Conversion Therapy With Ipilimumab N01 Combined With Sintilimab, Bevacizumab Biosimilar, and Hepatic Arterial Infusion Chemotherapy for Unresectable Intermediate-Advanced Hepatocellular Carcinoma: A Prospective, Single-Arm Phase II Study
Conversion therapy for unresectable intermediate-advanced hepatocellular carcinoma (uHCC) has evolved from systemic therapy to combined local-systemic approaches, but current regimens still have limited surgical conversion rates. This prospective, single-arm phase II study evaluates a combination regimen of PD-1 inhibitor (sintilimab) plus CTLA-4 inhibitor (ipilimumab N01), bevacizumab biosimilar, and HAIC for patients with initially unresectable intermediate-advanced HCC. The primary goal is to achieve a higher surgical conversion rate with manageable safety
• Written informed consent must be signed prior to initiation of any study-related procedures;
• Age ≥ 18 years, and ≤75 years, regardless of gender;
• Clinically diagnosed or histologically/cytologically confirmed hepatocellular carcinoma (HCC) according to the Guidelines for the Diagnosis and Treatment of Primary Liver Cancer (2024 Edition);
• No prior anti-tumor therapy for HCC before study treatment
• Unresectable locally advanced or advanced HCC (CNLC Stage IIa-IIIb).
• Expected overall survival \> 6 months.
• Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.
• Child-Pugh score class A or B
• Adequate organ function defined by the following laboratory parameters:
‣ Absolute neutrophil count (ANC) ≥ 1.5×10⁹/L without granulocyte colony-stimulating factor support within 14 days;
⁃ Platelet count ≥ 80×10⁹/L without transfusion within 14 days;
⁃ Hemoglobin \> 9 g/dL without transfusion or erythropoietin within 14 days;
⁃ Total bilirubin ≤ 1.5×upper limit of normal (ULN); or total bilirubin \> ULN with direct bilirubin ≤ ULN;
⁃ Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3×ULN;
⁃ Serum creatinine ≤ 1.5×ULN and creatinine clearance (calculated by Cockcroft-Gault formula) ≥ 60 mL/min;
⁃ Adequate coagulation function defined as international normalized ratio (INR) or prothrombin time (PT) ≤ 1.5×ULN;
⁃ Normal thyroid function defined as thyroid-stimulating hormone (TSH) within normal limits. Subjects with abnormal baseline TSH but normal total T3 (or FT3) and FT4 are also eligible;
⁃ Myocardial enzymes within normal limits; isolated laboratory abnormalities deemed clinically insignificant by the investigator are permitted.
• Female subjects of childbearing potential must have a negative urine or serum pregnancy test within 3 days before the first dose of study drug (Day 1 of Cycle 1). A blood pregnancy test is required if the urine test is inconclusive; They must agree to use adequate contraception during the study period and for 8 weeks after the last dose of study drug;
• All subjects (male or female) of reproductive potential must use a highly effective contraceptive method with an annual failure rate \< 1% throughout treatment and for 120 days after the last dose of immunotherapy or 180 days after the last dose of chemotherapy, whichever is longer.