Description:
This phase III trial studies how well vitamin D3 given with standard chemotherapy and
bevacizumab works in treating patients with colorectal cancer that has spread to other parts
of the body. Vitamin D3 helps the body use calcium and phosphorus to make strong bones and
teeth. Drugs used in chemotherapy, such as leucovorin calcium, fluorouracil, oxaliplatin, and
irinotecan hydrochloride, work in different ways to stop the growth of tumor cells by killing
the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy
with monoclonal antibodies, such as bevacizumab, may help the body's immune system attack the
cancer, and may interfere with the ability of tumor cells to grow and spread. Giving vitamin
D3 with chemotherapy and bevacizumab may work better in shrinking or stabilizing colorectal
cancer. It is not yet known whether giving high-dose vitamin D3 in addition to chemotherapy
and bevacizumab would extend patients' time without disease compared to the usual approach
(chemotherapy and bevacizumab).
Title
- Brief Title: Vitamin D3 With Chemotherapy and Bevacizumab in Treating Patients With Advanced or Metastatic Colorectal Cancer
- Official Title: Randomized Double-Blind Phase III Trial of Vitamin D3 Supplementation in Patients With Previously Untreated Metastatic Colorectal Cancer (SOLARIS)
Clinical Trial IDs
- ORG STUDY ID:
A021703
- SECONDARY ID:
NCI-2019-01034
- SECONDARY ID:
U10CA180821
- NCT ID:
NCT04094688
Conditions
- Colorectal Adenocarcinoma
Interventions
Drug | Synonyms | Arms |
---|
Bevacizumab | | Arm I (bevacizumab, chemotherapy, high-dose vitamin D3) |
Oxaliplatin | | Arm I (bevacizumab, chemotherapy, high-dose vitamin D3) |
Leucovorin Calcium | | Arm I (bevacizumab, chemotherapy, high-dose vitamin D3) |
Fluorouracil | | Arm I (bevacizumab, chemotherapy, high-dose vitamin D3) |
Irinotecan Hydrochloride | | Arm I (bevacizumab, chemotherapy, high-dose vitamin D3) |
Irinotecan | | Arm I (bevacizumab, chemotherapy, high-dose vitamin D3) |
Purpose
This phase III trial studies how well vitamin D3 given with standard chemotherapy and
bevacizumab works in treating patients with colorectal cancer that has spread to other parts
of the body. Vitamin D3 helps the body use calcium and phosphorus to make strong bones and
teeth. Drugs used in chemotherapy, such as leucovorin calcium, fluorouracil, oxaliplatin, and
irinotecan hydrochloride, work in different ways to stop the growth of tumor cells by killing
the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy
with monoclonal antibodies, such as bevacizumab, may help the body's immune system attack the
cancer, and may interfere with the ability of tumor cells to grow and spread. Giving vitamin
D3 with chemotherapy and bevacizumab may work better in shrinking or stabilizing colorectal
cancer. It is not yet known whether giving high-dose vitamin D3 in addition to chemotherapy
and bevacizumab would extend patients' time without disease compared to the usual approach
(chemotherapy and bevacizumab).
Detailed Description
PRIMARY OBJECTIVES:
I. To compare the progression-free survival (PFS) of patients receiving high-dose
cholecalciferol (vitamin D3) in combination with standard chemotherapy (leucovorin calcium,
fluorouracil, and oxaliplatin [FOLFOX] or leucovorin calcium, fluorouracil, and irinotecan
hydrochloride [FOLFIRI]) and bevacizumab versus those receiving standard-dose vitamin D3 in
combination with standard chemotherapy and bevacizumab.
SECONDARY OBJECTIVES:
I. To compare the objective response rate (ORR) of patients receiving high-dose vitamin D3 in
combination with standard chemotherapy + bevacizumab versus those receiving standard-dose
vitamin D3 in combination with standard chemotherapy + bevacizumab.
II. To compare the overall survival (OS) of patients receiving high-dose vitamin D3 in
combination with standard chemotherapy + bevacizumab versus those receiving standard-dose
vitamin D3 in combination with standard chemotherapy + bevacizumab.
III. To evaluate and compare the toxicity of adding high-dose vitamin D3 versus standard-dose
vitamin D3 to chemotherapy + bevacizumab.
IV. To assess the influence of diet, body mass index, physical activity, and other lifestyle
habits on PFS among patients with locally advanced/metastatic colorectal cancer.
V. To evaluate the incidence of vitamin D3 deficiency in participants with previously
untreated metastatic colorectal cancer.
VI. To compare the efficacy of high-dose vitamin D3 versus standard-dose vitamin D3 in
subgroups of patients defined by baseline plasma calcifediol (25[OH]D) levels.
