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

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ClinicalTrials.gov Identifier: NCT04051853
Recruitment Status : Terminated (Slow accrual.)
First Posted : August 9, 2019
Last Update Posted : August 21, 2019
Sponsor:
Collaborator:
Erasmus Medical Center
Information provided by (Responsible Party):
Heinz-Josef Klumpen, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

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.


Condition or disease Intervention/treatment Phase
BCLC Stage C HCC CP-B Liver Cirrhosis Drug: Sorafenib Other: Midazolam clearance test Other: CYP cocktail clearance test Phase 2

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

  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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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 5 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Population Pharmacokinetics and Pharmacodynamics of Sorafenib in HCC Patients With Child-Pugh B Liver Cirrhosis (SORBE-trial)
Actual Study Start Date : May 2014
Actual Primary Completion Date : March 2017
Actual Study Completion Date : March 2017


Arm Intervention/treatment
Experimental: Sorafenib with midazolam clearance 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
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.

Other: Midazolam clearance 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.

Experimental: Sorafenib with CYP cocktail 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
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.

Other: CYP cocktail clearance test
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 Measures :
  1. Sorafenib exposure (AUC). [ Time Frame: Through study completion, an average of 3 months ]
    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.

  2. Sorafenib peak plasma concentration [ Time Frame: Through study completion, an average of 3 months ]
    Peak plasma concentration (Cmax) for sorafenib.

  3. Sorafenib N-oxide exposure (AUC) [ Time Frame: Through study completion, an average of 3 months ]
    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.

  4. Sorafenib N-oxide peak plasma concentration. [ Time Frame: Through study completion, an average of 3 months ]
    Peak plasma concentration (Cmax) for the main sorafenib metabolite (N-oxide sorafenib).


Secondary Outcome Measures :
  1. Adverse events according to CTCAE v4.0 [ Time Frame: Through study completion, an average of 3 months. ]
    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.

  2. Progression-free survival [ Time Frame: Untill Progression or death (0-24 months) ]
    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.

  3. Overall survival [ Time Frame: Untill last follow-up or death (0-24 months) ]
    Overall surval is defined as the time from start sorafenib, to death or censored at last follow-up.

  4. CYP activity [ Time Frame: 4 weeks ]

    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.




Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04051853


Locations
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Netherlands
Academic Medical Center
Amsterdam, Netherlands, 1105 AZ
Sponsors and Collaborators
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Erasmus Medical Center
Investigators
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Principal Investigator: Heinz-Josef Klümpen, MD PhD Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Principal Investigator: Ferry ALM Eskens, MD PhD Erasmus MC Cancer Institute, Rotterdam
Principal Investigator: R. Bart Takkenberg, MD PhD Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Principal Investigator: Ron Mathot, PharmD PhD Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Study Director: Hans Romijn, MD PhD Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

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Responsible Party: Heinz-Josef Klumpen, Medical Oncologist & Principle Investigator, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
ClinicalTrials.gov Identifier: NCT04051853     History of Changes
Other Study ID Numbers: 2014_078#B2014419a
First Posted: August 9, 2019    Key Record Dates
Last Update Posted: August 21, 2019
Last Verified: August 2019

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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
Keywords provided by Heinz-Josef Klumpen, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA):
HCC
Liver cirrhosis
Additional relevant MeSH terms:
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Liver Cirrhosis
Fibrosis
Pathologic Processes
Liver Diseases
Digestive System Diseases
Sorafenib
Midazolam
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Adjuvants, Anesthesia
Hypnotics and Sedatives
Central Nervous System Depressants
Physiological Effects of Drugs
Anti-Anxiety Agents
Tranquilizing Agents
Psychotropic Drugs
Anesthetics, Intravenous
Anesthetics, General
Anesthetics
GABA Modulators
GABA Agents
Neurotransmitter Agents