Sequential and Concurrent FOLFOXIRI/Bevacizumab Regimens Versus FOLFOX/Bevacizumab in First-Line Metastatic Colorectal Cancer
Condition: Colorectal Neoplasms
MeSH terms: Colorectal Neoplasms
Intervention: 5-fluorouracil; bevacizumab; capecitabine; irinotecan; folinic acid; oxaliplatin
Intervention description: 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 .
Intervention MeSH terms: Leucovorin; Folic Acid; Bevacizumab; Capecitabine; Fluorouracil; Oxaliplatin; Irinotecan; Levoleucovorin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 280.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No

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.
    

Eligibility criteria:

        Inclusion Criteria:

          -  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

        Exclusion Criteria:

          -  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