Clinical trial NCT01357486: Palliative Treatment of Hepatocellular Carcinoma in Patient With CHILD B Cirrhosis
Official title: Phase II Randomized Trial Evaluating the Administration of Sorafenib or Pravastatin or Association Sorafenib-pravastatin or Best Supportive Care for the Palliative Treatment of Hepatocellular Carcinoma in Patient With CHILD B Cirrhosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Hepatocellular Carcinoma
CHILD B
Keywords: Hepatocellular Carcinoma
CHILD B
palliative management
Sorafenib
Pravastatin
Lead sponsor: University Hospital, Bordeaux
Sponsor class: OTHER
Collaborators: name: Federation Francophone de Cancerologie Digestive
name: UNICANCER
First posted: 2011-05-20
Enrollment: 160
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The incidence of Hepatocellular Carcinoma (HCC) is currently increasing in Europe and in France and about 2 / 3 of patients, are not eligible for curative treatment at the time of diagnosis. The palliative management of patients with advanced and symptomatic disease is complex and requires treatment combining anti-tumor activity and safety in patients with impaired liver functions. Sorafenib is the standard of care in a palliative setting, but the benefit of sorafenib in patient with altered liver function is uncertain. The aim of this trial is to study the interest of sorafenib in patients with HCC and impaired liver function compared to pravastatin (a drug with anti-tumoral activity in HCC) or to the combination sorafenib/pravastatin or to best supportive care (usually used in these patients).

Detailed description: The incidence of Hepatocellular Carcinoma (HCC) is currently increasing in Europe and in France. It almost always occurs on liver disease and in 80 to 90% of cases, at least in France, on liver with cirrhosis. If curative treatment may be proposed for some "small" HCC (transplantation, resection, percutaneous destruction), about 2 / 3 of patients, which represents nearly 4,000 new cases per year in France, are not eligible for such treatment. The palliative management of patients with advanced and symptomatic disease is complex and requires treatment combining anti-tumor activity and safety in patients with impaired liver functions. Indeed, in most cases the palliative treatment of HCC is applied to patients with altered liver function (stage B of the Child-Pugh classification).

To date, the proposed treatment in France for such patients is based on best supportive care.

The objective of this study is to assess the interest in this situation of 2 molecules - taken alone or in combination:

* Sorafenib, the reference in the palliative treatment of advanced hepatocellular carcinoma (Stage C of the BCLC classification). Yet the safety and efficacy of sorafenib in patients with altered liver function (CHILD B) are not clearly defined and its use remains discouraged by French recommendations in these patients.
* Pravastatin whose interest in the palliative treatment of HCC was suggested by several phase II studies with a good safety profile in cirrhotic patients.

In this French multicenter open randomized study, 160 patients will be included in 4 arms (40/arms): sorafenib, pravastatin, pravastatin + sorafenib, and supportive care.

The aim of this phase II multicenter study is to select the two best arms for further Phase III study in order to identify a reference treatment in this palliative situation.

Eligibility criteria: Inclusion Criteria:

- Male and female subjects \> 18 years age

- Hepatocellular carcinoma histologically diagnosed or in case of inability to perform a histology by non invasive radiological criteria in presence of known cirrhosis: (i) Hepatic lesion measuring between 1 and 2 cm in diameter : CT-scan + MRI (eventually an Ultrasound contrast) : HCC diagnosed with contrast uptake in the arterial phase and rapid wash out in the venous /late phase on two imaging techniques.

(ii)Hepatic lesion with a diameter \> 2 cm : CT-scan or MRI +alpha fetoprotein : HCC diagnosed with contrast uptake in the arterial phase and a rapid wash out in the venous /late phase or a alpha fetoprotein \> 200µg/L

* Patient not eligible for curative treatment (transplantation, resection, destruction or percutaneous chemo-embolization) or HCC still evolving after failure of a specific treatment
* Score CHILD B
* ECOG performance status 0/1/2
* Score BCLC B or C
* Adequate haematologic function with haemoglobin \> 8 g/dl, platelet count \> 50000x 109/L, absolute neutrophil count \> 1000 / mm3
* Creatinine \< 2 times the upper limit of normal
* Written informed consent

Exclusion Criteria:

* Any condition that is unstable or could jeopardize the safety of the subject and their compliance in the study
* Pregnancy
* Myocardial infarction less than 6 months, uncontrolled hypertension, congestive heart failure(NYHA class \> 2) , anti- arrhythmic treatment other than beta-blockers or digoxin
* Digestive bleeding within 30 days before inclusion
* Hepatic transplantation
* Patients receiving or having received a statine for less than 6 months before HCC diagnostic
* Prior use of sorafenib
* Psychiatric illness/social situations that would limit compliance with study requirements.
* Previous or concurrent cancer, except cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumor. Any cancer curatively treated \> 5 years prior to entry is permitted
* Known or suspected history of allergy to sorafenib or pravastatin.

