A Prospective, Randomized Study of TACE Combined With Sintilimab, Bevacizumab, and Ipilimumab N01 Treating Advanced HCC

The goal of this clinical trial is to evaluate the safety, tolerability, and preliminary efficacy of a combination therapy involving TACE, sintilimab, bevacizumab, and ipilimumab N01 for the treatment of advanced hepatocellular carcinoma (HCC). It also aims to explore the potential synergistic mechanisms of this combination. The main questions it aims to answer are:

Is the combination of TACE, sintilimab, bevacizumab, and ipilimumab N01 safe and tolerable for patients with advanced HCC? Does this combination therapy show preliminary efficacy in treating advanced HCC? How do different sequencing schedules of ipilimumab N01 (given 3 weeks after sintilimab vs. concurrently with sintilimab) compare in terms of safety and efficacy? What potential biomarkers can predict treatment response?

Researchers will compare three different treatment groups to assess the safety and efficacy of the combination and the role of ipilimumab N01 timing:

Group A: Receives a single dose of ipilimumab N01 (3mg/kg IV) administered 3 weeks after the first dose of sintilimab, in combination with sintilimab (200mg IV, Q3W), bevacizumab (15mg/kg IV, Q3W), and TACE.

Group B: Receives a single dose of ipilimumab N01 (3mg/kg IV) administered concurrently with the first dose of sintilimab, in combination with sintilimab (200mg IV, Q3W), bevacizumab (15mg/kg IV, Q3W), and TACE.

Group C: Receives sintilimab (200mg IV, Q3W), bevacizumab (15mg/kg IV, Q3W), and TACE (without ipilimumab N01).

Participants will:

Be screened for eligibility. Eligible participants (36 adults with advanced, previously untreated, unresectable or metastatic HCC) will provide informed consent and be randomly assigned to one of the three treatment groups (A, B, or C) using a central randomization system.

Receive the assigned study treatment according to their group's schedule. Undergo regular clinic visits for safety checkups, tumor imaging assessments (initially every 6 weeks, then every 12 weeks after 48 weeks), and response evaluation using RECIST v1.1 and RECICL criteria until disease progression, intolerable toxicity, or other study withdrawal criteria are met.

Provide biological samples for exploratory biomarker analysis, including:

Peripheral blood (10ml each time: 5ml in anticoagulant tube, 5ml in coagulant tube) at baseline and before each treatment cycle (every 3 weeks).

Tumor biopsy specimens at baseline and 6 weeks after the first treatment. Surgical specimens if the patient undergoes conversion surgery.

Participate in follow-up visits:

A safety follow-up visit 30 days (±7 days) after the last study drug dose or before starting new anti-cancer therapy (whichever comes first).

Subsequent survival follow-up contacts every 90 days (±7 days, which may be conducted via phone) to collect information on survival status and any subsequent anti-cancer treatments, until death, withdrawal of consent, or study closure.

Inclusion criteria

• Sign and date a written informed consent form prior to the implementation of any trial-related procedures.
• Patients with clinically confirmed unresectable or metastatic hepatocellular carcinoma (HCC).
• Male or female, ≥18 years old, ≤75 years old.
• ECOG Performance Status score of 0~1.
• Expected survival time >3 months.
• Barcelona Clinic Liver Cancer (BCLC) Stage B or C for unresectable HCC.
• Suitable for Transarterial Chemoembolization (TACE) treatment.
• Child-Pugh score ≤7.
• At least one measurable lesion according to RECIST 1.1 criteria.

