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Palliative Treatment of Hepatocellular Carcinoma in Patient With CHILD B Cirrhosis (PRODIGE 21)

Primary Purpose

Hepatocellular Carcinoma, CHILD B

Status
Completed
Phase
Phase 2
Locations
France
Study Type
Interventional
Intervention
sorafenib
Pravastatin
Sorafenib + Pravastatin
patients receiving best supportive care
Sponsored by
University Hospital, Bordeaux
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hepatocellular Carcinoma focused on measuring Hepatocellular Carcinoma, CHILD B, palliative management, Sorafenib, Pravastatin

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • CH d'Abbeville
  • CH Pays d'Aix
  • CH d'Auxerre
  • CH de la Côte Basque
  • AP-HP- Hôpital Jean-Verdier
  • CHU de Bordeaux
  • CH Duchenne
  • CH de Béziers
  • AP-HP Hôpital Henri Mondor
  • CHU Le Bocage
  • CH Départemental Vendée
  • CH Le Mans
  • CH de Bretagne Sud
  • Hôpital privé Jean Mermoz
  • AP-HM Hôpital de la Timone
  • CH de Meaux
  • CH Mont de Marsan
  • CHU de Nancy Hôpital Brabois
  • CHU de Nantes Hôpital de l'Hotel Dieu
  • CHU Nîmes
  • CHR d'Orléans - Hôpital La Source
  • Groupe Hospitalier Paris Saint Joseph
  • CH Perpignan
  • CHU de Bordeaux, Hôpital du Haut Lévèque
  • CH de la Région d'Annecy
  • Centre Eugène Marquis
  • Clinique Mathilde
  • Clinique Armoricaine de Radiologie
  • CH Saint-Malo
  • Centre René Gauducheau CLCC Nantes Atlantique
  • CH Gaston Ramon
  • Centre Régional de Lutte contre le Cancer Centre Paul Strauss
  • Hôpitaux Universitaires de Strasbourg Hôpital civil
  • Hôpitaux Universitaires de Strasbourg, Hôpital Hautepierre
  • CHRU de Tours

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Other

Arm Label

A

B

C

D

Arm Description

patients receiving sorafenib 400 mg - twice a day

patients receiving pravastatin 40 mg - once a day

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

patients receiving best supportive care

Outcomes

Primary Outcome Measures

Time to radiologic progression

Secondary Outcome Measures

Overall survival
Survival without progression
Time to treatment failure
Objective response rate at four months
Number and description of AE for toxicity and SAE
Quality of life

Full Information

First Posted
May 13, 2011
Last Updated
April 28, 2017
Sponsor
University Hospital, Bordeaux
Collaborators
Federation Francophone de Cancerologie Digestive, UNICANCER
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1. Study Identification

Unique Protocol Identification Number
NCT01357486
Brief Title
Palliative Treatment of Hepatocellular Carcinoma in Patient With CHILD B Cirrhosis
Acronym
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
Study Type
Interventional

2. Study Status

Record Verification Date
April 2017
Overall Recruitment Status
Completed
Study Start Date
November 14, 2011 (Actual)
Primary Completion Date
April 12, 2017 (Actual)
Study Completion Date
April 12, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University Hospital, Bordeaux
Collaborators
Federation Francophone de Cancerologie Digestive, UNICANCER

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hepatocellular Carcinoma, CHILD B
Keywords
Hepatocellular Carcinoma, CHILD B, palliative management, Sorafenib, Pravastatin

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
160 (Actual)

8. Arms, Groups, and Interventions

Arm Title
A
Arm Type
Experimental
Arm Description
patients receiving sorafenib 400 mg - twice a day
Arm Title
B
Arm Type
Experimental
Arm Description
patients receiving pravastatin 40 mg - once a day
Arm Title
C
Arm Type
Experimental
Arm Description
patients receiving sorafenib 400 mg (twice a day) and pravastatin 40 mg (once a day)
Arm Title
D
Arm Type
Other
Arm Description
patients receiving best supportive care
Intervention Type
Drug
Intervention Name(s)
sorafenib
Intervention Description
patients receiving sorafenib 400 mg - twice a day
Intervention Type
Drug
Intervention Name(s)
Pravastatin
Intervention Description
patients receiving pravastatin 40 mg - once a day
Intervention Type
Drug
Intervention Name(s)
Sorafenib + Pravastatin
Intervention Description
patients receiving sorafenib 400 mg (twice a day) and pravastatin 40 mg (once a day)
Intervention Type
Other
Intervention Name(s)
patients receiving best supportive care
Intervention Description
palliative management
Primary Outcome Measure Information:
Title
Time to radiologic progression
Time Frame
Every 4 weeks (CT-scan or MRI) until progression of HCC or date of last news (for patients alive or dead without progression)
Secondary Outcome Measure Information:
Title
Overall survival
Time Frame
End of the study (estimated date August 2012)
Title
Survival without progression
Time Frame
Every 4 weeks (CT-scan or MRI) until progression of HCC or date of last news (for patients alive or dead without progression)
Title
Time to treatment failure
Time Frame
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)
Title
Objective response rate at four months
Time Frame
Radiological evaluation at 4 months
Title
Number and description of AE for toxicity and SAE
Time Frame
Clinical evaluation every month
Title
Quality of life
Time Frame
Clinical evaluation every month

