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Sorafenib has proven efficacy in advanced hepatocellular carcinoma (HCC). Most patients with HCC have impaired liver function due to underlying liver cirrhosis. The severity of liver cirrhosis might have implications on sorafenib metabolism. To date, no data showing unequivocal activity and tolerability of sorafenib in patients with moderate cirrhosis (Child-Pugh (CP)-B) have been published.
To specifically address this issue, this study aims to explore population pharmacokinetics of sorafenib and to explore the relationship between sorafenib exposure and its efficacy and toxicity in CP-B patients with irresectable HCC.
Full description
Study design:
This is a prospective, open-label, national, multicenter observational study to investigate the tolerability, pharmacokinetics and clinical activity of sorafenib and its metabolites in patients with HCC and CP-B liver cirrhosis
Study population:
45 Patients with BCLC stage C HCC and CP-B liver cirrhosis
Treatment:
All patients will receive sorafenib at a starting dose of 200 mg twice daily. In the absence of toxicity dosage will be gradually escalated up to 400 mg BID.
Before start of treatment patients receive a single oral dose of midazolam to phenotype CYP3A4 activity. Blood samples will be taken at several time points to measure sorafenib and midazolam concentrations.
In a subgroup of 15 patients (in the Academic Medical Center Amsterdam), this test will be replaced by an oral cocktail of subclinical doses of caffeine, midazolam, omeprazole, warfarin and metoprolol and will be repeated after 4 weeks of treatment to assess the influence of sorafenib on cytochrome P450 (CYP) 1A2, 3A4, 2C19, 2C9 and 2D6 activity, respectively.
Main study parameters/endpoints:
Primary
Nature and extent of the burden and risks associated with participation, benefit and group relatedness:
Enrolled patients will be admitted in the hospital for three 8h visits for pharmacokinetic (PK) sampling of sorafenib and midazolam or the drug cocktail (used for CYP phenotyping). All PK blood samples will be drawn via an intravenous catheter. The total amount of blood taken will be ca 70 ml. The risks of these procedures are low.
Patients with advanced HCC and (mild) CP-B liver cirrhosis are often considered poor candidates for sorafenib treatment due to decreased tolerability. The aim of this study is to look for treatment optimization strategies of sorafenib in this subgroup of advanced HCC patients.
Enrollment
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Volunteers
Inclusion criteria
Male or female, 18 years of age or older
Diagnosis of HCC: diagnosis based on the following criteria:
Patients with advanced HCC - BCLC stage C
Cancer related symptoms (symptomatic tumors, ECOG Performance status 1-2), macrovascular invasion (either segmental or portal invasion) or extrahepatic spread (lymph node involvement or distant metastases)
Not eligible for TACE (; i.e. diffuse tumors, tumors larger than 5 cm)
Not eligible for curative resection or RFA
Patients with CP-B liver cirrhosis (CP-B score 7 or 8)
Capable of giving written informed consent
History of organ transplant (including prior liver transplantation) is allowed
HIV, congenital immune defect, any immunosuppressive therapy for autoimmune disease (rheumatoid arthritis) is allowed
Exclusion criteria
Subjects will not be enrolled in the study if any of the following criteria apply:
Additional exclusion criteria for cocktail test
Primary purpose
Allocation
Interventional model
Masking
5 participants in 2 patient groups
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Data sourced from clinicaltrials.gov
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