Assessment of Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of GKL-006 Injection in Combination With TACE in Unresectable Hepatocellular Carcinoma

Prior treatment

• Another malignancy within the previous 5 years or a concurrent uncontrolled malignancy, except cured basal cell carcinoma, carcinoma in situ, or breast cancer with no recurrence for \>3 years after curative surgery.
• Systemic corticosteroids (\>10 mg/day prednisone or equivalent) or other immunosuppressive therapy within 4 weeks before screening.
• Urine protein ≥2+ within 7 days before enrolment with confirmed 24-hour urine protein \>1.0 g.
• CTCAE v5.0 Grade ≥2 bleeding within 4 weeks before enrolment;
• Active infection within 2 weeks before enrolment.
• Receipt of a live attenuated vaccine or COVID-19 vaccine within 4 weeks before screening.

Other illness

• Hypersensitivity to immunotherapy or related medications.
• History of organ transplantation.
• Active, known, or suspected autoimmune disease.
• History or current evidence of idiopathic pulmonary fibrosis, interstitial pneumonitis, pneumoconiosis, drug-induced pneumonitis, or active pneumonitis on screening CT.
• Poorly controlled cardiovascular disease.
• Uncontrolled hypertension despite medication (systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg).
• Any of the following bleeding risks:
• tumour invasion of a major vessel or a high risk of life-threatening bleeding, as determined by the investigator;
• gastrointestinal bleeding within 6 months;
• known hereditary or acquired bleeding or thrombotic disorder.
• Congenital or acquired immunodeficiency, including HIV infection; syphilis; or another serious active infection.
• Any other condition that, in the investigator's opinion, makes the participant unsuitable for enrolment or study completion.

Lab values

• AST or ALT \>5 × ULN within 7 days before enrolment.
• Any serious concomitant disease, clinically significant laboratory abnormality, psychiatric condition, or family or social circumstance that may compromise participant safety or interfere with data or sample collection, as determined by the investigator.

Other

• Any contraindication to TACE, as determined by the investigator.
• Histologically or cytologically confirmed combined HCC-cholangiocarcinoma, fibrolamellar HCC, sarcomatoid HCC, or another mixed carcinoma.
• Infiltrative tumour growth or extrahepatic metastasis on imaging.
• Hepatic encephalopathy.
• Symptomatic ascites or pleural effusion.
• Arterial or venous thromboembolic event within 6 months.
• Signs or symptoms of intestinal or gastrointestinal obstruction within 1 month.
• Pregnant or breastfeeding women.
• Participation in another interventional clinical trial.

• Voluntarily participates and provides written informed consent.
• Aged ≥18 years, male or female.
• Unresectable primary hepatocellular carcinoma (HCC) confirmed by histology, cytology, or imaging (dynamic CT or MRI). Unresectable disease includes technically unresectable disease or disease for which surgery is not feasible or is declined for other reasons.
• CNLC stage II-IIIa.
• Suitable for TACE and total tumour volume ≤50% of the liver volume.
• At least one measurable HCC lesion per mRECIST.
• Tumour confined to the liver, with no extrahepatic spread or major vascular invasion (Vp3 or Vp4 portal vein tumour thrombus).
• Child-Pugh score ≤9 within 7 days before enrolment.
• ECOG performance status of 0-2
• Life expectancy ≥24 weeks.
• Adequate haematologic and organ function:
  • WBC ≥2 × 10\^9/L;
  • haemoglobin ≥90 g/L;
  • ANC ≥1.5 × 10\^9/L;
  • platelets ≥50 × 10\^9/L;
  • PT or APTT ≤2 × ULN;
  • serum creatinine ≤ULN;
  • AST and ALT ≤5 × ULN;
  • total bilirubin ≤3 × ULN.
• For patients with HBV or HCV infection, viral load must not exceed the lower limit of detection (HBV DNA ≤2,000 IU/mL and HCV RNA ≤100 IU/mL).
• No radiotherapy, chemotherapy, targeted therapy, or immunosuppressive therapy within 4 weeks before screening.
• Participants of reproductive potential must use at least one medically accepted contraceptive method during study treatment and for 6 months after treatment.
• Able to communicate with investigators, comply with study visits, and understand and follow study requirements.