PD-1/IL-2 Bispecific Antibody as Neoadjuvant Therapy for Early Recurrent Hepatocellular Carcinoma After Curative Hepatectomy

A Phase II Study to Evaluate the Efficacy and Safety of PD-1/IL-2 Bispecific Antibody as Neoadjuvant Therapy in Hepatocellular Carcinoma Patients With Early Recurrence After Curative Hepatectomy and Eligible for Re-resection

This is a single-arm, phase II clinical study designed to evaluate the efficacy and safety of a recombinant PD-1/IL-2 bispecific antibody, as neoadjuvant therapy in hepatocellular carcinoma (HCC) patients who experienced early recurrence after curative hepatectomy and were suitable for repeat surgical resection.

A total of approximately 30 eligible participants are planned to be enrolled. All patients will receive neoadjuvant treatment with PD-1/IL-2 bispecific antibody for 3 cycles. Curative re-resection will be performed 2 to 7 weeks after the last dose of PD-1/IL-2 bispecific antibody for patients with resectable lesions confirmed by imaging assessment. Tumor evaluation will be conducted per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) throughout the study. Postoperative pathological assessment and long-term follow-up will be implemented after surgery.

The primary endpoint is the major pathological response (MPR) rate. Secondary endpoints include complete pathological response (pCR) rate, event-free survival (EFS), overall survival (OS), R0 resection rate, objective response rate (ORR), disease control rate (DCR), and the safety and tolerability profile . Exploratory endpoints aim to analyze the correlation between biomarkers (e.g., PD-L1 expression, tumor microenvironment) and treatment efficacy.

This study intends to explore the clinical value of PD-1/IL-2 bispecific antibody in the neoadjuvant setting for recurrent resectable HCC, and provide evidence for its clinical application in this patient population.

Inclusion criteria:

1. Have signed the written informed consent form and be able to comply with all scheduled visits and study procedures specified in the protocol.

2. Aged between 18 and 75 years old (inclusive), with no restriction on gender.

3. Diagnosed with hepatocellular carcinoma (HCC) confirmed by histopathology or cytology, or meeting the clinical diagnostic criteria for HCC formulated by the American Association for the Study of Liver Diseases (AASLD) or the Guidelines for the Diagnosis and Treatment of Primary Liver Cancer.

4. Must provide tumor tissue specimens obtained from the initial surgical resection during the screening period.

5. Have a history of curative hepatectomy for HCC, with pathologically confirmed tumor recurrence occurring 3 months to 2 years after surgery. Candidates shall be assessed by a multidisciplinary team (MDT) and meet all the following criteria for repeat resection:

   CNLC stage Ia-Ib or IIa-IIb, with recurrent lesions confined to one hepatic lobe; Adequate liver function reserve with Child-Pugh Class A; The volume of the future liver remnant (FLR) accounts for ≥40% of the standard liver volume (SLV) in patients with chronic liver disease, liver parenchymal damage or liver cirrhosis, or ≥30% in patients without liver fibrosis or cirrhosis; No vascular tumor thrombus; No extrahepatic metastasis.

6. Have at least one measurable lesion per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1), and the lesion has not received any local therapy.

7. Have adequate organ and bone marrow function. Laboratory test results obtained within 7 days prior to enrollment shall meet the following requirements. No blood products, erythropoietin, colony-stimulating factors, thrombopoietin, albumin or other parenteral corrective medications are allowed within 14 days before laboratory testing:

   Hematology: Hemoglobin (HGB) ≥ 90 g/L; Absolute Neutrophil Count (ANC) ≥ 1.5×10⁹/L; Platelet (PLT) count ≥ 100×10⁹/L.

   Liver function: Total Bilirubin (TBIL) ≤ 1.5 × Upper Limit of Normal (ULN). Participants with TBIL > 1.5 × ULN but conjugated bilirubin ≤ ULN are also eligible; Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ≤ 5 × ULN; Alkaline Phosphatase (ALP) ≤ 4 × ULN; Serum albumin ≥ 30 g/L.