Exclusion criteria

• Previous histological/cytological confirmation of HCC with fibrolamellar, sarcomatoid, or cholangiocarcinoma components.
• History of liver transplantation or hepatic encephalopathy.
• Diffuse liver cancer.
• Inability to tolerate TACE or prior history of TACE treatment.
• Prior treatment with Transarterial Chemoembolization (TACE), Transarterial Embolization (TAE), or Transarterial Radioembolization (TARE).
• Prior systemic anti-tumor therapy or radiotherapy for HCC.
• Portal vein main trunk tumor thrombus without adequate collateral circulation, or concurrent involvement of the superior mesenteric vein; inferior vena cava tumor thrombus.
• Clinically symptomatic pleural effusion, ascites, or pericardial effusion requiring drainage.
• Any history of renal disease or nephrotic syndrome.
• History of esophageal or gastric variceal bleeding due to portal hypertension within the past 6 months; presence of severe (Grade 3) varices on endoscopy known within 3 months prior to first dose; evidence of portal hypertension (including splenomegaly on imaging) with high risk of bleeding as assessed by the investigator.
• Any life-threatening bleeding event within the past 3 months, requiring transfusion, surgery, local therapy, or continuous medication.
• 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. Except for catheter-related thrombosis from implanted ports or superficial venous thrombosis if stable under routine anticoagulation.
• Significant bleeding tendency or coagulopathy, or undergoing thrombolytic therapy.
• Prophylactic use of low-dose low molecular weight heparin (e.g., enoxaparin 40 mg/day) is allowed, but not vitamin K antagonists (e.g., warfarin).
• Requirement for long-term use of platelet function inhibitors such as aspirin, dipyridamole, or clopidogrel.
• Uncontrolled hypertension (systolic blood pressure >150 mmHg or diastolic blood pressure >90 mmHg despite optimal medical therapy), history of hypertensive crisis or hypertensive encephalopathy.
• Symptomatic congestive heart failure (New York Heart Association Class II-IV), symptomatic or poorly controlled arrhythmia, history of congenital long QT syndrome, or corrected QT interval (QTc) >500 ms on screening ECG (using Fridericia's formula).
• History of gastrointestinal perforation and/or fistula, intestinal obstruction (including incomplete obstruction requiring parenteral nutrition) within the past 6 months; extensive intestinal resection (partial colectomy or extensive small bowel resection with chronic diarrhea), Crohn's disease, ulcerative colitis, or chronic long-term diarrhea.
• Major surgical procedure (craniotomy, thoracotomy, or laparotomy) within 4 weeks prior to first dose, or unhealed wounds, ulcers, or fractures; tissue biopsy or other minor surgical procedures within 7 days prior to first dose (except venous catheter placement for intravenous infusion).
• History or current presence of pulmonary diseases such as pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, drug-induced pneumonia, or severe impaired lung function.
• Subjects with a history or ongoing Hepatitis C virus (HCV) infection are eligible. HCV-treated subjects must have completed treatment at least 1 month prior to start of study treatment. Subjects with Hepatitis B virus (HBV) are eligible if they meet the following: Patients with HBV viral load ≥10,000 IU/mL must receive anti-HBV therapy concurrent with HCC treatment; subjects on anti-HBV therapy with viral load <10,000 IU/mL should continue the same therapy throughout study treatment. Subjects who are anti-HBc positive, HBsAg negative, anti-HBs negative or positive, and with HBV viral load <10,000 IU/mL do not require anti-HBV prophylaxis.
• Active tuberculosis (TB), currently on anti-TB treatment or received anti-TB treatment within 1 year prior to first dose.
• Known human immunodeficiency virus (HIV) infection (positive HIV 1/2 antibodies), known syphilis infection.
• Active or poorly controlled severe infection. Severe infection within 4 weeks prior to first dose, including but not limited to hospitalization for infection complications, bacteremia, or severe pneumonia.
• Active autoimmune disease requiring systemic treatment (e.g., disease-modifying agents, corticosteroids, or immunosuppressants) within 2 years prior to first dose. Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement for adrenal or pituitary insufficiency) is allowed. Known history of primary immunodeficiency. Subjects with only positive autoimmune antibodies should be evaluated by the investigator to confirm the absence of autoimmune disease.
• Use of immunosuppressive medication within 4 weeks prior to first dose, excluding intranasal, inhaled, topical corticosteroids, or systemic corticosteroids at physiologic doses (not exceeding 10 mg/day prednisone or equivalent). Temporary use of corticosteroids for conditions like asthma or COPD is allowed.
• Administration of a live attenuated vaccine within 4 weeks prior to first dose or planned during the study.
• Use of traditional Chinese medicine with anti-tumor indications or immunomodulatory drugs (including thymosin, interferon, interleukin; except for local use to control pleural or ascitic fluid) within 2 weeks prior to first dose.
• Uncontrolled/uncorrectable metabolic disorders, other non-malignant organ/systemic diseases, or cancer-related sequelae that could lead to higher medical risk and/or uncertainty in survival evaluation.
• Diagnosis of other malignancies within 5 years prior to first dose, except for radically treated basal cell carcinoma, squamous cell carcinoma of the skin, and/or carcinoma in situ. If diagnosis of other malignancy was more than 5 years prior, pathological/cytological diagnosis of recurrent/metastatic lesions is required.
• Prior treatment with any anti-PD-1 antibody, anti-PD-L1/L2 antibody, anti-CTLA-4 antibody, or other immunotherapy.
• Known allergy to Sintilimab, Bevacizumab, or their excipients, or history of severe hypersensitivity to other monoclonal antibodies.
• Treatment with other investigational agents within 4 weeks prior to first dose.
• Pregnant or breastfeeding female patients.
• Any other acute or chronic disease, psychiatric condition, or abnormal laboratory finding that, in the investigator's judgment, may increase the risk associated with study participation or study drug administration, or interfere with the interpretation of study results, and make the patient unsuitable for entry into this study.