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

Roche

Status and phase: Completed; Phase 1

Conditions: Hepatic Insufficiency

Treatments: Drug: entrectinib

Study type: Interventional

Funder types: Industry

Identifiers

NCT04226833

GP41174

2019-003065-17 (EudraCT Number)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 38 patients

Sex: All

Ages: 18 to 75 years old

Volunteers: Accepts Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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38 participants in 4 patient groups

Mild

Experimental group

Description:

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.

Treatment:

Drug: entrectinib

Moderate

Experimental group

Description:

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.

Treatment:

Drug: entrectinib

Severe

Experimental group

Description:

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.

Treatment:

Drug: entrectinib

Normal

Experimental group

Description:

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.

Treatment:

Drug: entrectinib