BCLC Stage C HCCPhase 2SORBENCT04051853

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

A Phase 2 study testing Sorafenib, Midazolam clearance test and CYP cocktail clearance test in people with BCLC Stage C HCC and CP-B Liver Cirrhosis, run by Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) at 1 site in Netherlands.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record

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Trial summary

Who is it for?: Ages 18 years and older
Conditions the study is for: BCLC Stage C HCC, CP-B Liver Cirrhosis
What is being tested?: Sorafenib, Midazolam clearance test and CYP cocktail clearance test
Type of treatment: Pill or oral medicine
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 5 participants
Where: 1 siteNetherlands
Study dates: May 2014to Mar 2017
Phase: Phase 2
Are there results?: None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 years and older
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

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

Show all 13Show fewer

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

Who cannot join

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

Show all 21Show fewer

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

Trial locations and contacts

1 site in 1 country.

Netherlands1 site

Academic Medical Center
Amsterdam, 1105 AZ

Other trials in Netherlands

About this study

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

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.

Read the 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.

Conditions: BCLC Stage C HCC, CP-B Liver Cirrhosis
Being tested: Sorafenib, Midazolam clearance test, CYP cocktail clearance test
Keywords: HCC, Liver cirrhosis
Medical subject headings: Liver Cirrhosis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

SorafenibDrug
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.
Midazolam clearance testOther
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.
CYP cocktail clearance testOther
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.

Study groups in NCT04051853
Study group	Role	What they receive
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). Receives: 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). Receives: Drug: Sorafenib; Other: CYP cocktail clearance test

What is being measured

The primary outcome is the main question the study is designed to answer.

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.
Measured: Through study completion, an average of 3 months
Sorafenib peak plasma concentration
Peak plasma concentration (Cmax) for sorafenib.
Measured: 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.
Measured: 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).
Measured: Through study completion, an average of 3 months

Secondary outcomes (4)

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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 4 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

May 2014Mar 2017

First posted9 Aug 2019
Study startMay 2014
Primary completionMar 2017
Study completionMar 2017

Why it stopped: Slow accrual.

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Other trials for BCLC Stage C HCCStudies of the same condition, open and under way.
More trials run by Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)The sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 2
Primary purpose: Treatment
Allocation: Non-randomised
Intervention model: Single group
Masking: None (open label)
Enrolment: 5 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT04051853
Sponsor's protocol ID: 2014_078#B2014419a
Acronym: SORBE
Status last verified: Aug 2019
First submitted: 11 Feb 2016
Last updated: 21 Aug 2019
Results posted: No
Data monitoring committee: Yes
FDA-regulated drug: No
FDA-regulated device: No

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

See locations

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All BCLC Stage C HCC trials

Study at a glance

From the registry record, last updated by the sponsor on 21 Aug 2019. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Population Pharmacokinetics and Pharmacodynamics of Sorafenib in HCC Patients With Child-Pugh B Liver Cirrhosis (SORBE-trial)
ClinicalTrials.gov ID: NCT04051853
Acronym / sponsor ID: SORBE / 2014_078#B2014419a
Conditions: BCLC Stage C HCC, CP-B Liver Cirrhosis
Keywords: HCC, Liver cirrhosis
Phase: Phase 2
Study type: Interventional
Recruitment status: TerminatedReason stopped: Slow accrual.
Enrolment: 5 participants (actual)
Lead sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)University, hospital or other
Collaborators: Erasmus Medical Center
Study start: May 2014 (actual)
Primary completion: Mar 2017 (actual)
Study completion: Mar 2017 (actual)
First posted: 9 Aug 2019 (actual)
Results: Not posted in the source record

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

Study design:

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.

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:

Study design

Primary purpose: Treatment
Allocation: Non-randomised
Intervention model: Single group
Masking: None (open label)
Number of arms: 2

Arm	Type	Receives
Sorafenib with midazolam clearance test	Experimental	Drug: Sorafenib, Other: Midazolam clearance testBefore 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).
Sorafenib with CYP cocktail test	Experimental	Drug: Sorafenib, Other: CYP cocktail clearance testIn 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).

Who may qualify

Ages: 18 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (13 listed)

Male or female, 18 years of age or older
Diagnosis of HCC: diagnosis based on the following criteria:
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)

Key exclusion criteria (21 listed)

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

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
SorafenibPatients 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.	Drug	Sorafenib with CYP cocktail test, Sorafenib with midazolam clearance test
Midazolam clearance testBefore 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.	Other	Sorafenib with midazolam clearance test
CYP cocktail clearance testIn 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.	Other	Sorafenib with CYP cocktail test

Primary outcome

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

4 secondary outcomes

Adverse events according to CTCAE v4.0
Time frame: Through study completion, an average of 3 months.
Progression-free survival
Time frame: Untill Progression or death (0-24 months)
Overall survival
Time frame: Untill last follow-up or death (0-24 months)
CYP activity
Time frame: 4 weeks

Results and safety

The study was stopped early (reason given: Slow accrual.). Results are not available in the source record.

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 21 Aug 2019.

Related trials for BCLC Stage C HCC

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Heinz-Josef Klümpen, MD PhD principal investigator

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

Ferry ALM Eskens, MD PhD principal investigator

Erasmus MC Cancer Institute, Rotterdam

R. Bart Takkenberg, MD PhD principal investigator

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

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 13 inclusion and 21 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 21 Aug 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was stopped early (reason given: Slow accrual.). Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Sorafenib exposure (AUC). (time frame: Through study completion, an average of 3 months). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04051853.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Aug 2019.