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    Clinical Trial Results:
    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

    Summary
    EudraCT number
    		 2019-000783-15
    Trial protocol
    		 GB  
    Global end of trial date
    09 Aug 2019

    Results information
    Results version number
    		 v2(current)
    This version publication date
    20 Sep 2020
    First version publication date
    22 Aug 2020
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    GP41341
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03961100
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124., Basel, Switzerland, CH-4070
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    09 Aug 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Aug 2019
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The main objectives for this study were to explore the relative bioavailability of entrectinib from two multi-particulate formulations and the reference F06 capsule formulation under fed conditions (Part 1) and to explore the relative bioavailability of two entrectinib F06 capsule formulations under fasted conditions (Part 2).
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 Jun 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 31
    Worldwide total number of subjects
    31
    EEA total number of subjects
    31
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    31
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This was a single center study conducted in the United Kingdom

    Pre-assignment
    Screening details
    		 The study was conducted in healthy volunteers. The screening period was 28 days.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Part 1 T1T2R Sequence
    Arm description
    		 Subjects were randomly assigned to one of the three treatment sequences (T1T2R, T2RT1, RT1T2). In each treatment sequences, subjects 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.
    Arm type
    		 Experimental

    Investigational medicinal product name
    entrectinib
    Investigational medicinal product code
    Other name
    test formulation 1 (T1)/F15
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    600 mg (240 × 2.5 mg) entrectinib (T1/F15) film-coated mini-tablets were administered as a single oral dose under fed condition in each period

    Investigational medicinal product name
    entrectinib
    Investigational medicinal product code
    Other name
    test formulation 2 (T2)/F16
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    600 mg (240 × 2.5 mg) entrectinib (T2/F16) film-coated mini-tablets were administered as a single oral dose under fed condition in each period

    Investigational medicinal product name
    entrectinib
    Investigational medicinal product code
    Other name
    reference formulation (R)/F06
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    600 mg (3 x 200 mg) entrectinib (R/F06) hard capsule was administered as a single oral dose under fed condition in each period

    Arm title
    		 Part 1 T2RT1 Sequence
    Arm description
    		 Subjects were randomly assigned to one of the three treatment sequences (T1T2R, T2RT1, RT1T2). In each treatment sequences, subjects 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.
    Arm type
    		 Experimental

    Investigational medicinal product name
    entrectinib
    Investigational medicinal product code
    Other name
    test formulation 1 (T1)/F15
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    600 mg (240 × 2.5 mg) entrectinib (T1/F15) film-coated mini-tablets were administered as a single oral dose under fed condition in each period

    Investigational medicinal product name
    entrectinib
    Investigational medicinal product code
    Other name
    test formulation 2 (T2)/F16
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    600 mg (240 × 2.5 mg) entrectinib (T2/F16) film-coated mini-tablets were administered as a single oral dose under fed condition in each period

    Investigational medicinal product name
    entrectinib
    Investigational medicinal product code
    Other name
    reference formulation (R)/F06
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    600 mg (3 x 200 mg) entrectinib (R/F06) hard capsule was administered as a single oral dose under fed condition in each period

    Arm title
    		 Part 1 RT1T2 Sequence
    Arm description
    		 Subjects were randomly assigned to one of the three treatment sequences (T1T2R, T2RT1, RT1T2). In each treatment sequences, subjects 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.
    Arm type
    		 Experimental

    Investigational medicinal product name
    entrectinib
    Investigational medicinal product code
    Other name
    test formulation 1 (T1)/F15
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    600 mg (240 × 2.5 mg) entrectinib (T1/F15) film-coated mini-tablets were administered as a single oral dose under fed condition in each period

    Investigational medicinal product name
    entrectinib
    Investigational medicinal product code
    Other name
    test formulation 2 (T2)/F16
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    600 mg (240 × 2.5 mg) entrectinib (T2/F16) film-coated mini-tablets were administered as a single oral dose under fed condition in each period

    Investigational medicinal product name
    entrectinib
    Investigational medicinal product code
    Other name
    reference formulation (R)/F06
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    600 mg (3 x 200 mg) entrectinib (R/F06) hard capsule was administered as a single oral dose under fed condition in each period

    Arm title
    		 Part 2 TR Sequence
    Arm description
    		 Subjects were randomly assigned to one of the two treatment sequences (TR, RT). In each treatment sequences, subjects 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.
    Arm type
    		 Experimental

    Investigational medicinal product name
    entrectinib
    Investigational medicinal product code
    Other name
    test formulation (T)/F06 coarse
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    200 mg (1 x 200 mg) entrectinib (T/F06 coarse) hydroxypropyl methylcellulose (HPMC) capsule was administered as a single oral dose under fasted condition in each period