   Renal function: Serum Creatinine (Cr) ≤ 1.5 × ULN, or Creatinine Clearance (CCr) ≥ 50 mL/min (calculated by the Cockcroft-Gault formula using actual body weight). Urinalysis shows urine protein < 2+. For participants with urine protein ≥ 2+ at baseline, the 24-hour urinary protein quantification shall be < 1 g.

   Coagulation function: International Normalized Ratio (INR) ≤ 1.5 × ULN; Partial Thromboplastin Time (PTT) / Activated Partial Thromboplastin Time (aPTT) ≤ 1.5 × ULN. Participants on stable-dose anticoagulant therapy shall remain within the expected therapeutic range of the prescribed anticoagulants.

8. Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 or 1.

9. Expected survival time of no less than 6 months.

10. Female participants of childbearing potential and male participants whose partners are of childbearing potential must agree to use effective contraception throughout the treatment period and for 6 months after the last study drug administration.

Exclusion criteria:

1. Histologically or cytologically confirmed diagnosis of tumors containing components such as fibrolamellar hepatocellular carcinoma, sarcomatoid hepatocellular carcinoma, mixed carcinoma, and intrahepatic cholangiocarcinoma.

2. Prior treatment with anti-PD-1/PD-L1 agents or other antitumor immunotherapies.

3. Presence of unresolved Grade >1 toxicities related to any previous antitumor therapy (persistent Grade 2 alopecia, anemia, peripheral neuropathy, electrolyte abnormalities manageable with treatment, and endocrine disorders well-controlled with hormone replacement therapy are excluded).

4. History of hepatic encephalopathy or seizures; presence of active, newly diagnosed or untreated central nervous system metastases, spinal cord compression, carcinomatous meningitis or leptomeningeal metastases.

5. Presence of clinically significant cardiovascular and cerebrovascular diseases, including:

   • Severe conduction disorders (e.g., third-degree atrioventricular block);
   • Symptomatic, clinically unstable arrhythmias or arrhythmias requiring clinical intervention;
   • Corrected QT interval (QTc, calculated via Fridericia's formula) ≥ 480 ms;
   • Uncontrolled hypertension (systolic blood pressure >160 mmHg and/or diastolic blood pressure >90 mmHg despite optimal medical treatment), or history of hypertensive crisis or hypertensive encephalopathy;
   • History of myocarditis;
   • Symptomatic congestive heart failure (New York Heart Association Class II-IV) or left ventricular ejection fraction (LVEF) < 50% on cardiac ultrasonography;
   • Any arterial thrombosis, embolism or ischemic event within 6 months prior to the first study drug administration, including myocardial infarction, unstable angina, cerebrovascular accident or transient ischemic attack;
   • History of deep vein thrombosis, pulmonary embolism or other severe thromboembolic events within 6 months before enrollment (Thrombosis related to implantable venous access ports, catheters or superficial phlebitis is not defined as severe thromboembolism). Patients with adequately treated deep vein thrombosis may be enrolled if deemed stable by the investigator.

6. Current or prior history of interstitial pneumonia, pulmonary fibrosis, pneumoconiosis, drug-induced pneumonitis, radiation pneumonitis, severe pulmonary dysfunction or other restrictive lung diseases requiring corticosteroids or other treatments.

7. History of severe or uncontrolled allergic diathesis, drug allergy, asthma or atopic dermatitis.

8. Known allergy to IL-2, sintilimab, other monoclonal antibodies or their excipients.

9. Symptomatic pleural effusion, ascites or pericardial effusion requiring repeated drainage (Patients with effusions not requiring drainage or with no obvious reaccumulation within 3 days after drainage discontinuation are eligible for enrollment).

10. History of active autoimmune diseases requiring systemic therapy (e.g., disease-modifying drugs, corticosteroids or immunosuppressants) within 2 years prior to the first drug administration. Replacement therapies (e.g., levothyroxine, insulin, physiological corticosteroids for adrenal or pituitary insufficiency) are not regarded as systemic treatment.

