Hepatic InsufficiencyPhase 1NCT04226833
A Study to Investigate the Effect of Impaired Hepatic Function on the Pharmacokinetics of Entrectinib in Volunteers With Different Levels of Hepatic Function
A Phase 1 study testing entrectinib in people with Hepatic Insufficiency, run by Hoffmann-La Roche at 3 sites in 3 countries.
Trial summary
This is a non-randomized, open-label, one treatment, four group, parallel group study to investigate the effect of impaired hepatic function on the pharmacokinetics of entrectinib in participants with different levels of hepatic function. Read more about this study
- Who is it for?
- Ages 18 to 75 yearsHealthy volunteers can take part
- Conditions the study is for
- Hepatic Insufficiency
- What is being tested?
- entrectinib
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 38 participants
- Where
- 3 sitesin 3 countries
- Study dates
- 11 Feb 2020to 27 Sep 2021
- Phase
- Phase 1
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
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 to 75 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- All participants:
- A body mass index (BMI) between 18.0 and 38.0 kg/m2, and weighing at least 50 kg
- Agreement to comply with measures to prevent pregnancy and restrictions on sperm donation.
- Participants with normal hepatic function:
- Normal hepatic function and no history of clinically significant hepatic dysfunction.
- Healthy for age-group in the opinion of the Investigator.
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- Participants with hepatic impairment:
- Mild, moderate or severe hepatic dysfunction (i.e. Child-Pugh A, B or C, NCIODWG Mild, Moderate or Severe) arising from cirrhosis of the liver as the result of parenchymal liver disease.
- Stable hepatic function.
Who cannot join
- Transjugular intrahepatic portosystemic shunt or other porta-caval shunt.
- A history of gastrointestinal hemorrhage due to esophageal varices or peptic ulcers.
- Recent history or signs of severe hepatic encephalopathy (e.g., a portal systemic encephalopathy score >2).
- Advanced ascites or ascites which require emptying and albumin supplementation.
- Hepatocellular carcinoma, acute liver disease or serum ALT or AST not consistent with stable disease.
- Recipient of a liver transplant.
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- Uncontrolled hypertension.
- Clinically significant impairment of renal function.
- A history of gastrointestinal surgery or other gastrointestinal disorder that might affect absorption of medicines from the gastrointestinal tract.
- Clinically significant change in health status, or any major illness, or clinically significant acute infection or febrile illness.
- Women who are pregnant or lactating.
- Presence of any abnormal ECG finding, which is clinically significant.
- Use of moderate or potent inhibitors or inducers of cytochrome P450 3A4 enzyme.
- Participation in any other clinical study involving administration of an investigational medicinal product or use of an unapproved device.
- A positive test result for human immunodeficiency virus (HIV).
- Known history of clinically significant hypersensitivity, or severe allergic reaction, to entrectinib or related compounds or other excipients in the entrectinib formulation.
Trial locations and contacts
3 sites in 3 countries.
3 sites in 3 countries
Slovakia1 site
Summit Clinical Research s.r.o.; Oddelenie internej mediciny a klinickej farmakologie
Bratislava, 831 01
About this study
Official title: An Open-Label, One Treatment, Four Group, Parallel Group Study to Investigate the Effect of Impaired Hepatic Function on the Pharmacokinetics of Entrectinib in Volunteers With Different Levels of Hepatic Function
This is a non-randomized, open-label, one treatment, four group, parallel group study to investigate the effect of impaired hepatic function on the pharmacokinetics of entrectinib in participants with different levels of hepatic function. Participants with mild, moderate or severe hepatic impairment ('Mild', 'Moderate' and 'Severe' groups), and control participants with normal hepatic function ('Normal' group) will each receive a single 100 mg dose of entrectinib after consumption of a standardized meal.
Read the detailed description
Participants with reduced hepatic function will be assigned to a functional category based on assessments at the Screening visit. Each individual will be categorized according to the Child Pugh system for classifying hepatic impairment and also according to the National Cancer Institute organ dysfunction working group (NCI-ODWG) system. Recruitment will be staggered to allow review of pharmacokinetic and safety data from at least three participants in each of the Mild and Moderate groups before participants are enrolled into the Severe group. Recruitment of the Severe group will only proceed if there is agreement between the Sponsor and the Investigator that data from this group are necessary to fulfill the objectives of the study and that dosing is not anticipated to present an unacceptable risk to those individuals. The control group of participants with normal hepatic function will be enrolled after the full complement of participants with hepatic dysfunction has been dosed.