VII. To evaluate the prognostic effect of highest-achieved 25(OH)D levels with PFS.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM I: Patients receive bevacizumab intravenously (IV) over 30-90 minutes on day 1 and
oxaliplatin IV over 2 hours on day 1, leucovorin calcium IV over 2 hours on day 1, and
fluorouracil IV on days 1-3 or irinotecan hydrochloride IV on day 1, leucovorin calcium IV
over 90 minutes on day 1, and fluorouracil IV on days 1-3. Patients also receive high-dose
cholecalciferol orally (PO) once daily (QD) on days 1-14. Cycles repeat every 14 days for 5
years in the absence of disease progression or unacceptable toxicity.
ARM II: Patients receive bevacizumab and chemotherapy as in Arm I. Patients also receive
standard-dose cholecalciferol PO QD on days 1-14. Cycles repeat every 14 days for 5 years in
the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed every 6 months for 5 years.
Trial Arms
Name | Type | Description | Interventions |
---|
Arm I (bevacizumab, chemotherapy, high-dose vitamin D3) | Experimental | Patients receive bevacizumab IV over 30-90 minutes on day 1 and oxaliplatin IV over 2 hours on day 1, leucovorin calcium IV over 2 hours on day 1, and fluorouracil IV on days 1-3 or irinotecan hydrochloride IV on day 1, leucovorin calcium IV over 90 minutes on day 1, and fluorouracil IV on days 1-3. Patients also receive high-dose cholecalciferol PO QD on days 1-14. Cycles repeat every 14 days for 5 years in the absence of disease progression or unacceptable toxicity. | - Bevacizumab
- Oxaliplatin
- Leucovorin Calcium
- Fluorouracil
- Irinotecan Hydrochloride
- Irinotecan
|
Arm II (bevacizumab, chemotherapy, standard-dose vitamin D3) | Active Comparator | Patients receive bevacizumab and chemotherapy as in Arm I. Patients also receive standard-dose cholecalciferol PO QD on days 1-14. Cycles repeat every 14 days for 5 years in the absence of disease progression or unacceptable toxicity. | - Bevacizumab
- Oxaliplatin
- Leucovorin Calcium
- Fluorouracil
- Irinotecan Hydrochloride
- Irinotecan
|
Eligibility Criteria
Inclusion Criteria:
- Histologically confirmed advanced/metastatic colorectal adenocarcinoma for which
metastasectomy is not planned.
- No known mismatch repair deficiency (dMMR) or high-frequency microsatellite
instability (MSI-H) disease.
- Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version
(v) 1.1.
- No prior systemic treatment for metastatic disease.
- Patients may have received prior neoadjuvant or adjuvant chemotherapy and/or
chemoradiation. The last course of adjuvant therapy must have been completed > 12
months prior to colorectal cancer recurrence.
- Patients may have received prior standard rectal cancer chemoradiation. Previous
radiation therapy must have been completed >= 4 weeks prior to registration.
- No continuous daily use of vitamin D supplements >= 2,000 IU per day for the 12 months
prior to registration. Patients may have had continuous daily use of vitamin D
supplements >= 2,000 IU per day if total duration < 12 months in the 12 months prior
to registration. Patients may have had continuous daily use of vitamin D supplements <
2,000 IU per day for any duration prior to registration.
- Patients must have completed any major surgery or open biopsy >= 4 weeks prior to
registration and must have completed any minor surgery or core biopsy >= 1 week prior
to registration. (Note: insertion of a vascular access device is not considered major
or minor surgery.) Patients must have recovered from the effects of any surgery (e.g.
wound is healed, no active infection, no drains, etc.) prior to registration.
- Not pregnant and not nursing. This study involves an agent that has known genotoxic,
mutagenic, and teratogenic effects. Therefore, for women of childbearing potential
only, a negative serum or urine pregnancy test done =< 14 days prior to registration
is required.
- Eastern Cooperative Oncology Group (ECOG) performance status: 0-1.
- Absolute neutrophil count >= 1,500/mm^3.
- Platelet count >= 100,000/mm^3.
- Hemoglobin >= 9 g/dL.
- Creatinine =< 1.5 x upper limit of normal (ULN) OR calculated (Calc.) creatinine
clearance (CrCl) > 30 mL/min.
- Calcium =< 1.0 x ULN.
* Corrected for albumin level if albumin not within institutional limits of normal.
- Total bilirubin =< 1.5 x ULN.
* If Gilbert's disease, use direct bilirubin instead of total bilirubin; direct
bilirubin =< 1.5 x ULN if patient to receive FOLFIRI; direct bilirubin =< 3.0 x ULN if
patient to receive leucovorin, infusional fluorouracil, and oxaliplatin (modified
[m]FOLFOX6).
- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x ULN.
* AST/ALT < 5 x ULN if clearly attributable to liver metastases.
