Sorafenib PK in Patients With Advanced HCC and Child-Pugh B

Study Overview
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Brief Summary
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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.

Detailed Description
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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 Exposure and intra- and inter-patient variability in exposure to sorafenib and its metabolites Identification of predictive factors for sorafenib exposure, i.e. bilirubin, CYP3A4 activity Secondary Correlation between sorafenib exposure and adverse events and progression free survival 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.

Official Title
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Population Pharmacokinetics and Pharmacodynamics of Sorafenib in HCC Patients With Child-Pugh B Liver Cirrhosis (SORBE-trial)

Conditions
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BCLC Stage C HCC, CP-B Liver Cirrhosis

Intervention / Treatment
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* Drug: Sorafenib
* Other: Midazolam clearance test
* Other: CYP cocktail clearance test


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, 18 years of age or older Diagnosis of HCC: diagnosis based on the following criteria: 1 radiologic technique: Focal lesion >1 cm with arterial hypervascularization in 4-phase CT or dynamic contrast enhanced MRI OR 2 coincidental dynamic radiologic techniques (CT or MRI) in case one imaging technique is non-conclusive and lesion > 1 cm OR biopsy proven HCC 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: CP-B9 liver cirrhosis CP-C liver cirrhosis Mental conditions rendering the subject incapable to understand the nature, scope, and consequences of the trial Concurrent antitumoral treatment for HCC or other malignancies Not eligible for sorafenib treatment Bilirubin > 51 micromol/L If female, pregnant or breast feeding (females of child-bearing potential must use adequate contraception and must have a negative pregnancy test performed within 7 days prior to inclusion into this study) If male, not using adequate birth control measures One or more of the following: - WBC <2,500 cells/mm3, - ANC <1,500 cells/mm3, - platelets <50,000/mm3, ECOG performance status >2 Patients with known GFR <30 mL/min/1.73m2 Significant cardiovascular disease; e.g., myocardial infarction within 6 months of inclusion, chronic heart failure (New York Heart Association class III or IV), unstable coronary artery disease Uncontrolled hypertension i.e. systolic blood pressure > 150 mm Hg and/or diastolic blood pressure > 90 mm Hg despite optimal medical management (2 classes of antihypertensive drugs) History of hemorrhage / bleeding events of grade 3 or worse within 30 days before inclusion into this study Previous variceal bleeding within the past 3 months Additional exclusion criteria for cocktail test Consumption of grapefruit or grapefruit juice and/or kumquats, pummelos, exotic citrus fruit (i.e., star fruit, bitter melon) or grapefruit hybrids from seven days prior to the first dose of cocktail. Use of herbal medicine or medication that induce or inhibit CYP3A4/5, CYP2C9, CYP2D6, CYP1A2 and CYP2C19 Use of omeprazole, warfarin, metoprolol, caffeine or midazolam (=medication of the probe cocktail) Concurrent anticoagulant therapy

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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sorafenib with midazolam clearance test<br>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<br>* 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.<br>Other: Midazolam clearance test<br>* 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.<br>|
| Experimental: Sorafenib with CYP cocktail test<br>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<br>* 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.<br>Other: CYP cocktail clearance test<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Through study completion, an average of 3 months | 
| Sorafenib peak plasma concentration | Peak plasma concentration (Cmax) for sorafenib. | 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. | 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). | Through study completion, an average of 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 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. | 4 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HCC, Liver cirrhosis