The ImmunoXXL Study

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Hepatocellular Carcinoma

Intervention / Treatment
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* Procedure: Liver Transplantation


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Intervention/Treatment |
| --- |
|Procedure: Liver Transplantation|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 the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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 | 
| 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 | monthly, up to 2 years | 
| 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 | up to 2 years | 
| 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 | every 3 months for the first six months, then every 6 months up to 2 years | 
| 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) | up to 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Liver transplantation, Immune checkpoint inhibitors, Downstaging