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jean-Frédéric BLANC, MD-PhD
Organizational Affiliation
University Hospital, Bordeaux
Official's Role
Principal Investigator
Facility Information:
Facility Name
CH d'Abbeville
City
Abbeville
ZIP/Postal Code
80142
Country
France
Facility Name
CH Pays d'Aix
City
Aix-en-provence
ZIP/Postal Code
13616
Country
France
Facility Name
CH d'Auxerre
City
Auxerre
ZIP/Postal Code
89011
Country
France
Facility Name
CH de la Côte Basque
City
Bayonne
ZIP/Postal Code
64109
Country
France
Facility Name
AP-HP- Hôpital Jean-Verdier
City
Bondy
ZIP/Postal Code
93143
Country
France
Facility Name
CHU de Bordeaux
City
Bordeaux
ZIP/Postal Code
33075
Country
France
Facility Name
CH Duchenne
City
Boulogne Sur Mer
ZIP/Postal Code
62321
Country
France
Facility Name
CH de Béziers
City
Béziers
ZIP/Postal Code
34525
Country
France
Facility Name
AP-HP Hôpital Henri Mondor
City
Creteil
ZIP/Postal Code
94010
Country
France
Facility Name
CHU Le Bocage
City
Dijon
ZIP/Postal Code
21079
Country
France
Facility Name
CH Départemental Vendée
City
La Roche-sur-yon
ZIP/Postal Code
85925
Country
France
Facility Name
CH Le Mans
City
Le Mans
ZIP/Postal Code
72037
Country
France
Facility Name
CH de Bretagne Sud
City
Lorient
ZIP/Postal Code
56100
Country
France
Facility Name
Hôpital privé Jean Mermoz
City
Lyon
ZIP/Postal Code
69008
Country
France
Facility Name
AP-HM Hôpital de la Timone
City
Marseille
ZIP/Postal Code
13385
Country
France
Facility Name
CH de Meaux
City
Meaux
ZIP/Postal Code
77104
Country
France
Facility Name
CH Mont de Marsan
City
Mont-de-marsan
ZIP/Postal Code
40024
Country
France
Facility Name
CHU de Nancy Hôpital Brabois
City
Nancy
ZIP/Postal Code
54511
Country
France
Facility Name
CHU de Nantes Hôpital de l'Hotel Dieu
City
Nantes
ZIP/Postal Code
44093
Country
France
Facility Name
CHU Nîmes
City
Nimes
ZIP/Postal Code
30029
Country
France
Facility Name
CHR d'Orléans - Hôpital La Source
City
Orleans
ZIP/Postal Code
45067
Country
France
Facility Name
Groupe Hospitalier Paris Saint Joseph
City
Paris
ZIP/Postal Code
75014
Country
France
Facility Name
CH Perpignan
City
Perpignan
ZIP/Postal Code
66046
Country
France
Facility Name
CHU de Bordeaux, Hôpital du Haut Lévèque
City
Pessac
ZIP/Postal Code
33604
Country
France
Facility Name
CH de la Région d'Annecy
City
Pringy
ZIP/Postal Code
74374
Country
France
Facility Name
Centre Eugène Marquis
City
Rennes
ZIP/Postal Code
35042
Country
France
Facility Name
Clinique Mathilde
City
Rouen
ZIP/Postal Code
76000
Country
France
Facility Name
Clinique Armoricaine de Radiologie
City
Saint Brieuc
ZIP/Postal Code
22015
Country
France
Facility Name
CH Saint-Malo
City
Saint Malo
ZIP/Postal Code
35400
Country
France
Facility Name
Centre René Gauducheau CLCC Nantes Atlantique
City
Saint-herblain
ZIP/Postal Code
44805
Country
France
Facility Name
CH Gaston Ramon
City
Sens
ZIP/Postal Code
89100
Country
France
Facility Name
Centre Régional de Lutte contre le Cancer Centre Paul Strauss
City
Strasbourg
ZIP/Postal Code
67065
Country
France
Facility Name
Hôpitaux Universitaires de Strasbourg Hôpital civil
City
Strasbourg
ZIP/Postal Code
67091
Country
France
Facility Name
Hôpitaux Universitaires de Strasbourg, Hôpital Hautepierre
City
Strasbourg
ZIP/Postal Code
67098
Country
France
Facility Name
CHRU de Tours
City
Tours
ZIP/Postal Code
37044
Country
France

12. IPD Sharing Statement

Citations:
PubMed Identifier
18650514
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.
Results Reference
background
PubMed Identifier
16935385
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.
Results Reference
background
PubMed Identifier
11286466
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.
Results Reference
background
PubMed Identifier
15239254
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.
Results Reference
background
PubMed Identifier
16581333
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.
Results Reference
background
PubMed Identifier
18477802
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.
Results Reference
background
PubMed Identifier
33420951
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.
Results Reference
derived

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Palliative Treatment of Hepatocellular Carcinoma in Patient With CHILD B Cirrhosis

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