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

Phase 2/Phase 3
18 Years
65 Years
Open (Enrolling)
Carcinoma, Hepatocellular, Cirrhosis

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Trial Information

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

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

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.

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

- 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

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

For Phase II - Time to Tumoral Event (TTE)

Outcome Description:

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.

Outcome Time Frame:

Every 4 months

Safety Issue:


Principal Investigator

Vincenzo Mazzaferro, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Istituto Nazionale Tumori, Milano


Italy: Ethics Committee

Study ID:

INT 80/09



Start Date:

January 2011

Completion Date:

January 2014

Related Keywords:

  • Carcinoma, Hepatocellular
  • Cirrhosis
  • Hepatocellular Carcinoma
  • Liver Transplantation
  • Downstaging
  • Trans-arterial chemoembolization (TACE)
  • Radiofrequency ablation (RFA)
  • Liver resection
  • Sorafenib
  • Carcinoma
  • Liver Cirrhosis
  • Fibrosis
  • Carcinoma, Hepatocellular