- Conditions
- Hepatic Insufficiency
- Being tested
- entrectinib
- Keywords
- Hepatic Impairment
- Medical subject headings
- Hepatic Insufficiency
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
entrectinibDrug
Also called F06 formulation, Rozlytrek
1x100 milligram (mg) capsule given with approximately 240 milliliter (mL) of water within 30 minutes of consumption of a standardized meal
| Study group | Role | What they receive |
|---|---|---|
| Mild | Experimental | Participants with mild hepatic impairment will receive 1x100 milligram (mg) F06 (entrectinib) capsule administered orally with approximately 240 milliliter (mL) water within 30 minutes after consumption of a standardized meal. Receives: Drug: entrectinib |
| Moderate | Experimental | Participants with moderate hepatic impairment will receive 1x100 mg F06 (entrectinib) capsule administered orally with approximately 240 mL water within 30 minutes after consumption of a standardized meal. Receives: Drug: entrectinib |
| Severe | Experimental | Participants with severe hepatic impairment will receive 1x100 mg F06 (entrectinib) capsule administered orally with approximately 240 mL water within 30 minutes after consumption of a standardized meal. Receives: Drug: entrectinib |
| Normal | Experimental | Participants with normal hepatic function will receive 1x100 mg F06 (entrectinib) capsule administered orally with approximately 240 mL water within 30 minutes after consumption of a standardized meal. Receives: Drug: entrectinib |
What is being measured
The primary outcome is the main question the study is designed to answer.
Maximum Observed Plasma Concentration (Cmax) of Entrectinib
Maximum observed plasma concentration. Observed peak analyte concentration obtained directly from the experimental data without interpolation, expressed in concentration units
Measured: From Day 1 to Day 7
Area Under the Plasma Concentration-time Curve From Time 0 Extrapolated to Infinity (AUCinf) of Entrectinib
Measured: From Day 1 to Day 7
Area Under the Plasma Concentration-time Curve From Time 0 to the Last Measurable Concentration (AUClast) of Entrectinib
Measured: From Day 1 to Day 7
Time of Maximum Observed Plasma Concentration (Tmax) of Entrectinib
First observed time to reach peak analyte concentration obtained directly from the experimental data without interpolation, expressed in time units
Measured: From Day 1 to Day 7
Apparent Terminal Elimination Half-life (t1/2) of Entrectinib
Measured: From Day 1 to Day 7
Apparent Terminal Elimination Rate Constant (Lz) of Entrectinib
Measured: From Day 1 to Day 7
Apparent Oral Clearance (CL/F) of Entrectinib
Obtained by dividing the total dose of parent drug by its corresponding AUCinf
Measured: From Day 1 to Day 7
The Apparent Volume of Distribution (Vz/F) of Entrectinib
Obtained by dividing Dose by the product of AUCinf and λz
Measured: From Day 1 to Day 7
Maximum Observed Plasma Concentration (Cmax) of M5
Maximum observed plasma concentration. Observed peak analyte concentration obtained directly from the experimental data without interpolation, expressed in concentration units
Measured: From Day 1 to Day 7
Area Under the Plasma Concentration-time Curve From Time 0 Extrapolated to Infinity (AUCinf) of M5
Measured: From Day 1 to Day 7
Area Under the Plasma Concentration-time Curve From Time 0 to the Last Measurable Concentration (AUClast) of M5
Measured: From Day 1 to Day 7
Time of Maximum Observed Plasma Concentration (Tmax) of M5
First observed time to reach peak analyte concentration obtained directly from the experimental data without interpolation, expressed in time units
Measured: From Day 1 to Day 7
Apparent Terminal Elimination Rate Constant (Lz) of M5
Measured: From Day 1 to Day 7
Apparent Terminal Elimination Half-life (t1/2) of M5
Measured: From Day 1 to Day 7
Secondary outcomes (1)
Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
AE=adverse event TEAE=treatment-emergent adverse event
Measured: 4 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Jan 2020
- Study start11 Feb 2020
- Primary completion27 Sep 2021
- Study completion27 Sep 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Hepatic InsufficiencyStudies of the same condition, open and under way.
