Background: In a RECOURSE phase III study, TAS-102 significantly improved progression-free survival (PFS) and overall survival (OS) over placebo in patients (pts) with metastatic colorectal cancer (mCRC) refractory to standard therapies. We reported the combination of TAS-102 with bevacizumab (C-TASK FORCE trial) showed promising anti-tumor activities with mild toxicities (Kuboki Y, et al. ASCO 2015). Nintedanib is a triple angiokinase inhibitor of vascular endothelial growth factor receptors (1,2,3), platelet-derived growth factor receptors (a, β), and fibroblast growth factor receptors (1,2,3). A global phase III study, called as the LUME-Colon 1, comparing nintedanib monotherapy versus placebo in pts with mCRC refractory to standard therapies is ongoing, on the basis of promising anti-tumor activities with mild toxicities in a phase I clinical study of nintedanib monotherapy (Mross et al.). Therefore, we initiated phase I/II study to assess efficacy and safety for the combination of TAS-102 with nintedanib. Methods: The key eligibility criteria were pts with mCRC refractory or intolerant to fluoropyrimidine, irinotecan, oxaliplatin, anti-angiogenesis inhibitor and anti-EGFR antibody (if wild-type RAS) and without prior regorafenib and TAS-102; at least one measurable lesion; and ECOG performance status of 0 or 1. Phase I part was designed to determine the recommended phase II dose (RP2D) in a “3+3” cohort-based dose escalation design of nintedanib (150mg BID every day on level 1 and 200mg BID every day on level 2) with a fixed dose of TAS-102 (35 mg/m² BID on days 1–5 and 8–12 q4w). Primary endpoint of the phase II part was an investigator-assessed PFS rate at 16 weeks in pts receiving the combination with RP2D. Using a single stage binomial design, this study required 52 pts, with an investigator-assessed PFS rate at 16 weeks of 40% deemed promising and 25% unacceptable (one-sided alpha = 0.1; beta = 0.2). Secondary endpoints included OS, PFS, objective response rate, disease control rate, safety, and pharmacokinetic parameters. The enrollment to phase II part began in January 2016. Clinical trial information: UMIN000017114. Clinical trial information: 000017114.