Introduction The exact role of hepatic arterial infusion chemotherapy (HAIC) in advanced hepatocellular carcinoma (aHCC) is still unknown. The combination of HAIC and sorafenib has been proven to be more effective than sorafenib alone in the first-line treatment of aHCC. The aim of the study is to evaluate the efficacy and safety of HAIC plus regorafenib in the second-line treatment of aHCC. Methods and analysis This is a multicenter, open-label, randomised controlled phase III trial. A total of 294 patients with aHCC, who are unable to tolerate the first-line systemic therapy or progress after the first-line systemic therapy, will be enrolled in the study. The patients will be randomly (2:1) assigned into the combination treatment group (HAIC plus regorafenib, n=196) and the control group (regorafenib alone, n=98). HAIC and regorafenib (160 mg/day) will be given in a 4-week cycle. The primary endpoint is overall survival in the intention-to-treat population. The second endpoints include progression-free survival, overall response rate, time to progression, etc. The radiological assessments will be based on the criteria of Response Evaluation Criteria in Solid Tumors 1.1. Ethics and dissemination This study is approved by the ethics committee of Cancer Hospital, Chinese Academy of Medical Sciences. All participants are required to provide written informed consent. The results of this study will be disseminated through peer-reviewed publications and esteemed academic conferences. Trial registration number Chinese Clinical Trial Registry (ChiCTR2300073075).
