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

Primary Purpose

Hepatic Insufficiency

Status

Completed

Phase

Phase 1

Locations

International

Study Type

Interventional

Intervention

entrectinib

About this trial

This is an interventional treatment trial for Hepatic Insufficiency focused on measuring Hepatic Impairment

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesAccepts 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.

Sites / Locations

Pharmaceutical Research Associates CZ, s.r.o.
CRU Hungary Kft
Summit Clinical Research s.r.o.; Oddelenie internej mediciny a klinickej farmakologie

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Arm Label

Mild

Moderate

Severe

Normal

Arm 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.

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.

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.

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.

Outcomes

Primary Outcome Measures

Maximum observed plasma concentration (Cmax) of entrectinib and its metabolite (M5)

Area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUCinf) of entrectinib and its metabolite (M5)

Cmax of entrectinib of individual treatment groups assessed by Child-Pugh and National Cancer Institute-organ dysfunction working group (NCI-ODWG) classifications

AUCinf of entrectinib of individual treatment groups assessed by Child-Pugh and NCI-ODWG classifications

Secondary Outcome Measures

Percentage of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)

Full Information

NCT ID

NCT04226833

First Posted

January 10, 2020

Last Updated

January 14, 2022

Sponsor

Hoffmann-La Roche

1. Study Identification

Unique Protocol Identification Number

NCT04226833

Brief Title

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

2. Study Status

Record Verification Date

January 2022

Overall Recruitment Status

Completed

Study Start Date

February 11, 2020 (Actual)

Primary Completion Date

September 27, 2021 (Actual)

Study Completion Date

September 27, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Hoffmann-La Roche

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Hepatic Insufficiency

Keywords

Hepatic Impairment

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

24 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Mild

Arm Type

Experimental

Arm Description

Arm Title

Moderate

Arm Type

Experimental

Arm Description

Arm Title

Severe

Arm Type

Experimental

Arm Description

Arm Title

Normal

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

entrectinib

Other Intervention Name(s)

F06 formulation, Rozlytrek

Intervention Description

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

Primary Outcome Measure Information:

Title

Maximum observed plasma concentration (Cmax) of entrectinib and its metabolite (M5)

Time Frame

From Day 1 to Day 7

Title

Area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUCinf) of entrectinib and its metabolite (M5)

Time Frame

From Day 1 to Day 7

Title

Cmax of entrectinib of individual treatment groups assessed by Child-Pugh and National Cancer Institute-organ dysfunction working group (NCI-ODWG) classifications

Time Frame

From Day 1 to Day 7

Title

AUCinf of entrectinib of individual treatment groups assessed by Child-Pugh and NCI-ODWG classifications

Time Frame

From Day 1 to Day 7

Secondary Outcome Measure Information:

Title

Percentage of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)

Time Frame

4 weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

75 Years

Accepts Healthy Volunteers

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Clinical Trials

Organizational Affiliation

Hoffmann-La Roche

Official's Role

Study Director

Facility Information:

Facility Name

Pharmaceutical Research Associates CZ, s.r.o.

City

Praha 7

ZIP/Postal Code

170 00

Country

Czechia

Facility Name

CRU Hungary Kft

City

Miskolc

ZIP/Postal Code

3529

Country

Hungary

Facility Name

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

City

Bratislava

ZIP/Postal Code

831 01

Country

Slovakia

12. IPD Sharing Statement

Plan to Share IPD

IPD Sharing 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).

Learn more about this trial

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

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