A Study to Evaluate the Efficacy and Safety of IBI310 and Sintilimab Combination Therapy in Patients With Hepatocellular Carcinoma as First-line Treatment.

A Randomized, Open-label, Multicenter Study to Evaluate the Efficacy and Safety of IBI310 and Sintilimab Combination Therapy as First-line Treatment in Previously Untreated Patients With Unresectable or Metastatic Hepatocellular Carcinoma

This study is a randomized, controlled, open-label, multicenter, seamless Phase II/III trial designed to evaluate the efficacy and safety of the combination regimen of IBI310 and sintilimab in participants with locally advanced or metastatic hepatocellular carcinoma (HCC) who are: (1) treatment-naive to systemic therapy; and (2) either unsuitable for curative-intent surgical resection or local therapy, or have experienced disease progression following prior surgical resection or local therapy.

Inclusion criteria:

1. Histologically or cytologically confirmed hepatocellular carcinoma (HCC).
2. Age ≥18 years and ≤75 years.
3. Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 or 1.
4. Barcelona Clinic Liver Cancer (BCLC) staging of Stage C, or Stage B that is unsuitable for curative-intent surgery and/or locoregional therapy.
5. No prior systemic antineoplastic therapy for HCC before first dose.
6. At screening, per RECIST 1.1, there must be at least one measurable lesion that has not undergone local therapy, or a measurable lesion that has clearly progressed following local therapy (per RECIST 1.1).
7. Child-Pugh score ≤7.
8. Adequate organ and bone marrow function.
9. Expected survival ≥12 weeks at the time of treatment initiation.
10. Female participants of childbearing potential, or male participants whose sexual partners are of childbearing potential, must use effective contraception throughout the treatment period and for 15 months after the last dose of oxaliplatin (for females) / 12 months after the last dose of oxaliplatin (for males), or for 6 months after the last dose of any other investigational drug-whichever period ends later.
11. Signed written informed consent form, and ability to comply with scheduled visits and all protocol-specified procedures.

Exclusion criteria:

1. Histologically or cytologically confirmed diagnosis of fibrolamellar hepatocellular carcinoma (HCC), sarcomatoid HCC, cholangiocarcinoma, or other mixed hepatic malignancies containing these components.
2. History of hepatic encephalopathy or prior liver transplantation.
3. Clinically symptomatic pleural effusion, ascites, or pericardial effusion requiring therapeutic drainage; participants with only minimal (radiologically detected), asymptomatic effusions may be enrolled.
4. Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection:
5. Known central nervous system (CNS) metastases or symptomatic spinal cord compression.
6. Esophageal or gastric variceal bleeding due to portal hypertension within the past 6 months; Grade 3 (G3) esophageal/gastric varices documented by endoscopy within 3 months prior to first dose; or evidence of portal hypertension.
7. Life-threatening hemorrhagic event within the past 3 months, including but not limited to events requiring blood transfusion, surgical or local intervention, or ongoing pharmacologic hemostatic therapy.
8. Metastatic lesions invading major vessels, airways, or the mediastinum with clinically significant bleeding risk.
9. Arterial or venous thromboembolic event within the past 6 months, including myocardial infarction, unstable angina, cerebrovascular accident (stroke), transient ischemic attack (TIA), pulmonary embolism, deep vein thrombosis, or other severe thromboembolic conditions.
10. Portal vein tumor thrombus (PVTT) involving both the main portal vein and left/right branch; PVTT extending into the superior mesenteric vein; or PVTT involving the inferior vena cava.
11. Use of aspirin (>325 mg/day) or other known platelet-function-inhibiting agents (e.g., dipyridamole or clopidogrel) for therapeutic purposes within 10 days prior to randomization. Prophylactic use of anticoagulants is permitted.
12. Uncontrolled hypertension: systolic blood pressure >150 mmHg and/or diastolic blood pressure >100 mmHg despite optimal medical management; history of hypertensive crisis or hypertensive encephalopathy.
13. Persistent treatment-related toxicities from prior anticancer therapy not resolved to Grade 0 or Grade 1 according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0 at the time of randomization.
14. Symptomatic congestive heart failure (New York Heart Association [NYHA] Class II-IV); symptomatic or inadequately controlled arrhythmias; history of congenital long QT syndrome; or baseline corrected QT interval (QTcF, calculated using Fridericia's formula) >500 ms.
15. Severe bleeding diathesis or coagulopathy; or current thrombolytic therapy.
16. History of gastrointestinal perforation and/or fistula within the past 6 months; unresolved intestinal obstruction (including incomplete obstruction requiring parenteral nutrition); extensive bowel resection (e.g., partial colectomy or extensive small bowel resection leading to chronic diarrhea); Crohn's disease; ulcerative colitis; or chronic diarrhea of prolonged duration.
17. Prior radiotherapy within 3 weeks before randomization.
18. Clinically significant pre-existing pulmonary disease.
19. Active tuberculosis (TB), currently receiving anti-TB therapy, or having completed anti-TB therapy within the past year.
20. Known human immunodeficiency virus (HIV) infection (positive HIV-1/2 antibody test).
21. Active or inadequately controlled severe infection.
22. Known or suspected active autoimmune disease, or history of active autoimmune disease within the past 2 years.
23. Systemic immunosuppressive therapy within 2 weeks prior to randomization.
24. Receipt of live attenuated vaccines within 4 weeks prior to randomization, or planned administration during the study.
25. Major surgery (e.g., craniotomy, thoracotomy, laparotomy) or presence of unhealed wounds, ulcers, or fractures within 4 weeks prior to randomization.
26. Local therapy for HCC within 4 weeks prior to first dose.
27. Use of Traditional Chinese Medicine (TCM) with antitumor indications, or immunomodulatory agents (e.g., thymosin, interferons, interleukins), within 2 weeks prior to first dose.
28. Uncontrolled or uncorrectable metabolic disorders, non-malignant organ dysfunction, systemic illness, or cancer-related paraneoplastic syndromes posing substantial medical risk or introducing uncertainty in survival assessment - as determined by the investigator; or any other condition deemed unsuitable for enrollment by the investigator.
29. Diagnosis of another primary malignancy within 5 years prior to randomization.
30. Prior treatment with any anti-PD-1, anti-PD-L1/L2, anti-CTLA-4 antibodies, or other immune checkpoint inhibitors.
31. Known hypersensitivity to any active ingredient or excipient of the investigational product; or history of severe allergic reaction (e.g., anaphylaxis) to other monoclonal antibodies.
32. Receipt of treatment in another interventional clinical trial within 4 weeks prior to randomization.
33. Female participants who are pregnant or breastfeeding.
34. Any other acute or chronic medical condition, psychiatric disorder, or clinically significant laboratory abnormality that, in the Investigator's judgment: increases the risks associated with participation in the study or administration of the investigational product; or may interfere with the interpretation of study results - rendering the participant unsuitable for enrollment.