Primary outcomes:
measure: Time to radiologic progression
timeFrame: Every 4 weeks (CT-scan or MRI) until progression of HCC or date of last news (for patients alive or dead without progression)
Secondary outcomes:
measure: Overall survival
timeFrame: End of the study (estimated date August 2012)
measure: Survival without progression
timeFrame: Every 4 weeks (CT-scan or MRI) until progression of HCC or date of last news (for patients alive or dead without progression)
measure: Time to treatment failure
timeFrame: every 4 weeks (CT-scan or MRI) until clinical or radiological progression of HCC or date of last news (for patients alive or dead without progression)
measure: Objective response rate at four months
timeFrame: Radiological evaluation at 4 months
measure: Number and description of AE for toxicity and SAE
timeFrame: Clinical evaluation every month
measure: Quality of life
timeFrame: Clinical evaluation every month
Other outcomes:
Locations:
city: Abbeville
country: France
facility: CH d'Abbeville
city: Aix-en-provence
country: France
facility: CH Pays d'Aix
city: Auxerre
country: France
facility: CH d'Auxerre
city: Bayonne
country: France
facility: CH de la Côte Basque
city: Bondy
country: France
facility: AP-HP- Hôpital Jean-Verdier
city: Bordeaux
country: France
facility: CHU de Bordeaux
city: Boulogne Sur Mer
country: France
facility: CH Duchenne
city: Béziers
country: France
facility: CH de Béziers
city: Creteil
country: France
facility: AP-HP Hôpital Henri Mondor
city: Dijon
country: France
facility: CHU Le Bocage
city: La Roche-sur-yon
country: France
facility: CH Départemental Vendée
city: Le Mans
country: France
facility: CH Le Mans
city: Lorient
country: France
facility: CH de Bretagne Sud
city: Lyon
country: France
facility: Hôpital privé Jean Mermoz
city: Marseille
country: France
facility: AP-HM Hôpital de la Timone
city: Meaux
country: France
facility: CH de Meaux
city: Mont-de-marsan
country: France
facility: CH Mont de Marsan
city: Nancy
country: France
facility: CHU de Nancy Hôpital Brabois
city: Nantes
country: France
facility: CHU de Nantes Hôpital de l'Hotel Dieu
city: Nimes
country: France
facility: CHU Nîmes
city: Orleans
country: France
facility: CHR d'Orléans - Hôpital La Source
city: Paris
country: France
facility: Groupe Hospitalier Paris Saint Joseph
city: Perpignan
country: France
facility: CH Perpignan
city: Pessac
country: France
facility: CHU de Bordeaux, Hôpital du Haut Lévèque
city: Pringy
country: France
facility: CH de la Région d'Annecy
city: Rennes
country: France
facility: Centre Eugène Marquis
city: Rouen
country: France
facility: Clinique Mathilde
city: Saint Brieuc
country: France
facility: Clinique Armoricaine de Radiologie
city: Saint Malo
country: France
facility: CH Saint-Malo
city: Saint-herblain
country: France
facility: Centre René Gauducheau CLCC Nantes Atlantique
city: Sens
country: France
facility: CH Gaston Ramon
city: Strasbourg
country: France
facility: Centre Régional de Lutte contre le Cancer Centre Paul Strauss
city: Strasbourg
country: France
facility: Hôpitaux Universitaires de Strasbourg Hôpital civil
city: Strasbourg
country: France
facility: Hôpitaux Universitaires de Strasbourg, Hôpital Hautepierre
city: Tours
country: France
facility: CHRU de Tours
Study officials:
affiliation: University Hospital, Bordeaux
name: Jean-Frédéric BLANC, MD-PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I, Haussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J; SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008 Jul 24;359(4):378-90. doi: 10.1056/NEJMoa0708857.
citation: Taras D, Blanc JF, Rullier A, Dugot-Senant N, Laurendeau I, Vidaud M, Rosenbaum J. Pravastatin reduces lung metastasis of rat hepatocellular carcinoma via a coordinated decrease of MMP expression and activity. J Hepatol. 2007 Jan;46(1):69-76. doi: 10.1016/j.jhep.2006.06.015. Epub 2006 Jul 28.
citation: Kawata S, Yamasaki E, Nagase T, Inui Y, Ito N, Matsuda Y, Inada M, Tamura S, Noda S, Imai Y, Matsuzawa Y. Effect of pravastatin on survival in patients with advanced hepatocellular carcinoma. A randomized controlled trial. Br J Cancer. 2001 Apr 6;84(7):886-91. doi: 10.1054/bjoc.2000.1716.
citation: Lersch C, Schmelz R, Erdmann J, Hollweck R, Schulte-Frohlinde E, Eckel F, Nader M, Schusdziarra V. Treatment of HCC with pravastatin, octreotide, or gemcitabine--a critical evaluation. Hepatogastroenterology. 2004 Jul-Aug;51(58):1099-103.
citation: Cohen DE, Anania FA, Chalasani N; National Lipid Association Statin Safety Task Force Liver Expert Panel. An assessment of statin safety by hepatologists. Am J Cardiol. 2006 Apr 17;97(8A):77C-81C. doi: 10.1016/j.amjcard.2005.12.014. Epub 2006 Feb 3.
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: Blanc JF, Khemissa F, Bronowicki JP, Monterymard C, Perarnau JM, Bourgeois V, Obled S, Abdelghani MB, Mabile-Archambeaud I, Faroux R, Seitz JF, Locher C, Senellart H, Villing AL, Audemar F, Costentin C, Deplanque G, Manfredi S, Edeline J; PRODIGE 21 collaborators. Phase 2 trial comparing sorafenib, pravastatin, their combination or supportive care in HCC with Child-Pugh B cirrhosis. Hepatol Int. 2021 Feb;15(1):93-104. doi: 10.1007/s12072-020-10120-3. Epub 2021 Jan 9.