CAREFOL: A phase 3, randomized, open-label, multicenter trial of camrelizumab and rivoceranib with or without intravenous FOLFOX chemotherapy as first-line treatment for unresectable hepatocellular carcinoma.

TPS4257 Background: The combination of camrelizumab (an anti-PD-1 IgG4 monoclonal antibody) and rivoceranib (a VEGFR2-TKI) is a standard of care, first-line (1L) therapy for advanced hepatocellular carcinoma (HCC). However, immune therapy resistance leads to ineffective initial treatment and difficulty in maintaining long-term efficacy in some patients. Several studies have shown that oxaliplatin and fluorouracil can induce immunogenic cell death in tumor cells and induce antitumor immune response in the body. Intravenous FOLFOX chemotherapy may regulate the liver tumor microenvironment and improve clinical benefit, a hypothesis supported by positive efficacy signals in the Phase II VIC-TRIPLETS study (NCT05412589). Here we present the design of a phase III randomized controlled study. Methods: This investigator-initiated, phase III, randomized, open-label, multicenter trial (NCT06280508) aims to compare the efficacy and safety of camrelizumab and rivoceranib combined with (CAREFOL) or without intravenous FOLFOX chemotherapy (CARE) as first-line treatment for unresectable HCC. Eligible patients are aged at least 18 years, with unresectable or metastatic HCC, no previous systemic treatment, with BCLC stage B or C disease (which is not amenable to or had progressed after surgical or locoregional therapy), at least one measurable lesion per RECIST 1.1 criteria, Child-Pugh class A liver function, an ECOG performance status of 0 or 1, and adequate organ function. Approximately 326 Participants will be randomly assigned (1:1) using a centralized interactive response system. Randomization is stratified by presence of extrahepatic metastasis (yes vs no), macrovascular invasion (Vp0-3 vs Vp4), and baseline α-fetoprotein level ( < 400 ng/mL vs ≥400 ng/mL). The experimental group consisted of camrelizumab 200 mg intravenously every 3 weeks plus rivoceranib 250 mg orally once daily combined with 21-day cycles of intravenous FOLFOX chemotherapy (oxaliplatin 85 mg/m 2 , levofolinate 200 mg/m 2 , 5-fluorouracil bolus 400 mg/m 2 on day 1, and 5-fluorouracil infusion 2400 mg/m 2 for 46 hours; up to 6 cycles). The control group is camrelizumab plus rivoceranib (same as experimental group). The dual primary endpoints are investigator-assessed progression-free survival per RECIST v1.1 and overall survival. Secondary endpoints include objective response rate, disease control rate, duration of response, surgical conversion rate, time-to-treatment failure, safety. The trial is currently screening eligible patients. Clinical trial information: NCT07267806 .