A Clinical Study Evaluating HAIC Combined With Iparomlimab and Tuvonralimab Injection Plus Bevacizumab in Patients With Initially Potentially Resectable Hepatocellular Carcinoma (ITBHaic Study)

This single-center, single-arm, phase II clinical study aims to evaluate the efficacy and safety of HAIC combined with Iparomlimab and Tuvonralimab injection (QL1706, an Anti-PD-1/CTLA-4 Combined Antibody) plus bevacizumab in patients with potentially resectable HCC. The study consists of four periods: screening, treatment, safety follow-up, and survival follow-up.Efficacy evaluation and safety monitoring should be performed throughout the study.

Inclusion criteria

• Subjects voluntarily join this study, sign the informed consent form, and demonstrate good compliance;
• Age ≥ 18 years, regardless of gender;
• HCC confirmed histologically/cytologically or meeting the clinical diagnostic criteria of the Chinese Guidelines for the Diagnosis and Treatment of Primary Liver Cancer (2024 Edition), with no evidence of extrahepatic metastasis;
• Potentially resectable HCC must meet ALL of the following criteria:

a. Deemed unsuitable for primary surgical resection at the current stage by the Multidisciplinary Team (MDT) assessment at the research center; b. At least one untreated measurable lesion according to RECIST v1.1 criteria. (Note: Subjects who received prior local therapy for non-target lesions are eligible. Local therapy must have been completed at least 4 weeks prior to baseline scans.); c. Largest tumor diameter ≥5 cm AND ≤3 tumor lesions; d. Absence of Vp3-Vp4 stage portal vein tumor thrombus (PVTT) as per the Japanese PVTT classification system; e. Oligometastasis is permitted;

• No prior systemic therapy for HCC (including investigational systemic agents);
• Child-Pugh score class A or well-compensated class B (score ≤7);
• Subjects with HBV or HCV infection must meet the following criteria:

• HBV-infected subjects (HBsAg positive or HBV-DNA positive): Must have received guideline-recommended antiviral therapy for at least 3 days prior to the first study treatment, demonstrating a decreasing trend in HBV-DNA levels. Must continue to receive standard antiviral therapy throughout the study period; 2) HCV-infected subjects (HCVAb positive or HCV RNA positive): Must be in a stable condition per investigator assessment. If receiving antiviral therapy, must continue treatment throughout the study period; 3) Co-infection with HBV and HCV is not allowed. (Note: A history of HCV infection with undetectable HCV-RNA is considered absence of current HCV infection); 8.ECOG Performance Status score of 0-1 (Appendix 1); 9.Life expectancy ≥3 months; 10.Adequate organ function within 7 days prior to treatment, meeting all the following criteria: Hemoglobin (Hb) ≥90 g/L; White blood cell count (WBC) ≥3.5 × 10⁹/L; Absolute neutrophil count (ANC) ≥1.5 × 10⁹/L; Platelet count (PLT) ≥75 × 10⁹/L; AST and ALT ≤5 × upper limit of normal (ULN); Total bilirubin ≤3 × ULN; Serum creatinine (Cr) ≤1.5 × ULN or creatinine clearance (CrCl) ≥40 mL/min (Appendix 2); Urinalysis showing urine protein <2+(For subjects with baseline urinalysis showing urine protein ≥2+, a 24-hour urine collection must demonstrate 24-hour urine protein <1 g); Adequate coagulation function, defined as: International Normalized Ratio (INR) ≤1.5 and activated partial thromboplastin time (APTT) ≤1.5 × ULN; Normal thyroid function, defined as: Thyroid-stimulating hormone (TSH) within normal range. (Subjects with baseline TSH outside normal range may enroll if free triiodothyronine (FT3) or total T3 and free thyroxine (FT4) are within normal limits); 11.Male subjects and subjects of childbearing potential must use highly effective contraception from informed consent signing until 6 months after last study treatment. Subjects of childbearing potential must have a negative pregnancy test within 7 days prior to first treatment.

Exclusion criteria

• Pregnant or lactating women;
• Histologically/cytologically confirmed HCC containing fibrolamellar, sarcomatoid, or cholangiocarcinoma components;
• History of other primary malignancies within 5 years (except adequately treated and stable non-melanoma skin cancer, basal cell carcinoma, squamous cell carcinoma, or carcinoma in situ of the cervix);
• Current or prior central nervous system (CNS) metastases or leptomeningeal metastasis;
• Bleeding tendency, high bleeding risk, or coagulation dysfunction: including but not limited to thromboembolic events (e.g., cerebrovascular accident, deep vein thrombosis, pulmonary embolism) within 6 months prior to screening; and/or history of hemoptysis (≥2.5 ml bright red blood per episode) within 3 months prior to screening; current use of full-dose oral or parenteral anticoagulants or thrombolytic agents for treatment; significant risk of gastrointestinal bleeding as judged by the investigator;
• Presence of unhealed fractures, wound dehiscence requiring intervention, wound healing complications; tracheoesophageal fistula, gastrointestinal perforation or fistula, or intra-abdominal abscess within 6 months prior to screening;
• Major surgery within 4 weeks before first dose (defined as Grade III or higher surgical procedures, excluding central venous catheter placement, tumor biopsy, etc.) or significant trauma with incomplete recovery;
• Significant cardiovascular diseases (e.g., NYHA Class II or higher heart failure, myocardial infarction, or cerebrovascular events within 3 months before initiating study treatment), unstable arrhythmias, or unstable angina;
• Active autoimmune diseases or history of autoimmune disorders including but not limited to interstitial pneumonia, uveitis, inflammatory bowel disease, hepatitis, hypophysitis, vasculitis, systemic lupus erythematosus; Note: Excludes hypothyroidism stabilized with physiologic hormone replacement, type I diabetes controlled with stable insulin therapy, or autoimmune thyroiditis managed with stable hormone replacement.
• Diagnosed immunodeficiency or anticipated need for systemic immunosuppressive therapy during study treatment, or prior use of systemic corticosteroids/immunosuppressants before first treatment; Note: Excludes topical/nasal/inhaled corticosteroids, physiologic systemic corticosteroids (≤10 mg/day prednisone equivalents), and transient corticosteroid use for COPD/asthma/allergy prophylaxis;
• History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonia, idiopathic pneumonia, or evidence of active pneumonia on screening chest CT scan;
• Severe infection within 4 weeks before initiating study treatment, including but not limited to complications requiring hospitalization, sepsis, or severe pneumonia; active infection requiring systemic anti-infective therapy within 2 weeks before first dose (excluding antiviral therapy for HBV/HCV);
• Poorly controlled comorbidities despite optimal management before first treatment: Uncontrolled hyperglycemia (defined as fasting blood glucose ≥7 mmol/L, unstable oral hypoglycemic regimen, or unstable glycemic control per specialist assessment); Uncontrolled hypertension (SBP >150 mmHg and/or DBP >100 mmHg after ≥2 antihypertensive agents) or history of hypertensive crisis/encephalopathy; Refractory malignant pleural effusion, ascites, or pericardial effusion (defined as symptomatic re-accumulation requiring re-intervention within 2 weeks after drainage);
• Known hypersensitivity to the investigational drug or its excipients;
• Any other severe/uncontrolled comorbidity that may compromise safety or efficacy assessments per investigator judgment (e.g., hepatic encephalopathy, uncorrectable coagulopathy, hepatorenal syndrome, or cachexia).