11. History of allogeneic organ transplantation (including liver transplantation) or allogeneic hematopoietic stem cell transplantation.

12. Active uncontrolled bleeding, known bleeding diathesis, unhealed severe wounds, ulcers or fractures; history of esophagogastric variceal bleeding caused by portal hypertension within the preceding 6 months. Grade 3 varices confirmed by endoscopy within 3 months before the first administration. Patients with evidence of portal hypertension (including splenomegaly on imaging) with high bleeding risk assessed by investigators shall undergo endoscopic evaluation.

13. Presence of major gastrointestinal diseases within 6 months prior to or at the time of drug administration, including gastrointestinal perforation, severe gastrointestinal fistula (with severely impaired gastrointestinal function or requiring invasive intervention), history of intestinal obstruction (including incomplete intestinal obstruction requiring parenteral nutrition), extensive bowel resection (partial colectomy or extensive small bowel resection complicated with chronic diarrhea), Crohn's disease, ulcerative colitis or long-standing chronic diarrhea.

14. Confirmed HIV positivity or history of acquired immunodeficiency syndrome (AIDS); active hepatitis B or hepatitis C (HCV), or history of infection with the above viruses.

    • For patients positive for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb), HBV DNA testing is required. Those with HBV DNA ≤ 10⁴ copies/mL, ≤ 2000 IU/mL or below the lower limit of quantification are eligible. HBsAg-positive patients must receive antiviral therapy throughout the study with regular HBV DNA monitoring.
    • Patients with positive HCV serology but undetectable HCV RNA are permitted to enroll.
    • Patients who have completed anti-HCV treatment with undetectable viral load are eligible for enrollment.

15. Active tuberculosis, patients currently receiving anti-tuberculosis treatment or those who received anti-tuberculosis therapy within 1 year before the first drug administration; patients with active syphilis requiring treatment.

16. Severe, active or uncontrolled infections, infections requiring intravenous systemic antibiotics, or unexplained fever (>38 °C) within 2 weeks prior to the first study drug administration.

17. Diagnosis of other pathologically confirmed malignant tumors within 5 years before enrollment. Exceptions include radically cured basal cell carcinoma, squamous cell carcinoma of the skin, completely resected carcinoma in situ, radically resected local prostate cancer and papillary thyroid carcinoma, as well as other malignancies with complete remission, no evidence of active disease for at least 2 years prior to enrollment and extremely low recurrence risk.

18. Excluded medications and treatments (None of the following interventions are allowed):

    a Last dose of antitumor therapies administered within 4 weeks before the first study drug: systemic chemotherapy (2-week washout period for oral fluoropyrimidines), endocrine therapy, targeted therapy (washout period of 2 weeks or 5 half-lives, whichever is longer), immunotherapy and tumor embolization. Traditional Chinese medicines for antitumor indications or immunomodulatory drugs (e.g., thymosin, interferon, interleukin) last administered within 1 week prior to the first dose.

    b. Participation in any medical device or other interventional clinical trials within 2 weeks before the first dose or during the study period.

    c. Palliative radiotherapy administered within 2 weeks before the first dose. d. Live vaccines for infectious disease prophylaxis administered within 4 weeks before the first dose.

    e. Immunosuppressants or systemic corticosteroids (equivalent to >10 mg prednisone per day) administered within 2 weeks before the first dose.

    f. Major surgery performed within 4 weeks before the first dose.

19. Pregnant or breastfeeding females, or females planning to become pregnant before drug administration, during treatment or within 6 months after the last dose of study drug.

20. Any concomitant disease, prior treatment, abnormal laboratory findings, history of substance abuse or current substance use, which in the investigator's judgment may compromise patient safety, hinder informed consent acquisition, affect treatment compliance or interfere with the safety assessment of the study drug.