Overview

This study is a single-arm, open-label study. To assess the efficacy and safety of AK112 therapy in patients with resectable hepatocellular carcinoma at high risk of recurrence. The primary endpoint is the 12-month RFS rate of resectable hepatocellular carcinoma.

Eligibility

Inclusion Criteria:

1. Signed written informed consent before any trial-related procedures. 2. Male or female aged between 18 and 75 years. 3. ECOG PS score 0-1. 4. Histologically/cytologically confirmed hepatocellular carcinoma (HCC) or meets clinical diagnosis criteria (per 2022 Chinese Primary Liver Cancer Diagnosis and Treatment Guidelines).
2. No preoperative HCC treatment (including chemotherapy, targeted therapy, immunotherapy, cell therapy, local radiotherapy, ablation, or intervention). No lymph node invasion/distant metastasis on preoperative imaging, and deemed suitable for radical surgery by the investigator.
3. At least one postoperative high-risk factor for HCC recurrence:
   1. Single lesion more than 5 cm in longest diameter.
   2. Microvascular or macrovascular invasion.
   3. More than 3 tumor nodules.
   4. Edmondson grade at least II on tumor pathology.
   5. AFP more than 400 μg/L in CNLC Ib-IIa patients.
   6. Tumor adjacent to blood vessels in CNLC Ib-IIa patients.
   7. Incomplete tumor capsule in CNLC Ib-IIa patients. 7. Child-Pugh score A or B7. 8. Expected survival more than 3 months. 9. At least one measurable lesion per RECIST 1.1. 10. Total T3 or free T3 and free T4 within normal range (thyroid replacement therapy allowed). Asymptomatic subjects with abnormal T3, free T3, or free T4 are eligible.
   8. Adequate organ and bone marrow function, with laboratory values meeting the following criteria within 7 days before randomization (no blood products, growth factors, albumin, or corrective treatments within 14 days before obtaining these results):
      1. Hematology: ANC at least 1.5×10⁹/L; PLT at least 75×10⁹/L; HGB at least 9.0 g/dL.
      2. Liver function: TBIL at most 3×ULN; ALT, AST, ALP at most 5×ULN; serum albumin at least 28 g/L.
      3. Renal function: Serum creatinine at most 1.5×ULN or CCr at least 50 mL/min (Cockcroft-Gault formula); urine protein less than 2+ on urinalysis. For subjects with baseline urine protein at least 2+, 24-hour urine protein less than 1 g.
      4. Coagulation: INR and APTT at most 1.5×ULN. 12. For female subjects of childbearing potential, a negative urine or serum pregnancy test within 3 days before the first study drug administration (Cycle 1, Day 1). If urine test is inconclusive, a blood pregnancy test is required. Postmenopausal females (for at least 1 year), surgically sterilized, or hysterectomized are not of childbearing potential.
      5. All subjects with pregnancy risk must use effective contraception throughout treatment until 120 days after the last study drug dose (or 180 days after last chemotherapy dose).

Exclusion Criteria:

1. Past histological/cytological diagnosis of fibrolamellar hepatocellular carcinoma (HCC), sarcomatoid HCC, cholangiocarcinoma, etc.
2. Other malignancies within 5 years before enrollment, except those locally treated HCC. Exceptions include basal/squamous cell skin cancer, superficial bladder cancer, cervical/ breast carcinoma in situ.
3. History of hepatic encephalopathy or liver transplantation.
4. Cancer thrombus in portal vein branches, superior mesenteric vein, or inferior vena cava.
5. Active hepatitis B/C infection, with HBV DNA more than 2000 IU/ml or 10⁴ copies/ml; HCV RNA more than 10³ copies/ml; co-positive HBsAg and anti-HCV. Those on antiviral therapy meeting the above criteria and willing to continue during the study are eligible.
6. Clinically symptomatic pleural effusion, ascites, or pericardial effusion requiring drainage.
7. Esophagogastric variceal bleeding due to portal hypertension within 6 months before first dose; current imaging shows significant esophagogastric varices.
8. History of significant bleeding tendency/coagulopathy; clinically significant bleeding within 1 month before first dose (e.g., GI bleeding, hemoptysis, epistaxis); continuous antiplatelet/anticoagulant therapy within 10 days before first dose.
9. Arterial/venous thromboembolism within past 6 months, including myocardial infarction, unstable angina, stroke, transient ischemic attack, pulmonary embolism, deep vein thrombosis. Exceptions: stable thrombosis after routine anticoagulation for implanted venous ports/ catheters or superficial vein thrombosis; low-dose LMWH (e.g., enoxaparin 40 mg/day) allowed.
10. History of myocarditis, cardiomyopathy, malignant arrhythmias. Unstable angina, MI, CHF (NYHA ≥Class 2), or vascular disease requiring hospitalization within 12 months before first dose; other cardiac impairments affecting drug safety assessment. Severe ulcers, unhealed wounds, GI perforation, fistula, obstruction, abscess, or acute GI bleeding within 6 months before first dose; thromboembolic events, TIA, stroke within 6 months before first dose; COPD exacerbation, hypertensive crisis/encephalopathy within 1 month before first dose; current hypertension uncontrolled by oral medication (systolic BP more than 150 mmHg or diastolic BP more than 90 mmHg).
11. History or current non-infectious pneumonia/interstitial lung disease requiring systemic corticosteroids; active or past definite inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis, chronic diarrhea); active autoimmune disease requiring systemic treatment within past 2 years (e.g., DMARDs, corticosteroids, immunosuppressants). Replacement therapy (e.g., thyroid hormones, insulin, physiological corticosteroids for adrenal/pituitary insufficiency) is not considered systemic treatment.
12. History of immunodeficiency; positive HIV antibody test; current long-term use of systemic corticosteroids or other immunosuppressants (except short-term corticosteroids for COPD-related dyspnea or temporary allergy prevention).
13. Known active tuberculosis (TB); suspected active TB requires clinical exclusion; known active syphilis infection.
14. Severe infection within 4 weeks before first dose (e.g., requiring hospitalization, sepsis, severe pneumonia); active infection treated with systemic anti-infectives within 2 weeks before first dose (excluding antiviral therapy for hepatitis B/C).
15. Past systemic chemotherapy or bevacizumab/biosimilar treatment.
16. Past immunotherapy, including immune checkpoint inhibitors (e.g., anti-PD-1/L1, CTLA-4, CD47, SIRPα, LAG-3 antibodies), immune checkpoint agonists (e.g., ICOS, CD40, CD137, GITR, OX40 antibodies), or any immunotherapy targeting tumor immune mechanisms.
17. Past local therapy for liver lesions, including TACE, TARE, HAIC, or radiotherapy.
18. Systemic anti-tumor traditional Chinese medicine or immunomodulatory drugs (e.g., thymosin, interferon, interleukin) within 2 weeks before first dose (except those locally used to control pleural/ascitic fluid).
19. Live/attenuated vaccine administration within 30 days before first dose or planned during study; inactivated vaccines are allowed.
20. Known allergy to any study drug component; history of severe hypersensitivity to other monoclonal antibodies.
21. Known psychiatric disease, drug abuse, alcoholism, or substance addiction.
22. Pregnant or breastfeeding women.
23. Any condition, disease, or abnormality that may interfere with study results, hinder study participation, or pose additional risk, as determined by the investigator.