Clovis, California 93611

  • Colorectal Adenocarcinoma

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).


Study summary:

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.


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.


Study is Available At:


Original ID:

A021703


NCT ID:

NCT04094688


Secondary ID:

NCI-2019-01034


Study Acronym:

SOLARIS


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)


Overall Status:

Recruiting


Study Phase:

Phase 3


Genders:

N/A


Minimum Age:

18 Years


Maximum Age:

N/A


Quick Facts

Healthy Volunteers
Oversight Has DMC
Study Is FDA Regulated
Study Is Section 801
Has Expanded Access

Study Source:

Alliance for Clinical Trials in Oncology


Oversight Authority:

There was an error processing this request


Reasons Why Stopped:


Study Type:

Interventional


Study Design:


Number of Arms:

2


Number of Groups:

0


Total Enrollment:

400


Enrollment Type:

Anticipated


Overall Contact Information

Official Name:Kimmie Ng, MD, MPH
Study Chair
Dana-Farber Cancer Institute
Primary Contact:Kimmie Ng, MD, MPH
617-632-4150
kimmie_ng@dfci.harvard.edu

Study Dates

Start Date:September 30, 2019
Completion Date:July 2024
Completion Type:Anticipated
Primary Completion Date:January 1, 2024
Primary Completion Type:Anticipated
Verification Date:September 2022
Last Changed Date:September 25, 2022
First Received Date:September 17, 2019

Study Outcomes

Outcome Type:Primary Outcome
Measure:Progression-free survival (PFS)
Time Frame:From randomization to the first documentation of disease progression or death, assessed up to 5 year
Safety Issues:False
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 m
Outcome Type:Secondary Outcome
Measure:Objective response
Time Frame:Up to 5 years
Safety Issues:False
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) dur
Outcome Type:Secondary Outcome
Measure:Overall survival (OS)
Time Frame:From randomization to death due to any cause, assessed up to 5 years
Safety Issues:False
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 alo
Outcome Type:Secondary Outcome
Measure:Incidence of adverse events
Time Frame:Up to 5 years
Safety Issues:False
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 evalua
Outcome Type:Secondary Outcome
Measure:Physical activity (PA) and progression-free survival (PFS)
Time Frame:Up to 5 years
Safety Issues:False
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-equi
Outcome Type:Secondary Outcome
Measure:Incidence of vitamin D3 deficiency
Time Frame:At baseline
Safety Issues:False
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 c
Outcome Type:Secondary Outcome
Measure:25(OH)D levels
Time Frame:At baseline
Safety Issues:False
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 (>= 2
Outcome Type:Secondary Outcome
Measure:Prognostic effect of highest achieved 25(OH)D
Time Frame:Up to 5 years
Safety Issues:False
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 samp

Study Interventions

Intervention Type:Drug
Name:Bevacizumab
Description:Given IV
Arm Name:Arm I (bevacizumab, chemotherapy, high-dose vitami
Intervention Type:Drug
Name:Oxaliplatin
Description:Given IV
Arm Name:Arm I (bevacizumab, chemotherapy, high-dose vitami
Intervention Type:Drug
Name:Leucovorin Calcium
Description:Given IV
Arm Name:Arm I (bevacizumab, chemotherapy, high-dose vitami
Intervention Type:Drug
Name:Fluorouracil
Description:Given IV
Arm Name:Arm I (bevacizumab, chemotherapy, high-dose vitami
Intervention Type:Drug
Name:Irinotecan Hydrochloride
Description:Given IV
Arm Name:Arm I (bevacizumab, chemotherapy, high-dose vitami
Intervention Type:Drug
Name:Irinotecan
Description:Given IV
Arm Name:Arm I (bevacizumab, chemotherapy, high-dose vitami
Intervention Type:Dietary Supplement
Name:Cholecalciferol
Description:Given PO
Arm Name:Arm I (bevacizumab, chemotherapy, high-dose vitami
Other Name:Vitamin D3
Intervention Type:Other
Name:Quality-of-Life Assessment
Description:Ancillary studies
Arm Name:Arm I (bevacizumab, chemotherapy, high-dose vitami
Intervention Type:Other
Name:Questionnaire Administration
Description:Ancillary studies
Arm Name:Arm I (bevacizumab, chemotherapy, high-dose vitami

Study Arms

Study Arm Type:Experimental
Arm Name:Arm I (bevacizumab, chemotherapy, high-dose vitamin D3)
Description: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.
Study Arm Type:Active Comparator
Arm Name:Arm II (bevacizumab, chemotherapy, standard-dose vitamin D3)
Description: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.

Study Agencies

Agency Class:Other
Agency Type:Lead Sponsor
Agency Name:Alliance for Clinical Trials in Oncology
Agency Class:NIH
Agency Type:Collaborator
Agency Name:National Cancer Institute (NCI)

Sample and Retention Information

There are no available Sample and Retention Information

Study References

There are no available Study References

Data Source: ClinicalTrials.gov

Date Processed: February 02, 2023

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