Metastatic Colorectal Cancer
Conditions
Keywords
previously untreated
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.
Interventions
DRUGFOLFOX + bevacizumab
DIETARY_SUPPLEMENTVitamin D
Sponsors
Dana-Farber Cancer Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Median Progression-free Survival (PFS) | 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. | 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
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate | Disease was evaluated every 4 cycles on treatment. Median (maximum) treatment duration was 7.3 (28.5) months. | 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 | 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. | 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 | 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. |
| Median Overall Survival (OS) | 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. | 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. |
| Plasma 25-hydroxyvitamin D Levels | 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. | 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 | Baseline Plasma 25(OH)D Level and up to 28.5m for evaluation of 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 | Baseline Plasma 25(OH)D Level and up to maximum 56.7 months for evaluation of 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. |
| Vitamin D Sufficiency Rate | 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. | 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. |
Countries
United States
Participant flow
Recruitment details
Participants enrolled from April 2012 through November 2016.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 70 |
| Chemotherapy + Higher Dose Vitamin D 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. | 69 |
| Total | 139 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 4 |
| Overall Study | Death | 1 | 1 |
| Overall Study | Disease Progression | 38 | 34 |
| Overall Study | Intercurrent Illness | 1 | 0 |
| Overall Study | Nonadherence | 2 | 3 |
| Overall Study | Physician Decision | 6 | 3 |
| Overall Study | Potentially Curative Resection | 6 | 12 |
| Overall Study | Prolonged Treatment Delay | 5 | 1 |
| Overall Study | Withdrawal by Subject | 9 | 11 |
Baseline characteristics
| Characteristic | Total | Chemotherapy + Higher Dose Vitamin D | Chemotherapy + Standard Dose Vitamin D |
|---|---|---|---|
| Age, Continuous | 55 Years | 54 Years | 56 Years |
| ECOG performance status 0 | 69 Participants | 29 Participants | 40 Participants |
| ECOG performance status 1 | 70 Participants | 40 Participants | 30 Participants |
| Primary Tumor Location Left colon (splenic flexure, descending colon, sigmoid, rectosigmoid, rectum) | 92 Participants | 49 Participants | 43 Participants |
| Primary Tumor Location Right colon (cecum, ascending colon, hepatic flexure) | 35 Participants | 16 Participants | 19 Participants |
| Primary Tumor Location Transverse colon | 12 Participants | 4 Participants | 8 Participants |
| Primary tumor resected | 47 Participants | 26 Participants | 21 Participants |
| Race/Ethnicity, Customized >1 race | 3 Participants | 2 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Black | 10 Participants | 4 Participants | 6 Participants |
| Race/Ethnicity, Customized Other | 18 Participants | 11 Participants | 7 Participants |
| Race/Ethnicity, Customized White | 107 Participants | 52 Participants | 55 Participants |
| Received prior adjuvant therapy | 11 Participants | 6 Participants | 5 Participants |
| Region of Enrollment United States | 139 Participants | 69 Participants | 70 Participants |
| Sex: Female, Male Female | 60 Participants | 28 Participants | 32 Participants |
| Sex: Female, Male Male | 79 Participants | 41 Participants | 38 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 54 / 67 | 45 / 68 |
| other Total, other adverse events | 65 / 67 | 67 / 68 |
| serious Total, serious adverse events | 39 / 67 | 47 / 68 |
Outcome results
Primary
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.
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.
Population: the analysis population is comprised of all randomized patients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Chemotherapy + Standard Dose Vitamin D | Median Progression-free Survival (PFS) | 11 Months |
| Chemotherapy + Higher Dose Vitamin D | Median Progression-free Survival (PFS) | 13 Months |
p-value: 0.07Log Rank
Secondary
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.
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.
Population: The analysis population is comprised of the subset evaluable for adverse events.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Chemotherapy + Standard Dose Vitamin D | Grade 3-5 Treatment-Related Neutropenia Toxicity Rate | 31 percentage of participants |
| Chemotherapy + Higher Dose Vitamin D | Grade 3-5 Treatment-Related Neutropenia Toxicity Rate | 35 percentage of participants |
Secondary
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.
