A Phase 2 interventional study of Sorafenib and Midazolam clearance test in BCLC Stage C HCC and CP-B Liver Cirrhosis, sponsored by Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA). Terminated at 1 site in Netherlands. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2019-08-21.
Sponsored by Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) · Phase 2, Interventional, and Treatment
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
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.
1,668 studies on the registry are indexed under Liver Cirrhosis; 360 are open to participants now.
This study's enrollment of 5 is below the median of 72 across 1,003 interventional studies indexed under Liver Cirrhosis.
Browse Liver Cirrhosis studies →Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) is the lead sponsor of 532 studies on the registry; 185 are open to participants now.
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Diagnosis of HCC: diagnosis based on the following criteria:
Exclusion Criteria:
Subjects will not be enrolled in the study if any of the following criteria apply:
Additional exclusion criteria for cocktail test
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. Patients will receive sorafenib at a starting dose of 200 mg twice daily. In the absence of toxicity dosage will be escalated with weekly intervals up to 400 mg BID (max dose).
Drug: Sorafenib · Other: Midazolam clearance test
In this subgroup of 15 patients (in the Academic Medical Center Amsterdam), the midazolam 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. Patients will receive sorafenib at a starting dose of 200 mg twice daily. In the absence of toxicity dosage will be escalated with weekly intervals up to 400 mg BID (max dose).
Drug: Sorafenib · Other: CYP cocktail clearance test
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.
Sorafenib exposure (AUC).
Area under the plasma concentration versus time curve (AUC). Exposure and intra- and inter-patient variability in exposure to sorafenib. The population PK analysis will be performed using nonlinear mixed effects modelling (NONMEM). Predictive factors for sorafenib exposure, i.e. bilirubin, CYP3A4 activity, shall be explored.
Time frame: Through study completion, an average of 3 months
Sorafenib peak plasma concentration
Peak plasma concentration (Cmax) for sorafenib.
Time frame: Through study completion, an average of 3 months
Sorafenib N-oxide exposure (AUC)
Area under the plasma concentration versus time curve (AUC) for the main sorafenib metabolite (N-oxide sorafenib). Exposure and intra- and inter-patient variability in exposure to N-oxide sorafenib. The population PK analysis will be performed using nonlinear mixed effects modelling (NONMEM). Predictive factors for N-oxide sorafenib exposure, i.e. bilirubin, CYP3A4 activity, shall be explored.
Time frame: Through study completion, an average of 3 months
Sorafenib N-oxide peak plasma concentration.
Peak plasma concentration (Cmax) for the main sorafenib metabolite (N-oxide sorafenib).
Time frame: Through study completion, an average of 3 months
Adverse events according to CTCAE v4.0
Adverse events are defined as any undesirable experience occurring to a subject during the study, whether or not considered related to sorafenib or drug cocktail. All adverse events reported spontaneously by the subject or observed by the investigator or his staff will be recorded while receiving treatment and for 30 days after the last dose of Sorafenib, in order to detect delayed toxicity. Toxicity will be scored according NCI CTCAE version 4.0 The population PK analysis will be performed using nonlinear mixed effects modelling (NONMEM). Power calculations are not possible in NONMEM. Nevertheless, as a rule of thumb, 40 patients allow one to identify ca. 3 clinical significant correlations between PK parameters and patient characteristics. To be sure to have 40 evaluable patients we aim to recruit 45 patients.
Time frame: Through study completion, an average of 3 months.
Progression-free survival
Progression free survival (PFS) is defined as the time from the date of start sorafenib to the first date of progressive disease (symptomatic or objective) or death to any cause, whichever occurs first.
Time frame: Untill Progression or death (0-24 months)
Overall survival
Overall surval is defined as the time from start sorafenib, to death or censored at last follow-up.
Time frame: Untill last follow-up or death (0-24 months)
CYP activity
In order to assess CYP3A4 activity prior to the start of sorafenib treatment, a single oral dose of 0.03 mg/kg midazolam will be administered. Substudy in 15 patients: 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.
Time frame: 4 weeks
Ran from May 2014 to primary completion in Mar 2017, 34 months.
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This study is terminated, as verified in Aug 2019. You cannot join it, but the record below documents what was studied.
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