Trial Outcomes & Findings for A Performance and Bioavailability Study of Entrectinib in Healthy Volunteers. (NCT NCT03961100)

NCT ID: NCT03961100

Last Updated: 2020-09-07

Results Overview

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

31 participants

Primary outcome timeframe

At pre-defined intervals from study Day 1 to Day 5 of each periods (each period=7 days)

Results posted on

2020-09-07

Participant Flow

Participant milestones

Participant milestones
Measure	Part 1 T1T2R Sequence Participants were randomly assigned to one of the three treatment sequences (T1T2R, T2RT1, RT1T2). In each treatment sequences, participants crossed over to three periods (each period=7 days) taking different formulations of entrectinib. Entrectinib was 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. The washout period between entrectinib doses was at least 14 days.	Part 1 T2RT1 Sequence Participants were randomly assigned to one of the three treatment sequences (T1T2R, T2RT1, RT1T2). In each treatment sequences, participants crossed over to three periods (each period=7 days) taking different formulations of entrectinib. Entrectinib was 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. The washout period between entrectinib doses was at least 14 days.	Part 1 RT1T2 Sequence Participants were randomly assigned to one of the three treatment sequences (T1T2R, T2RT1, RT1T2). In each treatment sequences, participants crossed over to three periods (each period=7 days) taking different formulations of entrectinib. Entrectinib was 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. The washout period between entrectinib doses was at least 14 days.	Part 2 TR Sequence Participants were randomly assigned to one of the two treatment sequences (TR, RT). In each treatment sequences, participants crossed over to two periods (each period=7 days) taking different formulations of entrectinib. Entrectinib was 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. The washout period between entrectinib doses was at least 14 days.	Part 2 RT Sequence Participants were randomly assigned to one of the two treatment sequences (TR, RT). In each treatment sequences, participants crossed over to two periods (each period=7 days) taking different formulations of entrectinib. Entrectinib was 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. The washout period between entrectinib doses was at least 14 days.
Part 1 STARTED	5	5	5	0	0
Part 1 COMPLETED	5	5	5	0	0
Part 1 NOT COMPLETED	0	0	0	0	0
Part 2 STARTED	0	0	0	8	8
Part 2 COMPLETED	0	0	0	8	8
Part 2 NOT COMPLETED	0	0	0	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

