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

Cirrhosis Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01387503
• Other study ID #: INT 80/09
• Status: Completed
• Phase: N/A
• Start date: January 2011
• Est. completion date: July 31, 2019

Study information

• Verified date: October 2021
• Source: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 74
• Est. completion date: July 31, 2019
• Est. primary completion date: March 31, 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Hepatocellular
• Cirrhosis

Intervention

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

Locations

Country	Name	City	State
Italy	Ospedali Riuniti di Bergamo	Bergamo
Italy	Azienda Ospedaliera Ospedale Niguarda Ca' Granda	Milano
Italy	Istituto Nazionale Tumori	Milano
Italy	Ospedale Maggiore di Milano Policlinico	Milano
Italy	Azienda Ospedaliera Universitaria di Padova	Padova
Italy	Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione (ISMETT)	Palermo
Italy	Ospedale "Lazzaro Spallanzani"	Roma
Italy	Ospedale Umberto Iº Policlinico di Roma	Roma
Italy	Policlinico Tor Vergata	Roma
Italy	Ospedale Universitario Molinette S. Giovanni Battista di Torino	Torino

Sponsors (8)

Lead Sponsor	Collaborator
Fondazione IRCCS Istituto Nazionale dei Tumori, Milano	AISF (Associazione Italiana per lo Studio del Fegato), Associazione Italiana per la Ricerca sul Cancro, Basilicata Region, CNT (Centro Nazionale Trapianti), Ministero della Salute, Italy, NITp (Nord Italia Transplant project), OCST (Organizzazione Centro Sud Trapianti)

Country where clinical trial is conducted

Italy, 

References & Publications (4)

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. Review. — View 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. Review. — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	For Phase II - Time to Tumoral Event (TTE)	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.	Every 4 months
Primary	For Phase III - Overall Survival	Time form the date of randomization and the date of death, with censoring at the date of last contact for event-free patients	Every 4 months
Secondary	Transplant vs. non transplant strategy cost-benefit analysis	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	Approx. 1 year after the last patient randomized
Secondary	Validation of modified RECIST criteria of radiological response to downstaging treatments	Radiology/pathology correlation on efficacy of downstaging treatments in achieving tumor response, as a basis for possible validation of modified RECIST criteria.	Approx. 8 months after the last patient randomized
Secondary	Validation of the Metroticket model for the prognosis of survival after liver transplantation in patients exceeding Milan Criteria	http://www.hcc-olt-metroticket.org/	Approx. 1 year after the last patient randomized

External Links

•   The system will calculate the 3 and 5 year predicted survival of a given patient with HCC undergoing liver transplantation