Sequential and Concurrent FOLFOXIRI/Bevacizumab Regimens Versus FOLFOX/Bevacizumab in First-Line Metastatic Colorectal Cancer
- Conditions
- Colorectal Neoplasms
- Interventions
- Registration Number
- NCT01765582
- Lead Sponsor
- Hoffmann-La Roche
- Brief Summary
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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 280
- Histologically confirmed colorectal cancer with at least one measurable metastatic lesion by RECIST v 1.1, that is considered unresectable at baseline
- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 if age less than (<) 71 years; ECOG status of 0 if age 71 to 75 years
- Adequate hematological, renal and liver function
- Participants with treated brain metastases are eligible for study participation; participants may not receive ongoing treatment with steroids at screening, anticonvulsants (at stable dose) are allowed
- Females of childbearing potential and males must agree to use effective contraception as defined by protocol during the treatment period and for at least 6 months after the last dose of study drug
- Any prior treatment for metastatic colorectal cancer, except for use of palliative radiosensitizers
- Adjuvant chemotherapy for colorectal cancer completed < 12 months prior to study consent
- Sensory peripheral neuropathy greater than or equal to (>/=) Grade 2
- Evidence of Gilbert's Syndrome or homozygosity for the Uridine 5-diphospho-glucuronosyltransferase (UGT) 1A1*28 allele
- Positive for human immunodeficiency virus (HIV) infection
- Malignancies other than metastatic colorectal cancer within 5 years prior to randomization, except for adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer treated surgically with curative intent, and ductal carcinoma in situ treated surgically with curative intent
- Radiotherapy to any site for any reason within 28 days prior to randomization, except for palliative radiotherapy to bone lesions within 14 days prior to randomization
- Clinically significant third-space fluid collections (e.g. ascites or pleural effusion) that cannot be controlled by drainage or other procedures prior to study entry
- Treatment with any other investigational agent, or participation in another investigational drug trial within 28 days prior to randomization
- Any disease or condition or laboratory finding giving reasonable suspicion of disease or condition that contraindicates the use of bevacizumab or puts the participant at high risk for treatment-related complications
- Inadequately controlled hypertension
- Clinically significant (that is [i.e.] active) cardiovascular disease (For example [e.g.] cerebrovascular accident or myocardial infarction within 6 months prior to randomization), unstable angina, congestive heart failure (New York Heart Association Class >/= II) or serious cardiac arrhythmia that is uncontrolled by medication or may interfere with the administration of the study treatment
- Known hypersensitivity to bevacizumab or any of its excipients or any other study drug
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Arm A: Concurrent FOLFOXIRI + Bevacizumab 5-fluorouracil Participants will receive concurrent FOLFOXIRI along with 5 mg/kg of bevacizumab with treatment cycle of 2 weeks during first 4 month induction phase (plus optional 2 months of induction for participants who exhibit good response and tolerate the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) will be administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion. Arm A: Concurrent FOLFOXIRI + Bevacizumab bevacizumab Participants will receive concurrent FOLFOXIRI along with 5 mg/kg of bevacizumab with treatment cycle of 2 weeks during first 4 month induction phase (plus optional 2 months of induction for participants who exhibit good response and tolerate the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) will be administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion. Arm A: Concurrent FOLFOXIRI + Bevacizumab capecitabine Participants will receive concurrent FOLFOXIRI along with 5 mg/kg of bevacizumab with treatment cycle of 2 weeks during first 4 month induction phase (plus optional 2 months of induction for participants who exhibit good response and tolerate the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) will be administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion. Arm A: Concurrent FOLFOXIRI + Bevacizumab irinotecan Participants will receive concurrent FOLFOXIRI along with 5 mg/kg of bevacizumab with treatment cycle of 2 weeks during first 4 month induction phase (plus optional 2 months of induction for participants who exhibit good response and tolerate the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) will be administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion. Arm A: Concurrent FOLFOXIRI + Bevacizumab folinic acid Participants will receive concurrent FOLFOXIRI along with 5 mg/kg of bevacizumab with treatment cycle of 2 weeks during first 4 month induction phase (plus optional 2 months of induction for participants who exhibit good response and tolerate the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) will be administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion. Arm A: Concurrent FOLFOXIRI + Bevacizumab oxaliplatin Participants will receive concurrent FOLFOXIRI along with 5 mg/kg of bevacizumab with treatment cycle of 2 weeks during first 4 month induction phase (plus optional 2 months of induction for participants who exhibit good response and tolerate the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) will be administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion. Arm B: Sequential FOLFOXIRI + Bevacizumab 5-fluorouracil Participants will receive alternating 4-week administrations of FOLFOX/bevacizumab and folinic acid (leucovorin), 5-FU, and