NCT04226833

A Study to Investigate the Effect of Impaired Hepatic Function on the Pharmacokinetics of Entrectinib in Volunteers With Different Levels of Hepatic Function

Completed Phase 1 Results posted Last updated 2 August 2024

What this trial tests

Phase 1 trial testing entrectinib in Hepatic Insufficiency in 38 participants. Completed in 27 September 2021.

Timeline

11 February 2020

Primary endpoint
27 September 2021

27 September 2021

Quick facts

Lead sponsor	Hoffmann-La Roche
Phase	Phase 1
Status	Completed
Study type	INTERVENTIONAL
Allocation	non randomized
Design	parallel
Masking	none
Primary purpose	treatment
Enrollment	38
Start date	11 February 2020
Primary completion	27 September 2021
Estimated completion	27 September 2021
Sites	3 locations across Slovakia, Hungary, Czechia

Drugs / interventions tested

• entrectinib (entrectinib) — full drug profile →

Conditions studied

• Hepatic Insufficiency — all drugs for Hepatic Insufficiency →

Sponsor

Hoffmann-La Roche — full company profile →

Who can join

Adults 18 to 75, any sex, with Hepatic Insufficiency. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Maximum Observed Plasma Concentration (Cmax) of Entrectinib Primary · 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

Group	Value	95% CI
Mild	296.140	± 40.6
Moderate	213.570	± 36.7
Severe	183.680	± 34.3
Normal	235.990	± 46.1

Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) Secondary · 4 weeks

AE=adverse event TEAE=treatment-emergent adverse event

Total Subjects With at Least 1 AE

Group	Value	95% CI
Mild	0
Moderate	1
Severe	2
Normal	2

Subjects With at Least 1 TEAE

Group	Value	95% CI
Mild	0
Moderate	1
Severe	2
Normal	2

Total Subjects with at Least 1 Serious TEAE

Group	Value	95% CI
Mild	0
Moderate	0
Severe	1
Normal	0

Area Under the Plasma Concentration-time Curve From Time 0 Extrapolated to Infinity (AUCinf) of Entrectinib Primary · From Day 1 to Day 7

Group	Value	95% CI
Mild	5525.6	± 47.0
Moderate	5401.9	± 49.1
Severe	6329.0	± 58.5
Normal	3512.7	± 50.8

Area Under the Plasma Concentration-time Curve From Time 0 to the Last Measurable Concentration (AUClast) of Entrectinib Primary · From Day 1 to Day 7

Group	Value	95% CI
Mild	5263.9	± 48.4
Moderate	4952.3	± 49.0
Severe	5747.9	± 53.6
Normal	3283.2	± 51.5

Time of Maximum Observed Plasma Concentration (Tmax) of Entrectinib Primary · 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

Group	Value	95% CI
Mild	4.000	2.05 – 4.83
Moderate	5.000	2.95 – 8.05
Severe	3.000	1.00 – 5.97
Normal	2.950	1.00 – 4.88

Apparent Terminal Elimination Half-life (t1/2) of Entrectinib Primary · From Day 1 to Day 7

Group	Value	95% CI
Mild	30.75	± 18.7
Moderate	30.43	± 36.5
Severe	43.92	± 30.2
Normal	21.34	± 36.8

Apparent Terminal Elimination Rate Constant (Lz) of Entrectinib Primary · From Day 1 to Day 7

Group	Value	95% CI
Mild	0.0229	± 0.00430
Moderate	0.0241	± 0.00858
Severe	0.0165	± 0.00544
Normal	0.0345	± 0.01359

Apparent Oral Clearance (CL/F) of Entrectinib Primary · From Day 1 to Day 7

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

Group	Value	95% CI
Mild	0.0200	± 47.0
Moderate	0.0200	± 49.1
Severe	43.92	± 30.2
Normal	0.0300	± 50.8

The Apparent Volume of Distribution (Vz/F) of Entrectinib Primary · From Day 1 to Day 7

Obtained by dividing Dose by the product of AUCinf and λz

Group	Value	95% CI
Mild	0.8000	± 47.7
Moderate	0.8100	± 37.6
Severe	1.0000	± 35.2
Normal	0.8800	± 43.8

Maximum Observed Plasma Concentration (Cmax) of M5 Primary · 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

Group	Value	95% CI
Mild	41.310	± 71.0
Moderate	26.390	± 68.6
Severe	17.710	± 58.3
Normal	60.330	± 41.7

Area Under the Plasma Concentration-time Curve From Time 0 Extrapolated to Infinity (AUCinf) of M5 Primary · From Day 1 to Day 7

Group	Value	95% CI
Mild	2432.1	± 17.2
Moderate	2024.3	± 58.8
Severe	NA	± NA
Normal	2229.9	± 40.3

Area Under the Plasma Concentration-time Curve From Time 0 to the Last Measurable Concentration (AUClast) of M5 Primary · From Day 1 to Day 7

Group	Value	95% CI
Mild	1255.2	± 67.8
Moderate	1297.3	± 52.4
Severe	1202.8	± 62.9
Normal	1715.6	± 48.7

Adverse events — posted to ClinicalTrials.gov

Time frame: Baseline up to 4 Weeks. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Entrectinib - Normal

Serious: 0/8 (0%)

Deaths: 0/8

Entrectinib Mild

Serious: 0/7 (0%)

Deaths: 0/7

Entrectinib Moderate

Serious: 0/12 (0%)

Deaths: 0/12

Entrectinib Severe

Serious: 1/11 (9%)

Deaths: 1/11

Serious adverse events (1 terms)

Reaction	System	Entrectinib - Normal	Entrectinib Mild	Entrectinib Moderate	Entrectinib Severe
Gastroenteritis	Infections and infestations	—	—	—	—

Other adverse events (3 terms — click to expand)

Reaction	System	Entrectinib - Normal	Entrectinib Mild	Entrectinib Moderate	Entrectinib Severe
Headache	Nervous system disorders	—	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—	—
Ventricular extrasystoles	Cardiac disorders	—	—	—	—

Most-reported serious reactions: Gastroenteritis.

Data from ClinicalTrials.gov NCT04226833 adverse events section.

Sponsor's own description

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.

Publications & conference data

1 peer-reviewed publication reference this trial (live from Europe PMC):

1. Clinical Exploration and Physiologically Based Modelling of the Impact of Hepatic Impairment on Entrectinib Pharmacokinetics.
   Ozbey AC, Meneses-Lorente G, Simmons B, McCallum S, et al · · 2025 · cited 2× · PMID 39934586 · DOI 10.1007/s40262-024-01468-y