NCT05475613 Downstaging Protocol Containing Immunotherapy for HCC Beyond the Milan Criteria Before Liver Transplantation

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What to Expect as a Participant

You will actively receive the study intervention — which may be a drug, biologic, device, or procedure.

In Phase 2, researchers evaluate early signs of effectiveness. You may be randomized to receive the active treatment or a comparator. Monitoring continues closely.

This trial targets 59 participants in total. It began in 2023-06-21 with a primary completion date of 2027-08-01.

Brief Summary

Hepatocellular Carcinoma (HCC) is the most common liver malignancy and the third leading cause of cancer death worldwide. Due to the shortage of donor organs and the risk of tumor recurrence after transplantation, the restrictive Milan criteria is the standard guideline for liver transplantation (LT) in patients with HCC and liver cirrhosis. The XXL study (Mazzaferro et al, 2020) is the first prospective trial validating that effective and sustained downstage therapy could expand the selection criteria and improve the prognosis of recipients with HCC beyond Milan criteria. However, the optimal DT protocol is poorly defined, especially in the Asian population. Recently, immunotherapies such as immune-checkpoint inhibitors (ICIs) are revolutionizing the management of advanced HCC, the combination of the ICI and other treatment regimens (Anti-VEGF, locoregional therapies et al) produced superior results in patients with advanced-stage HCC compared to those with traditional therapeutic regimens. Therefore, we hypothesize an intensive downstage regimen containing immunotherapy could expand the selection criteria for HCC LT

Eligibility Criteria

Inclusion Criteria: 1. Written informed consent must be obtained prior to any screening procedures. Willing and able to comply with scheduled visits, treatment plan and laboratory tests. 2. Patients must have pathologically or cytologically or by radiological criteria proven hepatocellular carcinoma based on the AASLD practice guidelines 3. Patients with HCC must be beyond Milan criteria without extrahepatic metastases or lymph node metastases: 3.1 Patients without previous treatment: Barcelona clinic liver cancer B-C (China liver cancer stage IIb-IIIa) HCC with or without portal vein tumor thrombus (PVTT 1-3 according to Japanese Vp classification). 3.2 Patients with late recurrent HCC: The recurrent HCC must be identified no less than 2 years after primary curative treatment (Resection or Radiofrequency, et al), and the recurrent lesions must be localized in the liver and beyond Milan criteria. 3.3 Patients with early recurrent HCC: The recurrent HCC must be identified within 2 years after primary curative treatment (R0 resection or radiofrequency, et al), and the primary tumor must be within Milan criteria, and the accumulating tumor burden(Primary tumor plus recurrent tumor) must be beyond Milan criteria. 4. Child-Pugh score≤7, with no encephalopathy. Ascites that diuretics can control are permitted in this study. 5. Eastern Cooperative Oncology Group (ECOG) Scale for Assessment of Patient Performance Status (PS score) ≤ 2; KPS score ≥60. 6. Have not received any immunotherapies 6 months before enrollment. 7. Adequate bone marrow, liver, and renal function. 8. The estimated survival before liver transplantation must be more than 12 weeks (Based on the Model for end-stage liver disease, MELD). 9. No other lethal malignancy outside the liver in the past 5 years, such as leukemia, lung cancer, melanoma, etc. 10. Patients with a history of hypertension should be well-controlled (\< 140/90 mmHg) on a regimen of anti-hypertensive therapy. 11. Both men and women enrolled in this trial must use adequate barrier birth control measures during the trial and 6 months after the completion of the trial. 12. Patients voluntarily joined the study and signed informed consent with good compliance and follow-up. Exclusion Criteria Participants who meet any of the following criteria are not eligible for this study: 1. Histologically/cytologically confirmed cholangiocellular carcinoma, mixed-type liver cancer, or other rare types of liver cancer; 2. Recurrent liver cancer with inadequate initial treatment (i.e., no complete remission or R0 resection); 3. Presence of uncontrollable systemic infections, alcoholism or drug abuse, organic diseases of the heart, lungs, or brain, uncontrolled psychiatric disorders, severe mental illnesses, HIV infection, active tuberculosis, etc.; 4. Presence of severe portal hypertension with a high bleeding risk as assessed by the investigator; 5. History of bleeding events due to portal hypertension in the past 6 months; 6. History of any life-threatening event in the past 6 months, including but not limited to acute myocardial infarction, unstable angina, congestive heart failure, cerebrovascular accidents, pulmonary embolism, major bleeding from other sites, etc.; 7. Severe splenomegaly or splenomegaly-induced neutropenia (ANC \< 1.5 × 10⁹/L) or thrombocytopenia (platelet count \< 50 × 10⁹/L); 8. History of grade III hepatic encephalopathy or clinical symptoms requiring long-term drainage of pleural effusion, ascites, pericardial effusion, etc.; 9. Uncontrolled hypertension, history of hypertensive crisis or hypertensive encephalopathy; 10. Severe pulmonary hypertension that cannot be controlled by medication; 11. Severe coagulopathy, or those receiving thrombolytic treatment or requiring continuous anticoagulant or antiplatelet therapy for any reason; 12. History of autoimmune diseases such as rheumatoid arthritis, lupus, psoriasis, Crohn's disease, ulcerative colitis, etc.; 13. Major surgical procedure within 4 weeks before the first dose; History of severe allergy to any of the study drugs; 14. Female patients who are pregnant or breastfeeding; 15. Presence of severe psychiatric or psychological disorders.

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