Cetuximab, Capecitabine, Oxaliplatin and Bevacizumab in Advanced Colorectal Cancer

Primary objective: To assess the efficacy, defined as progression-free survival (PFS), of adding cetuximab to capecitabine/oxaliplatin/bevacizumab for advanced CRC. Secondary objectives: To assess tumour response (CR, PR or SD), response duration, overall survival, toxicity profile, quality of life, translational research. Methodology: Open, randomised multicenter phase III study. The number of patients is 750. Test products: All cycles will be administered q 3 weeks. Oxaliplatin will be discontinued after 6 cycles in both study arms. The dose of capecitabine will be increased to 1250 mg/m2 b.i.d. as of cycle 7. Arm A: capecitabine 1000 mg/m2 orally b.i.d. on day 1-14 (1250 mg/m2 after 6 cycles), oxaliplatin 130 mg/m2 i.v. infusion on day 1 during 6 cycles, bevacizumab 7.5 mg/kg i.v. infusion on day 1. Arm B: capecitabine 1000 mg/m2 orally b.i.d. on day 1-14 (1250 mg/m2 after 6 cycles), oxaliplatin 130 mg/m2 i.v. infusion on day 1 during 6 cycles, bevacizumab 7.5 mg/kg i.v. infusion on day 1. Cetuximab 400 mg/m2 i.v. day 1 of cycle 1, thereafter weekly 250 mg/m2 i.v. Duration of treatment and follow-up: Treatment is continued until disease progression, or unacceptable toxicity. Patients will be evaluated every 9 weeks for response while on treatment, or at any other time point when progression is suspected. After cessation of therapy for reasons other than disease progression, patients will be followed every 3 months until progression or death. Death and/or progression should be reported whenever it occurs. In case chemotherapy (i.e. capecitabine and/or oxaliplatin) is discontinued for reasons of toxicity, treatment with bevacizumab (arm A) or bevacizumab + cetuximab (Arm B) should be continued until progression or unacceptable toxicity. Also, if chemotherapy plus bevacizumab is discontinued in Arm B for reasons of toxicity, treatment with cetuximab should be continued until progression or unacceptable toxicity. Criteria for evaluation: Efficacy: All eligible patients will be included in the analysis (intent-to-treat). All patients receiving \> 9 weeks of treatment (i.e. 3 cycles) will be considered evaluable for response, unless documented progression occurred earlier. Safety profile: Safety will be analysed in each treatment group. Patients having received ≥ 1 treatment doses are evaluable for toxicity. Evaluation will be performed on the safety population (having received treatment, assignment to treatment groups as treated). Clinical and laboratory toxicity/symptomatology will be graded according to NCI common toxicity criteria, version 3.0. The adverse events which are not reported in NCI common toxicity criteria will be graded as: mild, moderate, severe, life threatening. Statistical methodology: The main endpoint of the study is the progression free survival interval (PFS). PFS curves will be constructed by means of the Kaplan Meier method. Comparisons of PFS curves will performed by mean of the log rank test. Similar methods will be used to analyse the duration of survival. All analyses will be done according to the intention-to-treat principle. The expected median PFS in Arm A (standard arm) is 11 months. The minimum increase in PFS in Arm B (experimental arm) will be 3 months (21% hazard ratio reduction). 540 events are required for 80% power. 740 patients are needed to show this difference (\>=0.05, 2-tailed test). To allow for ineligibility in some patients, a total of 750 patients will be included. Stratification parameters: Patients will be stratified for the following parameters: * Prior adjuvant therapy (yes versus no); * Number of organs affected (1 versus \> 1, in case the primary tumour is in situ this will count as one organ); * Serum LDH (normal versus above normal); * Per participating institution. Side studies: Side studies on prognostic factors in tumour samples from included patients will be performed, as well as on circulating tumour cells and endothelial cells and serum proteomics.