A Performance and Bioavailability Study of Entrectinib in Healthy Volunteers.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Part 1 T1T2R Sequence n=5 Participants Participants were randomly assigned to one of the three treatment sequences (T1T2R, T2RT1, RT1T2). In each treatment sequences, participants crossed over to three periods (each period=7 days) taking different formulations of entrectinib. Entrectinib was 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. The washout period between entrectinib doses was at least 14 days.	Part 1 T2RT1 Sequence n=5 Participants Participants were randomly assigned to one of the three treatment sequences (T1T2R, T2RT1, RT1T2). In each treatment sequences, participants crossed over to three periods (each period=7 days) taking different formulations of entrectinib. Entrectinib was 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. The washout period between entrectinib doses was at least 14 days.	Part 1 RT1T2 Sequence n=5 Participants Participants were randomly assigned to one of the three treatment sequences (T1T2R, T2RT1, RT1T2). In each treatment sequences, participants crossed over to three periods (each period=7 days) taking different formulations of entrectinib. Entrectinib was 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. The washout period between entrectinib doses was at least 14 days.	Part 2 TR Sequence n=8 Participants Participants were randomly assigned to one of the two treatment sequences (TR, RT). In each treatment sequences, participants crossed over to two periods (each period=7 days) taking different formulations of entrectinib. Entrectinib was 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. The washout period between entrectinib doses was at least 14 days.	Part 2 RT Sequence n=8 Participants Participants were randomly assigned to one of the two treatment sequences (TR, RT). In each treatment sequences, participants crossed over to two periods (each period=7 days) taking different formulations of entrectinib. Entrectinib was 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. The washout period between entrectinib doses was at least 14 days.	Total n=31 Participants Total of all reporting groups
Age, Continuous	38.6 Years STANDARD_DEVIATION 17.3 • n=5 Participants	47.2 Years STANDARD_DEVIATION 15.2 • n=7 Participants	39.8 Years STANDARD_DEVIATION 15.2 • n=5 Participants	40.6 Years STANDARD_DEVIATION 11.5 • n=4 Participants	46.8 Years STANDARD_DEVIATION 15.3 • n=21 Participants	42.8 Years STANDARD_DEVIATION 14.1 • n=8 Participants
Sex: Female, Male Female	1 Participants n=5 Participants	2 Participants n=7 Participants	1 Participants n=5 Participants	2 Participants n=4 Participants	4 Participants n=21 Participants	10 Participants n=8 Participants
Sex: Female, Male Male	4 Participants n=5 Participants	3 Participants n=7 Participants	4 Participants n=5 Participants	6 Participants n=4 Participants	4 Participants n=21 Participants	21 Participants n=8 Participants
Race/Ethnicity, Customized Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	1 Participants n=4 Participants	0 Participants n=21 Participants	2 Participants n=8 Participants
Race/Ethnicity, Customized Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants	0 Participants n=21 Participants	1 Participants n=8 Participants
Race/Ethnicity, Customized White	5 Participants n=5 Participants	5 Participants n=7 Participants	4 Participants n=5 Participants	6 Participants n=4 Participants	8 Participants n=21 Participants	28 Participants n=8 Participants
Race/Ethnicity, Customized Not Hispanic or Latino	5 Participants n=5 Participants	5 Participants n=7 Participants	5 Participants n=5 Participants	8 Participants n=4 Participants	8 Participants n=21 Participants	31 Participants n=8 Participants

PRIMARY outcome

Timeframe: At pre-defined intervals from study Day 1 to Day 5 of each periods (each period=7 days)

Population: The analysis population included all participants in Part 1 and Part 2, who received at least one dose of entrectinib. Only participants for whom data were collected are included in the analysis.

Outcome measures

Outcome measures
Measure	Part 1 T1/F15 (Test Formulation 1) n=15 Participants Participants who received a single oral dose of 600 mg (240 × 2.5 mg) entrectinib film-coated mini-tablets in each period (one period=7 days) sprinkled on to, and mixed with, one tablespoon (15 mL) of yoghurt within 30 minutes of consumption of a standardized light "pediatric" breakfast. The washout period between entrectinib doses was at least 14 days.	Part 1 T2/F16 (Test Formulation 2) n=15 Participants Participants who received a single oral dose of 600 mg (240 × 2.5 mg) entrectinib film-coated mini-tablets in each period (one period=7 days) sprinkled on to, and mixed with, one tablespoon (15 mL) of yoghurt within 30 minutes of consumption of a standardized light "pediatric" breakfast. The washout period between entrectinib doses was at least 14 days.	Part 1 R/F06 (Reference Formulation) n=15 Participants Participants who received a single oral dose of 600 mg (3 × 200 mg) entrectinib hard capsule in each period (one period=7 days) swallowed whole with approximately 240 mL of water within 30 minutes of consumption of a standardized light "pediatric" breakfast. The washout period between entrectinib doses was at least 14 days.	Part 2 T/F06 Coarse (Test Formulation) n=16 Participants Participants who received a single oral dose of 1 x 200 mg entrectinib hydroxypropyl methylcellulose (HPMC) capsule in each period (one period=7 days) swallowed whole with approximately 240 mL of water after an overnight fast (minimum 8 hours). The washout period between entrectinib doses was at least 14 days.	Part 2 R/F06 Fine (Reference Formulation) n=16 Participants Participants who received a single oral dose of 1 x 200 mg entrectinib hard capsule in each period (one period=7 days) swallowed whole with approximately 240 mL of water after an overnight fast (minimum 8 hours). The washout period between entrectinib doses was at least 14 days.
Area Under the Concentration-Time Curve From Time 0 to Infinity (AUC0-inf) of Entrectinib	41500 nmol*h/L Geometric Coefficient of Variation 38.2	46600 nmol*h/L Geometric Coefficient of Variation 34.5	43400 nmol*h/L Geometric Coefficient of Variation 40.9	9860 nmol*h/L Geometric Coefficient of Variation 64.7	10100 nmol*h/L Geometric Coefficient of Variation 56.0

