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Hepatocellular CarcinomaImmunoXXLNCT05879328

The ImmunoXXL Study

An observational study of Hepatocellular Carcinoma, run by Fondazione IRCCS Istituto Nazionale dei Tumori, Milano at 1 site in Italy.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record
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Trial summary

This study is aimed at confirming data of efficacy and safety of liver transplantation (LT) in patients with hepatocellular carcinoma (HCC) beyond current transplant criteria who demonstrate a sustained partial or complete radiological response to the atezolizumab and bevacizumab combination treatment, prescribed… Read more about this study

Who is it for?
Ages 18 to 75 years
Conditions the study is for
Hepatocellular Carcinoma
What is being tested?
Liver Transplantation
Type of treatment
Surgery or procedure
How many people
12 participants
Where
1 siteItaly
Study dates
23 Dec 2022to 31 Dec 2024
Phase
Observational
Are there results?
None posted in the registry

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

Study population: Intermediate-advanced HCC patients achieving complete response (CR) or partial response (PR) on treatment with atezolizumab and bevacizumab (approved dosages). Radiological response has to be sustained (for at least 3 months) and accompanied by a level of alpha fetoprotein (AFP) ≤ 100 UI/ml if levels > 100 UI/ml at baseline or by decrease of the level of AFP parallel to the mRECIST response, if baseline levels >100 UI/ml, to confirm a partial response (PR).

Who may be able to join

  • age ≥ 18 and < 75 years
  • signed Informed Consent Form
  • hepatocellular carcinoma (HCC) previously diagnosed by histology/cytology or clinically by the American Association for the Study of Liver Disease (AASLD) criteria in cirrhotic patients. Patients without cirrhosis require compulsory histological confirmation of diagnosis.
  • hepatocellular carcinoma (HCC) at diagnosis beyond "AFP-adjusted up-to-seven criteria" not amenable to loco-regional treatments and with sustained (at least 3 months) complete o partial response according to mRECIST after systemic treatment with atezolizumab and bevacizumab
  • no major contraindications (cardiological, pulmonary, mental and social) to transplantation.

Who cannot join

  • presence of extra-hepatic spread (EHS) defined as organ involvement other than the liver and hilar lymphnodes with short axis > 2 cm
  • presence of tumoral portal vein thrombosis invading the main portal trunk for more than 1 cm in cranio-caudal extension (measured at coronal reconstructions scans at contrast enhanced CT/MRI).

Trial locations and contacts

1 site in 1 country.

Sherrie Bhoori, MD contact

+39022390 ext. 2760

sherrie.bhoori@istitutotumori.mi.it

Valentina Bellia, MD contact

+39022390 ext. 2354

valentina.bellia@istitutotumori.mi.it

Italy1 site, 1 recruiting

  • Fondazione IRCCS Istituto Nazionale dei Tumori

    Milan, MI, 20133

    Vincenzo Mazzaferro, MD, PhD, +39 02 2390 ext. 2760, vincenzo.mazzaferro@istitutotumori.mi.it

    Sherrie Bhoori, MD, +39 02 23902338 ext. 3474, sherrie.bhoori@istitutotumori.mi.it

    Recruiting

Other trials in Italy

About this study

Official title: Liver Transplantation in Patients With Partial or Complete Response After Atezolizumab Plus Bevacizumab for Intermediate-advanced Stage Hepatocellular Carcinoma: the ImmunoXXL Study

This study is aimed at confirming data of efficacy and safety of liver transplantation (LT) in patients with hepatocellular carcinoma (HCC) beyond current transplant criteria who demonstrate a sustained partial or complete radiological response to the atezolizumab and bevacizumab combination treatment, prescribed after completion of loco-regional therapies or as a first line systemic treatment.

The aim of the study is to demonstrate that liver transplantation, after effective HCC downstaging with atezolizumab and bevacizumab combination, may confer a survival benefit over atezolizumab and bevacizumab maintained treatment alone and that this strategy (tested in a consecutive non-randomized cohort) is not undermined by added risks.

Read the detailed description

Liver transplantation (LT) is an accepted treatment for hepatocellular carcinoma (HCC). For patients with intermediate-advanced stage hepatocellular carcinoma (HCC) otherwise not eligible to curative treatments, tumor downstaging to LT is now an accepted strategy, as transplantation after a successful downstaging with loco-regional treatments confers a significant benefit in survival and recurrence/progression free survival compared to non-transplant strategies. Immune checkpoint inhibitors (ICIs) efficacy has been proven both as an adjuvant treatment in surgically treated HCCs and as a first line systemic therapy for advanced stage patients; in both cases with more than tolerable safety profiles. Therefore there is interest in using immunotherapy as a downstaging treatment prior to curative liver transplantation (LT).

