The DoHAICs Study Expansion Phase

Inclusion criteria

• Voluntarily participate in the trial and provide written informed consent.
• Age between 18 and 80 years (inclusive), regardless of gender.
• Patients with hepatocellular carcinoma (HCC) clinically diagnosed per the "Standard for Diagnosis and Treatment of Primary Liver Cancer (2024 Edition)" or confirmed by histology/cytology.
• Patients with inoperable or metastatic hepatocellular carcinoma.
• No prior systemic therapy for advanced disease. Patients who received adjuvant chemotherapy following local therapy are eligible if chemotherapy was completed >12 months ago and disease progression or metastasis has occurred.
• Completion of the last interventional therapy, radiotherapy, or ablation therapy >4 weeks prior.
• For patients with prior hepatectomy, resection must have been R0, and tumor recurrence must have occurred more than 24 months after surgery.
• At least one measurable lesion as defined by RECIST 1.1 criteria.
• Life expectancy ≥3 months.
• Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.
• Child-Pugh score ≤7.
• Able and willing to comply with the protocol for the observation of adverse events and efficacy.
• Adequate organ function, defined as meeting the following criteria:
• Hematological function (without transfusion or granulocyte colony-stimulating factor [G-CSF] support within 14 days prior to screening):
• Hemoglobin ≥90 g/L.
• Absolute neutrophil count (ANC) ≥1.5 × 10⁹/L.
• Platelet count ≥75 × 10⁹/L.
• Biochemical tests (without albumin infusion within 14 days prior to screening):
• Albumin ≥28 g/L.
• Total bilirubin ≤2 × upper limit of normal (ULN).
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤5 × ULN.
• Alkaline phosphatase (ALP) ≤5 × ULN.
• Serum creatinine ≤1.5 × ULN.
• Coagulation function:
• International normalized ratio (INR) or prothrombin time (PT) ≤1.5 × ULN.
• Activated partial thromboplastin time (APTT) ≤1.5 × ULN.

Exclusion criteria

• Histologically/cytologically confirmed components such as fibrolamellar hepatocellular carcinoma, sarcomatoid hepatocellular carcinoma, or cholangiocarcinoma.
• History of malignancies other than hepatocellular carcinoma, except under the following circumstances:
• The patient has undergone potentially curative treatment with no evidence of that disease for 5 years.
• Successfully resected basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, carcinoma in situ of the cervix, or other carcinoma in situ.
• Diffuse tumor lesions.
• History of hepatic encephalopathy, hepatorenal syndrome, or liver transplantation.
• Clinically symptomatic pleural effusion, ascites, or pericardial effusion requiring drainage.
• Central nervous system metastases.
• History of severe psychiatric illness.
• Diseases affecting the absorption, distribution, metabolism, or excretion of the investigational drug (e.g., severe vomiting, chronic diarrhea, intestinal obstruction, malabsorption, etc.).
• Prior allogeneic stem cell or solid organ transplantation.
• Prior treatment with anti-VEGF/VEGFR, RAF, MEK pathway targeted therapies (e.g., sorafenib, lenvatinib, regorafenib) or immunomodulators (e.g., anti-PD-1, anti-PD-L1, anti-CTLA-4 antibodies).
• Prior other systemic anti-tumor therapy, including Chinese herbal medicine with anti-tumor indications, completed less than 2 weeks before study drug initiation; or patients with adverse events from prior therapy not recovered to ≤ Grade 1 per CTCAE (excluding alopecia and Grade 1/2 neuropathy caused by oxaliplatin).
• Concurrent use of medications known to prolong QTc interval and/or induce Torsades de Pointes (TdP), or medications that affect drug metabolism.
• Past or present congenital or acquired immunodeficiency diseases.
• Active or history of autoimmune or inflammatory diseases (including but not limited to: autoimmune hepatitis, interstitial pneumonia, inflammatory bowel disease, systemic lupus erythematosus, vasculitis, uveitis, hypophysitis, hyper- or hypothyroidism, asthma requiring bronchodilators, etc.). Patients with vitiligo or asthma that was fully resolved in childhood and requires no intervention in adulthood may be included.
• Use of systemic immunosuppressive medication within 2 weeks prior to enrollment, or anticipated requirement for such medication during the study, except for:
• Intranasal, inhaled, topical, or local corticosteroid injections (e.g., intra-articular).
• Systemic corticosteroids at physiological doses not exceeding 10 mg/day prednisone or equivalent.
• Prophylactic use of corticosteroids for hypersensitivity reactions.
• Known or suspected hypersensitivity to donafenib, drugs of the same class, or history of hypersensitivity to chimeric or humanized antibodies or fusion proteins, or allergy to any excipient of the investigational drug.
• Active bleeding or coagulation disorders, bleeding tendency, or undergoing thrombolytic, anticoagulant, or antiplatelet therapy.
• Thrombotic or thromboembolic events within the past 6 months, such as stroke and/or transient ischemic attack, deep vein thrombosis, pulmonary embolism, etc.
• History of esophageal or gastric variceal bleeding due to portal hypertension within the past 6 months, or any life-threatening bleeding event within the past 3 months.
• Significant cardiovascular disease, including but not limited to: acute myocardial infarction, severe/unstable angina, or coronary artery bypass grafting within the past 6 months; congestive heart failure (NYHA class >2); poorly controlled arrhythmias requiring pacemaker treatment; uncontrolled hypertension (systolic BP ≥140 mmHg and/or diastolic BP ≥90 mmHg).
• Other clinically significant abnormalities, deemed by the investigator to affect safety evaluation, such as uncontrolled diabetes, chronic kidney disease, Grade II or higher peripheral neuropathy (CTCAE v6.0), abnormal thyroid function, etc.
• Active or poorly controlled severe infection; active infections including:
• Positive for Human Immunodeficiency Virus (HIV) (HIV1/2 antibodies).
• Active Hepatitis B (HBsAg positive or HBV DNA >2000 IU/mL with abnormal liver function).
• Active Hepatitis C (HCV antibody positive or HCV RNA ≥10³ copies/mL with abnormal liver function).
• Active tuberculosis.
• Other uncontrolled active infections (CTCAE v6.0 > Grade 2).
• Incomplete recovery from surgery, such as unhealed wounds or severe postoperative complications.
• Pregnancy, lactation, or patients of childbearing potential unwilling or unable to use effective contraception.