NIVO+IPI Neoadjuvant Therapy for Recurrent Resectable HCC (CA209-1594)

Inclusion Criteria:

1. The subject or their legally authorized representative must sign a written informed consent form (ICF) approved by the IRB/IEC, with the date indicated, prior to undergoing any study-related procedures.

2. Subjects must be willing and able to comply with the scheduled visits, treatment regimen, laboratory assessments, and other study requirements.

3. Male and female subjects aged >= 18 and <= 75 years.

4. Expected life expectancy of >= 3 months.

5. Subjects must have histologically, cytologically, or clinically confirmed HCC.

6. Subjects should, as much as possible, provide tumor tissue specimens from the initial surgical resection of HCC (1 formalin-fixed paraffin-embedded [FFPE] tissue block or 20 unstained tumor tissue slides) during the screening period.

7. Subjects must have intrahepatic recurrence confirmed by imaging (contrast-enhanced CT or MRI) occurring 3 months to 2 years after initial liver resection.

8. Subjects must be assessed by the investigator as eligible for repeat hepatic resection, in accordance with the Chinese Expert Consensus on Prevention and Treatment of Postoperative Recurrence of Hepatocellular Carcinoma (2020 edition):

   • Subjects in generally good condition.
   • Liver function Child-Pugh class A, with none or only mild portal hypertension.
   • No severe underlying diseases of major organs such as heart, lung, or kidney.
   • Lesion(s) are either solitary or multiple (<= 3) with the maximum diameter of a single lesion <= 3 cm, and technically resectable; for multiple lesions, enrollment is allowed only after investigator assessment of the remaining liver volume and surgical safety margins.
   • Expected residual liver volume after repeat hepatectomy sufficient to maintain adequate liver function.
   • No major vascular invasion or extrahepatic distant metastasis.

9. Subjects must have at least one previously untreated lesion that is measurable according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1).

   • The lesion must be accurately measured in at least one dimension using contrast-enhanced spiral computed tomography (CT) or contrast-enhanced dynamic magnetic resonance imaging (MRI), with a result >= 10 mm. Note: for malignant lymph nodes, the short axis must be >= 15 mm.
   • The lesion must not have been previously treated with surgery, radiotherapy, and/or local regional therapy (e.g., RFA, PEI or PAI, cryoablation, HIFU, TACE, TAE, etc.).

10. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0.

11. Subjects must not have received prior systemic immune checkpoint inhibitor therapy.

12. Subjects must have adequate organ and bone marrow function. Screening laboratory values must meet the following criteria and must be obtained within 7 days prior to enrollment (administration of any blood products, growth factors, albumin, or other corrective treatments is not permitted within 14 days prior to obtaining the laboratory assessments):

    • Adequate hematologic function:
    • Absolute neutrophil count (ANC) >= 1.5 x 10^9/L
    • Platelet count (PLT) >= 75 x 10^9/L
    • Hemoglobin (HGB) >= 9.0 g/dL
    • Adequate hepatic function:
    • Serum total bilirubin (TBIL) <= 2 x upper limit of normal (ULN)
    • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <= 5 x ULN
    • Serum albumin >= 28 g/L
    • Alkaline phosphatase (ALP) <= 5 x ULN
    • In the Child-Pugh classification, only one of the 2 parameters, albumin or bilirubin, may be scored as 2 points.
    • Adequate renal function:
    • Serum creatinine (Cr) <= 1.5 x ULN or creatinine clearance (CCr) >= 50 mL/min (calculated using the Cockcroft-Gault formula)
    • Urinalysis showing protein < 2+
    • For subjects with baseline urinalysis showing protein >= 2+, a 24-hour urine collection must be performed, with 24-hour urine protein < 1g
    • Adequate coagulation function:
    • International Normalized Ratio (INR) and activated partial thromboplastin time (APTT) <= 1.5 x ULN

13. Subjects with HBV or HCV infection must meet the following criteria:

    • HBV infection: If HBsAg positive, HBV-DNA must be measured, and HBV-DNA must be < 2000 IU/mL or < 10^4 copies/mL. Subjects must have received at least 1 week of anti-HBV therapy prior to enrollment and be willing to continue antiviral therapy throughout the study.
    • HCV infection: HCV-RNA positive subjects (RNA < 10^3 copies/mL) must receive antiviral therapy according to treatment guidelines.

14. Women of childbearing potential (WOCBP) must have a serum pregnancy test within 7 days prior to enrollment, with a negative result (minimum sensitivity 25 IU/L or equivalent HCG units).

15. Female subjects must not be breastfeeding.

16. Female subjects of reproductive potential and their partners must agree to use effective contraception during the study and for at least 6 months after the last dose. WOCBP must also agree not to donate oocytes during this period.