irinotecan (FOLFIRI) /Bevacizumab with a treatment cycle of 2 weeks during first 4-month induction phase (plus optional 2 months of induction for participants who exhibit good response and tolerate the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) will be administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion. Arm B: Sequential FOLFOXIRI + Bevacizumab bevacizumab Participants will receive alternating 4-week administrations of FOLFOX/bevacizumab and folinic acid (leucovorin), 5-FU, and irinotecan (FOLFIRI) /Bevacizumab with a treatment cycle of 2 weeks during first 4-month induction phase (plus optional 2 months of induction for participants who exhibit good response and tolerate the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) will be administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion. Arm B: Sequential FOLFOXIRI + Bevacizumab capecitabine Participants will receive alternating 4-week administrations of FOLFOX/bevacizumab and folinic acid (leucovorin), 5-FU, and irinotecan (FOLFIRI) /Bevacizumab with a treatment cycle of 2 weeks during first 4-month induction phase (plus optional 2 months of induction for participants who exhibit good response and tolerate the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) will be administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion. Arm B: Sequential FOLFOXIRI + Bevacizumab irinotecan Participants will receive alternating 4-week administrations of FOLFOX/bevacizumab and folinic acid (leucovorin), 5-FU, and irinotecan (FOLFIRI) /Bevacizumab with a treatment cycle of 2 weeks during first 4-month induction phase (plus optional 2 months of induction for participants who exhibit good response and tolerate the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) will be administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion. Arm B: Sequential FOLFOXIRI + Bevacizumab folinic acid Participants will receive alternating 4-week administrations of FOLFOX/bevacizumab and folinic acid (leucovorin), 5-FU, and irinotecan (FOLFIRI) /Bevacizumab with a treatment cycle of 2 weeks during first 4-month induction phase (plus optional 2 months of induction for participants who exhibit good response and tolerate the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) will be administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion. Arm C: FOLFOX + Bevacizumab bevacizumab Participants will receive FOLFOX along with 5 mg/kg of bevacizumab with treatment cycle of 2 weeks during first 4-month induction phase (plus optional 2 months of induction for participants who exhibit good response and tolerate the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) will be administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion. Arm B: Sequential FOLFOXIRI + Bevacizumab oxaliplatin Participants will receive alternating 4-week administrations of FOLFOX/bevacizumab and folinic acid (leucovorin), 5-FU, and irinotecan (FOLFIRI) /Bevacizumab with a treatment cycle of 2 weeks during first 4-month induction phase (plus optional 2 months of induction for participants who exhibit good response and tolerate the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) will be administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion. Arm C: FOLFOX + Bevacizumab 5-fluorouracil Participants will receive FOLFOX along with 5 mg/kg of bevacizumab with treatment cycle of 2 weeks during first 4-month induction phase (plus optional 2 months of induction for participants who exhibit good response and tolerate the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) will be administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion. Arm C: FOLFOX + Bevacizumab capecitabine Participants will receive FOLFOX along with 5 mg/kg of bevacizumab with treatment cycle of 2 weeks during first 4-month induction phase (plus optional 2 months of induction for participants who exhibit good response and tolerate the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) will be administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion. Arm C: FOLFOX + Bevacizumab folinic acid Participants will receive FOLFOX along with 5 mg/kg of bevacizumab with treatment cycle of 2 weeks during first 4-month induction phase (plus optional 2 months of induction for participants who exhibit good response and tolerate the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) will be administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion. Arm C: FOLFOX + Bevacizumab oxaliplatin Participants will receive FOLFOX along with 5 mg/kg of bevacizumab with treatment cycle of 2 weeks during first 4-month induction phase (plus optional 2 months of induction for participants who exhibit good response and tolerate the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) will be administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.
- Primary Outcome Measures
Name Time Method Percentage of Participants With Overall Response During First-Line Therapy (ORR1) Randomization up to disease progression during first-line therapy or death, whichever occurs first (up to approximately 3 years) 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
Progression-Free Survival During First-Line Therapy (PFS1) Randomization up to disease progression during first-line therapy or death, whichever occurs first (up to approximately 3 years) 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.
- Secondary Outcome Measures
Name Time Method Time to PFS2 Randomization up to disease progression during second-line therapy or death, whichever occurs first (up to approximately 3 years) 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.
Overall Survival (OS) Randomization until death due to any cause (up to approximately 3 years) OS was defined as the time from the date of randomization to the date of death from any cause.
