A Study of AK112, a PD-1/ VEGF Bispecific Antibody, for Resectable Hepatocellular Carcinoma With High Recurrence Risk

Inclusion Criteria:

1. Signed written informed consent before any trial-related procedures. 2. Male orfemale aged between 18 and 75 years. 3. ECOG PS score 0-1. 4.Histologically/cytologically confirmed hepatocellular carcinoma (HCC) or meetsclinical diagnosis criteria (per 2022 Chinese Primary Liver Cancer Diagnosis andTreatment Guidelines).

2. No preoperative HCC treatment (including chemotherapy, targeted therapy,immunotherapy, cell therapy, local radiotherapy, ablation, or intervention). Nolymph node invasion/distant metastasis on preoperative imaging, and deemed suitablefor radical surgery by the investigator.

3. At least one postoperative high-risk factor for HCC recurrence:

4. Single lesion more than 5 cm in longest diameter.

5. Microvascular or macrovascular invasion.

6. More than 3 tumor nodules.

7. Edmondson grade at least II on tumor pathology.

8. AFP more than 400 μg/L in CNLC Ib-IIa patients.

9. Tumor adjacent to blood vessels in CNLC Ib-IIa patients.

10. 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 replacementtherapy allowed). Asymptomatic subjects with abnormal T3, free T3, or free T4 areeligible.

11. Adequate organ and bone marrow function, with laboratory values meeting thefollowing criteria within 7 days before randomization (no blood products,growth factors, albumin, or corrective treatments within 14 days beforeobtaining these results):

12. Hematology: ANC at least 1.5×10⁹/L; PLT at least 75×10⁹/L; HGB at least 9.0g/dL.

13. Liver function: TBIL at most 3×ULN; ALT, AST, ALP at most 5×ULN; serum albuminat least 28 g/L.

14. 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. Forsubjects with baseline urine protein at least 2+, 24-hour urine protein lessthan 1 g.

15. Coagulation: INR and APTT at most 1.5×ULN. 12. For female subjects ofchildbearing potential, a negative urine or serum pregnancy test within 3 daysbefore the first study drug administration (Cycle 1, Day 1). If urine test isinconclusive, a blood pregnancy test is required. Postmenopausal females (forat least 1 year), surgically sterilized, or hysterectomized are not ofchildbearing potential.

16. All subjects with pregnancy risk must use effective contraception throughouttreatment until 120 days after the last study drug dose (or 180 days after lastchemotherapy dose).

Exclusion Criteria:

1. Past histological/cytological diagnosis of fibrolamellar hepatocellularcarcinoma (HCC), sarcomatoid HCC, cholangiocarcinoma, etc.

2. Other malignancies within 5 years before enrollment, except those locallytreated HCC. Exceptions include basal/squamous cell skin cancer, superficialbladder 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 inferiorvena cava.

5. Active hepatitis B/C infection, with HBV DNA more than 2000 IU/ml or 10⁴copies/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 continueduring the study are eligible.

6. Clinically symptomatic pleural effusion, ascites, or pericardial effusionrequiring drainage.

7. Esophagogastric variceal bleeding due to portal hypertension within 6 monthsbefore first dose; current imaging shows significant esophagogastric varices.

8. History of significant bleeding tendency/coagulopathy; clinically significantbleeding within 1 month before first dose (e.g., GI bleeding, hemoptysis,epistaxis); continuous antiplatelet/anticoagulant therapy within 10 days beforefirst dose.

9. Arterial/venous thromboembolism within past 6 months, including myocardialinfarction, unstable angina, stroke, transient ischemic attack, pulmonaryembolism, deep vein thrombosis. Exceptions: stable thrombosis after routineanticoagulation for implanted venous ports/ catheters or superficial veinthrombosis; 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 safetyassessment. 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; COPDexacerbation, hypertensive crisis/encephalopathy within 1 month before firstdose; current hypertension uncontrolled by oral medication (systolic BP morethan 150 mmHg or diastolic BP more than 90 mmHg).

11. History or current non-infectious pneumonia/interstitial lung disease requiringsystemic corticosteroids; active or past definite inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis, chronic diarrhea); activeautoimmune disease requiring systemic treatment within past 2 years (e.g.,DMARDs, corticosteroids, immunosuppressants). Replacement therapy (e.g.,thyroid hormones, insulin, physiological corticosteroids for adrenal/pituitaryinsufficiency) is not considered systemic treatment.

12. History of immunodeficiency; positive HIV antibody test; current long-term useof systemic corticosteroids or other immunosuppressants (except short-termcorticosteroids for COPD-related dyspnea or temporary allergy prevention).

13. Known active tuberculosis (TB); suspected active TB requires clinicalexclusion; known active syphilis infection.

14. Severe infection within 4 weeks before first dose (e.g., requiringhospitalization, sepsis, severe pneumonia); active infection treated withsystemic anti-infectives within 2 weeks before first dose (excluding antiviraltherapy 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 tumorimmune mechanisms.

17. Past local therapy for liver lesions, including TACE, TARE, HAIC, orradiotherapy.

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 orplanned during study; inactivated vaccines are allowed.

20. Known allergy to any study drug component; history of severe hypersensitivityto 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 theinvestigator.