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

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

Status

Completed

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT04226833

Enrollment

Registered

2020-01-13

Start date

2020-02-11

Completion date

2021-09-27

Last updated

2024-08-02

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Hepatic Insufficiency

Keywords

Hepatic Impairment

Brief 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.

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.

Interventions

DRUGentrectinib

1x100 milligram (mg) capsule given with approximately 240 milliliter (mL) of water within 30 minutes of consumption of a standardized meal

Study design

Allocation

NON_RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to 75 Years

Healthy volunteers

Yes

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

* 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.

Design outcomes

Primary

Measure	Time frame	Description
Apparent Terminal Elimination Half-life (t1/2) of M5	From Day 1 to Day 7	—
Maximum Observed Plasma Concentration (Cmax) of Entrectinib	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	From Day 1 to Day 7	—
Area Under the Plasma Concentration-time Curve From Time 0 to the Last Measurable Concentration (AUClast) of Entrectinib	From Day 1 to Day 7	—
Time of Maximum Observed Plasma Concentration (Tmax) of Entrectinib	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	From Day 1 to Day 7	—
Apparent Terminal Elimination Rate Constant (Lz) of Entrectinib	From Day 1 to Day 7	—
Apparent Oral Clearance (CL/F) of Entrectinib	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	From Day 1 to Day 7	Obtained by dividing Dose by the product of AUCinf and λz
Maximum Observed Plasma Concentration (Cmax) of M5	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	From Day 1 to Day 7	—
Area Under the Plasma Concentration-time Curve From Time 0 to the Last Measurable Concentration (AUClast) of M5	From Day 1 to Day 7	—
Time of Maximum Observed Plasma Concentration (Tmax) of M5	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	From Day 1 to Day 7	—

Secondary

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

Countries

Czechia, Hungary, Slovakia

Participant flow

Pre-assignment details

Participants with reduced hepatic function were assigned to a functional category based on assessments at the Screening visit.

Participants by arm

Arm	Count
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.	7
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.	12
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.	11
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.	8
Total	38

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003
Overall Study	Death	0	0	1	0

Baseline characteristics

Characteristic	Mild	Total	Normal	Severe	Moderate
Age, Continuous	59.9 Years STANDARD_DEVIATION 8.86	57.3 Years STANDARD_DEVIATION 9.88	54.3 Years STANDARD_DEVIATION 11.99	57.3 Years STANDARD_DEVIATION 10.08	58.0 Years STANDARD_DEVIATION 9.49
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	7 Participants	38 Participants	8 Participants	11 Participants	12 Participants
Sex: Female, Male Female	2 Participants	9 Participants	3 Participants	1 Participants	3 Participants
Sex: Female, Male Male	5 Participants	29 Participants	5 Participants	10 Participants	9 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	0 / 8	0 / 7	0 / 12	1 / 11
other Total, other adverse events	2 / 8	0 / 7	1 / 12	2 / 11
serious Total, serious adverse events	0 / 8	0 / 7	0 / 12	1 / 11