Evaluate the Safety and Efficacy of Combination Therapy With SYS6090 Injection for Hepatocellular Carcinoma

The study design consists of two phases. Phase Ib is a dose-escalation and dose-expansion study, with the primary objectives to evaluate the safety, tolerability and preliminary efficacy of SYS6090 combination therapy and identify the recommended dose for the combination regimen. Phase II is a randomized controlled trial (RCT) that with the objective to further assesses the efficacy and safety of SYS6090 combination therapy versus a positive control group.

Inclusion criteria

• The participant voluntarily signs the informed consent form.
• Aged ≥18 years at the time of informed consent acquisition.
• Confirmed diagnosis of hepatocellular carcinoma (HCC) via histopathology, cytopathology, or clinical diagnosis in accordance with the Guidelines for Diagnosis and Treatment of Primary Liver Cancer (2026 Edition).
• Barcelona Clinic Liver Cancer (BCLC) Stage C; or BCLC Stage B unsuitable for curative surgery and/or locoregional therapy.
• Child-Pugh score <7 and no history of hepatic encephalopathy.
• No prior systemic anti-tumor therapy for HCC. Prior systemic therapy administered in the neoadjuvant or adjuvant setting is permitted, provided that the time from the last dose of prior therapy to tumor recurrence is ≥6 months.
• At least one measurable lesion per RECIST Version 1.1. Lesions previously treated with interventional therapy, radiotherapy or ablation may be counted as measurable lesions if clear disease progression is documented per RECIST v1.1 and the lesion meets measurable lesion criteria.
• Eastern Cooperative Oncology Group (ECOG) performance status ≤1.
• Expected survival ≥3 months.
• Adequate organ function as defined below:

• Hematology: PLT ≥100×10⁹/L; Hb ≥90 g/L; ANC ≥1.5×10⁹/L (no blood transfusion, platelet transfusion or hematopoietic stimulating factor administered within 14 days prior to hematology testing at screening);
• Liver function: AST and ALT ≤5×ULN; TBIL ≤1.5×ULN;
• Renal function: Ccr >50 mL/min (calculated by the Cockcroft-Gault formula); urine protein <2+; participants with urine protein ≥2+ must have a 24-hour urine protein quantification <1 g;
• Coagulation function: APTT ≤1.5×ULN; INR ≤1.5×ULN. Participants receiving full-dose oral anticoagulants must maintain a stable dose for a minimum of 14 days;
• Albumin: ≥30 g/L (equivalent to ≥3.0 g/dL).
• Fertile eligible participants (male and female) must agree to use reliable contraceptive methods together with their partners throughout the study period and for at least 7 months after the last study drug administration (hormonal contraceptives, barrier methods, or abstinence). Females of childbearing potential must have a negative serum pregnancy test within 7 days prior to enrollment.
• Willing and able to comply with all study requirements.

