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

NCT04226833 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: GP411742019-003065-17
• Study Type: interventional
• Target: 38
• Locations: 3 countries
• Sites: 3

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.

Conditions

Hepatic Insufficiency

Keywords

Hepatic Impairment

Outcome Measures

Primary Outcomes (14)

• 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 Outcomes (1)

• Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

  4 weeks

Study Arms (4)

Mild

EXPERIMENTAL

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

Moderate

EXPERIMENTAL

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

Severe

EXPERIMENTAL

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

Normal

EXPERIMENTAL

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

Interventions

entrectinib DRUG

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

Also known as: F06 formulation, Rozlytrek

Mild; Moderate; Normal; Severe

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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).

Sponsors & Collaborators

• Hoffmann-La Roche: lead

Study Sites (3)

Pharmaceutical Research Associates CZ, s.r.o.

Prague, 170 00, Czechia

Location

CRU Hungary Kft

Miskolc, 3529, Hungary

Location

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

Bratislava, 831 01, Slovakia

Location

Related Publications (1)

• 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.

  PMID: 39934586 DERIVED

MeSH Terms

Conditions

Hepatic Insufficiency

Interventions

entrectinib

Condition Hierarchy (Ancestors)

Liver Diseases; Digestive System Diseases

Results Point of Contact

• Title: Medical Communications
• Organization: Genentech, Inc

genentech@druginfo.com

800 821-8590

Study Officials

• Clinical Trials

  Hoffmann-La Roche

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 10, 2020
• First Posted: January 13, 2020
• Study Start: February 11, 2020
• Primary Completion: September 27, 2021
• Study Completion: September 27, 2021
• Last Updated: August 2, 2024
• Results First Posted: August 2, 2024

Record last verified: 2024-02

Data Sharing

• IPD Sharing: Will not share

Locations

SL (1); CZ (1); HU (1)