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

NCT04051853 | Terminated Phase 2 DMC

• 1 other identifier: 2014_078#B2014419a
• Study Type: interventional
• Target: 5
• Locations: 1 country
• Sites: 1

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.

Conditions

BCLC Stage C HCC; CP-B Liver Cirrhosis

Keywords

HCC; Liver cirrhosis

Outcome Measures

Primary Outcomes (4)

• 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 Outcomes (4)

• Adverse events according to CTCAE v4.0

  Through study completion, an average of 3 months.

• Progression-free survival

  Untill Progression or death (0-24 months)

• Overall survival

  Untill last follow-up or death (0-24 months)

• CYP activity

  4 weeks

Study Arms (2)

Sorafenib with midazolam clearance test

EXPERIMENTAL

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

Sorafenib with CYP cocktail test

EXPERIMENTAL

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

Interventions

Sorafenib DRUG

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.

Sorafenib with CYP cocktail test; Sorafenib with midazolam clearance test

Midazolam clearance test OTHER

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.

Sorafenib with midazolam clearance test

CYP cocktail clearance test OTHER

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 with CYP cocktail test

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female, 18 years of age or older
• Diagnosis of HCC: diagnosis based on the following criteria:
• radiologic technique: Focal lesion \>1 cm with arterial hypervascularization in 4-phase CT or dynamic contrast enhanced MRI OR
• 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

You may not qualify if:

• 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 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
• 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)
• Previous variceal bleeding within the past 3 months
• 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

Sponsors & Collaborators

• Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA): lead
• Erasmus Medical Center: collaborator

Study Sites (1)

Academic Medical Center

Amsterdam, 1105 AZ, Netherlands

Location

MeSH Terms

Conditions

Liver Cirrhosis

Interventions

Sorafenib

Condition Hierarchy (Ancestors)

Liver Diseases; Digestive System Diseases; Fibrosis; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Phenylurea Compounds; Urea; Amides; Organic Chemicals; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Niacinamide; Nicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring

Study Officials

• 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)

  PRINCIPAL INVESTIGATOR

• Hans Romijn, MD PhD

  Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Medical Oncologist & Principle Investigator

Study Record Dates

• First Submitted: February 11, 2016
• First Posted: August 9, 2019
• Study Start: May 1, 2014
• Primary Completion: March 1, 2017
• Study Completion: March 1, 2017
• Last Updated: August 21, 2019

Record last verified: 2019-08

Locations

NL (1)