- More trials run by Hoffmann-La RocheThe 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 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 38 participants (actual)
Sponsor and investigators
- Lead sponsor
- Hoffmann-La Roche
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Clinical Trials, Study director, Hoffmann-La Roche
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04226833
- Sponsor's protocol ID
- GP41174
- Other IDs
- 2019-003065-17, 2019
- Status last verified
- Feb 2024
- First submitted
- 10 Jan 2020
- Last updated
- 2 Aug 2024
- Results posted
- Yes, on ClinicalTrials.gov
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No: Qualified researchers may request access to individual patient level data through the clinical study data request platform (www.clinicalstudydatarequest.com). Further details on Roche's criteria for eligible studies are available here (https://clinicalstudydatarequest.com/Study-Sponsors/Study-Sponsors-Roche.aspx). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research\_and\_development/who\_we\_are\_how\_we\_work/clinical\_trials/our\_commitment\_to\_data\_sharing.htm).
Publications
Ozbey AC, Meneses-Lorente G, Simmons B, McCallum S, Annaert P, Parrott N, Umehara K. Clinical Exploration and Physiologically Based Modelling of the Impact of Hepatic Impairment on Entrectinib Pharmacokinetics. Clin Pharmacokinet. 2025 Mar;64(3):437-451. doi: 10.1007/s40262-024-01468-y. Epub 2025 Feb 11.
PubMed 39934586
Study at a glance
From the registry record, last updated by the sponsor on 2 Aug 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- An Open-Label, One Treatment, Four Group, Parallel Group Study to Investigate the Effect of Impaired Hepatic Function on the Pharmacokinetics of Entrectinib in Volunteers With Different Levels of Hepatic Function
- ClinicalTrials.gov ID
- NCT04226833
- Acronym / sponsor ID
- GP41174
- Conditions
- Hepatic Insufficiency
- Keywords
- Hepatic Impairment
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 38 participants (actual)
- Lead sponsor
- Hoffmann-La RocheIndustry (pharma, biotech, devices)
- Study start
- 11 Feb 2020 (actual)
- Primary completion
- 27 Sep 2021 (actual)
- Study completion
- 27 Sep 2021 (actual)
- First posted
- 13 Jan 2020 (actual)
- Results
- Posted 2 Aug 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This is a non-randomized, open-label, one treatment, four group, parallel group study to investigate the effect of impaired hepatic function on the pharmacokinetics of entrectinib in participants with different levels of hepatic function. Participants with mild, moderate or severe hepatic impairment ('Mild', 'Moderate' and 'Severe' groups), and control participants with normal hepatic function ('Normal' group) will each receive a single 100 mg dose of entrectinib after consumption of a standardized meal.
Detailed description
Participants with reduced hepatic function will be assigned to a functional category based on assessments at the Screening visit. Each individual will be categorized according to the Child Pugh system for classifying hepatic impairment and also according to the National Cancer Institute organ dysfunction working group (NCI-ODWG) system. Recruitment will be staggered to allow review of pharmacokinetic and safety data from at least three participants in each of the Mild and Moderate groups before participants are enrolled into the Severe group. Recruitment of the Severe group will only proceed if there is agreement between the Sponsor and the Investigator that data from this group are necessary to fulfill the objectives of the study and that dosing is not anticipated to present an unacceptable risk to those individuals. The control group of participants with normal hepatic function will be enrolled after the full complement of participants with hepatic dysfunction has been dosed.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Mild | Experimental | Drug: entrectinibParticipants with mild hepatic impairment will receive 1x100 milligram (mg) F06 (entrectinib) capsule administered orally with approximately 240 milliliter (mL) water within 30 minutes after consumption of a standardized meal. |
| Moderate | Experimental | Drug: entrectinibParticipants with moderate hepatic impairment will receive 1x100 mg F06 (entrectinib) capsule administered orally with approximately 240 mL water within 30 minutes after consumption of a standardized meal. |
| Severe | Experimental | Drug: entrectinibParticipants with severe hepatic impairment will receive 1x100 mg F06 (entrectinib) capsule administered orally with approximately 240 mL water within 30 minutes after consumption of a standardized meal. |
| Normal | Experimental | Drug: entrectinibParticipants with normal hepatic function will receive 1x100 mg F06 (entrectinib) capsule administered orally with approximately 240 mL water within 30 minutes after consumption of a standardized meal. |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (9 listed)
- A body mass index (BMI) between 18.0 and 38.0 kg/m2, and weighing at least 50 kg
- Agreement to comply with measures to prevent pregnancy and restrictions on sperm donation.
- Normal hepatic function and no history of clinically significant hepatic dysfunction.
- Healthy for age-group in the opinion of the Investigator.
- Mild, moderate or severe hepatic dysfunction (i.e. Child-Pugh A, B or C, NCIODWG Mild, Moderate or Severe) arising from cirrhosis of the liver as the result of parenchymal liver disease.
