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

NCT ID: NCT04226833

Last Updated: 2024-08-02

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 38 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-02-11
• Study Completion Date: 2021-09-27

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.

Conditions

Hepatic Insufficiency

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

entrectinib

Intervention Type: DRUG

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

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.

Group Type: EXPERIMENTAL

entrectinib

Intervention Type: DRUG

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

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.

Group Type: EXPERIMENTAL

entrectinib

Intervention Type: DRUG

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

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.

Group Type: EXPERIMENTAL

entrectinib

Intervention Type: DRUG

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

Interventions

entrectinib

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

Intervention Type: DRUG

Other Intervention Names

F06 formulation; Rozlytrek

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Hoffmann-La Roche

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Clinical Trials

Role: STUDY_DIRECTOR

Hoffmann-La Roche

Locations

Pharmaceutical Research Associates CZ, s.r.o.

Prague, , Czechia

CRU Hungary Kft

Miskolc, , Hungary

Summit Clinical Research s.r.o.; Oddelenie internej mediciny a klinickej farmakologie

Bratislava, , Slovakia

Countries

Czechia; Hungary; Slovakia

References

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.

Reference Type: DERIVED

PMID: 39934586 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

2019-003065-17

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

GP41174

Identifier Type: -

Identifier Source: org_study_id