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

Primary Purpose

BCLC Stage C HCC, CP-B Liver Cirrhosis

Status
Terminated
Phase
Phase 2
Locations
Netherlands
Study Type
Interventional
Intervention
Sorafenib
Midazolam clearance test
CYP cocktail clearance test
Sponsored by
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for BCLC Stage C HCC focused on measuring HCC, Liver cirrhosis

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Male or female, 18 years of age or older

  • Diagnosis of HCC: diagnosis based on the following criteria:

    1. 1 radiologic technique: Focal lesion >1 cm with arterial hypervascularization in 4-phase CT or dynamic contrast enhanced MRI OR
    2. 2 coincidental dynamic radiologic techniques (CT or MRI) in case one imaging technique is non-conclusive and lesion > 1 cm OR
    3. 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

Sites / Locations

  • Academic Medical Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Sorafenib with midazolam clearance test

Sorafenib with CYP cocktail test

Arm Description

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).

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).

Outcomes

Primary Outcome Measures

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.
Sorafenib peak plasma concentration
Peak plasma concentration (Cmax) for sorafenib.
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.
Sorafenib N-oxide peak plasma concentration.
Peak plasma concentration (Cmax) for the main sorafenib metabolite (N-oxide sorafenib).

Secondary Outcome Measures

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.
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.
Overall survival
Overall surval is defined as the time from start sorafenib, to death or censored at last follow-up.
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.

Full Information

First Posted
February 11, 2016
Last Updated
August 20, 2019
Sponsor
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Collaborators
Erasmus Medical Center
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1. Study Identification

Unique Protocol Identification Number
NCT04051853
Brief Title
Sorafenib PK in Patients With Advanced HCC and Child-Pugh B
Acronym
SORBE
Official Title
Population Pharmacokinetics and Pharmacodynamics of Sorafenib in HCC Patients With Child-Pugh B Liver Cirrhosis (SORBE-trial)
Study Type
Interventional

2. Study Status

Record Verification Date
August 2019
Overall Recruitment Status
Terminated
Why Stopped
Slow accrual.
Study Start Date
May 2014 (Actual)
Primary Completion Date
March 2017 (Actual)
Study Completion Date
March 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Collaborators
Erasmus Medical Center

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
BCLC Stage C HCC, CP-B Liver Cirrhosis
Keywords
HCC, Liver cirrhosis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
5 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Sorafenib with midazolam clearance test
Arm Type
Experimental
Arm Description
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).
Arm Title
Sorafenib with CYP cocktail test
Arm Type
Experimental
Arm Description
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).
Intervention Type
Drug
Intervention Name(s)
Sorafenib
Intervention Description
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.
Intervention Type
Other
Intervention Name(s)
Midazolam clearance test
Intervention Description
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.
Intervention Type
Other
Intervention Name(s)
CYP cocktail clearance test
Intervention Description
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.
Primary Outcome Measure Information:
Title
Sorafenib exposure (AUC).
Description
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
Title
Sorafenib peak plasma concentration
Description
Peak plasma concentration (Cmax) for sorafenib.
Time Frame
Through study completion, an average of 3 months
Title
Sorafenib N-oxide exposure (AUC)
Description
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
Title
Sorafenib N-oxide peak plasma concentration.
Description
Peak plasma concentration (Cmax) for the main sorafenib metabolite (N-oxide sorafenib).
Time Frame
Through study completion, an average of 3 months
Secondary Outcome Measure Information:
Title
Adverse events according to CTCAE v4.0
Description
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.
Title
Progression-free survival
Description
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)
Title
Overall survival
Description
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)
Title
CYP activity
Description
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Heinz-Josef Klümpen, MD PhD
Organizational Affiliation
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Ferry ALM Eskens, MD PhD
Organizational Affiliation
Erasmus MC Cancer Institute, Rotterdam
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
R. Bart Takkenberg, MD PhD
Organizational Affiliation
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Ron Mathot, PharmD PhD
Organizational Affiliation
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Hans Romijn, MD PhD
Organizational Affiliation
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Official's Role
Study Director
Facility Information:
Facility Name
Academic Medical Center
City
Amsterdam
ZIP/Postal Code
1105 AZ
Country
Netherlands

12. IPD Sharing Statement

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

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