Background: Trifluridine/tipiracil is an oral combination preparation approved for the treatment of patients with metastatic colorectal cancer (mCRC). Trifluridine is a thymidine analog, and tipiracil is a thymidine phosphorylase inhibitor that improves the bioavailability of trifluridine. Phase I/II C-TASK FORCE study of trifluridine/tipiracil plus bevacizumab (Bev) for patients with refractory mCRC demonstrated a promising efficacy results with mild toxicity profile (Kuboki Y, et al. Lancet Oncology, 2017). Methods: We are conducting a randomized multicenter phase II/III non-inferiority study (JapicCTI-173618) to compare trifluridine/tipiracil plus Bev versus FOLFIRI plus Bev (in the control arm, S-1 can replace 5-FU) in second-line mCRC patients who have failed first-line oxaliplatin-based chemotherapy. Key eligibility criteria are a histologically confirmed colorectal adenocarcinoma, refractory to first-line chemotherapy including a fluoropyrimidine, oxaliplatin, and either Bev or an anti-EGFR antibody (if RAS wild-type), an age of 20 years or older, ECOG performance status of 0-1, and adequate oral intake. Patients are randomized in a 1:1 ratio to receive trifluridine/tipiracil plus Bev or FOLFIRI plus Bev using the minimization method stratified by RAS status, prior therapy (Bev/anti-EGFR antibody), and primary tumor sidedness. The primary endpoint is overall survival. The non-inferiority hypothesis will be achieved if the upper limit of the two-sided 95% CI of the HR is below 1.33 (as HR scale, power 0.80). If achieved, the non-inferiority hypothesis with the margin of 1.25 (as HR) and the superiority will be consequently tested. Secondary endpoints include progression-free survival, time to treatment failure, response rate, disease control rate, subsequent treatment, time to post-study treatment failure, the quality of life, and adverse events. The target sample size is 524 patients. Patients will be enrolled from October 2017. Clinical trial information: 173618.