CompletedNCT04226833Updated Aug 2, 2024Results posted

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 interventional study of entrectinib in Hepatic Insufficiency, sponsored by Hoffmann-La Roche. Completed at 3 sites in 3 countries. Open to participants aged 18 Years to 75 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2024-08-02.

Sponsored by Hoffmann-La Roche · Phase 1, Interventional, and Treatment

Phase: Phase 1
Study type: Interventional
Enrollment: 38
Allocation: Non-randomized
Ages: 18 Years to 75 Years
Sex: All

Study 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. 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 studied

Hepatic Insufficiency

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Hepatic Insufficiency 329

Keywords

Hepatic Impairment

In context

Hepatic Insufficiency

329 studies on the registry are indexed under Hepatic Insufficiency; 53 are open to participants now.

This study's enrollment of 38 is close to the median of 36 across 222 interventional studies indexed under Hepatic Insufficiency.

Browse Hepatic Insufficiency studies →

Lead sponsor

Hoffmann-La Roche is the lead sponsor of 2,099 studies on the registry; 88 are open to participants now.

Of its 324 completed or terminated interventional studies of FDA-regulated products, 245 (76%) have results posted.

Browse Hoffmann-La Roche studies →

Counted across the registry records on this site, refreshed daily.

Who can participate

Ages eligible: 18 Years to 75 Years
Sexes eligible: All
Accepts healthy volunteers: Yes

Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.

Inclusion criteria

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.

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.

Exclusion criteria

Exclusion Criteria:

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.
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.

Study design

Phase: Phase 1
Primary purpose: Treatment
Allocation: Non-randomized
Intervention model: Parallel assignment
Masking: None (open label)
Enrollment: 38 participants (actual)

Study arms

Experimental
Mild
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.
Drug: entrectinib
Experimental
Moderate
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.
Drug: entrectinib
Experimental
Severe
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.
Drug: entrectinib
Experimental
Normal
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.
Drug: entrectinib

Interventions

Drugentrectinib
1x100 milligram (mg) capsule given with approximately 240 milliliter (mL) of water within 30 minutes of consumption of a standardized meal
Also known as: F06 formulation, Rozlytrek

What researchers measure

Primary outcomes

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
Time frame: From Day 1 to Day 7
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
First observed time to reach peak analyte concentration obtained directly from the experimental data without interpolation, expressed in time units
Time frame: From Day 1 to Day 7
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
Obtained by dividing the total dose of parent drug by its corresponding AUCinf
Time frame: 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
Time frame: 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
Time frame: From Day 1 to Day 7
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
First observed time to reach peak analyte concentration obtained directly from the experimental data without interpolation, expressed in time units
Time frame: From Day 1 to Day 7
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

Secondary outcomes

Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
AE=adverse event TEAE=treatment-emergent adverse event
Time frame: 4 weeks

Results

Posted Aug 2, 2024

Participant flow

Participant flow — Overall Study
Milestone	Mild	Moderate	Severe	Normal
Started	7	12	11	8
Completed	7	12	10	8
Not completed	0	0	1	0
Withdrew: Death	0	0	1	0

Outcome measures

PrimaryMaximum 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

Time frame:: From Day 1 to Day 7
Reported as:: Geometric mean · nmol/L

Maximum Observed Plasma Concentration (Cmax) of Entrectinib
nmol/L	Mild	Moderate	Severe	Normal
Maximum Observed Plasma Concentration (Cmax) of Entrectinib	296.140 ± 40.6	213.570 ± 36.7	183.680 ± 34.3	235.990 ± 46.1

SecondaryPercentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

AE=adverse event TEAE=treatment-emergent adverse event

Time frame:: 4 weeks
Reported as:: Number · Participants

Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Participants	Moderate	Severe	Normal
Total Subjects With at Least 1 AE	1	2	2
Subjects With at Least 1 TEAE	1	2	2
Total Subjects with at Least 1 Serious TEAE	0	1	0

PrimaryArea Under the Plasma Concentration-time Curve From Time 0 Extrapolated to Infinity (AUCinf) of Entrectinib

Time frame:: From Day 1 to Day 7
Reported as:: Geometric mean · h*nmol/L

Area Under the Plasma Concentration-time Curve From Time 0 Extrapolated to Infinity (AUCinf) of Entrectinib
h*nmol/L	Mild	Moderate	Severe	Normal
Area Under the Plasma Concentration-time Curve From Time 0 Extrapolated to Infinity (AUCinf) of Entrectinib	5525.6 ± 47.0	5401.9 ± 49.1	6329.0 ± 58.5	3512.7 ± 50.8

PrimaryArea 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
Reported as:: Geometric mean · h*nmol/L

Area Under the Plasma Concentration-time Curve From Time 0 to the Last Measurable Concentration (AUClast) of Entrectinib
h*nmol/L	Mild	Moderate	Severe	Normal
Area Under the Plasma Concentration-time Curve From Time 0 to the Last Measurable Concentration (AUClast) of Entrectinib	5263.9 ± 48.4	4952.3 ± 49.0	5747.9 ± 53.6	3283.2 ± 51.5