- Urine protein to creatinine (UPC) ratio =< 1 mg/dL OR urine protein =< 1+.
* If urine protein is above 1, then 24-hour urine must be ≤ 1 g/24 hours.
- No resectable metastatic disease for which potentially curative metastasectomy is
planned.
- No "currently active" second malignancy other than non-melanoma skin cancers or
cervical carcinoma in situ. Patients are not considered to have a "currently active"
malignancy if they have completed therapy and have been free of disease for >= 3
years.
- No significant history of bleeding events or bleeding diathesis =< 6 months of
registration unless the source of bleeding has been resected.
- No history of arterial thrombotic events, including, but not limited to, transient
ischemic attack, cerebrovascular accident, unstable angina, angina requiring surgical
or medical intervention, or myocardial infarction =< 6 months of registration.
- No history of clinically significant peripheral artery disease =< 6 months of
registration.
- No history of uncontrolled congestive heart failure defined as New York Heart
Association (NYHA) class III or greater.
- No history of gastrointestinal (GI) perforation =< 12 months of registration except
for GI perforation related to a primary colorectal tumor that has since been fully
resected.
- No history of malabsorption, uncontrolled vomiting or diarrhea, or any other disease
significantly affecting GI function that could interfere with the absorption of oral
agents.
- No history of allergic reaction attributed to compounds of similar chemical or
biological composition to the study agents.
- No uncontrolled hypertension (defined as blood pressure [BP] > 160/90).
- No serious or non-healing wound, ulcer, or bone fracture.
- No uncontrolled intercurrent illness, including, but not limited to, psychiatric
illness/social situations that, in the opinion of the treating physician, may increase
the risks associated with participation or treatment on the study or may interfere
with the conduct of the study or interpretation of the study results.
- Patients positive for human immunodeficiency virus (HIV) are eligible only if they
meet all of the following:
- On effective anti-retroviral therapy
- Undetectable HIV viral load by standard clinical assay =< 6 months of
registration.
- No known pre-existing hypercalcemia =< 6 months of registration.
- No known active hyperparathyroid disease or other serious disturbance of calcium
metabolism =< 5 years of registration.
- No predisposing colonic or small bowel disorders in which symptoms are uncontrolled as
indicated by > 3 watery or soft stools daily in patients without a colostomy or
ileostomy. Patients with a colostomy or ileostomy are allowed per treating physician
discretion.
- No symptomatic genitourinary stones =< 12 months of registration.
- Patients with treated brain metastases are eligible if follow-up imaging after central
nervous system (CNS)-directed therapy shows no evidence of progression >= 28 days
prior to registration.
- Patients with new or progressive brain metastases (active brain metastases) or
leptomeningeal disease are eligible if the treating physician determines that
immediate CNS-specific treatment is not required and is unlikely to be required during
the first cycle of protocol-specified therapy after registration.
- No uncontrolled seizure disorders.
- No grade >=2 peripheral neuropathy, neurosensory toxicity, or neuromotor toxicity per
Common Terminology Criteria for Adverse Events (CTCAE) v5.0 regardless of causality.
- Patients must be able to swallow oral formulations of the agent.
- Concurrent use of supplemental calcium and/or vitamin D is not permitted. Patients
must discontinue the supplement(s) at least 7 days prior to registration.
- Concurrent use of thiazide diuretics (e.g. hydrochlorothiazide) is not permitted.
Patients must discontinue the drug(s) or switch to an alternative anti-hypertensive
agent at least 7 days prior to registration.
- Chronic concomitant treatment with oral corticosteroids, lithium, phenytoin,
quinidine, isoniazid, and/or rifampin are not permitted. Patients must discontinue the
agent(s) at least 7 days prior to registration. Short-term use of corticosteroids as
antiemetic therapy is acceptable.
- Concurrent use of other anti-cancer therapy including chemotherapy, targeted, and/or
biological agents is not permitted.
