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

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.

Study Overview

• Status: Completed
• Conditions: Hepatic Insufficiency
• Intervention / Treatment: Drug: entrectinib

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 Type: Interventional
• Enrollment (Actual): 38
• Phase: Phase 1

Contacts and Locations

Study Locations

• Czechia
  • Praha 7, Czechia, 170 00
    • Pharmaceutical Research Associates CZ, s.r.o.
• Hungary
  • Miskolc, Hungary, 3529
    • CRU Hungary Kft
• Slovakia
  • Bratislava, Slovakia, 831 01
    • Summit Clinical Research s.r.o.; Oddelenie internej mediciny a klinickej farmakologie

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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; 1x100 milligram (mg) capsule given with approximately 240 milliliter (mL) of water within 30 minutes of consumption of a standardized meal; Other Names: Rozlytrek; F06 formulation
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; 1x100 milligram (mg) capsule given with approximately 240 milliliter (mL) of water within 30 minutes of consumption of a standardized meal; Other Names: Rozlytrek; F06 formulation
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; 1x100 milligram (mg) capsule given with approximately 240 milliliter (mL) of water within 30 minutes of consumption of a standardized meal; Other Names: Rozlytrek; F06 formulation
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; 1x100 milligram (mg) capsule given with approximately 240 milliliter (mL) of water within 30 minutes of consumption of a standardized meal; Other Names: Rozlytrek; F06 formulation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	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
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	First observed time to reach peak analyte concentration obtained directly from the experimental data without interpolation, expressed in time units	From Day 1 to Day 7
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	Obtained by dividing the total dose of parent drug by its corresponding AUCinf	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	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	From Day 1 to Day 7
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	First observed time to reach peak analyte concentration obtained directly from the experimental data without interpolation, expressed in time units	From Day 1 to Day 7
Apparent Terminal Elimination Rate Constant (Lz) of M5		From Day 1 to Day 7
Apparent Terminal Elimination Half-life (t1/2) of M5		From Day 1 to Day 7

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche
• Investigators: Study Director: Clinical Trials, Hoffmann-La Roche

Study record dates

Study Major Dates

• Study Start (Actual): February 11, 2020
• Primary Completion (Actual): September 27, 2021
• Study Completion (Actual): September 27, 2021

Study Registration Dates

• First Submitted: January 10, 2020
• First Submitted That Met QC Criteria: January 10, 2020
• First Posted (Actual): January 13, 2020

Study Record Updates

• Last Update Posted (Actual): August 2, 2024
• Last Update Submitted That Met QC Criteria: February 15, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Hepatic Impairment
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Liver Failure; Hepatic Insufficiency; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; Entrectinib
• Other Study ID Numbers: GP41174; 2019-003065-17 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: 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).

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No