Clinical trial NCT01387503: Expansion of Conventional Criteria for Liver Transplantation in Hepatocellular Carcinoma Through Downstaging
Official title: Controlled Expansion of Conventional Criteria for Liver Transplantation in Hepatocellular Carcinoma Through Downstaging Procedures: a Randomized Trial (XXL Trial)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Carcinoma, Hepatocellular
Cirrhosis
Keywords: Hepatocellular Carcinoma
Liver Transplantation
Downstaging
Trans-arterial chemoembolization (TACE)
Radiofrequency ablation (RFA)
Liver resection
Sorafenib
Lead sponsor: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Sponsor class: OTHER
Collaborators: name: AISF (Associazione Italiana per lo Studio del Fegato)
name: CNT (Centro Nazionale Trapianti)
name: NITp (Nord Italia Transplant project)
name: OCST (Organizzazione Centro Sud Trapianti)
name: Associazione Italiana per la Ricerca sul Cancro
name: Ministero della Salute, Italy
name: Basilicata Region
First posted: 2011-07-04
Enrollment: 74
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

* Patient's age ≥ 18 yrs and ≤ 65 yrs
* Presence of cirrhosis of any etiology
* Child-Pugh class ≤ B7
* ECOG Performance Status ≤ 1
* Diagnosis of HCC either by biopsy or according to AASLD criteria
* HCC exceeding Milan Criteria with a 5-yr estimated survival after transplantation \>50% according to the Metroticket calculator (http://www.hcc-olt-metroticket.org/calculator)
* Women of child bearing potential with a negative serum pregnancy test performed before enrolment
* Absence of general contraindications to sorafenib/molecular targeted therapies

Exclusion Criteria:

* Presence of extra-hepatic tumor spread
* Presence of macrovascular invasion
* Sorafenib therapy started \> 2 months before enrolment
* Concurrent cancer, distinct from HCC (except cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors)
* Previous history of any cancer, even if curatively treated, \< 5 years prior to entry
* Active intra-venous or alcohol abusers
* HIV infection
* History of serious cardiac disease
* Severe pulmonary hypertension not treatable by medical therapy
* Patients with a life expectancy of less than 3 months due to HCC or less than 6 months due to any other disease

Primary outcomes:
measure: For Phase II - Time to Tumoral Event (TTE)
timeFrame: Every 4 months
measure: For Phase III - Overall Survival
timeFrame: Every 4 months
Secondary outcomes:
measure: Transplant vs. non transplant strategy cost-benefit analysis
timeFrame: Approx. 1 year after the last patient randomized
measure: Validation of modified RECIST criteria of radiological response to downstaging treatments
timeFrame: Approx. 8 months after the last patient randomized
measure: Validation of the Metroticket model for the prognosis of survival after liver transplantation in patients exceeding Milan Criteria
timeFrame: Approx. 1 year after the last patient randomized
Other outcomes:
Locations:
city: Bergamo
country: Italy
facility: Ospedali Riuniti di Bergamo
city: Milano
country: Italy
facility: Ospedale Maggiore di Milano Policlinico
city: Milano
country: Italy
facility: Istituto Nazionale Tumori
city: Milano
country: Italy
facility: Azienda Ospedaliera Ospedale Niguarda Ca' Granda
city: Padova
country: Italy
facility: Azienda Ospedaliera Universitaria di Padova
city: Palermo
country: Italy
facility: Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione (ISMETT)
city: Roma
country: Italy
facility: Policlinico Tor Vergata
city: Roma
country: Italy
facility: Ospedale "Lazzaro Spallanzani"
city: Roma
country: Italy
facility: Ospedale Umberto Iº Policlinico di Roma
city: Torino
country: Italy
facility: Ospedale Universitario Molinette S. Giovanni Battista di Torino
Study officials:
affiliation: Istituto Nazionale Tumori, Milano
name: Vincenzo Mazzaferro, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Mazzaferro V, Llovet JM, Miceli R, Bhoori S, Schiavo M, Mariani L, Camerini T, Roayaie S, Schwartz ME, Grazi GL, Adam R, Neuhaus P, Salizzoni M, Bruix J, Forner A, De Carlis L, Cillo U, Burroughs AK, Troisi R, Rossi M, Gerunda GE, Lerut J, Belghiti J, Boin I, Gugenheim J, Rochling F, Van Hoek B, Majno P; Metroticket Investigator Study Group. Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis. Lancet Oncol. 2009 Jan;10(1):35-43. doi: 10.1016/S1470-2045(08)70284-5. Epub 2008 Dec 4.
citation: Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, Montalto F, Ammatuna M, Morabito A, Gennari L. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 1996 Mar 14;334(11):693-9. doi: 10.1056/NEJM199603143341104.
citation: Llovet JM, Di Bisceglie AM, Bruix J, Kramer BS, Lencioni R, Zhu AX, Sherman M, Schwartz M, Lotze M, Talwalkar J, Gores GJ; Panel of Experts in HCC-Design Clinical Trials. Design and endpoints of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst. 2008 May 21;100(10):698-711. doi: 10.1093/jnci/djn134. Epub 2008 May 13.
citation: Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis. 2010 Feb;30(1):52-60. doi: 10.1055/s-0030-1247132. Epub 2010 Feb 19.
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.