Background: Several strategies using chemotherapy and molecular targeted drugs are available for the treatment of unresectable metastatic colorectal cancer. Recent and ongoing randomized trials evaluate chemotherapy with bevacizumab or epidermal growth factor receptor (EGFR) inhibitors, but the prior and/or subsequent lines are not fixed and the imbalanced cross-overs will not allow to interpret overall survival. This STRATEGIC-1 trial is a study designed to determine the best sequence of therapy and to define subset populations that will benefit most from one sequence. Methods: This is an ongoing randomized, two-arm, phase III study comparing two multi-line therapeutic strategies in patients wild-type RAS unresectable metastatic colorectal adenocarcinoma, ECOG PS 0-2 and age ≥ 18years. Randomization is stratified by center, GERCOR prognostic score (using PS and LDH level), prior use of oxaliplatin in adjuvant setting and the extent of metastatic disease. Patients (n=474) are randomized (1:1) to either (arm A) FOLFIRI/cetuximab, followed by an oxaliplatin-based chemotherapy with bevacizumab or (arm B) OPTIMOX/bevacizumab, followed by an irinotecan-based chemotherapy with bevacizumab, followed by anti-EGFR mab (cetuximab or panitumumab) with or without irinotecan. The primary endpoint is Duration of Disease Control (DDC). The sample size was planned for testing the primary variable DDC with a two-sided 5% α type one error and a 10% β type two error (Software: EAST 5.3) and a planned interim analysis. A 33% reduction in the risk of event (HR 0.67) was assumed under H₁ in the arm B. Secondary endpoints include OS, HR-QoL, TFS, ORR and PFS per sequence, salvage surgery rate, safety and correlations between biomarkers and clinical outcome. CRC tissue (primary or met.) and blood collection are mandatory for biomarker analyses. Enrolment began in October 2013. Clinical trial information: NCT01910610.