A Performance and Bioavailability Study of Entrectinib in Healthy Volunteers.

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Solid Tumor

Intervention / Treatment
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* Drug: Entrectinib 600 mg (T1)
* Drug: Entrectinib 600 mg (T2)
* Drug: Entrectinib 200 mg (R)
* Drug: Entrectinib 200 mg (T)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1<br>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)<br>* Test formulation 1 (T1): Multi-particulate formulation 1: entrectinib film-coated mini-tablets<br>Drug: Entrectinib 600 mg (T2)<br>* Test formulation 2 (T2): Multi-particulate formulation 2: entrectinib film-coated mini-tablets<br>Drug: Entrectinib 200 mg (R)<br>* Reference formulation (R): entrectinib hard capsules<br>|
| Experimental: Part 2<br>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)<br>* Reference formulation (R): entrectinib hard capsules<br>Drug: Entrectinib 200 mg (T)<br>* Test formulation (T): entrectinib HPMC capsules<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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) |