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

Phase 1

Completed

• Conditions: Hepatic Insufficiency
• Interventions: Drug: entrectinib

• Registration Number: NCT04226833
• Lead Sponsor: Hoffmann-La Roche

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.

Study Timeline

• Study First Submitted: 2020-01-10
• Study First Submitted QC: 2020-01-10
• Study First Posted: 2020-01-13
• Study Start: 2020-02-11
• Primary Completion: 2021-09-27
• Study Completion: 2021-09-27
• Results First Submitted: 2022-09-26
• Status Verified: 2024-02
• Results First Submitted QC: 2024-02-15
• Last Update Submitted: 2024-02-15
• Results First Posted: 2024-08-02
• Last Update Posted: 2024-08-02

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 38

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Moderate	entrectinib	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.
Mild	entrectinib	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.
Severe	entrectinib	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.
Normal	entrectinib	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.

Primary Outcome Measures

Name	Time	Method
Area Under the Plasma Concentration-time Curve From Time 0 to the Last Measurable Concentration (AUClast) 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
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
Apparent Terminal Elimination Half-life (t1/2) of Entrectinib	From Day 1 to Day 7
Apparent Terminal Elimination Rate Constant (Lz) of M5	From Day 1 to Day 7
Area Under the Plasma Concentration-time Curve From Time 0 Extrapolated to Infinity (AUCinf) 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 M5	From Day 1 to Day 7
Apparent Terminal Elimination Rate Constant (Lz) of Entrectinib	From Day 1 to Day 7
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 to the Last Measurable Concentration (AUClast) of M5	From Day 1 to Day 7
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
Area Under the Plasma Concentration-time Curve From Time 0 Extrapolated to Infinity (AUCinf) 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

Secondary Outcome Measures

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

Trial Locations

Locations (3)

Pharmaceutical Research Associates CZ, s.r.o.; 🇨🇿 Praha 7, Czechia

Summit Clinical Research s.r.o.; Oddelenie internej mediciny a klinickej farmakologie; 🇸🇰 Bratislava, Slovakia

CRU Hungary Kft; 🇭🇺 Miskolc, Hungary