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

NCT05475613 | Recruiting Phase 2 DMC

• 1 other identifier: SYSKY-2022-145-01
• Study Type: interventional
• Target: 59
• Locations: 1 country
• Sites: 1

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

Conditions

Liver Transplantation; Hepatocellular Carcinoma

Keywords

Liver transplantation; Hepatocellular Carcinoma; Milan Criteria; Downstaging therapy; Locoregional therapies; Targeted therapy; PD1 inhibitor

Outcome Measures

Primary Outcomes (1)

• For patients with liver transplantation: The 2-year event-free survival rate

  From the date of transplantation to the date of tumor recurrence or the date of tumor progression otherwise, with censoring at the date of death or last contact for event-free patients.

  2 years

Secondary Outcomes (5)

• For patients with liver transplantation: The 2-year overall survival

  2 years

• For all patients with HCC downstaging: 1, 2 year overall survival rate

  1, 2 years

• For patients with liver transplantation: Rate of early allograft dysfunction (EAD)

  1 week posttransplantation

• For patients with liver transplantation: Rate of allograft rejection

  1 year

• For all patients with HCC downstaging: Rate of successful tumor downstaging

  1 year

Study Arms (1)

Downstaging group

EXPERIMENTAL

Eligible patients (See inclusion and exclusion criteria) will undergo downstaging treatment containing Anti-PD-1 inhibitor (tislelizumab, pembrolizumab, nivolumab et al). Anti-PD-1 inhibitor will be given every 3-4 weeks intravenously. Other combination regimens, such as locoregional therapies and targeted therapies will be given to patients according to the protocol decided by the multidisciplinary team of Centers. Patients that have reached the Criteria for Successful Downstage within 12 cycles of downstaging treatment will proceed to the observation phase, while those who fail to meet the Criteria for Successful Downstage after the maximum length of downstaging procedures will drop out from the study.

Procedure: Downstaging procedures containing immunotherapy; Procedure: Liver transplantation

Interventions

Downstaging procedures containing immunotherapy PROCEDURE

Anti-PD-1 inhibitor will be given every 3-4 weeks intravenously according to the manufacturer's instruction. Other combination regimens, such as locoregional therapies or targeted therapies will be given to patients according to the protocol decided by the multidisciplinary team of Centers.

Downstaging group

Liver transplantation PROCEDURE

Patients with successful downstaging therapy at the end of the observation phase will enroll and undergo liver transplantation unless major medical or oncological contraindications should occur during the waiting phase.

Downstaging group

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent must be obtained prior to any screening procedures. Willing and able to comply with scheduled visits, treatment plan and laboratory tests.
• Patients must have pathologically or cytologically or by radiological criteria proven hepatocellular carcinoma based on the AASLD practice guidelines
• Patients with HCC must be beyond Milan criteria without extrahepatic metastases or lymph node metastases:
• 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).
• 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.
• 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.
• Child-Pugh score≤7, with no encephalopathy. Ascites that diuretics can control are permitted in this study.
• Eastern Cooperative Oncology Group (ECOG) Scale for Assessment of Patient Performance Status (PS score) ≤ 2; KPS score ≥60.
• Have not received any immunotherapies 6 months before enrollment.
• Adequate bone marrow, liver, and renal function.
• The estimated survival before liver transplantation must be more than 12 weeks (Based on the Model for end-stage liver disease, MELD).
• No other lethal malignancy outside the liver in the past 5 years, such as leukemia, lung cancer, melanoma, etc.
• Patients with a history of hypertension should be well-controlled (\< 140/90 mmHg) on a regimen of anti-hypertensive therapy.
• 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.
• Patients voluntarily joined the study and signed informed consent with good compliance and follow-up.

You may not qualify if:

• Participants who meet any of the following criteria are not eligible for this study:
• Histologically/cytologically confirmed cholangiocellular carcinoma, mixed-type liver cancer, or other rare types of liver cancer;
• Recurrent liver cancer with inadequate initial treatment (i.e., no complete remission or R0 resection);
• 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.;
• Presence of severe portal hypertension with a high bleeding risk as assessed by the investigator;
• History of bleeding events due to portal hypertension in the past 6 months;
• 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.;
• Severe splenomegaly or splenomegaly-induced neutropenia (ANC \< 1.5 × 10⁹/L) or thrombocytopenia (platelet count \< 50 × 10⁹/L);
• History of grade III hepatic encephalopathy or clinical symptoms requiring long-term drainage of pleural effusion, ascites, pericardial effusion, etc.;
• Uncontrolled hypertension, history of hypertensive crisis or hypertensive encephalopathy;
• Severe pulmonary hypertension that cannot be controlled by medication;
• Severe coagulopathy, or those receiving thrombolytic treatment or requiring continuous anticoagulant or antiplatelet therapy for any reason;
• History of autoimmune diseases such as rheumatoid arthritis, lupus, psoriasis, Crohn's disease, ulcerative colitis, etc.;
• Major surgical procedure within 4 weeks before the first dose; History of severe allergy to any of the study drugs;
• Female patients who are pregnant or breastfeeding;