Exclusion Criteria:

1. Histologically confirmed fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma-HCC.

2. Prior liver transplantation.

3. Presence of extrahepatic metastases or unresectable lesions confirmed by imaging within 1 month prior to enrollment.

4. Recurrence within less than 3 months after surgery.

5. Lesions assessed as unresectable.

6. Prior systemic antitumor therapy for recurrent HCC, including but not limited to immunotherapy (PD-1, PD-L1, CTLA-4 antibodies, or bispecific/combination antibodies).

7. Prior local therapy after recurrence, including transarterial chemoembolization (TACE), ablation (radiofrequency ablation, microwave ablation, cryoablation, etc.), or radiotherapy.

8. Active co-infection with hepatitis B and hepatitis C or hepatitis B and hepatitis D that is not effectively controlled.

9. Known human immunodeficiency virus (HIV)-positive history or known AIDS history, or currently receiving systemic corticosteroid therapy. Note: HIV testing must be performed at a locally authorized institution.

10. Active bacterial, fungal, or viral infection requiring systemic therapy within 1 week prior to enrollment.

11. History of hepatic encephalopathy (>= Grade 2) within 12 months prior to enrollment.

12. Clinically significant ascites, defined as:

    • Ascites previously requiring treatment and ongoing prophylaxis, or
    • Ascites currently requiring treatment.

13. Presence of portal hypertension with a history of bleeding from esophageal or gastric varices within 6 months prior to enrollment.

14. Uncontrolled cardiac clinical symptoms or diseases, including but not limited to:

    • Uncontrolled hypertension despite optimal therapy, defined as systolic blood pressure > 150 mmHg or diastolic blood pressure > 90 mmHg.
    • History of congestive heart failure greater than New York Heart Association (NYHA) class II.
    • Active coronary artery disease, unstable or newly diagnosed angina, or myocardial infarction within 6 months prior to screening.
    • Arrhythmias requiring antiarrhythmic therapy other than beta-blockers or digoxin at screening.
    • Cardiac valvular disease graded > Grade 2 according to CTCAE.
    • QTc interval (Fridericia formula) > 480 ms on 2 consecutive ECGs.

15. Symptomatic or potentially interfering interstitial lung disease that may affect the detection or management of drug-related pulmonary toxicity.

16. History of gastrointestinal or non-gastrointestinal fistula or gastrointestinal perforation.

17. History of non-healing wounds or skin ulcers within 3 months prior to enrollment.

18. History of thrombotic or embolic events (excluding HCC tumor thrombus) within 6 months prior to enrollment, such as cerebrovascular accidents (including transient ischemic attacks) or pulmonary embolism.

19. History of any CTCAE Grade >= 3 hemorrhagic events within 8 weeks prior to enrollment, or currently receiving thrombolytic therapy.

20. Systemic treatment with corticosteroids (> 10 mg/day prednisone or equivalent) or other immunosuppressive agents within 14 days prior to study drug administration.

21. Immunological contraindications or concurrent severe autoimmune diseases where the investigator considers immune checkpoint inhibitor therapy to carry excessive risk, including but not limited to:

    • Active severe autoimmune diseases (e.g., systemic lupus erythematosus, Sjogren's syndrome, myasthenia gravis, ulcerative colitis, Crohn's disease, refractory psoriasis, etc.) requiring medium- to high-dose immunosuppressive therapy for maintenance.
    • Confirmed severe combined immunodeficiency, acquired immunodeficiency syndrome (AIDS), or immunodeficiency states such as critically low CD4+ T-cell counts.
    • Recent (e.g., <= 14 days) or ongoing use of high-dose systemic corticosteroids (> 10 mg/day prednisone equivalent) or other drugs affecting immune function (short-term use for irAE management or perioperative period is not included).
    • Requirement for ongoing immunosuppressive therapy due to organ transplantation.
    • Investigator's assessment based on medical history or current condition indicates other high-risk immunologic abnormalities that make the subject unsuitable for immune checkpoint inhibitor therapy.

22. Known hypersensitivity to Nivolumab, Ipilimumab, any of their excipients, or history of severe hypersensitivity reactions to other monoclonal antibodies.

23. Presence of concomitant malignancy requiring treatment (at screening) or history of active prior malignancy within 2 years prior to enrollment. Note: Subjects with a history of prior malignancy are eligible if treatment was completed >= 2 years ago and there is no evidence of disease. Additionally, subjects with a history of prior early-stage basal/squamous cell skin cancer or non-invasive/in situ carcinoma are eligible if they received targeted therapy at any time.

24. Any serious or uncontrolled medical condition that, in the investigator's opinion, may increase the risk of participation, compromise the subject's ability to receive study treatment, or interfere with the interpretation of study results.

25. History of major surgical procedures, open biopsies, or significant trauma within 4 weeks prior to enrollment, or minor surgical procedures (e.g., core needle biopsy) within 1 week prior to enrollment.

26. Subjects with a history of life-threatening toxicities related to prior systemic anticancer therapy, except for those unlikely to recur after standard-of-care management.

27. Pregnant or breastfeeding women of childbearing potential (WOCBP).