BCLC Stage C HCC Clinical Trial
Official title:
Population Pharmacokinetics and Pharmacodynamics of Sorafenib in HCC Patients With Child-Pugh B Liver Cirrhosis (SORBE-trial)
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.
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
1. Exposure and intra- and inter-patient variability in exposure to sorafenib and its
metabolites
2. Identification of predictive factors for sorafenib exposure, i.e. bilirubin, CYP3A4
activity Secondary
3. Correlation between sorafenib exposure and adverse events and progression free survival
4. Difference in exposure to 5 CYP probe drugs following administration of an oral cocktail
of these agents after 4 weeks of sorafenib treatment in comparison with exposure to
these cocktail probe drugs before initiation of sorafenib (substudy in 15 patients).
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.
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