PrimaryTime 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

Time frame:: From Day 1 to Day 7
Reported as:: Median · h

Time of Maximum Observed Plasma Concentration (Tmax) of Entrectinib
h	Mild	Moderate	Severe	Normal
Time of Maximum Observed Plasma Concentration (Tmax) of Entrectinib	4.000 (2.05 to 4.83)	5.000 (2.95 to 8.05)	3.000 (1.00 to 5.97)	2.950 (1.00 to 4.88)

PrimaryApparent Terminal Elimination Half-life (t1/2) of Entrectinib

Time frame:: From Day 1 to Day 7
Reported as:: Geometric mean · h

Apparent Terminal Elimination Half-life (t1/2) of Entrectinib
h	Mild	Moderate	Severe	Normal
Apparent Terminal Elimination Half-life (t1/2) of Entrectinib	30.75 ± 18.7	30.43 ± 36.5	43.92 ± 30.2	21.34 ± 36.8

PrimaryApparent Terminal Elimination Rate Constant (Lz) of Entrectinib

Time frame:: From Day 1 to Day 7
Reported as:: Mean · 1/h

Apparent Terminal Elimination Rate Constant (Lz) of Entrectinib
1/h	Mild	Moderate	Severe	Normal
Apparent Terminal Elimination Rate Constant (Lz) of Entrectinib	0.0229 ± 0.00430	0.0241 ± 0.00858	0.0165 ± 0.00544	0.0345 ± 0.01359

PrimaryApparent Oral Clearance (CL/F) of Entrectinib

Obtained by dividing the total dose of parent drug by its corresponding AUCinf

Time frame:: From Day 1 to Day 7
Reported as:: Geometric mean · mg/(h*nmol/L)

Apparent Oral Clearance (CL/F) of Entrectinib
mg/(h*nmol/L)	Mild	Moderate	Severe	Normal
Apparent Oral Clearance (CL/F) of Entrectinib	0.0200 ± 47.0	0.0200 ± 49.1	43.92 ± 30.2	0.0300 ± 50.8

PrimaryThe Apparent Volume of Distribution (Vz/F) of Entrectinib

Obtained by dividing Dose by the product of AUCinf and λz

Time frame:: From Day 1 to Day 7
Reported as:: Geometric mean · mg/(nmol/L)

The Apparent Volume of Distribution (Vz/F) of Entrectinib
mg/(nmol/L)	Mild	Moderate	Severe	Normal
The Apparent Volume of Distribution (Vz/F) of Entrectinib	0.8000 ± 47.7	0.8100 ± 37.6	1.0000 ± 35.2	0.8800 ± 43.8

PrimaryMaximum 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

Time frame:: From Day 1 to Day 7
Reported as:: Geometric mean · nmol/L

Maximum Observed Plasma Concentration (Cmax) of M5
nmol/L	Mild	Moderate	Severe	Normal
Maximum Observed Plasma Concentration (Cmax) of M5	41.310 ± 71.0	26.390 ± 68.6	17.710 ± 58.3	60.330 ± 41.7

PrimaryArea Under the Plasma Concentration-time Curve From Time 0 Extrapolated to Infinity (AUCinf) of M5

Time frame:: From Day 1 to Day 7
Reported as:: Geometric mean · h*nmol/L

Area Under the Plasma Concentration-time Curve From Time 0 Extrapolated to Infinity (AUCinf) of M5
h*nmol/L	Mild	Moderate	Severe	Normal
Area Under the Plasma Concentration-time Curve From Time 0 Extrapolated to Infinity (AUCinf) of M5	2432.1 ± 17.2	2024.3 ± 58.8	NA ± NA	2229.9 ± 40.3

PrimaryArea 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
Reported as:: Geometric mean · h*nmol/L

Area Under the Plasma Concentration-time Curve From Time 0 to the Last Measurable Concentration (AUClast) of M5
h*nmol/L	Mild	Moderate	Severe	Normal
Area Under the Plasma Concentration-time Curve From Time 0 to the Last Measurable Concentration (AUClast) of M5	1255.2 ± 67.8	1297.3 ± 52.4	1202.8 ± 62.9	1715.6 ± 48.7

PrimaryTime 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

Time frame:: From Day 1 to Day 7
Reported as:: Median · h

Time of Maximum Observed Plasma Concentration (Tmax) of M5
h	Mild	Moderate	Severe	Normal
Time of Maximum Observed Plasma Concentration (Tmax) of M5	5.000 (4.83 to 8.00)	5.955 (3.00 to 35.50)	4.920 (2.83 to 71.80)	4.985 (2.98 to 7.97)

PrimaryApparent Terminal Elimination Rate Constant (Lz) of M5

Time frame:: From Day 1 to Day 7
Reported as:: Mean · 1/h

Apparent Terminal Elimination Rate Constant (Lz) of M5
1/h	Mild	Moderate	Severe	Normal
Apparent Terminal Elimination Rate Constant (Lz) of M5	0.02000 ± 2.5	0.0200 ± 30.4	NA ± NA	0.0200 ± 22.8

