Ipilimumab N01 Combined With Sintilimab, Bevacizumab Biosimilar, and Hepatic Arterial Infusion Chemotherapy as Conversion Therapy for Unresectable Intermediate-Advanced Hepatocellular Carcinoma

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

Inclusion Criteria:

• 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:

  1. Absolute neutrophil count (ANC) ≥ 1.5×10⁹/L without granulocyte colony-stimulating factor support within 14 days;
  2. Platelet count ≥ 80×10⁹/L without transfusion within 14 days;
  3. Hemoglobin > 9 g/dL without transfusion or erythropoietin within 14 days;
  4. Total bilirubin ≤ 1.5×upper limit of normal (ULN); or total bilirubin > ULN with direct bilirubin ≤ ULN;
  5. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3×ULN;
  6. Serum creatinine ≤ 1.5×ULN and creatinine clearance (calculated by Cockcroft-Gault formula) ≥ 60 mL/min;
  7. Adequate coagulation function defined as international normalized ratio (INR) or prothrombin time (PT) ≤ 1.5×ULN;
  8. 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;
  9. 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.

Exclusion Criteria:

• Target disease exceptions:

  1. Fibrolamellar HCC, sarcomatoid HCC, or combined hepatocellular-cholangiocarcinoma.
  2. Recurrent HCC.
  3. Clinically diagnosed hepatic encephalopathy within the most recent 6 months.

• Autoimmune hepatitis (requiring liver biopsy confirmation);

• History of organ transplantation or history of hepatic encephalopathy;

• Diffuse hepatocellular carcinoma;

• Symptomatic pleural effusion, ascites, or pericardial effusion requiring drainage;

• History of any renal disease or nephrotic syndrome.

• Variceal bleeding (esophageal or gastric varices) due to portal hypertension within the past 6 months;severe (Grade 3) varices on endoscopy within 3 months before first dose;evidence of portal hypertension (e.g., splenomegaly >10 cm in longest diameter with platelets <100×10⁹/L on imaging) with high bleeding risk as assessed by the investigator;

• Arterial or venous thromboembolic events within the past 6 months, including myocardial infarction, unstable angina, cerebrovascular accident, transient ischemic attack, pulmonary embolism, deep vein thrombosis, or other severe thromboembolism.Excluded are catheter-related or port-related thrombosis or superficial venous thrombosis that is stable with standard anticoagulation;

• Severe bleeding tendency or coagulopathy, or ongoing thrombolytic therapy;

• Prophylactic low-molecular-weight heparin (e.g., enoxaparin 40 mg daily) is permitted; vitamin K antagonists (e.g., warfarin) are excluded;

• Long-term use of anti-platelet agents including aspirin, dipyridamole, clopidogrel, or other similar medications;

• Uncontrolled hypertension despite optimal medical management (systolic BP >140 mmHg or diastolic BP >90 mmHg); history of hypertensive crisis or hypertensive encephalopathy;

• Symptomatic congestive heart failure (NYHA Class II-IV); symptomatic or poorly controlled arrhythmia; congenital long QT syndrome or QTcF >500 ms at screening;

• History of gastrointestinal perforation and/or fistula within the past 6 months; history of bowel obstruction (including partial obstruction requiring parenteral nutrition); extensive bowel resection, Crohn's disease, ulcerative colitis, or chronic diarrhea;

• Major surgical procedure (cranial, thoracic, or abdominal) within 4 weeks before first dose, or non-healing wounds, ulcers, or fractures.Core needle biopsy or minor surgery within 7 days before first dose is excluded, except for venous catheter placement for intravenous access;

• History of pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, drug-induced pneumonitis, or severe pulmonary dysfunction;

• Acute or chronic active hepatitis B or C infection:HBV DNA >2000 IU/mL or 10⁴ copies/mL;HCV RNA >10³ copies/mL;coinfection with HBsAg and anti-HCV antibody;

• Active tuberculosis (TB), ongoing anti-TB treatment, or anti-TB treatment within 1 year before first dose;

• Human immunodeficiency virus (HIV) infection (positive HIV 1/2 antibody) or active syphilis;

• Active or poorly controlled severe infection; severe infection requiring hospitalization (including sepsis, bacteremia, or severe pneumonia) within 4 weeks before first dose;

• Active autoimmune disease requiring systemic therapy (e.g., disease-modifying agents, corticosteroids, or immunosuppressants) within 2 years before first dose.Replacement therapy (e.g., thyroxine, insulin, or physiological corticosteroids for adrenal/pituitary insufficiency) is permitted.History of primary immunodeficiency.Subjects with isolated positive autoimmune antibodies will be evaluated at the investigator's discretion;

• Systemic immunosuppressive drugs within 4 weeks before first dose, excluding topical, inhaled, or intranasal corticosteroids or physiological systemic corticosteroids (≤10 mg/day prednisone or equivalent).Temporary corticosteroids for acute dyspnea in asthma or COPD are permitted;

• Live attenuated vaccine within 4 weeks before first dose or planned use during the study period;

• Chinese herbal medicine with anti-tumor indications, or immunomodulatory agents (including thymosin, interferon, interleukin) within 2 weeks before first dose, except for local administration for pleural effusion or ascites;

• Uncontrolled or irreversible metabolic disorders, other acute or chronic non-malignant organ diseases, systemic illnesses, or paraneoplastic syndromes that may increase medical risk or confound survival assessment;

• Diagnosis of another malignancy within 5 years before first dose, except for radically treated basal cell carcinoma, squamous cell carcinoma of the skin, or carcinoma in situ.For other malignancies diagnosed >5 years before enrollment, pathological or cytological confirmation of recurrent/metastatic lesions is required;

• Prior treatment with anti-PD-1, anti-PD-L1/L2, anti-CTLA-4 antibodies, or other immune checkpoint inhibitors;

• Known hypersensitivity to sintilimab, bevacizumab, ipilimumab N01 or their excipients, or severe hypersensitivity to other monoclonal antibodies;

• Participation in another interventional clinical trial within 4 weeks before first dose;

• Female subjects who are pregnant or breastfeeding;

• Any other acute or chronic diseases, psychiatric disorders, or abnormal laboratory values that may increase risks associated with study participation or study drug administration, or interfere with the interpretation of study results, and that, in the investigator's judgment, render the patient ineligible for participation in this study.