A Performance and Bioavailability Study of Entrectinib in Healthy Volunteers.

A Randomized, Open-Label, Two Part Study to Explore the Performance of Entrectinib Prototype Mini-Tablet Formulations and the Effect of Drug Substance Particle Size On Entrectinib Bioavailability in Healthy Volunteers

This study will evaluate the bioavailability, palatability, safety and tolerability of entrectinib in healthy volunteers. Part 1 of the study will explore the performance of entrectinib multi-particle formulation. Part 2 will evaluate the effect of drug substance particle size on entrectinib bioavailability.

Study Overview

• Status: Completed
• Conditions: Solid Tumor
• Intervention / Treatment: Drug: Entrectinib 600 mg (T1); Drug: Entrectinib 600 mg (T2); Drug: Entrectinib 200 mg (R); Drug: Entrectinib 200 mg (T)

• Study Type: Interventional
• Enrollment (Actual): 31
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Nottingham, United Kingdom, NG11 6JS
    • Quotient Clinical Ltd, Clinical Research Unit

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• A body mass index (BMI) between 18.0 and 32.0 kilogram per square meter (kg/m2), inclusive, and weighing >/=50 kg.
• Agreement to comply with measures to prevent pregnancy and restrictions on egg and sperm donation

Exclusion Criteria:

• Women of childbearing potential, women who are pregnant or breastfeeding, or intending to become pregnant during the study or within 14 days after the final dose of entrectinib or have a pregnant partner
• A clinical significant medical history of gastrointestinal surgery (e.g., gastric bypass) or other gastrointestinal disorder (e.g., malabsorption syndrome) that might affect absorption of medicines from the gastrointestinal tract
• Presence of a clinically significant disease, illness, medical condition or disorder, or any other medical history determined by the investigator to be clinically significant and relevant
• Clinically significant change in health status, or any major illness, or clinically significant acute infection or febrile illness
• Use of moderate or potent inhibitors or inducers of CYP P450 3A4 enzyme or P-gp transporter, or use of other prohibited medications
• Participation in any other clinical study involving an investigational medicinal product (IMP) or device
• A positive test result for hepatitis B, hepatitis C (HCV), or human immunodeficiency virus (HIV)
• Current smokers and those who have smoked, or users of e-cigarettes and nicotine replacement products within the last 12 months
• Known history of clinically significant hypersensitivity, or severe allergic reaction, to entrectinib or related compounds

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Part 1; Participants will be randomly assigned to one of the three treatment sequences (T1T2R, T2RT1, RT1T2). In each treatment sequences, participants will cross-over to three periods taking different formulations of entrectinib. Entrectinib will be administered as a single 600 milligram (mg) oral dose under fed condition in three different formulations. Test formulation 1 (T1): film-coated mini-tablet; Test formulation 2 (T2): film-coated mini-tablet; Reference formulation (R): hard capsule.	Drug: Entrectinib 600 mg (T1); Test formulation 1 (T1): Multi-particulate formulation 1: entrectinib film-coated mini-tablets; Drug: Entrectinib 600 mg (T2); Test formulation 2 (T2): Multi-particulate formulation 2: entrectinib film-coated mini-tablets; Drug: Entrectinib 200 mg (R); Reference formulation (R): entrectinib hard capsules
EXPERIMENTAL: Part 2; Participants will be randomly assigned to one of the two treatment sequences (TR, RT). In each treatment sequences, participants will cross-over to two periods taking different formulations of entrectinib. Entrectinib will be administered as a single 200 mg oral dose under fasted condition in two different formulations. Test formulation (T): hydroxypropyl methylcellulose (HPMC) capsule; Reference formulation (R): hard capsule.	Drug: Entrectinib 200 mg (R); Reference formulation (R): entrectinib hard capsules; Drug: Entrectinib 200 mg (T); Test formulation (T): entrectinib HPMC capsules

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Area Under the Concentration-Time Curve From Time 0 to Infinity (AUC0-inf) of Entrectinib	At pre-defined intervals from study Day 1 to Day 5 of each periods (each period=7 days)
AUC0-inf of Entrectinib Active Metabolite M5	At pre-defined intervals from study Day 1 to Day 5 of each periods (each period=7 days)
Maximum Plasma Concentration (Cmax) of Entrectinib	At pre-defined intervals from study Day 1 to Day 5 of each periods (each period=7 days)
Cmax of Entrectinib Active Metabolite M5	At pre-defined intervals from study Day 1 to Day 5 of each periods (each period=7 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs)	An adverse event (AE) is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. Treatment-emergent adverse events (TEAEs) are AEs that were not present before the first dose of study drug or that were present before the first dose of study drug but worsened in intensity during exposure to study drug.	From Day -1 to Day 5 of each periods (each period=7 days)

Collaborators and Investigators

• Sponsor: Genentech, Inc.

Study record dates

Study Major Dates

• Study Start (ACTUAL): June 6, 2019
• Primary Completion (ACTUAL): August 9, 2019
• Study Completion (ACTUAL): August 9, 2019

Study Registration Dates

• First Submitted: May 22, 2019
• First Submitted That Met QC Criteria: May 22, 2019
• First Posted (ACTUAL): May 23, 2019

Study Record Updates

• Last Update Posted (ACTUAL): September 7, 2020
• Last Update Submitted That Met QC Criteria: September 4, 2020
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; Entrectinib
• Other Study ID Numbers: GP41341; 2019-000783-15 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Qualified researchers may request access to individual patient level data through the clinical study data request platform (www.vivli.org). Further details on Roche's criteria for eligible studies are available here (https://vivli.org/ourmember/roche/). 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).

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No