Hepatic arterial infusion or intravenous infusion of adebrelimab, combined with bevacizumab and HAIC of the FOLFOX regimen for advanced unresectable hepatocellular carcinoma (HAIBrave-001 trial): a study protocol of a prospective, double-arm, phase II trial.

Background: Although atezolizumab plus bevacizumab is recommended as a first-line treatment for advanced unresectable hepatocellular carcinoma (HCC), its objective response rate (ORR) remains only about 30%. Hepatic arterial infusion chemotherapy (HAIC) using the FOLFOX regimen not only increases local drug concentration but may also enhance the efficacy of immune checkpoint inhibitors (ICIs) by inducing immunogenic cell death (ICD). Furthermore, delivering programmed cell death ligand 1 (PD-L1) inhibitors directly via hepatic arterial infusion (HAI) may maximize local antibody concentration in the tumor microenvironment and further potentiate regional immune responses. This study aims to explore the preliminary efficacy and safety of the PD-L1 inhibitor adebrelimab delivered via either HAI or the intravenous (IV) route, each combined with bevacizumab and HAIC-FOLFOX, for advanced HCC. Methods: This is a multicenter, randomized, non-comparative, open-label phase II trial. Seventy-six patients with previously untreated Barcelona Clinic Liver Cancer (BCLC) stage C HCC will be enrolled and randomly assigned (1:1) to either the HAI or IV cohort. To obtain independent efficacy estimates, Simon's two-stage design will be applied separately to each arm. Both groups will first receive HAIC-FOLFOX. The HAI group receives adebrelimab (1,200 mg) via HAI, followed by intravenous bevacizumab (15 mg/kg). The IV group receives both adebrelimab (1,200 mg) and bevacizumab (15 mg/kg) intravenously. Treatment continues for up to six cycles, after which HAIC-FOLFOX will be discontinued, and non-progressing patients will receive maintenance IV adebrelimab plus bevacizumab. The primary endpoint is investigator-assessed ORR per RECIST v1.1, evaluated independently for each arm. Secondary endpoints include progression-free survival, time to progression, overall survival and safety. Exploratory objectives include biomarker identification and evaluation of the regimen's effects on the tumor microenvironment and peripheral immune cells. Discussion: This is among the first studies to prospectively evaluate parallel cohorts receiving a PD-L1 inhibitor via hepatic arterial or intravenous delivery alongside HAIC-FOLFOX and bevacizumab. By utilizing a randomized non-comparative design, the trial will provide independent efficacy and safety profiles for each administration route. These findings will determine whether either regimen warrants further investigation, optimize immunotherapy delivery routes, and inform the design of future phase III comparative trials. Trial Registration: ClinicalTrials.gov (NCT06737913).