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Metastatic Colorectal CancerPhase 2NCT01516216

Study of Vitamin D in Untreated Metastatic Colorectal Cancer

A Phase 2 study testing FOLFOX + bevacizumab and Vitamin D in people with Metastatic Colorectal Cancer, run by Dana-Farber Cancer Institute at 18 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Metastatic Colorectal Cancer
What is being tested?
FOLFOX + bevacizumab and Vitamin D
Could I receive a placebo?
No, everyone receives an active treatment
How many people
139 participants
Where
18 sitesUnited States
Study dates
13 Apr 2012to 9 Nov 2019
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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

Who cannot join

  • 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
Show all 23Show fewer
  • 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

Trial locations and contacts

18 sites in 1 country.

18 sites in 1 country

United States18 sites
  • Mountain States Tumor Institute at St. Luke's Regional Medical Center

    Boise, Idaho, 83712

  • Massachusetts General Hospital

    Boston, Massachusetts, 02115

  • Beth Israel Deaconess Medical Center

    Boston, Massachusetts, 02215

  • Dana-Farber Cancer Institute

    Boston, Massachusetts, 02215

  • The Robert H. Lurie Comprehensive Cancer Center of Northwestern University

    Chicago, Illinois

  • New Hampshire Oncology Hematology-P.A.

    Concord, New Hampshire

  • Mountain States Tumor Institute- Fruitland

    Fruitland, Idaho, 83619

  • New Hampshire Oncology Hematology-P.A.

    Hooksett, New Hampshire

  • New Hampshire Oncology Hematology-P.A.

    Laconia, New Hampshire

  • Dana-Farber/New Hampshire Oncology-Hematology

    Londonderry, New Hampshire

  • Lowell General Hospital

    Lowell, Massachusetts

  • Mountain States Tumor Institute - Meridian

    Meridian, Idaho, 83642

  • Dana-Farber/Brigham and Women's Cancer Center at Milford Regional Medical Center

    Milford, Massachusetts

  • Mountain States Tumor Institute- Nampa

    Nampa, Idaho, 83686

  • Vanderbilt-Ingram Cancer Center

    Nashville, Tennessee, 37232

  • Newton-Wellesley Hospital

    Newton, Massachusetts

  • Dana-Farber/Brigham and Women's Cancer Center in clinical affiliation with South Shore Hospital

    South Weymouth, Massachusetts

  • Mountain States Tumor Institute- Twin Falls

    Twin Falls, Idaho, 83301

Other trials in United States

About this study

Official title: 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.

Read the 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.

Being tested
FOLFOX + bevacizumab, Vitamin D
Keywords
previously untreated
Medical subject headings
Colorectal Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • FOLFOX + bevacizumabDrug

    Also called 5-FU (5-fluorouracil), Leucovorin, Oxaliplatin (Eloxatin), Bevacizumab (Avastin)

  • Vitamin DDietary supplement

Study groups in NCT01516216
Study groupRoleWhat they receive
Chemotherapy + Standard Dose Vitamin DActive comparatorFOLFOX-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.
Receives: Drug: FOLFOX + bevacizumab; Dietary Supplement: Vitamin D
Chemotherapy + Higher DoseActive comparatorFOLFOX-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.
Receives: Drug: FOLFOX + bevacizumab; Dietary Supplement: Vitamin D

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: 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 (8)
  1. 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.

    Measured: 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.

  2. 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.

    Measured: Disease was evaluated every 4 cycles on treatment. Median (maximum) treatment duration was 7.3 (28.5) months.

  3. 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.

    Measured: 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.

  4. 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.

    Measured: Baseline

  5. 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.

    Measured: 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.

  6. 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.

    Measured: 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.

  7. 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.

    Measured: Baseline Plasma 25(OH)D Level and up to 28.5m for evaluation of PFS.

  8. 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.

    Measured: Baseline Plasma 25(OH)D Level and up to maximum 56.7 months for evaluation of OS.

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted24 Jan 2012 (estimated)
  2. Study start13 Apr 2012
  3. Primary completion9 Nov 2019
  4. Study completion9 Nov 2019

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Double blind
Who is masked
Participant, Investigator
Enrolment
139 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01516216
Sponsor's protocol ID
11-436
Status last verified
Apr 2022
First submitted
13 Jan 2012
Last updated
26 Apr 2022
Data monitoring committee
Yes

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.

    PubMed 30964527

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing FOLFOX + bevacizumab and Vitamin D in people with Metastatic Colorectal Cancer, run by Dana-Farber Cancer Institute at 18 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 7 inclusion and 23 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 26 Apr 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 18 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 23 Mar 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Median Progression-free Survival (PFS) (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.). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01516216, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Apr 2022.

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