Background: Regorafenib (RE) and cetuximab (CE) are both effective treatments for patients (pts) with metastatic colorectal cancer (mCRC) with the current standard sequence as CE followed by RE. For optimal continuum of care for mCRC pts, it is important to compare efficacy and safety of different sequential treatments. Furthermore, several possible biomarkers including oncogenic mutations and serum protein have been identified for both RE and CE treatment so far. The objective of this study is to evaluate the efficacy and safety of sequential treatment of RE followed by CE as compared with CE followed by RE. Exploratory objective is to investigate several biomarkers with an aim of producing findings that may be useful in elucidating the mechanism of resistance to each agent and contribute to future individualized therapy. Methods: This multicenter randomized phase II trial will enroll pts with KRAS wild-type mCRC after failure of chemotherapy including fluoropyrimidine, oxaliplatin, and irinotecan (UMIN000011294). Pts will be randomized (1:1; stratified by prior use of bevacizumab and intent to use irinotecan in combination with CE) to receive sequential treatment with RE followed by CE ± irinotecan or reverse sequence (CE ± irinotecan followed by RE). Primary endpoint is overall survival (OS). Secondary endpoints include time to sequential treatment failure (TTF), progression-free survival (PFS) of sequential treatment, anti-tumor effects (response rate, disease control rate) of RE or CE, safety, and patients reported outcome of quality of life (QOL). Exploratory endpoint is to investigate possible biomarkers including oncogenic mutations from circulating cell free DNA by liquid biopsy with serial measurement and multiple serum proteins related to epidermal growth factor receptor or vascular endothelial growth factor pathway change over time at several point of sequential treatment. To evaluate the similarity of OS between both arms (HR between 0.8 and 1.25), the sample size was planned as 180 subjects in total to observe 132 deaths with 1.5-year enrollment and subsequent 1.5-year follow-up periods. As of 21 Jan 2014, eight pts have been enrolled. Clinical trial information: UMIN000011294.