Proportion of Participants Who Underwent Liver Metastases Resections Randomization up to approximately 3 years 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.
Proportion of Participants Considered by the Investigator to be Unresectable on Study Enrollment Who Subsequently Underwent Attempted Curative Resections of Metastases Randomization up to approximately 3 years 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.
Percentage of Participants With Adverse Events Randomization up to approximately 3 years 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.
Trial Locations
- Locations (45)
USC Norris Cancer Center
🇺🇸Los Angeles, California, United States
Johns Hopkins Univ; Bunting Blaustein Cancer Center
🇺🇸Baltimore, Maryland, United States
Tufts Medical Center
🇺🇸Boston, Massachusetts, United States
Seattle Cancer Care Alliance
🇺🇸Seattle, Washington, United States
Cheyenne Oncology & Hematology Associates
🇺🇸Cheyenne, Wyoming, United States
Sibley Memorial Hospital
🇺🇸Washington, D.C., District of Columbia, United States
University Cancer & Blood Center, LLC
🇺🇸Athens, Georgia, United States
Medical Oncology Associates
🇺🇸Spokane, Washington, United States
Edward Cancer Center Plainfield
🇺🇸Plainfield, Illinois, United States
Florida Cancer Specialists - Fort Myers (Colonial Center Dr)
🇺🇸Fort Myers, Florida, United States
Summit Cancer Care PC
🇺🇸Savannah, Georgia, United States
Sacramento Center for Hematolo
🇺🇸Sacramento, California, United States
Dartmouth Hitchcock Med Center
🇺🇸Lebanon, New Hampshire, United States
Milton S. Hershey Medical Center; Penn State Cancer Inst.
🇺🇸Hershey, Pennsylvania, United States
Yale Cancer Center
🇺🇸New Haven, Connecticut, United States
Pacific Cancer Care - Monterey
🇺🇸Monterey, California, United States
Oncology Hematology Care Inc
🇺🇸Cincinnati, Ohio, United States
University of Oklahoma; Stephenson Oklahoma Canc Ctr
🇺🇸Oklahoma City, Oklahoma, United States
University of South Alabama; Mitchell Cancer Institute
🇺🇸Mobile, Alabama, United States
Chattanooga Oncology and Hematology Associates, PC
🇺🇸Chattanooga, Tennessee, United States
Washington University School of Medicine
🇺🇸Saint Louis, Missouri, United States
St. Joseph Mercy Hospital; Cancer Care Center.
🇺🇸Ann Arbor, Michigan, United States
Karmanos Cancer Institute..
🇺🇸Detroit, Michigan, United States
Southeast Nebraska Cancer Center;; Southeast Nebraska Hematology and Oncology
🇺🇸Lincoln, Nebraska, United States
West Clinic
🇺🇸Germantown, Tennessee, United States
Sarah Cannon Cancer Center and Research Institute
🇺🇸Nashville, Tennessee, United States
Scott and White Hospital; Cancer Center
🇺🇸Temple, Texas, United States
Virginia Cancer Institute
🇺🇸Richmond, Virginia, United States
UT Southwestern MC at Dallas
🇺🇸Dallas, Texas, United States
Vince Lombardi Cancer Center
🇺🇸Green Bay, Wisconsin, United States
LAC-USC Medical Center
🇺🇸Los Angeles, California, United States
Long Beach Memorial Medical Center; Oncology
🇺🇸Long Beach, California, United States
Kaiser Permanente - Franklin
🇺🇸Denver, Colorado, United States
Pacific Cancer Care
🇺🇸Salinas, California, United States
Florida Cancer Specialist, North Region
🇺🇸Saint Petersburg, Florida, United States
Emory University Clinic
🇺🇸Atlanta, Georgia, United States
University of Kentucky Medical Center
🇺🇸Lexington, Kentucky, United States
Central Georgia Cancer Care PC
🇺🇸Macon, Georgia, United States
Ingalls Memorial Hosp
🇺🇸Harvey, Illinois, United States
Edward Cancer Center Naperville
🇺🇸Naperville, Illinois, United States
Nebraska Methodist Hospital; Cancer Center
🇺🇸Omaha, Nebraska, United States
Ctr for Cancer and Blood Disorders
🇺🇸Fort Worth, Texas, United States
Seattle Cancer Care Alliance - Evergreen Health
🇺🇸Kirkland, Washington, United States
Medical College of Wisconsin; Dept Froedtert Clin Can Ctr
🇺🇸Milwaukee, Wisconsin, United States
Aurora Research Institute
🇺🇸Wauwatosa, Wisconsin, United States