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

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ClinicalTrials.gov Identifier: NCT01387503
Recruitment Status : Unknown
Verified June 2011 by Fondazione IRCCS Istituto Nazionale dei Tumori, Milano.
Recruitment status was:  Recruiting
First Posted : July 4, 2011
Last Update Posted : July 4, 2011
Information provided by:

Study Description
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.

Condition or disease Intervention/treatment Phase
Carcinoma, Hepatocellular Cirrhosis Procedure: Liver transplantation Phase 2 Phase 3

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.

Study Design

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 260 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Controlled Expansion of Conventional Criteria for Liver Transplantation in Hepatocellular Carcinoma Through Downstaging Procedures: a Randomized Trial (XXL Trial)
Study Start Date : January 2011
Estimated Primary Completion Date : January 2013
Estimated Study Completion Date : January 2014

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Arms and Interventions

Arm Intervention/treatment
Experimental: Group 1 - Transplant strategy
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
Procedure: Liver transplantation
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
No Intervention: Group 2 - Non-transplant strategy
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

Outcome Measures

Primary Outcome Measures :
  1. For Phase II - Time to Tumoral Event (TTE) [ Time Frame: Every 4 months ]
    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.

  2. For Phase III - Overall Survival [ Time Frame: Every 4 months ]
    Time form the date of randomization and the date of death, with censoring at the date of last contact for event-free patients

Secondary Outcome Measures :
  1. Transplant vs. non transplant strategy cost-benefit analysis [ Time Frame: Approx. 1 year after the last patient randomized ]
    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

  2. Validation of modified RECIST criteria of radiological response to downstaging treatments [ Time Frame: Approx. 8 months after the last patient randomized ]
    Radiology/pathology correlation on efficacy of downstaging treatments in achieving tumor response, as a basis for possible validation of modified RECIST criteria.

  3. Validation of the Metroticket model for the prognosis of survival after liver transplantation in patients exceeding Milan Criteria [ Time Frame: Approx. 1 year after the last patient randomized ]

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01387503

Contact: Vincenzo Mazzaferro, MD +39 02 23902760 Trial.XXL@istitutotumori.mi.it

Ospedali Riuniti di Bergamo Recruiting
Bergamo, Italy, 24125
Ospedale Maggiore di Milano Policlinico Recruiting
Milano, Italy, 20122
Istituto Nazionale Tumori Recruiting
Milano, Italy, 20133
Azienda Ospedaliera Ospedale Niguarda Ca' Granda Recruiting
Milano, Italy, 20162
Azienda Ospedaliera Universitaria di Padova Recruiting
Padova, Italy, 35128
Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione (ISMETT) Recruiting
Palermo, Italy, 90133
Policlinico Tor Vergata Recruiting
Roma, Italy, 00133
Ospedale "Lazzaro Spallanzani" Recruiting
Roma, Italy, 00149
Ospedale Umberto Iº Policlinico di Roma Recruiting
Roma, Italy, 00161
Ospedale Universitario Molinette S. Giovanni Battista di Torino Recruiting
Torino, Italy, 10126
Sponsors and Collaborators
Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
AISF (Associazione Italiana per lo Studio del Fegato)
CNT (Centro Nazionale Trapianti)
NITp (Nord Italia Transplant project)
OCST (Organizzazione Centro Sud Trapianti)
Associazione Italiana per la Ricerca sul Cancro
Ministero della Salute, Italy
Basilicata Region
Principal Investigator: Vincenzo Mazzaferro, MD Istituto Nazionale Tumori, Milano
More Information

Responsible Party: Vincenzo Mazzaferro, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
ClinicalTrials.gov Identifier: NCT01387503     History of Changes
Other Study ID Numbers: INT 80/09
First Posted: July 4, 2011    Key Record Dates
Last Update Posted: July 4, 2011
Last Verified: June 2011

Keywords provided by Fondazione IRCCS Istituto Nazionale dei Tumori, Milano:
Hepatocellular Carcinoma
Liver Transplantation
Trans-arterial chemoembolization (TACE)
Radiofrequency ablation (RFA)
Liver resection

Additional relevant MeSH terms:
Carcinoma, Hepatocellular
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Liver Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases
Liver Extracts