Clinical trial NCT05879328: The ImmunoXXL 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
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Hepatocellular Carcinoma
Keywords: Liver transplantation
Immune checkpoint inhibitors
Downstaging
Lead sponsor: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Sponsor class: OTHER
First posted: 2023-05-30
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
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).

Brief 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 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.

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.

Eligibility criteria: Inclusion Criteria:

* 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.

Exclusion Criteria:

* 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).

Primary outcomes:
measure: Recurrence-free survival (RFS)
timeFrame: up to 2 years
Secondary outcomes:
measure: Tumor response
timeFrame: 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
measure: Complication rate
timeFrame: monthly, up to 2 years
measure: Overall survival (OS)
timeFrame: up to 2 years
measure: Patients' reported outcomes (PROs)
timeFrame: every 3 months for the first six months, then every 6 months up to 2 years
measure: Comparison with historical series
timeFrame: up to 2 years
Other outcomes:
Locations:
city: Milano
country: Italy
facility: Fondazione IRCCS Istituto Nazionale dei Tumori
state: MI
Study officials:
affiliation: Fondazione Istituto Nazionale Tumori Milano - Italy
name: Vincenzo Mazzaferro, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.