PRIMARY outcome

Timeframe: At pre-defined intervals from study Day 1 to Day 5 of each periods (each period=7 days)

Outcome measures

Outcome measures
Measure	Part 1 T1/F15 (Test Formulation 1) n=15 Participants Participants who received a single oral dose of 600 mg (240 × 2.5 mg) entrectinib film-coated mini-tablets in each period (one period=7 days) sprinkled on to, and mixed with, one tablespoon (15 mL) of yoghurt within 30 minutes of consumption of a standardized light "pediatric" breakfast. The washout period between entrectinib doses was at least 14 days.	Part 1 T2/F16 (Test Formulation 2) n=15 Participants Participants who received a single oral dose of 600 mg (240 × 2.5 mg) entrectinib film-coated mini-tablets in each period (one period=7 days) sprinkled on to, and mixed with, one tablespoon (15 mL) of yoghurt within 30 minutes of consumption of a standardized light "pediatric" breakfast. The washout period between entrectinib doses was at least 14 days.	Part 1 R/F06 (Reference Formulation) n=15 Participants Participants who received a single oral dose of 600 mg (3 × 200 mg) entrectinib hard capsule in each period (one period=7 days) swallowed whole with approximately 240 mL of water within 30 minutes of consumption of a standardized light "pediatric" breakfast. The washout period between entrectinib doses was at least 14 days.	Part 2 T/F06 Coarse (Test Formulation) n=16 Participants Participants who received a single oral dose of 1 x 200 mg entrectinib hydroxypropyl methylcellulose (HPMC) capsule in each period (one period=7 days) swallowed whole with approximately 240 mL of water after an overnight fast (minimum 8 hours). The washout period between entrectinib doses was at least 14 days.	Part 2 R/F06 Fine (Reference Formulation) n=16 Participants Participants who received a single oral dose of 1 x 200 mg entrectinib hard capsule in each period (one period=7 days) swallowed whole with approximately 240 mL of water after an overnight fast (minimum 8 hours). The washout period between entrectinib doses was at least 14 days.
AUC0-inf of Entrectinib Active Metabolite M5	12400 nmol*h/L Geometric Coefficient of Variation 31.1	12200 nmol*h/L Geometric Coefficient of Variation 20.9	13600 nmol*h/L Geometric Coefficient of Variation 31.7	3900 nmol*h/L Geometric Coefficient of Variation 42.8	3780 nmol*h/L Geometric Coefficient of Variation 28.1

PRIMARY outcome

Timeframe: At pre-defined intervals from study Day 1 to Day 5 of each periods (each period=7 days)

