This randomized, open-label, multicenter study will evaluate the efficacy and safety of folinic acid (leucovorin), 5-fluorouracil (5-FU), oxaliplatin, and irinotecan (FOLFOXIRI) / bevacizumab regimens (concurrent and sequential) versus folinic acid (leucovorin), 5-fluorouracil, and oxaliplatin (FOLFOX) / bevacizumab in first-line in participants with metastatic colorectal cancer. Participants will be randomized to receive bevacizumab 5 milligrams per kilogram (mg/kg) intravenously every 2 weeks with either concurrent or sequential FOLFOXIRI or with FOLFOX for 4 to 6 months of induction therapy, followed by maintenance therapy with bevacizumab plus either leucovorin/5-fluorouracil or capecitabine until disease progression occurs. After disease progression, participants will receive treatment with a fluoropyrimidine-based chemotherapy plus bevacizumab.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
280
Participants in Arm A will receive 3200 milligrams per square meter (mg/m\^2) by 48-hour continuous intravenous (IV) infusion every 2 weeks, during the 4-6 months' induction followed by maintenance therapy including bolus dose of 400 mg/m\^2, followed by a 46-hour continuous infusion (2400 mg/m\^2) every 2 weeks per investigator's discretion. Participants in Arm B and C will receive a bolus dose of 400 mg/m\^2, followed by a 46-hour continuous infusion (2400 mg/m\^2) every 2 weeks during the 4-6 months of induction and maintenance per investigator's discretion.
Participants will receive 5 mg/kg IV every 2 weeks during the first 4-6 months induction phase, followed by 5 mg/kg IV every 2 weeks or 7.5 mg/kg IV every 3 weeks during maintenance therapy, and 2.5 mg/kg per week reinduction after disease progression.
Participants will receive 1000 or 850 mg/kg orally twice daily as per investigator's discretion on Day 1 to 14, repeated every 3 weeks in maintenance phase.
Participants will receive IV infusion of 165 mg/m\^2 over 1 hour every 2 weeks (Arm A) or IV infusion of 180 mg/m\^2 over 1 hour in 2 x 2 weeks cycles alternating months (in Arm B), during 4-6 months induction phase.
Participants will receive IV infusion of 200 mg/m\^² (Arm A) or 400 mg/m\^2 (Arm B or C) over 2 hours every 2 weeks, during 4-6 months induction phase followed by IV infusion of 400 mg/m\^2 in the maintenance therapy.
Participants will receive 85 mg/m\^2 over 2 hours as IV infusion every 2 weeks (Arm A, C ) or 2 x 2 week cycles alternating months (Arm B), during 4-6 months induction phase .
University of South Alabama; Mitchell Cancer Institute
Mobile, Alabama, United States
Long Beach Memorial Medical Center; Oncology
Long Beach, California, United States
LAC-USC Medical Center
Los Angeles, California, United States
USC Norris Cancer Center
Los Angeles, California, United States
Pacific Cancer Care - Monterey
Monterey, California, United States
Percentage of Participants With Overall Response During First-Line Therapy (ORR1)
ORR1 was the percentage of participants with complete response (CR) or partial response (PR) during first-line therapy as assessed by investigator according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v.1.1). CR was defined as disappearance of all extranodal target lesions and all pathological lymph nodes had to have decreased to \<10 millimeter (mm) in short axis. PR was defined as at least a 30% decrease in the sum of longest diameters of target lesions, taking as reference the baseline sum diameters. ORR1 = CR + PR
Time frame: Randomization up to disease progression during first-line therapy or death, whichever occurs first (up to approximately 3 years)
Progression-Free Survival During First-Line Therapy (PFS1)
PFS1 was defined as time from randomization to the first occurrence of disease progression during first-line therapy, as assessed by the Investigator using RECIST v1.1, or death from any cause, whichever occurs first. Disease progression was defined as sum of longest diameters increased by at least 20% from the smallest value on study. The sum of longest diameters must also demonstrate an absolute increase of at least 5 mm.
Time frame: Randomization up to disease progression during first-line therapy or death, whichever occurs first (up to approximately 3 years)
Time to PFS2
Time to PFS2 was defined as time from randomization to the first occurrence of disease progression after reinduction of second-line therapy, as assessed by the Investigator using RECIST v1.1, or death from any cause, whichever occurs first. Disease progression was defined as sum of longest diameters increased by at least 20% from the smallest value on study. The sum of longest diameters must also demonstrate an absolute increase of at least 5mm.
Time frame: Randomization up to disease progression during second-line therapy or death, whichever occurs first (up to approximately 3 years)
Overall Survival (OS)
OS was defined as the time from the date of randomization to the date of death from any cause.
Time frame: Randomization until death due to any cause (up to approximately 3 years)
Proportion of Participants Who Underwent Liver Metastases Resections
Reported here is the proportion of participants who underwent liver metastases resections calculated as follows: number of participants who underwent liver metastases resections divided by total number of participants in each arm.
Time frame: Randomization up to approximately 3 years
Proportion of Participants Considered by the Investigator to be Unresectable on Study Enrollment Who Subsequently Underwent Attempted Curative Resections of Metastases
The proportion of participants considered by the investigator to be unresectable at study enrollment who subsequently underwent attempted curative resections of metastases was calculated as follows: number of participants considered by the investigator to be unresectable at study enrollment who subsequently underwent attempted curative resections of metastases divided by total number of participants in each arm. This outcome represents a measure of the rate of conversion from unresectable to resectable disease.
Time frame: Randomization up to approximately 3 years
Percentage of Participants With Adverse Events
An adverse event is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.
Time frame: Randomization up to approximately 3 years
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Sacramento Center for Hematolo
Sacramento, California, United States
Pacific Cancer Care
Salinas, California, United States
Kaiser Permanente - Franklin
Denver, Colorado, United States
Yale Cancer Center
New Haven, Connecticut, United States
Sibley Memorial Hospital
Washington D.C., District of Columbia, United States
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