Key exclusion criteria (16 listed)
- Transjugular intrahepatic portosystemic shunt or other porta-caval shunt.
- A history of gastrointestinal hemorrhage due to esophageal varices or peptic ulcers.
- Recent history or signs of severe hepatic encephalopathy (e.g., a portal systemic encephalopathy score >2).
- Advanced ascites or ascites which require emptying and albumin supplementation.
- Hepatocellular carcinoma, acute liver disease or serum ALT or AST not consistent with stable disease.
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 |
|---|---|---|
| entrectinibAlso: F06 formulation, Rozlytrek1x100 milligram (mg) capsule given with approximately 240 milliliter (mL) of water within 30 minutes of consumption of a standardized meal | Drug | Mild, Moderate, Normal, Severe |
Primary outcome
Maximum Observed Plasma Concentration (Cmax) of Entrectinib
Time frame: From Day 1 to Day 7
Maximum observed plasma concentration. Observed peak analyte concentration obtained directly from the experimental data without interpolation, expressed in concentration units
Area Under the Plasma Concentration-time Curve From Time 0 Extrapolated to Infinity (AUCinf) of Entrectinib
Time frame: From Day 1 to Day 7
Area Under the Plasma Concentration-time Curve From Time 0 to the Last Measurable Concentration (AUClast) of Entrectinib
Time frame: From Day 1 to Day 7
Time of Maximum Observed Plasma Concentration (Tmax) of Entrectinib
Time frame: From Day 1 to Day 7
First observed time to reach peak analyte concentration obtained directly from the experimental data without interpolation, expressed in time units
Apparent Terminal Elimination Half-life (t1/2) of Entrectinib
Time frame: From Day 1 to Day 7
Apparent Terminal Elimination Rate Constant (Lz) of Entrectinib
Time frame: From Day 1 to Day 7
Apparent Oral Clearance (CL/F) of Entrectinib
Time frame: From Day 1 to Day 7
Obtained by dividing the total dose of parent drug by its corresponding AUCinf
The Apparent Volume of Distribution (Vz/F) of Entrectinib
Time frame: From Day 1 to Day 7
Obtained by dividing Dose by the product of AUCinf and λz
Maximum Observed Plasma Concentration (Cmax) of M5
Time frame: From Day 1 to Day 7
Maximum observed plasma concentration. Observed peak analyte concentration obtained directly from the experimental data without interpolation, expressed in concentration units
Area Under the Plasma Concentration-time Curve From Time 0 Extrapolated to Infinity (AUCinf) of M5
Time frame: From Day 1 to Day 7
Area Under the Plasma Concentration-time Curve From Time 0 to the Last Measurable Concentration (AUClast) of M5
Time frame: From Day 1 to Day 7
Time of Maximum Observed Plasma Concentration (Tmax) of M5
Time frame: From Day 1 to Day 7
First observed time to reach peak analyte concentration obtained directly from the experimental data without interpolation, expressed in time units
Apparent Terminal Elimination Rate Constant (Lz) of M5
Time frame: From Day 1 to Day 7
Apparent Terminal Elimination Half-life (t1/2) of M5
Time frame: From Day 1 to Day 7
1 secondary outcome
Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Time frame: 4 weeks
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 Aug 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 39934586Ozbey AC, Meneses-Lorente G, Simmons B, McCallum S, Annaert P, Parrott N, Umehara K. Clinical Exploration and Physiologically Based Modelling of the Impact of Hepatic Impairment on Entrectinib Pharmacokinetics. Clin Pharmacokinet. 2025 Mar;64(3):437-451. doi: 10.1007/s40262-024-01468-y. Epub 2025 Feb 11.
- Individual participant dataSharing planned: No. Qualified researchers may request access to individual patient level data through the clinical study data request platform (www.clinicalstudydatarequest.com). Further details on Roche's criteria for eligible studies are available here (https://clinicalstudydatarequest.com/Study-Sponsors/Study-Sponsors-Roche.aspx). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).
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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.
Clinical Trials study director
Hoffmann-La Roche
3 sites in 3 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing entrectinib in people with Hepatic Insufficiency, run by Hoffmann-La Roche at 3 sites in 3 countries.
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 9 inclusion and 16 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: finished, as of the sponsor's last update on 2 Aug 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in Czechia, Hungary, Slovakia. 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 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 2 Aug 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
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?
Maximum Observed Plasma Concentration (Cmax) of Entrectinib (time frame: From Day 1 to Day 7). The study lists 14 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 NCT04226833, which also lists 1 linked publication.
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 2 Aug 2024.