD, MPH
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.