BACKGROUND: Regorafenib is an oral multikinase inhibitor for metastatic colorectal cancer (mCRC) previously treated with fluoropyrimidines, irinotecan, oxaliplatin, monoclonal antibodies targeting vascular endothelial growth factor, and monoclonal antibodies targeting epidermal growth factor receptor. A dose reduction from 160 mg to 120 mg regorafenib reduces regorafenib-associated adverse events (AEs). Dose adjustment of irinotecan in a 5-fluorouracil/leucovorin/irinotecan (FOLFIRI) regimen on the basis of an individual uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1) genotype provides optimal oncological outcomes with acceptable AEs. The aim of this study is to address the efficacy and safety of a dose-adjusted combination of regorafenib and FOLFIRI for patients with mCRC. METHODS: A prospective, multicenter, randomized in a 2:1 ratio, controlled, clinical trial with two parallel arms will be conducted to compare irinotecan dose-escalated FOLFIRI according to UGT1A1 genotyping plus 120 mg regorafenib with 120 mg regorafenib alone in previously treated patients with mCRC. The primary endpoint is progression-free survival, and the secondary endpoints are overall survival, disease control rate, time to progression, and duration of treatment. Safety assessments will also be recorded. DISCUSSION: Dose adjustment for regorafenib and irinotecan makes treatment-related AEs tolerable and makes the concomitant treatment practicable. This study will provide initial evidence regarding the efficacy and safety of a new combination of chemotherapy and a targeted agent for mCRC. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03880877. Prospectively registered on 19 March 2019.