Palliative Treatment of Hepatocellular Carcinoma in Patient With CHILD B Cirrhosis

NCT ID: NCT01357486

Last Updated: 2017-05-01

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 160 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-11-14
• Study Completion Date: 2017-04-12

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.

Conditions

Hepatocellular Carcinoma; CHILD B

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

A

patients receiving sorafenib 400 mg - twice a day

Group Type: EXPERIMENTAL

sorafenib

Intervention Type: DRUG

patients receiving sorafenib 400 mg - twice a day

B

patients receiving pravastatin 40 mg - once a day

Group Type: EXPERIMENTAL

Pravastatin

Intervention Type: DRUG

patients receiving pravastatin 40 mg - once a day

C

patients receiving sorafenib 400 mg (twice a day) and pravastatin 40 mg (once a day)

Group Type: EXPERIMENTAL

Sorafenib + Pravastatin

Intervention Type: DRUG

patients receiving sorafenib 400 mg (twice a day) and pravastatin 40 mg (once a day)

D

patients receiving best supportive care

Group Type: OTHER

patients receiving best supportive care

Intervention Type: OTHER

palliative management

Interventions

sorafenib

patients receiving sorafenib 400 mg - twice a day

Intervention Type: DRUG

Pravastatin

patients receiving pravastatin 40 mg - once a day

Intervention Type: DRUG

Sorafenib + Pravastatin

patients receiving sorafenib 400 mg (twice a day) and pravastatin 40 mg (once a day)

Intervention Type: DRUG

patients receiving best supportive care

palliative management

Intervention Type: OTHER

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Federation Francophone de Cancerologie Digestive

OTHER

Sponsor Role: collaborator

UNICANCER

OTHER

Sponsor Role: collaborator

University Hospital, Bordeaux

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Jean-Frédéric BLANC, MD-PhD

Role: PRINCIPAL_INVESTIGATOR

University Hospital, Bordeaux

Locations

CH d'Abbeville

Abbeville, , France

CH Pays d'Aix

Aix-en-Provence, , France

CH d'Auxerre

Auxerre, , France

CH de la Côte Basque

Bayonne, , France

CH de Béziers

Béziers, , France

AP-HP- Hôpital Jean-Verdier

Bondy, , France

CHU de Bordeaux

Bordeaux, , France

CH Duchenne

Boulogne-sur-Mer, , France

AP-HP Hôpital Henri Mondor

Créteil, , France

CHU Le Bocage

Dijon, , France

CH Départemental Vendée

La Roche-sur-Yon, , France

CH Le Mans

Le Mans, , France

CH de Bretagne Sud

Lorient, , France

Hôpital privé Jean Mermoz

Lyon, , France

AP-HM Hôpital de la Timone

Marseille, , France

CH de Meaux

Meaux, , France

CH Mont de Marsan

Mont-de-Marsan, , France

CHU de Nancy Hôpital Brabois

Nancy, , France

CHU de Nantes Hôpital de l'Hotel Dieu

Nantes, , France

CHU Nîmes

Nîmes, , France

CHR d'Orléans - Hôpital La Source

Orléans, , France

Groupe Hospitalier Paris Saint Joseph

Paris, , France

CH Perpignan

Perpignan, , France

CHU de Bordeaux, Hôpital du Haut Lévèque

Pessac, , France

CH de la Région d'Annecy

Pringy, , France

Centre Eugène Marquis

Rennes, , France

Clinique Mathilde

Rouen, , France

Clinique Armoricaine de Radiologie

Saint-Brieuc, , France

Centre René Gauducheau CLCC Nantes Atlantique

Saint-Herblain, , France

CH Gaston Ramon

Sens, , France

CH Saint-Malo

St-Malo, , France

Centre Régional de Lutte contre le Cancer Centre Paul Strauss

Strasbourg, , France

Hôpitaux Universitaires de Strasbourg Hôpital civil

Strasbourg, , France

Hôpitaux Universitaires de Strasbourg, Hôpital Hautepierre

Strasbourg, , France

CHRU de Tours

Tours, , France

Countries

France

References

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.

Reference Type: BACKGROUND

PMID: 18650514 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 16935385 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 11286466 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 15239254 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 16581333 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 18477802 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 33420951 (View on PubMed)

Other Identifiers

CHUBX 2010/22

Identifier Type: -

Identifier Source: org_study_id