Palliative Treatment of Hepatocellular Carcinoma in Patient With CHILD B Cirrhosis

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Hepatocellular Carcinoma, CHILD B

Intervention / Treatment
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* Drug: sorafenib
* Drug: Pravastatin
* Drug: Sorafenib + Pravastatin
* Other: patients receiving best supportive care


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A<br>patients receiving sorafenib 400 mg - twice a day | Drug: sorafenib<br>* patients receiving sorafenib 400 mg - twice a day<br>|
| Experimental: B<br>patients receiving pravastatin 40 mg - once a day | Drug: Pravastatin<br>* patients receiving pravastatin 40 mg - once a day<br>|
| Experimental: C<br>patients receiving sorafenib 400 mg (twice a day) and pravastatin 40 mg (once a day) | Drug: Sorafenib + Pravastatin<br>* patients receiving sorafenib 400 mg (twice a day) and pravastatin 40 mg (once a day)<br>|
| Other: D<br>patients receiving best supportive care | Other: patients receiving best supportive care<br>* palliative management<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival |  | End of the study (estimated date August 2012) | 
| 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) | 
| 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) | 
| Objective response rate at four months |  | Radiological evaluation at 4 months | 
| Number and description of AE for toxicity and SAE |  | Clinical evaluation every month | 
| Quality of life |  | Clinical evaluation every month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hepatocellular Carcinoma, CHILD B, palliative management, Sorafenib, Pravastatin