Back to resultsStudy of Vitamin D in Untreated Metastatic Colorectal Cancer
Primary Purpose
Metastatic Colorectal Cancer
Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
FOLFOX + bevacizumab
Vitamin D
Sponsored by
About this trial
This is an interventional treatment trial for Metastatic Colorectal Cancer focused on measuring previously untreated
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
Sites / Locations
- Mountain States Tumor Institute at St. Luke's Regional Medical Center
- Mountain States Tumor Institute- Fruitland
- Mountain States Tumor Institute - Meridian
- Mountain States Tumor Institute- Nampa
- Mountain States Tumor Institute- Twin Falls
- The Robert H. Lurie Comprehensive Cancer Center of Northwestern University
- Massachusetts General Hospital
- Beth Israel Deaconess Medical Center
- Dana-Farber Cancer Institute
- Lowell General Hospital
- Dana-Farber/Brigham and Women's Cancer Center at Milford Regional Medical Center
- Newton-Wellesley Hospital
- Dana-Farber/Brigham and Women's Cancer Center in clinical affiliation with South Shore Hospital
- New Hampshire Oncology Hematology-P.A.
- New Hampshire Oncology Hematology-P.A.
- New Hampshire Oncology Hematology-P.A.
- Dana-Farber/New Hampshire Oncology-Hematology
- Vanderbilt-Ingram Cancer Center
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
Active Comparator
Arm Label
Chemotherapy + Standard Dose Vitamin D
Chemotherapy + Higher Dose
Arm Description
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.
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.
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
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.
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.
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.
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.
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 25-hydroxyvitamin D Levels
Plasma 25-hydroxyvitamin D [25(OH)D] levels as measured in one batch per established methods by an independent laboratory.
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.
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.
Full Information
NCT ID
NCT01516216
First Posted
January 13, 2012
Last Updated
April 5, 2022
Sponsor
Dana-Farber Cancer Institute
1. Study Identification
Unique Protocol Identification Number
NCT01516216
Brief Title
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
2. Study Status
Record Verification Date
April 2022
Overall Recruitment Status
Completed
Study Start Date
April 13, 2012 (Actual)
Primary Completion Date
November 9, 2019 (Actual)
Study Completion Date
November 9, 2019 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Dana-Farber Cancer Institute
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Metastatic Colorectal Cancer
Keywords
previously untreated
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
139 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Chemotherapy + Standard Dose Vitamin D
Arm Type
Active Comparator
Arm Description
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.
Arm Title
Chemotherapy + Higher Dose
Arm Type
Active Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
FOLFOX + bevacizumab
Other Intervention Name(s)
5-FU (5-fluorouracil), Leucovorin, Oxaliplatin (Eloxatin), Bevacizumab (Avastin)
Intervention Type
Dietary Supplement
Intervention Name(s)
Vitamin D
Primary Outcome Measure Information:
Title
Median Progression-free Survival (PFS)
Description
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 Outcome Measure Information:
Title
Median Overall Survival (OS)
Description
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.
Title
Objective Response Rate
Description
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.
Time Frame
Disease was evaluated every 4 cycles on treatment. Median (maximum) treatment duration was 7.3 (28.5) months.
Title
Grade 3-5 Treatment-Related Neutropenia Toxicity Rate
Description
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.
Time Frame
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.
Title
Number of Participants With Vitamin D Deficiency at Baseline
Description
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.
Time Frame
Baseline
Title
Vitamin D Sufficiency Rate
Description
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.
Time Frame
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.
Title
Plasma 25-hydroxyvitamin D Levels
Description
Plasma 25-hydroxyvitamin D [25(OH)D] levels as measured in one batch per established methods by an independent laboratory.
Time Frame
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.
Title
Hazard Ratio Between Baseline Plasma 25(OH)D Level and PFS
Description
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.
Time Frame
Baseline Plasma 25(OH)D Level and up to 28.5m for evaluation of PFS.
Title
Hazard Ratio Between Baseline Plasma 25(OH)D Levels and OS
Description
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.
Time Frame
Baseline Plasma 25(OH)D Level and up to maximum 56.7 months for evaluation of OS.
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Kimmie Ng, MD, MPH
Organizational Affiliation
Dana-Farber Cancer Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
Mountain States Tumor Institute at St. Luke's Regional Medical Center
City
Boise
State/Province
Idaho
ZIP/Postal Code
83712
Country
United States
Facility Name
Mountain States Tumor Institute- Fruitland
City
Fruitland
State/Province
Idaho
ZIP/Postal Code
83619
Country
United States
Facility Name
Mountain States Tumor Institute - Meridian
City
Meridian
State/Province
Idaho
ZIP/Postal Code
83642
Country
United States
Facility Name
Mountain States Tumor Institute- Nampa
City
Nampa
State/Province
Idaho
ZIP/Postal Code
83686
Country
United States
Facility Name
Mountain States Tumor Institute- Twin Falls
City
Twin Falls
State/Province
Idaho
ZIP/Postal Code
83301
Country
United States
Facility Name
The Robert H. Lurie Comprehensive Cancer Center of Northwestern University
City
Chicago
State/Province
Illinois
Country
United States
Facility Name
Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
Beth Israel Deaconess Medical Center
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Facility Name
Dana-Farber Cancer Institute
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Facility Name
Lowell General Hospital
City
Lowell
State/Province
Massachusetts
Country
United States
Facility Name
Dana-Farber/Brigham and Women's Cancer Center at Milford Regional Medical Center
City
Milford
State/Province
Massachusetts
Country
United States
Facility Name
Newton-Wellesley Hospital
City
Newton
State/Province
Massachusetts
Country
United States
Facility Name
Dana-Farber/Brigham and Women's Cancer Center in clinical affiliation with South Shore Hospital
City
South Weymouth
State/Province
Massachusetts
Country
United States
Facility Name
New Hampshire Oncology Hematology-P.A.
City
Concord
State/Province
New Hampshire
Country
United States
Facility Name
New Hampshire Oncology Hematology-P.A.
City
Hooksett
State/Province
New Hampshire
Country
United States
Facility Name
New Hampshire Oncology Hematology-P.A.
City
Laconia
State/Province
New Hampshire
Country
United States
Facility Name
Dana-Farber/New Hampshire Oncology-Hematology
City
Londonderry
State/Province
New Hampshire
Country
United States
Facility Name
Vanderbilt-Ingram Cancer Center
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37232
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
30964527
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.
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