Time frame: Baseline Plasma 25(OH)D Level and up to 28.5m for evaluation of PFS.
Population: The analysis population is comprised of all participants with evaluable Plasma 25(OH)D Level samples at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Chemotherapy + Standard Dose Vitamin D | Hazard Ratio Between Baseline Plasma 25(OH)D Level and PFS | 1.00 hazard ratio |
p-value: 0.9801Chi-squared
Secondary
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.
Time frame: Baseline Plasma 25(OH)D Level and up to maximum 56.7 months for evaluation of OS.
Population: The analysis population is comprised of all participants with evaluable Plasma 25(OH)D Level samples at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Chemotherapy + Standard Dose Vitamin D | Hazard Ratio Between Baseline Plasma 25(OH)D Levels and OS | 0.995 hazard ratio |
p-value: 0.7444Chi-squared
Secondary
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.
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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Chemotherapy + Standard Dose Vitamin D | Median Overall Survival (OS) | 24.3 Months |
| Chemotherapy + Higher Dose Vitamin D | Median Overall Survival (OS) | 24.3 Months |
p-value: 0.43Log Rank
Secondary
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.
Time frame: Baseline
Population: The analysis population is comprised of the subset with evaluable plasma samples at baseline.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Chemotherapy + Standard Dose Vitamin D | Number of Participants With Vitamin D Deficiency at Baseline | 39 Participants |
| Chemotherapy + Higher Dose Vitamin D | Number of Participants With Vitamin D Deficiency at Baseline | 48 Participants |
p-value: 0.68Chi-squared
Secondary
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.
Time frame: Disease was evaluated every 4 cycles on treatment. Median (maximum) treatment duration was 7.3 (28.5) months.
Population: The analysis population is comprised of the response evaluable subset.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Chemotherapy + Standard Dose Vitamin D | Objective Response Rate | 63 percentage of participants |
| Chemotherapy + Higher Dose Vitamin D | Objective Response Rate | 58 percentage of participants |
p-value: 0.27Chi-squared
Secondary
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.
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.
Population: The analysis population is comprised of the subset with evaluable plasma samples at each collection timepoint.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Chemotherapy + Standard Dose Vitamin D | Plasma 25-hydroxyvitamin D Levels | Baseline plasma 25(OH)D levels | 18.7 ng/mL |
| Chemotherapy + Standard Dose Vitamin D | Plasma 25-hydroxyvitamin D Levels | First restaging plasma 25(OH)D levels | 18.7 ng/mL |
| Chemotherapy + Standard Dose Vitamin D | Plasma 25-hydroxyvitamin D Levels | Second restaging plasma 25(OH)D levels | 18.5 ng/mL |
| Chemotherapy + Standard Dose Vitamin D | Plasma 25-hydroxyvitamin D Levels | At treatment discontinuation plasma 25(OH)D levels | 18.7 ng/mL |
| Chemotherapy + Higher Dose Vitamin D | Plasma 25-hydroxyvitamin D Levels | At treatment discontinuation plasma 25(OH)D levels | 34.9 ng/mL |
| Chemotherapy + Higher Dose Vitamin D | Plasma 25-hydroxyvitamin D Levels | Baseline plasma 25(OH)D levels | 16.1 ng/mL |
| Chemotherapy + Higher Dose Vitamin D | Plasma 25-hydroxyvitamin D Levels | Second restaging plasma 25(OH)D levels | 35.2 ng/mL |
| Chemotherapy + Higher Dose Vitamin D | Plasma 25-hydroxyvitamin D Levels | First restaging plasma 25(OH)D levels | 32 ng/mL |
Secondary
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.
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.
Population: The analysis population is comprised of the subset with evaluable plasma samples at each collection timepoint.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Chemotherapy + Standard Dose Vitamin D | Vitamin D Sufficiency Rate | 9.8 percentage of participants |
| Chemotherapy + Higher Dose Vitamin D | Vitamin D Sufficiency Rate | 71.4 percentage of participants |