PrimaryApparent Terminal Elimination Half-life (t1/2) of M5

Time frame:: From Day 1 to Day 7
Reported as:: Geometric mean · h

Apparent Terminal Elimination Half-life (t1/2) of M5
h	Mild	Moderate	Severe	Normal
Apparent Terminal Elimination Half-life (t1/2) of M5	43.60 ± 2.5	39.50 ± 30.4	NA ± NA	38.33 ± 22.8

Adverse events

Collected over Baseline up to 4 Weeks. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
Group	Deaths	Serious	Other
Entrectinib - Normal	0/8 (0%)	0/8 (0%)	2/8 (25%)
Entrectinib Mild	0/7 (0%)	0/7 (0%)	0/7 (0%)
Entrectinib Moderate	0/12 (0%)	0/12 (0%)	1/12 (8.3%)
Entrectinib Severe	1/11 (9.1%)	1/11 (9.1%)	2/11 (18.2%)

Most frequent serious events

Most frequent serious events
Event	Entrectinib - Normal	Entrectinib Mild	Entrectinib Moderate	Entrectinib Severe
GastroenteritisInfections and infestations	0/8	0/7	0/12	1/11

Most frequent other events

Most frequent other events
Event	Entrectinib - Normal	Entrectinib Mild	Entrectinib Moderate	Entrectinib Severe
HeadacheNervous system disorders	2/8	0/7	0/12	0/11
DiarrhoeaGastrointestinal disorders	2/8	0/7	1/12	1/11
Ventricular extrasystolesCardiac disorders	0/8	0/7	0/12	1/11

Baseline characteristics

Age, Continuous
Age, Continuous(Years)	Mild	Moderate	Severe	Normal	Total
Mean	59.9 ± 8.86	58.0 ± 9.49	57.3 ± 10.08	54.3 ± 11.99	57.3 ± 9.88

Sex: Female, Male
Sex: Female, Male(Participants)	Mild	Moderate	Severe	Normal	Total
Female	2	3	1	3	9
Male	5	9	10	5	29

Race (NIH/OMB)
Race (NIH/OMB)(Participants)	Mild	Moderate	Severe	Normal	Total
American Indian or Alaska Native	0	0	0	0	0
Asian	0	0	0	0	0
Native Hawaiian or Other Pacific Islander	0	0	0	0	0
Black or African American	0	0	0	0	0
White	7	12	11	8	38
More than one race	0	0	0	0	0
Unknown or Not Reported	0	0	0	0	0

Study locations

3 sites

Pharmaceutical Research Associates CZ, s.r.o.
Prague, 170 00, Czechia
CRU Hungary Kft
Miskolc, 3529, Hungary
Summit Clinical Research s.r.o.; Oddelenie internej mediciny a klinickej farmakologie
Bratislava, 831 01, Slovakia

References and documents

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 documents

Protocol and statistical analysis plan · Feb 3, 2020

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: 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).

Timeline

Tracking since Sep 25, 2026

ElapsedEstimatedEstimated, not yet reachedSimilar studies: half by the dot; the band is the middle halfHalf of similar studies reached it by the dot; the band is the middle half, from a quarter to three quarters

Ran from Feb 2020 to primary completion in Sep 2021, 19 months.

Results were first posted in Aug 2024, 2 years 10 months after primary completion.

Of 44 industry-sponsored phase 1 interventional studies under Hepatic Insufficiency, half reached primary completion within 9 months of starting (the median), counting those still running; a quarter within 5 and three quarters within 17. This study's 19 months is above that.

Counting every sponsor, half of 51 studies reached it within 9 months; a quarter within 5 and three quarters within 18.

How these figures are worked out, and which studies are left out of them.

Registered: Jan 10, 2020
First posted: Jan 13, 2020
StartActual: Feb 11, 2020
Primary completionActual: Sep 27, 2021
CompletionActual: Sep 27, 2021
Results first posted: Aug 2, 2024
Last update: Aug 2, 2024

What these dates mean

Start.: When the first participant enrolled; while estimated, when the study expects to open to recruitment.
Primary completion.: When the last participant was examined or treated to collect data for the study's main question, its primary outcome. A study that stopped early gives the date its data collection stopped.
Completion.: When the last participant's last visit took place, for every outcome, secondary ones and side effects included: the end of the study. Often later than primary completion, sometimes the same day.
Actual and Est.: Actual means the registry says the date has happened. Est. (estimated) is a date the sponsor plans or expects. It can still move, and the sponsor is expected to change it to actual once it has passed.

No changes since tracking began. The registry record was last updated on Aug 2, 2024, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗

Registry details

Key details

Study ID: NCT04226833
Lead sponsor: Hoffmann-La Roche
Responsible party: Sponsor
First posted: Jan 13, 2020
Start date: Feb 11, 2020
Primary completion: Sep 27, 2021
Completion: Sep 27, 2021
Results posted: Aug 2, 2024
Last update: Aug 2, 2024

Study contacts

Clinical Trials

study director · Hoffmann-La Roche

Oversight

FDA-regulated drug: Yes
FDA-regulated device: No

View the source record on ClinicalTrials.gov ↗

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