Palliative Treatment of Hepatocellular Carcinoma in Patient With CHILD B Cirrhosis

Hepatocellular Carcinoma Clinical Trial

— PRODIGE 21  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01357486
• Other study ID #: CHUBX 2010/22
• Status: Completed
• Phase: Phase 2
• First received: May 13, 2011
• Last updated: April 28, 2017
• Start date: November 14, 2011
• Est. completion date: April 12, 2017

Study information

• Verified date: April 2017
• Source: University Hospital, Bordeaux
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 160
• Est. completion date: April 12, 2017
• Est. primary completion date: April 12, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Hepatocellular
• CHILD B
• Hepatocellular Carcinoma

Intervention

Drug:
• sorafenib
patients receiving sorafenib 400 mg - twice a day
• Pravastatin
patients receiving pravastatin 40 mg - once a day
• Sorafenib + Pravastatin
patients receiving sorafenib 400 mg (twice a day) and pravastatin 40 mg (once a day)

Other:
• patients receiving best supportive care
palliative management

Locations

Country	Name	City	State
France	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	Creteil
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	Nimes
France	CHR d'Orléans - Hôpital La Source	Orleans
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	CH Saint-Malo	Saint Malo
France	Centre René Gauducheau CLCC Nantes Atlantique	Saint-herblain
France	CH Gaston Ramon	Sens
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

Sponsors (3)

Lead Sponsor	Collaborator
University Hospital, Bordeaux	Federation Francophone de Cancerologie Digestive, UNICANCER

Country where clinical trial is conducted

France, 

References & Publications (6)

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. Epub 2006 Feb 3. — View 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. — View 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. — 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

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, Häussinger 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. — View 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. Epub 2006 Jul 28. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Time to radiologic progression		Every 4 weeks (CT-scan or MRI) until progression of HCC or date of last news (for patients alive or dead without progression)
Secondary	Overall survival		End of the study (estimated date August 2012)
Secondary	Survival without progression		Every 4 weeks (CT-scan or MRI) until progression of HCC or date of last news (for patients alive or dead without progression)
Secondary	Time to treatment failure		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)
Secondary	Objective response rate at four months		Radiological evaluation at 4 months
Secondary	Number and description of AE for toxicity and SAE		Clinical evaluation every month
Secondary	Quality of life		Clinical evaluation every month