Bevacizumab Plus Iparomlimab/Tuvonralimab With Hepatic Artery Infusion Chemotherapy Followed by Stereotactic Body Radiotherapy in Patients With BCLC Stage C Hepatocellular Carcinoma With Thrombus and/or Extrahepatic Oligometastases (BITS-TO-HCC): Study Protocol of a Prospective, Multicenter, Single-Arm, Phase II Study
This multicenter, prospective, single-arm Phase II clinical trial is designed to evaluate the efficacy and safety of combining bevacizumab plus iparomlimab/tuvonralimab with hepatic artery infusion chemotherapy (HAIC) followed by stereotactic body radiotherapy (SBRT) in patients with Barcelona Clinic Liver Cancer (BCLC) stage C hepatocellular carcinoma (HCC) who present with portal vein tumor thrombus (PVTT) or extrahepatic oligometastatic disease. The study aims to determine whether this combination strategy can prolong progression-free survival (PFS), while also improving overall survival (OS), objective response rate (ORR), disease control rate (DCR), and local control rate (LCR), as well as maintaining quality of life (QoL). In addition, the trial will systematically evaluate the safety profile and treatment-related toxicities associated with this regimen.
• Male or female patients aged between 18 and 70 years.
• Unresectable HCC, BCLC Stage C according to the BCLC strategy-2025 update, with staging established via biopsy pathology and/or clinical diagnosis.
• Child-Pugh class A without clinically significant hepatic decompensation; Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Metastatic burden and SBRT eligibility
‣ Extrahepatic oligometastatic disease defined as ≤3 involved organs with ≤5 total metastatic lesions
⁃ All intended intrahepatic and/or extrahepatic SBRT targets must satisfy protocol-specified target-coverage, liver reserve, and organ-at-risk (OAR) constraints within a composite 5-fraction plan
• Prognosis \& measurable disease
‣ Life expectancy ≥3 months
⁃ ≥1 measurable lesion (per RECIST 1.1):
⁃ Tumor: ≥10 mm (CT long axis)
⁃ Lymph node: ≥15 mm (CT short axis)
• Prior therapy
‣ Prior locoregional therapy permitted：radiofrequency ablation (RFA), TACE, or HAIC, provided that:
⁃ Documented radiographic progression or intolerance after the prior therapy
⁃ Washout ≥28 days
⁃ Treatment-related toxicities recovered to ≤Grade 1 (alopecia and peripheral neuropathy ≤Grade 2 allowed)
• Laboratory and virologic requirements
‣ Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) ≤5 × upper limit of normal (ULN); total bilirubin ≤3 × ULN; serum albumin ≥28 g/L
⁃ Serum creatinine ≤1.5 × ULN or creatinine clearance ≥50 mL/min
⁃ Urine dipstick protein \<2+; if baseline dipstick proteinuria is ≥2+, 24-hour urinary protein must be \<1 g
⁃ International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤1.5 × ULN