A Study to Compare the Efficacy, Safety, Immunogenicity, and Pharmacokinetic Profile of HLX13 with YERVOY As a First-Line Treatment for Patients with Unresectable Hepatocellular Carcinoma

A Randomized, Multicenter, Double-Blind, Parallel-Controlled Integrated Phase I/III Clinical Study to Evaluate the Efficacy, Safety, Immunogenicity, and Pharmacokinetic Profile of Ipilimumab Biosimilar HLX13 Vs. YERVOY® (US-Sourced YERVOY® and EU-Sourced YERVOY®) As a First-Line Treatment for Patients with Unresectable Hepatocellular Carcinoma

This is a multicenter, randomized, double-blind, parallel-controlled integrated phase I/III clinical study to evaluate the efficacy, safety, PK, and immunogenicity of HLX13 and YERVOY® in patients with unresectable hepatocellular carcinoma who have not received prior systemic therapy.

This study includes three treatment groups. Patients will be randomly assigned at a 2:1:1 ratio to the HLX13, US-sourced YERVOY®, or EU-sourced YERVOY® group to receive the treatment of IMPs in combination with nivolumab.

Patients with good tolerability and disease control will receive HLX13 or YERVOY® in combination with nivolumab on the first day of every 3 weeks for up to 4 cycles. PK and immunogenicity blood sampling will be conducted during the treatment period. After the four treatment cycles, all subjects will be subsequently treated with nivolumab monotherapy until investigator-assessed disease progression, initiation of a new anti-neoplastic therapy, withdrawal of informed consent, death, unacceptable toxicity, or up to 1 year after randomization, whichever occurs first.

Inclusion Criteria:

• Histologically or cytologically diagnosed relapsed metastatic or advanced hepatocellular carcinoma not eligible for surgical or locoregional therapies according to the diagnostic criteria of the American Association for the Study of Liver Diseases (AASLD).
• At least one measurable lesion as assessed by IRRC based on RECIST v1.1 within 4 weeks prior to the first dose in this study.
• No systemic therapy for relapsed metastatic or advanced hepatocellular carcinoma prior to screening.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1.
• Child-Pugh Class A.
• Normal major organ functions.
• Women of childbearing potential should use highly effective methods of contraception during the study and within 5 months after the last study treatment; Male subjects capable of fathering a child must agree to use at least one highly effective method of contraception for the duration of the study and for at least 7 months after the last study treatment.

Exclusion Criteria:

• With other histopathological types of hepatocellular carcinoma.
• History of hepatic encephalopathy.
• Clinically significant ascites.
• Patients with tumor thrombus at the main portal vein, left or right portal (either or both) vein branch, or inferior vena cava.
• Presence of the central nervous system disorders at screening, except subjects who have previously received treatment for brain metastases can participate in the study treatment if their clinical symptoms have been stable for at least 4 weeks.
• Evidence of portal hypertension with bleeding esophageal or gastric varices within 6 months prior to the randomization.
• Known active or suspected autoimmune diseases.
• Active co-infection with both hepatitis B and C, or hepatitis D infection in subjects with hepatitis B.
• Uncontrolled cardiovascular diseases within 6 months.
• Known interstitial pneumonia, pneumoconiosis, radiation pneumonitis, drug-related pneumonitis, and severe lung function abnormalities that may impede the investigators' diagnosis and management of drug-related pulmonary toxicity prior to screening.
• Patients who have received any T-cell costimulatory agents or immune checkpoint blockade therapy, including but not limited to cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) inhibitors, PD-1 inhibitors, PD-L1/2 inhibitors, or other agents that target T cells.
• Patients who have other conditions not suitable for inclusion per investigator's judgments.