Sponsors & Collaborators

• Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University: lead

Study Sites (1)

Sun Yat-sen Memorial Hospital, Sun Yat-sen University

Guangzhou, Guangdong, 376032, China

RECRUITING

Related Publications (6)

• Mazzaferro V, Citterio D, Bhoori S, Bongini M, Miceli R, De Carlis L, Colledan M, Salizzoni M, Romagnoli R, Antonelli B, Vivarelli M, Tisone G, Rossi M, Gruttadauria S, Di Sandro S, De Carlis R, Luca MG, De Giorgio M, Mirabella S, Belli L, Fagiuoli S, Martini S, Iavarone M, Svegliati Baroni G, Angelico M, Ginanni Corradini S, Volpes R, Mariani L, Regalia E, Flores M, Droz Dit Busset M, Sposito C. Liver transplantation in hepatocellular carcinoma after tumour downstaging (XXL): a randomised, controlled, phase 2b/3 trial. Lancet Oncol. 2020 Jul;21(7):947-956. doi: 10.1016/S1470-2045(20)30224-2.

  PMID: 32615109 BACKGROUND

• Schwacha-Eipper B, Minciuna I, Banz V, Dufour JF. Immunotherapy as a Downstaging Therapy for Liver Transplantation. Hepatology. 2020 Oct;72(4):1488-1490. doi: 10.1002/hep.31234. No abstract available.

  PMID: 32171041 BACKGROUND

• Sangro B, Sarobe P, Hervas-Stubbs S, Melero I. Advances in immunotherapy for hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2021 Aug;18(8):525-543. doi: 10.1038/s41575-021-00438-0. Epub 2021 Apr 13.

  PMID: 33850328 BACKGROUND

• Tran NH, Munoz S, Thompson S, Hallemeier CL, Bruix J. Hepatocellular carcinoma downstaging for liver transplantation in the era of systemic combined therapy with anti-VEGF/TKI and immunotherapy. Hepatology. 2022 Oct;76(4):1203-1218. doi: 10.1002/hep.32613. Epub 2022 Jul 30.

  PMID: 35765265 BACKGROUND

• Tan DJH, Lim WH, Yong JN, Ng CH, Muthiah MD, Tan EX, Xiao J, Lim SY, Pin Tang AS, Pan XH, Kabir T, Bonney GK, Sundar R, Syn N, Kim BK, Dan YY, Noureddin M, Loomba R, Huang DQ. UNOS Down-Staging Criteria for Liver Transplantation of Hepatocellular Carcinoma: Systematic Review and Meta-Analysis of 25 Studies. Clin Gastroenterol Hepatol. 2023 Jun;21(6):1475-1484. doi: 10.1016/j.cgh.2022.02.018. Epub 2022 Feb 16.

  PMID: 35181565 BACKGROUND

• Tabrizian P, Holzner ML, Mehta N, Halazun K, Agopian VG, Yao F, Busuttil RW, Roberts J, Emond JC, Samstein B, Brown RS Jr, Najjar M, Chapman WC, Doyle MM, Florman SS, Schwartz ME, Llovet JM. Ten-Year Outcomes of Liver Transplant and Downstaging for Hepatocellular Carcinoma. JAMA Surg. 2022 Sep 1;157(9):779-788. doi: 10.1001/jamasurg.2022.2800.

  PMID: 35857294 BACKGROUND

MeSH Terms

Conditions

Carcinoma, Hepatocellular

Interventions

Liver Transplantation

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases

Intervention Hierarchy (Ancestors)

Tissue Transplantation; Cell- and Tissue-Based Therapy; Biological Therapy; Therapeutics; Digestive System Surgical Procedures; Surgical Procedures, Operative; Organ Transplantation; Transplantation

Study Officials

• Chao LIU, PhD

  Department of Biliary and Pancreatic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Li PANG, PhD

CONTACT

+86 13622860325; pangli5@mail.sysu.edu.cn

Leibo Xu, PhD

CONTACT

+86-18819182396; xuleibo3@mail.sysu.edu.cn

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Eligible patients will undergo downstaging treatment containing an Anti-PD-1 inhibitor (tislelizumab, pembrolizumab, nivolumab et al.). The anti-PD-1 inhibitor will be given intravenously every 3-4 weeks. Other combination regimens, such as locoregional therapies and targeted therapies, will be given to patients according to the protocol decided by the multidisciplinary team of Centers.

Study Record Dates

• First Submitted: July 24, 2022
• First Posted: July 27, 2022
• Study Start: June 21, 2023
• Primary Completion (Estimated): August 1, 2027
• Study Completion (Estimated): August 1, 2028
• Last Updated: November 29, 2024

Record last verified: 2024-11

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)