Outcome measures

Outcome measures
Measure	Part 1 T1/F15 (Test Formulation 1) n=15 Participants Participants who received a single oral dose of 600 mg (240 × 2.5 mg) entrectinib film-coated mini-tablets in each period (one period=7 days) sprinkled on to, and mixed with, one tablespoon (15 mL) of yoghurt within 30 minutes of consumption of a standardized light "pediatric" breakfast. The washout period between entrectinib doses was at least 14 days.	Part 1 T2/F16 (Test Formulation 2) n=15 Participants Participants who received a single oral dose of 600 mg (240 × 2.5 mg) entrectinib film-coated mini-tablets in each period (one period=7 days) sprinkled on to, and mixed with, one tablespoon (15 mL) of yoghurt within 30 minutes of consumption of a standardized light "pediatric" breakfast. The washout period between entrectinib doses was at least 14 days.	Part 1 R/F06 (Reference Formulation) n=15 Participants Participants who received a single oral dose of 600 mg (3 × 200 mg) entrectinib hard capsule in each period (one period=7 days) swallowed whole with approximately 240 mL of water within 30 minutes of consumption of a standardized light "pediatric" breakfast. The washout period between entrectinib doses was at least 14 days.	Part 2 T/F06 Coarse (Test Formulation) n=16 Participants Participants who received a single oral dose of 1 x 200 mg entrectinib hydroxypropyl methylcellulose (HPMC) capsule in each period (one period=7 days) swallowed whole with approximately 240 mL of water after an overnight fast (minimum 8 hours). The washout period between entrectinib doses was at least 14 days.	Part 2 R/F06 Fine (Reference Formulation) n=16 Participants Participants who received a single oral dose of 1 x 200 mg entrectinib hard capsule in each period (one period=7 days) swallowed whole with approximately 240 mL of water after an overnight fast (minimum 8 hours). The washout period between entrectinib doses was at least 14 days.
Maximum Plasma Concentration (Cmax) of Entrectinib	1930 nmol/L Geometric Coefficient of Variation 24.9	1940 nmol/L Geometric Coefficient of Variation 21.3	1880 nmol/L Geometric Coefficient of Variation 26.1	494 nmol/L Geometric Coefficient of Variation 54.7	522 nmol/L Geometric Coefficient of Variation 33.8

PRIMARY outcome

Timeframe: At pre-defined intervals from study Day 1 to Day 5 of each periods (each period=7 days)

Outcome measures

Outcome measures
Measure	Part 1 T1/F15 (Test Formulation 1) n=15 Participants Participants who received a single oral dose of 600 mg (240 × 2.5 mg) entrectinib film-coated mini-tablets in each period (one period=7 days) sprinkled on to, and mixed with, one tablespoon (15 mL) of yoghurt within 30 minutes of consumption of a standardized light "pediatric" breakfast. The washout period between entrectinib doses was at least 14 days.	Part 1 T2/F16 (Test Formulation 2) n=15 Participants Participants who received a single oral dose of 600 mg (240 × 2.5 mg) entrectinib film-coated mini-tablets in each period (one period=7 days) sprinkled on to, and mixed with, one tablespoon (15 mL) of yoghurt within 30 minutes of consumption of a standardized light "pediatric" breakfast. The washout period between entrectinib doses was at least 14 days.	Part 1 R/F06 (Reference Formulation) n=15 Participants Participants who received a single oral dose of 600 mg (3 × 200 mg) entrectinib hard capsule in each period (one period=7 days) swallowed whole with approximately 240 mL of water within 30 minutes of consumption of a standardized light "pediatric" breakfast. The washout period between entrectinib doses was at least 14 days.	Part 2 T/F06 Coarse (Test Formulation) n=16 Participants Participants who received a single oral dose of 1 x 200 mg entrectinib hydroxypropyl methylcellulose (HPMC) capsule in each period (one period=7 days) swallowed whole with approximately 240 mL of water after an overnight fast (minimum 8 hours). The washout period between entrectinib doses was at least 14 days.	Part 2 R/F06 Fine (Reference Formulation) n=16 Participants Participants who received a single oral dose of 1 x 200 mg entrectinib hard capsule in each period (one period=7 days) swallowed whole with approximately 240 mL of water after an overnight fast (minimum 8 hours). The washout period between entrectinib doses was at least 14 days.
Cmax of Entrectinib Active Metabolite M5	398 nmol/L Geometric Coefficient of Variation 32.2	325 nmol/L Geometric Coefficient of Variation 32.3	360 nmol/L Geometric Coefficient of Variation 30.1	100 nmol/L Geometric Coefficient of Variation 63.2	113 nmol/L Geometric Coefficient of Variation 42.4

SECONDARY outcome

Timeframe: From Day -1 to Day 5 of each periods (each period=7 days)

Population: The analysis population included all participants in Part 1 and Part 2, who received at least one dose of entrectinib.

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.