This observational prospective single-arm study enrols patients on the transplant list after the achievement of a sustained radiological partial response (PR) or complete response (CR) on treatment with atezolizumab (flat dose of 1200 mg) and bevacizumab (15 mg/Kg) given intravenously every three weeks for a non otherwise treatable intermediate-advanced HCC.

Radiological response has to be sustained (for at least 3 months) and accompanied by a level of alpha fetoprotein (AFP) ≤ 100 UI/ml, if levels > 100 UI/ml at baseline or by decrease of the level of AFP parallel to the modified response evaluation criteria in solid tumors (mRECIST), if baseline levels ≤ 100 UI/ml.

Radiological and biochemical responses need to satisfy a ≥60% post-transplant survival at 5 years according to the Metroticket 2.0 calculator (www.hcc-olt-metroticket.org).

While on the liver transplant waiting list, treatment with atezolizumab and bevacizumab will be stopped. Treatment may be restored, according to clinical judgement:

  • if waiting time on transplant list > 2 months
  • if radiological and/or AFP progression within transplant criteria (predicted 5 year survival according to Metroticket 2.0 calculator ≥60%).
  • if radiological and/or AFP progression beyond transplant criteria (predicted 5 year survival according to Metroticket 2.0 calculator < 60%); patients will be delisted (drop out) and treated according to clinical judgement and local standards.

Priority on the waiting list will follow local standards for candidates with HCC at risk of progression. Both donation after brain death (DBD) and after cardiac death (DCD) will be accepted for organ procurement.

Participants will also undergo a comprehensive blood immunomonitoring in order to explore the effect of liver transplantation and of related immunosuppressive regimens on the anti-tumoral immunomediated environment induced by the combination of atezolizumab and bevacizumab.

Being tested
Liver Transplantation
Keywords
Liver transplantation, Immune checkpoint inhibitors, Downstaging
Medical subject headings
Carcinoma, Hepatocellular

What participants receive

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

  • Liver TransplantationProcedure or surgery

    Liver transplantation (LT) is an accepted surgical therapy for hepatocellular carcinoma (HCC) in patients who achieve effective and sustained tumor downstaging; in this study liver transplantation will be performed in patients undergoing a successful hepatocellular carcinoma (HCC) downstaging with the combination of atezolizumab and bevacizumab.

What is being measured

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

  1. Recurrence-free survival (RFS)

    Recurrence-free survival (RFS) is defined as the interval (in months) between the date of transplantation and the date on which tumor recurrence is detected at any site at contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) scan, calculated in the entire collected patient population with censoring at the date of death or last follow-up in recurrence-free patients

    Measured: up to 2 years

Secondary outcomes (5)

  1. Tumor response

    Tumor response at radiology (contrast enhanced CT scan or MRI) is defined as overall response rate (ORR) that is the number of radiological responses divided by the number of patients:

    • complete response (CR) is defined by the disappearance of any arterial enhancement in all target lesions according to mRECIST criteria
    • partial response (PR) is defined by ≥50% decrease in the sum of diameters of viable target lesions, taking as reference the baseline sum of the diameters of target lesions

    Pathological response at histology is assessed as the percentage of surface with non-viable cancer cells (represented by necrosis or fibrosis) in relation to the total tumor area and is equal to: 100% - viable cancer cells (%). If there are multiple tumors, the mean percentage is used. Complete pathological response (pCR) is defined by the absence of viable tumor cells in any nodule

    Measured: From the time of signature of informed consent until the date of first documented progression or date of death from any cause, whichever comes first, assessed up to 48 months

  2. Complication rate

    Complication rate is defined as the number of complications, deviating from the normal post-operative course, divided by the number of patients; complications will be assessed according to Dindo-Clavien classification. The total number of both transplant-related and treatment-related adverse events (graft failure, histology confirmed acute rejection, hospital-treated infections) assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v.4.0 will also be divided by the number of participants

    Measured: monthly, up to 2 years

  3. Overall survival (OS)

    Overall survival (OS) is defined as the interval (in months) between the date of transplantation and the date of death for any reason in the entire collected patient population, with censoring at the date of last follow-up in alive patients

    Measured: up to 2 years

  4. Patients' reported outcomes (PROs)

    Patients' reported outcomes will be evaluated by the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30, version 3) filled in by all participants in order to measure health related quality of life.

