Objective: Regorafenib (BAY 73-4506) is an oral multikinase inhibitor that has been shown to inhibit various oncogenic stromal receptor tyrosine kinases and intracellular signaling kinase. The aim of the study is to confirm the safety and effectiveness of dose escalation therapy of regorafenib for the third- or fourth- treatments of patients with unresectable and recurrent colorectal cancer.Design: This study is designed as a single-arm, prospective, non-randomized, multi-centered open label phase II trial in Japan. The study regimen consists of 28-day cycles with escalated doses of regorafenib (80-160 mg/body on days 1 to 21). This study is a dose-escalation study using a starting dose of 80 mg/day during the first seven days. In case of no adverse events related to the administration after the first seven days of the starting dose, the administration dose will be increased to 120 mg/day on days 8 to 14. The administration dose will then be increased to 160 mg/day on days 15 to 21. Primary end point is progression free survival (PFS); secondary end points include time to treatment failure, response rate, overall survival, the interval between the initial of drug administration and performance status 2, the transition rate to the following line of treatment, the cumulative dose and the incidence of adverse events of grade 3 or higher, and genetic alterations (KRAS mutation/BRAF mutation) in circulating cell-free DNA.Conclusions: This study may contribute to determining the efficacy of the escalation of the administration dose in patients with metastatic colorectal cancer.