Exclusion criteria

• Histologically or cytologically confirmed fibrolamellar hepatocellular carcinoma, sarcomatoid hepatocellular carcinoma, intrahepatic cholangiocarcinoma, or mixed hepatocellular-cholangiocarcinoma.
• Received any anti-tumor therapy (including chemotherapy, targeted therapy, immunotherapy, etc.) or any investigational trial intervention within 4 weeks prior to the first study drug administration or within 5 half-lives of the most recent anti-tumor agent (whichever is shorter); or received Chinese patent medicines with anti-tumor indications, palliative radiotherapy, or locoregional therapy within 14 days prior to the first study drug administration.
• Underwent major visceral surgery (excluding core needle biopsy) or sustained severe trauma within 4 weeks prior to the first study drug administration, or planned elective surgery during the study period.
• Received systemic corticosteroids or other immunosuppressive agents within 14 days prior to the first study drug administration, except for the following scenarios: physiologic replacement doses of hydrocortisone or equivalent hormones (i.e., prednisone ≤10 mg/day or equivalent); topical, ophthalmic, intra-articular, intranasal, or inhaled corticosteroids; short-course corticosteroids for prophylaxis (e.g., prophylaxis against contrast medium allergy).
• Received live vaccines within 4 weeks prior to the first study drug administration. Note: Seasonal influenza vaccines are inactivated vaccines in general and are permitted. Intranasal influenza vaccines are live vaccines and are prohibited.
• Received strong CYP3A4 inhibitors/inducers, or OATP1B1/OATP1B3 inhibitors within 14 days prior to the first study drug administration, or require continuous use of such agents throughout the study period.
• Adverse reactions from prior anti-tumor therapy have not recovered to Grade ≤1 per NCI CTCAE v6.0 (excluding toxicities judged by the Investigator to carry no safety risks, such as alopecia, Grade 2 peripheral neuropathy, hypothyroidism stabilized with hormone replacement therapy, etc.).
• History of or current central nervous system metastases and/or carcinomatous meningitis; current untreated spinal cord compression (excluding participants with previously diagnosed treated spinal cord compression with documented clinically stable symptoms for more than 2 weeks prior to screening).
• Active infection requiring intravenous anti-infective therapy within 14 days prior to the first study drug administration.
• Symptomatic moderate or severe ascites within 14 days prior to the first dose or at screening (excluding minor ascites only visible on imaging without clinical symptoms); or uncontrolled moderate or larger pleural effusion or pericardial effusion.
• Tumor thrombus involving both the main portal vein and left/right portal branches simultaneously; tumor thrombus involving both the main portal vein and superior mesenteric vein simultaneously; or tumor thrombus involving the inferior vena cava.
• Esophageal or gastric variceal bleeding secondary to portal hypertension, or any life-threatening bleeding event within 6 months prior to the first study drug administration (including events requiring blood transfusion, surgery, locoregional intervention, or sustained medical treatment); known severe esophageal/gastric varices on endoscopy without definitive treatment within 3 months prior to the first study drug administration; other gastrointestinal bleeding events, active gastric or duodenal ulcer within 28 days prior to screening.
• History of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess, or intestinal obstruction within 6 months prior to the first study drug administration.
• Presence of severe unhealed wounds or untreated fractures at screening.
• Current interstitial pneumonia/interstitial lung disease; prior history of interstitial pneumonia/interstitial lung disease requiring corticosteroid treatment; or other pulmonary conditions that may interfere with the identification and management of immune-related pulmonary toxicity, such as pulmonary fibrosis, organizing pneumonia, active pulmonary tuberculosis, etc.
• Active hepatitis B at screening [positive HBsAg or HBcAb with active viral replication (HBV DNA ≥2000 IU/mL)]; hepatitis C (positive Anti-HCV antibody with positive HCV RNA PCR); active syphilis infection (positive TP-Ab plus positive TRUST/RPR); HIV infection; or concurrent co-infection with both hepatitis B and hepatitis C.
• History of severe cardiovascular and cerebrovascular diseases, including but not limited to:

• NYHA Class II or higher congestive heart failure, unstable angina, or myocardial infarction occurring within 6 months prior to the first study drug administration;
• Severe cardiac rhythm or conduction abnormalities requiring clinical intervention, such as ventricular arrhythmias, second- or third-degree atrioventricular block (participants may be eligible if the Investigator assesses no significant risks);
• Primary cardiomyopathy (e.g., dilated cardiomyopathy, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, restrictive cardiomyopathy, unclassified cardiomyopathy);
• Clinically significant history of QT interval prolongation, or QTcF (calculated via Fridericia's formula) > 480 ms at screening, or left ventricular ejection fraction < 50%;
• Arterial or venous thromboembolic events within 6 months prior to the first study drug administration, such as cerebrovascular accidents (including transient ischemic attack, cerebral hemorrhage, cerebral infarction), deep vein thrombosis, pulmonary embolism, etc. Participants with stable thrombosis may be enrolled if the Investigator determines no cardiovascular risks.
• Uncontrolled hypertension (systolic blood pressure > 160 mmHg and/or diastolic blood pressure > 100 mmHg).
• Active or recurrent autoimmune disease (e.g., systemic lupus erythematosus, rheumatoid arthritis, vasculitis, etc.), except for the following conditions:

• Autoimmune thyroid disease with clinically stable status;
• Type 1 diabetes managed with hormone replacement therapy;
• Autoimmune skin disorders well controlled with topical therapy (e.g., low-potency topical corticosteroids) without acute exacerbations requiring additional treatment within 12 months before screening (e.g., eczema, psoriasis, lichen simplex chronicus, or vitiligo involving <10% of total body surface area).
• Prior immunotherapy complicated with Grade ≥3 immune-related adverse events (irAEs) or Grade ≥2 immune-related myocarditis (excluding stabilized immune-related endocrine abnormalities).
• Known hypersensitivity to any component of the study treatment; history of hypersensitivity to premedications; or poorly controlled asthma (presentation of three or more asthma symptoms with partially controlled or uncontrolled status).
• Female participants who are pregnant or breastfeeding.
• History of other malignant tumors within 2 years prior to the first dose, or concurrent active malignant tumors (participants with cured localized tumors may be enrolled, including basal cell carcinoma of the skin, cutaneous squamous cell carcinoma, superficial bladder cancer, carcinoma in situ of the prostate, cervical carcinoma in situ, breast carcinoma in situ, etc.).
• Known alcohol or drug dependence; or other severe systemic medical conditions deemed by the Investigator to render the participant unsuitable for participation in this clinical study for any other reason.