    The QLQ-C30 is composed of 28 multi-item scales rated from 1 to 4 (where 1 is "not at all", 2 is "a little", 3 is "quite a bit" and 4 is "very much") and 2 single-item measures rated from 1 to 7, where 1 is "very poor" and 7 is "excellent". These items include five functional scales, three symptom scales, a global health status scale, and six single items. The scales produce a final score ranging from 0 to 100. A high scale score represents a higher response level. In detail:

    • a high score for a functional scale represents a high / healthy level of functioning
    • a high score for the global health status represents a high QoL
    • a high score for a symptom scale / item represents a high level of symptomatic problems

    Measured: every 3 months for the first six months, then every 6 months up to 2 years

  5. Comparison with historical series

    As this study has no comparator arm, overall survival (OS) and recurrence free survival (RFS) of the participants to the study will be compared with the overall survival (OS) and recurrence free survival (RFS) of historical series of patients with intermediate-advanced HCC downstaged using loco-regional treatments only (doi:10.1016/S1470-2045(20)30224-2, PMID 32615109) and of patients treated with and responding to atezolizumab and bevacizumab in the advanced tumor setting (doi:10.1056/NEJMoa1915745, PMID: 32402160)

    Measured: up to 2 years

Timeline

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

  1. First posted30 May 2023
  2. Study start23 Dec 2022
  3. Primary completion31 Dec 2024 (estimated)
  4. Study completion31 Dec 2024 (estimated)

Resources

More details

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

Study design
Study type
Observational
Observational model
Cohort
Time perspective
Prospective
Enrolment
12 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05879328
Sponsor's protocol ID
INT 30/23
Acronym
ImmunoXXL
Status last verified
May 2023
First submitted
24 Mar 2023
Last updated
30 May 2023
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Undecided

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

  • Reig M, Forner A, Rimola J, Ferrer-Fabrega J, Burrel M, Garcia-Criado A, Kelley RK, Galle PR, Mazzaferro V, Salem R, Sangro B, Singal AG, Vogel A, Fuster J, Ayuso C, Bruix J. BCLC strategy for prognosis prediction and treatment recommendation: The 2022 update. J Hepatol. 2022 Mar;76(3):681-693. doi: 10.1016/j.jhep.2021.11.018. Epub 2021 Nov 19.

    PubMed 34801630

  • Llovet JM, Castet F, Heikenwalder M, Maini MK, Mazzaferro V, Pinato DJ, Pikarsky E, Zhu AX, Finn RS. Immunotherapies for hepatocellular carcinoma. Nat Rev Clin Oncol. 2022 Mar;19(3):151-172. doi: 10.1038/s41571-021-00573-2. Epub 2021 Nov 11.

    PubMed 34764464

  • Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, Kudo M, Breder V, Merle P, Kaseb AO, Li D, Verret W, Xu DZ, Hernandez S, Liu J, Huang C, Mulla S, Wang Y, Lim HY, Zhu AX, Cheng AL; IMbrave150 Investigators. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med. 2020 May 14;382(20):1894-1905. doi: 10.1056/NEJMoa1915745.

    PubMed 32402160

  • Mazzaferro V, Sposito C, Zhou J, Pinna AD, De Carlis L, Fan J, Cescon M, Di Sandro S, Yi-Feng H, Lauterio A, Bongini M, Cucchetti A. Metroticket 2.0 Model for Analysis of Competing Risks of Death After Liver Transplantation for Hepatocellular Carcinoma. Gastroenterology. 2018 Jan;154(1):128-139. doi: 10.1053/j.gastro.2017.09.025. Epub 2017 Oct 5.

    PubMed 28989060

  • Hack SP, Spahn J, Chen M, Cheng AL, Kaseb A, Kudo M, Lee HC, Yopp A, Chow P, Qin S. IMbrave 050: a Phase III trial of atezolizumab plus bevacizumab in high-risk hepatocellular carcinoma after curative resection or ablation. Future Oncol. 2020 May;16(15):975-989. doi: 10.2217/fon-2020-0162. Epub 2020 Apr 30.

    PubMed 32352320

  • Bhoori S, Rivoltini L, Pinato DJ, Bellia V, Maspero M, Bongini M, de Cristofaro J, Vaiani M, Dosi M, Vergani E, Vergani B, Leoncini G, Daveri E, Di Maio G, Simonotti N, Cappetti B, Cova A, Rini F, Bergamini S, Lalli L, Sposito C, Mazzaferro V. Efficacy of liver transplantation after response to atezolizumab-bevacizumab downstaging of intermediate and advanced hepatocellular carcinoma (ImmunoXXL). J Hepatol. 2026 Jul;85(1):117-129. doi: 10.1016/j.jhep.2026.02.019. Epub 2026 Feb 26.

    PubMed 41763363

Questions about this trial

What is this clinical trial studying?

An observational study of Hepatocellular Carcinoma, run by Fondazione IRCCS Istituto Nazionale dei Tumori, Milano at 1 site in Italy.

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 5 inclusion and 2 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: status not confirmed, as of the sponsor's last update on 30 May 2023. 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 Italy. 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.

Are results available for this study?

Results are not available in the source record.

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

Contact Sherrie Bhoori, MD (+39022390 ext. 2760, sherrie.bhoori@istitutotumori.mi.it), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Recurrence-free survival (RFS) (time frame: up to 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 NCT05879328, which also lists 7 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 30 May 2023.

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