Sequential and Concurrent FOLFOXIRI/Bevacizumab Regimens Versus FOLFOX/Bevacizumab in First-Line Metastatic Colorectal Cancer

Study Overview
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Brief Summary
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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.

Official Title
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Steam (Sequencing Triplet With Avastin and Maintenance): FOLFOXIRI/Bevacizumab Regimens (Concurrent and Sequential) vs. FOLFOX/Bevacizumab in First-Line Metastatic Colorectal Cancer

Conditions
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Colorectal Neoplasms

Intervention / Treatment
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* Drug: 5-fluorouracil
* Drug: bevacizumab
* Drug: capecitabine
* Drug: irinotecan
* Drug: folinic acid
* Drug: oxaliplatin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: Concurrent FOLFOXIRI + Bevacizumab<br>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. | Drug: 5-fluorouracil<br>* 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.<br>Drug: bevacizumab<br>* 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.<br>* Other names: Avastin;Drug: capecitabine<br>* 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.<br>* Other names: Xeloda;Drug: irinotecan<br>* 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.<br>Drug: folinic acid<br>* 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.<br>* Other names: leucovorin;Drug: oxaliplatin<br>* 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 .<br>|
| Experimental: Arm B: Sequential FOLFOXIRI + Bevacizumab<br>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. | Drug: 5-fluorouracil<br>* 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.<br>Drug: bevacizumab<br>* 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.<br>* Other names: Avastin;Drug: capecitabine<br>* 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.<br>* Other names: Xeloda;Drug: irinotecan<br>* 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.<br>Drug: folinic acid<br>* 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.<br>* Other names: leucovorin;Drug: oxaliplatin<br>* 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 .<br>|
| Experimental: Arm C: FOLFOX + Bevacizumab<br>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. | Drug: 5-fluorouracil<br>* 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.<br>Drug: bevacizumab<br>* 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.<br>* Other names: Avastin;Drug: capecitabine<br>* 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.<br>* Other names: Xeloda;Drug: folinic acid<br>* 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.<br>* Other names: leucovorin;Drug: oxaliplatin<br>* 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 .<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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. | Randomization up to disease progression during first-line therapy or death, whichever occurs first (up to approximately 3 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 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. | 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. | Randomization up to approximately 3 years |