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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.

Liver Transplantation

Sherrie Bhoori, MD

Valentina Bellia, MD

Vincenzo Mazzaferro, MD, PhD

Carlo Sposito, MD

Marco Bongini, MD

Licia Rivoltini, MD

Nicola Cerioli, PhD

Michela Dosi, PhD

Francesca Rini, Lab Tech

Agata Cova, Lab Tech

Paola Squarcina, Lab Tech

Marta Vaiani, MD

Giuseppe Leoncini, MD

Monica Niger, MD

Federico Nicchetti, MD

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.

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.

Immune profiling is performed (on day of transplantation, 3, 7, 15, 30, 90 days after transplantation with additional sampling at 6 months) by high resolution flow cytometry (Cytoflex platform) quantifying T cell effector and memory cell subsets (CD3, CD4 and others), T cell subsets associated with response to immunotherapy (PD1, CD28 and others), T reg cell subsets and myeloid cell subsets. Specific antiviral (HCV, HBV, EBV and CMV) and anti-tumor (HCC antigen pool including NY-Eso1, AFP and others) T cell activity is analyzed through ex-vivo peptide stimulation and specific IFNg release detected by Elispot. Immunomodulating and inflammatory cyto- and chemokines levels are quantified through secretome analysis (Cytokine Bead-Array o Fireplex). PBMC and plasma biobanking is performed as backup and for subsequent functional analysis (miRNA profiling,TCR repertoire and Rnaseq of blood immune cell subsets).

The ImmunoXXL Study

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

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

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

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

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

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

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)

Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

Professor, MD, PhD

Symptoms and General Pathology

Liver Cirrhosis

Chlorotrianisene

Sorafenib

Patients randomized to Group 1 will be enlisted for liver transplantation and will undergo liver transplantation within 8 months unless oncological (i.e. extrahepatic disease) or medical (i.e. cardiac insufficiency) will occur

Patients randomized to Group 2 will continue to receive treatments according to their stage of disease, or will undergo only strict follow-up should a complete response after downstaging treatments have been achieved

Once randomized to Group 1, patients will be enlisted for liver transplantation at the recruiting Center. Prioritization is encouraged as a waiting time of more than 8 months could cause patients' drop-out from the study

Liver transplantation

Vincenzo Mazzaferro, MD

This clinical trial is aimed at extending the chance of liver transplantation, through downstaging procedures, to patients with hepatocellular carcinoma (HCC) exceeding conventional Milan Criteria.

Those patients that will achieve a sustained tumor response after downstaging will be randomized either to undergo liver transplantation or to proceed with conventional non-transplant treatments.

The aim of the study is to demonstrate unequivocally that liver transplantation may provide a survival benefit, with an acceptable survival rate of at least 60% at 5 years, to patients that demonstrate a radiological and sustained tumor response after downstaging. Noteworthy is that response is chosen rather than stage migration as endpoint of downstaging.

1. Downstaging phase

   Patients that will be considered eligible for the study will undergo downstaging procedures according their stage of disease and to Center's policies. Length and intensity of downstaging will be center specific and not centrally pre-determined, but should be inferior to 18 months. Downstaging procedures will be stopped when, according to the Investigators' judgement, the best possible tumor response has been achieved: at this timepoint a radiological evaluation of tumor response according to modified RECIST (mRECIST) criteria will be performed. Patients that have achieved a Complete or Partial Response (PR or CR) will proceed to Bridging Phase, while those with a Stable or Progressive disease (SD or PD) will drop-out from the study.
2. Bridging phase

   Patients that achieved PR or CR after downstaging will receive systemic therapy with sorafenib for three months. After three months radiological response will be assessed according to mRECIST criteria. If a sustained response will be demonstrated patients will proceed to randomization. PD during bridging phase will cause drop-out from the study.
3. Randomization and study period

Patients will be randomized in a 1:1 ratio, using computer generated list stratified by Center and by compliance to sorafenib treatment (based on whether ≤50% or \> 50% of the standard dosage (800 mg/day) has been administered).

1. The experimental group (Group 1 - transplant strategy) will be enlisted for transplantation and will undergo liver transplantation within 8 months unless major medical or oncological contraindications should occur.
2. The control group (Group 2 - non-transplant strategy) will continue with sorafenib until progression. Then they may be treated with either medical or locoregional/surgical therapies according to best practice and Centers' policy, excluding transplantation.

Expansion of Conventional Criteria for Liver Transplantation in Hepatocellular Carcinoma Through Downstaging

Controlled Expansion of Conventional Criteria for Liver Transplantation in Hepatocellular Carcinoma Through Downstaging Procedures: a Randomized Trial (XXL Trial)

TTE after randomization will be calculated as the interval between the randomization date and the date of tumour recurrence for tumor-free patients (either because of liver transplantation or complete response after downstaging procedures) or the date of tumour progression otherwise, with censoring at the date of last contact for event-free patients.

Time form the date of randomization and the date of death, with censoring at the date of last contact for event-free patients

Comparison between the cost/benefit of a downstaging strategy followed by liver transplantation (treatment group) Vs the cost/benefit of convenional therapies (control group), analyzed according to the Quality Adjusted Life Years (QALY) gained in the treatment group

Radiology/pathology correlation on efficacy of downstaging treatments in achieving tumor response, as a basis for possible validation of modified RECIST criteria.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
The ImmunoXXL Study	NCT05879328	Hepatocellular ...	Liver Transplan...	18 Years - 75 Years	Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Expansion of Conventional Criteria for Liver Transplantation in Hepatocellular Carcinoma Through Downstaging	NCT01387503	Carcinoma, Hepa... Cirrhosis	Liver transplan...	18 Years - 65 Years	Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Expansion of Conventional Criteria for Liver Transplantation in Hepatocellular Carcinoma Through Downstaging	NCT01387503	Carcinoma, Hepa... Cirrhosis	Liver transplan...	18 Years - 65 Years	Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

Spots Global Cancer Trial Database for downstaging

Every month we try and update this database with for downstaging cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for downstaging

Every month we try and update this database with for downstaging cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for downstaging cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.