Clinical trial NCT04226833: A Study to Investigate the Effect of Impaired Hepatic Function on the Pharmacokinetics of Entrectinib in Volunteers With Different Levels of Hepatic Function
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Hepatic Insufficiency
Keywords: Hepatic Impairment
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2020-01-13
Enrollment: 38
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Maximum Observed Plasma Concentration (Cmax) of Entrectinib
timeFrame: From Day 1 to Day 7
measure: Area Under the Plasma Concentration-time Curve From Time 0 Extrapolated to Infinity (AUCinf) of Entrectinib
timeFrame: From Day 1 to Day 7
measure: Area Under the Plasma Concentration-time Curve From Time 0 to the Last Measurable Concentration (AUClast) of Entrectinib
timeFrame: From Day 1 to Day 7
measure: Time of Maximum Observed Plasma Concentration (Tmax) of Entrectinib
timeFrame: From Day 1 to Day 7
measure: Apparent Terminal Elimination Half-life (t1/2) of Entrectinib
timeFrame: From Day 1 to Day 7
measure: Apparent Terminal Elimination Rate Constant (Lz) of Entrectinib
timeFrame: From Day 1 to Day 7
measure: Apparent Oral Clearance (CL/F) of Entrectinib
timeFrame: From Day 1 to Day 7
measure: The Apparent Volume of Distribution (Vz/F) of Entrectinib
timeFrame: From Day 1 to Day 7
measure: Maximum Observed Plasma Concentration (Cmax) of M5
timeFrame: From Day 1 to Day 7
measure: Area Under the Plasma Concentration-time Curve From Time 0 Extrapolated to Infinity (AUCinf) of M5
timeFrame: From Day 1 to Day 7
measure: Area Under the Plasma Concentration-time Curve From Time 0 to the Last Measurable Concentration (AUClast) of M5
timeFrame: From Day 1 to Day 7
measure: Time of Maximum Observed Plasma Concentration (Tmax) of M5
timeFrame: From Day 1 to Day 7
measure: Apparent Terminal Elimination Rate Constant (Lz) of M5
timeFrame: From Day 1 to Day 7
measure: Apparent Terminal Elimination Half-life (t1/2) of M5
timeFrame: From Day 1 to Day 7
Secondary outcomes:
measure: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: 4 weeks
Other outcomes:
Locations:
city: Praha 7
country: Czechia
facility: Pharmaceutical Research Associates CZ, s.r.o.
city: Miskolc
country: Hungary
facility: CRU Hungary Kft
city: Bratislava
country: Slovakia
facility: Summit Clinical Research s.r.o.; Oddelenie internej mediciny a klinickej farmakologie
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References: