Background: The FIRE-3 study proved that early tumor shrinkage (ETS) and DpR were superior with FOLFIRI plus cetuximab (cet) compared to bevacizumab (bev) in mCRC patients with RAS wild-type tumors (Stintzing S, et al. Lancet Oncol 2016). A retrospective analysis of treatment groups between FOLFOXIRI plus anti-EGFR antibody and bev showed significantly better DpR and ETS in the anti-EGFR antibody group (48.6% vs. 37.8% for the median DpR; 40.8% vs. 26.4% for the median ETS)(Salvatore L, et al. ESMO 2014). However, there have been few studies comparing cet with bev in combination with the FOLFOXIRI regimen used as a platform. Therefore, it is great interest to investigate whether cet will be more beneficial than bev when combined with the triplet regimen as a promising treatment option. Methods: Key eligibility criteria are as follows: histologically proven unresectable metastatic/recurrent CRC; RAS wild-type tumors; patients who have not received any prior chemotherapies or patients with relapse after at least 12 months following adjuvant chemotherapy. Primary endpoint of this study is the DpR until progression. Key secondary endpoints are the ETS at Week 8, progression-free survival, overall survival, and safety. After randomization, patients receive up to 12 cycles of FOLFOXIRI (irinotecan: 150 mg/m², oxaliplatin: 85 mg/m², l-levofolinate: 200 mg/m², continuous fluorouracil: 2400 mg/m², every two weeks) plus cet (initial: 400 mg/m², subsequent: 250 mg/m², weekly) or bev (5 mg/kg, every two weeks) as induction treatment. Thereafter, fluorouracil, l-levofolinate, and cet or bev are administrated as maintenance treatment. Based on previous reports, the difference of 12.5% in the median DpR between the cet and bev groups was assumed. Each standard deviation was estimated to be 42% (cet group) and 34% (bev group). Under the conditions of significance level of 0.05 for a two-sided test and power of 0.85, the required sample size was calculated to be 360 patients. Thirty-three patients have been enrolled by August 2016. Clinical trial information: 000018217.