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Liver TransplantationPhase 2NCT05475613

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

A Phase 2 study testing Downstaging procedures containing immunotherapy and Liver transplantation in people with Liver Transplantation and Hepatocellular Carcinoma, run by Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University at 1 site in China.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts
Official record
Search all trials

Trial 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… Read more about this study

Who is it for?
Ages 18 to 75 years
What is being tested?
Downstaging procedures containing immunotherapy and Liver transplantation
Could I receive a placebo?
No, everyone receives an active treatment
How many people
59 participants
Where
1 siteChina
Study dates
21 Jun 2023to 1 Aug 2028
Phase
Phase 2
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 75 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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:
  • 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.
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  • 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.

Who cannot join

  • 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;
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  • 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;
  • Presence of severe psychiatric or psychological disorders.

Trial locations and contacts

1 site in 1 country. Contact the study team or a site near you to ask about taking part.

Li PANG, PhD contact

+86 13622860325

pangli5@mail.sysu.edu.cn

Leibo Xu, PhD contact

+86-18819182396

xuleibo3@mail.sysu.edu.cn

China1 site, 1 recruiting

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

    Guangzhou, Guangdong, 376032

    Leibo XU, PhD, +86-20-34070840, xuleibo3@mail.sysu.edu.cn

    Li PANG, PhD, +86 13622860325, pangli5@mail.sysu.edu.cn

    Recruiting

Other trials in China

About this study

Official title: A Prospective, Single-arm Study of Downstaging Protocol Containing Immunotherapy for HCC Beyond the Milan Criteria Before Liver Transplantation

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

Read the detailed description

This will be a single-arm, open-label, non-randomized phase II study aiming to access the efficacy and safety of the downstage protocol containing immunotherapy for HCC beyond Milan Criteria. This study contains 4 phases:

  1. Screening and Downstaging phase 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. Criteria for Successful Downstage Patients that meet 1-4 criteria are considered to have achieved the downstaging goal, otherwise, the downstaging treatment is considered to have failed within 12 cycles of downstaging treatment:
  • CR or PR evaluated by iRECIST/mRECIST after at least 2 cycles of downstaging treatment.
  • Patients with onset AFP<400ng/ml: AFP <400ng/ml at the end of downstaging therapy; Patients with onset AFP>400ng/ml: AFP levels decrease more than 30%, and must be less than 1000ng/ml at the end of downstage therapy.
  • Estimated 5-year overall survival ≥60% at the end of downstaging therapy according to the Metroticket model (http://www.hcc-olt-metroticket.org/calculator).
  • For patients with portal vein tumor thrombus (PVTT1-3), tumor thrombus needs to retract above the bifurcation of the main portal vein, and portal vein anastomosis is feasible during liver transplantation according to the surgeons' judgment.
  1. Observation phase Patients that have reached the Criteria for Successful Downstage within 12 cycles of downstaging treatment will proceed to the observation phase ≥ 3 months. Patients at this phase can optionally receive TKIs (sorafenib, lenvatinib et al), and other anti-tumor treatments (such as locoregional therapies, surgery, and immunotherapies et al) are not allowed at this phase. Patients with a sustained response and whose tumors still meet the Criteria for Successful Downstage at the end of the observation phase will be enrolled in the waiting list for liver transplantation, while patients with tumor progression (PD) and their tumors fail to meet the Criteria for Successful Downstage at the end of observation phase will drop out from the study.
  2. Waiting and Bridging phase During the waiting period before liver transplantation, patients can optionally receive a non-immunotherapy protocol as bridging treatment determined by the multidisciplinary team (MDT). Surgery is not allowed at this phase.
  3. Liver transplantation and post-transplantation phase Patients will undergo liver transplantation unless major medical or oncological contraindications should occur during the waiting phase.
Being tested
Downstaging procedures containing immunotherapy, Liver transplantation
Keywords
Liver transplantation, Hepatocellular Carcinoma, Milan Criteria, Downstaging therapy, Locoregional therapies, Targeted therapy, PD1 inhibitor
Medical subject headings
Carcinoma, Hepatocellular

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Downstaging procedures containing immunotherapyProcedure or surgery

    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.

  • Liver transplantationProcedure or surgery

    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.

Study groups in NCT05475613
Study groupRoleWhat they receive
Downstaging groupExperimentalEligible 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.
Receives: Procedure: Downstaging procedures containing immunotherapy; Procedure: Liver transplantation

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: 2 years

Secondary outcomes (5)

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

    The time elapsed from the liver transplantation to death during the 2-year follow-up period.

    Measured: 2 years

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

    The probability of survival from the beginning of treatment to the end of 1-year and 2-year follow-up.

    Measured: 1, 2 years

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

    Number of recipients developing EAD after liver transplantation

    Measured: 1 week posttransplantation

  4. For patients with liver transplantation: Rate of allograft rejection

    Number of recipients developing allograft rejection after liver transplantation

    Measured: 1 year

  5. For all patients with HCC downstaging: Rate of successful tumor downstaging

    Number of patients reaching the successful downstaging criteria for liver transplantation

    Measured: 1 year

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted27 Jul 2022
  2. Study start21 Jun 2023
  3. Primary completion1 Aug 2027 (estimated)
  4. Study completion1 Aug 2028 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Model description
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.
Masking
None (open label)
Enrolment
59 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05475613
Sponsor's protocol ID
SYSKY-2022-145-01
Status last verified
Nov 2024
First submitted
24 Jul 2022
Last updated
29 Nov 2024
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • 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.

    PubMed 32615109

  • 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.

    PubMed 32171041

  • 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.

    PubMed 33850328

  • 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.

    PubMed 35765265

  • 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.

    PubMed 35181565

  • 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.

    PubMed 35857294

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Downstaging procedures containing immunotherapy and Liver transplantation in people with Liver Transplantation and Hepatocellular Carcinoma, run by Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University at 1 site in China.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 15 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: looking for participants now, as of the sponsor's last update on 29 Nov 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in China. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact Li PANG, PhD (+86 13622860325, pangli5@mail.sysu.edu.cn), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

For patients with liver transplantation: The 2-year event-free survival rate (time frame: 2 years). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05475613, which also lists 6 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Nov 2024.

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