HAIC Combined with Donafenib and Sintilimab As Perioperative Treatment for Resectable Hepatocellular Carcinoma Patients At High Risk of Recurrence

Inclusion Criteria:

• Voluntary enrollment with written informed consent obtained

• Age 18 to 75 years (inclusive), regardless of gender

• Histologically or pathologically confirmed previously untreated hepatocellularcarcinoma (HCC) or clinically diagnosed previously untreated HCC according to theAASLD guidelines.

• Initial resectable status as assessed by the investigator (expected to achieve R0resection, sufficient liver remnant volume, and Child-Pugh class A, as per the "Chinese Expert Consensus on Neoadjuvant Therapy for Liver Cancer (2023 Edition)").

• At least one measurable lesion according to mRECIST criteria.

• Tumor burden meets one of the following conditions:

1. A single tumor with a diameter > 5 cm;

2. Multiple tumors with the largest tumor diameter > 3 cm, with < 5 tumors intotal;

3. Presence of portal vein tumor thrombus (Vp1-Vp2).

• Liver function: Child-Pugh score of 5-6.

• ECOG 0-1

• Life expectancy of at least 3 months.

• Women of childbearing potential (defined as not postmenopausal or surgicallysterilized) must have a negative serum pregnancy test within 7 days prior to thestudy drug administration.

• Both women and men of childbearing potential must use reliable contraception duringthe study and for 60 days following the last dose of the study drug.

• For HBV-infected patients: If HBV-DNA is ≥ 10⁴ copies/ml within 14 days prior toenrollment, antiviral therapy (preferably entecavir) must be initiated to reduceHBV-DNA to < 10⁴ copies/ml before entering the study. Antiviral therapy shouldcontinue, with regular monitoring of liver function and HBV-DNA levels.

• Adequate organ function.

Exclusion Criteria:

• Patients with distant metastasis.

• Patients with portal vein tumor thrombosis (Vp3-Vp4).

• History of any other malignant tumor within the past 5 years, unless the patient hasreceived potentially curative treatment and there is no evidence of recurrence inthe past 5 years. This 5-year time requirement does not apply to patients who havesuccessfully undergone resection for basal cell carcinoma of the skin, squamous cellcarcinoma of the skin, superficial bladder cancer, cervical carcinoma in situ, orother carcinoma in situ.

• History or current presence of congenital or acquired immunodeficiency diseases.

• Active or previously documented autoimmune diseases or inflammatory disorders (including but not limited to: autoimmune hepatitis, interstitial pneumonia,inflammatory bowel disease, systemic lupus erythematosus, vasculitis, uveitis,pituitary inflammation, hyperthyroidism or hypothyroidism, asthma requiringbronchodilators for treatment, etc.). Patients with vitiligo or asthma fullyresolved in childhood and not requiring intervention as adults may be included.

• History of severe psychiatric disorders.

• Conditions affecting the absorption, distribution, metabolism, or elimination of thestudy drugs (e.g., severe vomiting, chronic diarrhea, bowel obstruction,malabsorption, etc.).

• Major surgery within 4 weeks prior to enrollment (as defined by the investigator).

• History of allogeneic stem cell or solid organ transplantation (except for cornealtransplantation).

• Received other systemic antitumor therapies (including traditional Chinese medicinewith antitumor indications) within 2 weeks or 5 half-lives (whichever is longer)prior to study drug administration, or unresolved adverse events related to priortreatments that have not recovered to ≤ CTCAE Grade 1.

• Use of systemic immunosuppressive drugs within 2 weeks prior to enrollment, oranticipated need for systemic immunosuppressive therapy during the study.

• Concurrent use of drugs that may prolong the QTc interval and/or induce Tdp, ordrugs affecting drug metabolism.

• Known or suspected allergy to donafenib, recombinant humanized PD-1 monoclonalantibodies, or similar agents, or a history of hypersensitivity reactions tochimeric or humanized antibodies or fusion proteins, or to excipients of the studydrugs.

• Uncontrolled hepatic encephalopathy, hepatorenal syndrome, ascites, pleuraleffusion, or pericardial effusion.

• Active bleeding or coagulation disorders, bleeding tendencies, or ongoing treatmentwith thrombolytics, anticoagulants, or antiplatelet therapy.

• History of gastrointestinal bleeding or clear gastrointestinal bleeding tendencieswithin the past 6 months (e.g., known active ulcerative lesions, positive stooloccult blood with ≥2+ results, requiring endoscopy if stool occult blood remainspositive), or other conditions that may lead to gastrointestinal bleeding asdetermined by the investigator (e.g., severe esophageal/gastric varices).

• History of gastrointestinal perforation, abdominal fistulas, or intra-abdominalabscesses within the past 6 months.

• History of thrombosis or thromboembolic events (e.g., stroke, transient ischemicattack, deep vein thrombosis, pulmonary embolism) within the past 6 months.

• Significant cardiovascular disease, including but not limited to: acute myocardialinfarction, severe/uncontrolled angina, coronary artery bypass grafting within thepast 6 months; congestive heart failure (NYHA class >2); poorly controlledarrhythmias requiring pacemaker treatment; drug-resistant hypertension (systolicblood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg).

• Active infection.

• Other significant clinical or laboratory abnormalities that may affect safetyevaluation, such as uncontrolled diabetes, chronic kidney disease, grade 2 or higherperipheral neuropathy (CTCAE v5.0), thyroid dysfunction, etc.

• Use of live attenuated vaccines within 4 weeks prior to enrollment or during thestudy.

• Pregnant or breastfeeding women, or women or men of childbearing potential unwillingor unable to use effective contraception.

• History of alcohol, drug, or substance abuse within the past 6 months.

• Participation in any other clinical trial involving investigational drugs or medicaldevices within 4 weeks prior to enrollment.

• Inability to comply with the study protocol for treatment or follow-up visits.

• Any other conditions that, in the opinion of the investigator, would precludeparticipation in the study.