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Progression-free survival (PFS) |
Time Frame: | From randomization to the first documentation of disease progression or death, assessed up to 5 years |
Safety Issue: | |
Description: | Per Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1. Progression-free survival (PFS) will be compared between treatment arms using the un-stratified log-rank test at one-sided level of 0.05 and the p-value will be used for decision making. The hazard ratio (HR) for PFS will be estimated using a Cox proportional hazards model and the 95% confidence interval (CI) for the HR will be provided. Results from a stratified analysis will also be provided. Kaplan-Meier methodology will be used to estimate the median PFS for each treatment arm, and Kaplan-Meier curves will be produced. Brookmeyer-Crowley methodology will be used to construct the 95% CI for the median PFS for each treatment arm. All randomized patients regardless of any treatment received will be included in the analysis. Patients will be assigned to the treatment group they were randomized to regardless of actual treatment received. |
Secondary Outcome Measures
Measure: | Objective response |
Time Frame: | Up to 5 years |
Safety Issue: | |
Description: | Per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Will be estimated using objective response rate (ORR) where ORR is defined as the number of evaluable patients achieving a response (partial response or complete response per RECIST v1.1) during treatment with study therapy divided by the total number of evaluable patients. Rates of response will be compared across arms using a Chi-Square test for proportion. Point estimates will be generated for objective response rates within each arm along with 95% binomial confidence intervals. All randomized patients regardless of any treatment received will be included in the analysis. Patients will be assigned to the treatment group they were randomized to regardless of actual treatment received. |
Measure: | Overall survival (OS) |
Time Frame: | From randomization to death due to any cause, assessed up to 5 years |
Safety Issue: | |
Description: | The distribution of survival time will be estimated using the method of Kaplan-Meier. Overall survival (OS) will be compared between treatment arms using the log-rank test. OS medians, survival rates at 3 years, and hazard ratio (HR) will be estimated along with 95% confidence intervals. |
Measure: | Incidence of adverse events |
Time Frame: | Up to 5 years |
Safety Issue: | |
Description: | As per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Toxicity is defined as adverse events that are classified as possibly, probably, or definitely related to study treatment. Toxicities will be evaluated via the ordinal CTCAE standard toxicity grading. Overall toxicity incidence as well as toxicity profiles by treatment arm will be explored and summarized. Frequency distributions, graphical techniques, and other descriptive measures will form the basis of the analysis. |
Measure: | Physical activity (PA) and progression-free survival (PFS) |
Time Frame: | Up to 5 years |
Safety Issue: | |
Description: | Progression-free survival (PFS) of patients receiving high-dose vitamin D3 versus (vs.) patients receiving standard-dose vitamin D3 will be compared in subgroups of physical activity (PA) levels. The levels will be defined as low PA (< 9 metabolic-equivalent task [MET]-hours/week) vs. high PA (>= 9 MET-hours/week). The distribution of PFS time will be estimated using the method of Kaplan-Meier within each subgroup and arm combination. PFS will be compared between treatment arms using the non-stratified log-rank test in each subgroup of PA levels. PFS medians, survival rates at 3 years, and hazard ratio (HR) will be estimated along with 95% confidence intervals within each subgroup and arm combination. Interaction between PA subgroups and treatment arms will be tested using likelihood ratio test. |
Measure: | Incidence of vitamin D3 deficiency |
Time Frame: | At baseline |
Safety Issue: | |
Description: | The baseline incidence of vitamin D3 deficiency will be defined as the number of evaluable vitamin D3 deficient patients divided by the total number of evaluable patients. The population of evaluable patients for this analysis will be all patients whose calcifediol (25(OH)D) level was successfully measured at baseline. Vitamin D3 deficiency is defined as 25(OH)D level < 20 ng/mL. Incidence rates of vitamin D3 deficiency will be compared across arms using a Chi-Square test for proportion. Point estimates will be generated for vitamin D3 deficiency rates within each arm along with 95% confidence intervals. |
Measure: | 25(OH)D levels |
Time Frame: | At baseline |
Safety Issue: | |
Description: | Progression-free survival (PFS) of patients receiving high-dose vitamin D3 vs. patients receiving standard-dose vitamin D3 will be compared in subgroups of baseline 25(OH)D levels. The levels will be defined as deficient (< 20 ng/mL) vs. other (>= 20 ng/mL). The distribution of PFS time will be estimated using the method of Kaplan-Meier within each subgroup and arm combination. PFS will be compared between treatment arms using the non-stratified log-rank test in each subgroup of baseline 25(OH)D levels. PFS medians, survival rates at 3 years, and hazard ratio (HR) will be estimated along with 95% confidence intervals within each subgroup and arm combination. Interaction between baseline 25(OH)D level subgroups and treatment arms will be tested using likelihood ratio test. |
Measure: | Prognostic effect of highest achieved 25(OH)D |
Time Frame: | Up to 5 years |
Safety Issue: | |
Description: | Progression-free survival (PFS) of patients will be compared in subgroups of highest achieved 25(OH)D levels. The levels will be defined by quartile of highest-achieved level among patients who have both baseline and at least one on-treatment 25(OH)D sample result. The distribution of PFS time will be estimated using the method of Kaplan-Meier within each subgroup. PFS will be compared across quartiles using the non-stratified log-rank test. PFS medians, survival rates at 3 years, and hazard ratio (HR) will be estimated along with 95% confidence intervals. Baseline 25(OH)D will be entered into the Cox model as a covariate. |
Details
Phase: | Phase 3 |
Primary Purpose: | Interventional |
Overall Status: | Recruiting |
Lead Sponsor: | Alliance for Clinical Trials in Oncology |
Last Updated
August 17, 2021