    Investigational medicinal product name
    entrectinib
    Investigational medicinal product code
    Other name
    reference formulation (R)/F06 fine
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    200 mg (1 x 200 mg) entrectinib (R/F06 fine) hard capsule was administered as a single oral dose under fasted condition in each period

    Arm title
    		 Part 2 RT Sequence
    Arm description
    		 Subjects were randomly assigned to one of the two treatment sequences (TR, RT). In each treatment sequences, subjects 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.
    Arm type
    		 Experimental

    Investigational medicinal product name
    entrectinib
    Investigational medicinal product code
    Other name
    test formulation (T)/F06 coarse
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    200 mg (1 x 200 mg) entrectinib (T/F06 coarse) hydroxypropyl methylcellulose (HPMC) capsule was administered as a single oral dose under fasted condition in each period

    Investigational medicinal product name
    entrectinib
    Investigational medicinal product code
    Other name
    reference formulation (R)/F06 fine
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    200 mg (1 x 200 mg) entrectinib (R/F06 fine) hard capsule was administered as a single oral dose under fasted condition in each period

    Number of subjects in period 1
    		Part 1 T1T2R Sequence Part 1 T2RT1 Sequence Part 1 RT1T2 Sequence Part 2 TR Sequence Part 2 RT Sequence
    Started
    5
    5
    5
    8
    8
    Completed
    5
    5
    5
    8
    8

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part 1 T1T2R Sequence
    Reporting group description
    		 Subjects were randomly assigned to one of the three treatment sequences (T1T2R, T2RT1, RT1T2). In each treatment sequences, subjects 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.

    Reporting group title
    Part 1 T2RT1 Sequence
    Reporting group description
    		 Subjects were randomly assigned to one of the three treatment sequences (T1T2R, T2RT1, RT1T2). In each treatment sequences, subjects 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.

    Reporting group title
    Part 1 RT1T2 Sequence
    Reporting group description
    		 Subjects were randomly assigned to one of the three treatment sequences (T1T2R, T2RT1, RT1T2). In each treatment sequences, subjects 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.

    Reporting group title
    Part 2 TR Sequence
    Reporting group description
    		 Subjects were randomly assigned to one of the two treatment sequences (TR, RT). In each treatment sequences, subjects 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.

    Reporting group title
    Part 2 RT Sequence
    Reporting group description
    		 Subjects were randomly assigned to one of the two treatment sequences (TR, RT). In each treatment sequences, subjects 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.

    Reporting group values
    		 Part 1 T1T2R Sequence Part 1 T2RT1 Sequence Part 1 RT1T2 Sequence Part 2 TR Sequence Part 2 RT Sequence Total
    Number of subjects
    		 5 5 5 8 8 31
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0 0
        Adults (18-64 years)
    		 5 5 5 8 8 31
        From 65-84 years
    		 0 0 0 0 0 0
        85 years and over
    		 0 0 0 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 38.6 ± 17.3 47.2 ± 15.2 39.8 ± 15.2 40.6 ± 11.5 46.8 ± 15.3 -
    Sex: Female, Male
    Units: Participants
        Female
    		 1 2 1 2 4 10
        Male
    		 4 3 4 6 4 21
    Race/Ethnicity, Customized
    Units: Subjects
        Asian
    		 0 0 1 1 0 2
        Black or African American
    		 0 0 0 1 0 1
        White
    		 5 5 4 6 8 28
    Race/Ethnicity, Customized
    Units: Subjects
        Not Hispanic or Latino
    		 5 5 5 8 8 31

    End points

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    End points reporting groups
    Reporting group title
    Part 1 T1T2R Sequence
    Reporting group description
    		 Subjects were randomly assigned to one of the three treatment sequences (T1T2R, T2RT1, RT1T2). In each treatment sequences, subjects 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.

    Reporting group title
    Part 1 T2RT1 Sequence
    Reporting group description
    		 Subjects were randomly assigned to one of the three treatment sequences (T1T2R, T2RT1, RT1T2). In each treatment sequences, subjects 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.

    Reporting group title
    Part 1 RT1T2 Sequence
    Reporting group description
    		 Subjects were randomly assigned to one of the three treatment sequences (T1T2R, T2RT1, RT1T2). In each treatment sequences, subjects 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.

    Reporting group title
    Part 2 TR Sequence
    Reporting group description
    		 Subjects were randomly assigned to one of the two treatment sequences (TR, RT). In each treatment sequences, subjects 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.

    Reporting group title
    Part 2 RT Sequence
    Reporting group description
    		 Subjects were randomly assigned to one of the two treatment sequences (TR, RT). In each treatment sequences, subjects 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.

    Subject analysis set title
    Part 1 T1/F15 (Test formulation 1)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects 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.

    Subject analysis set title
    Part 1 T2/F16 (Test formulation 2)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects 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.

    Subject analysis set title
    Part 1 R/F06 (Reference formulation)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects 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.

    Subject analysis set title
    Part 2 T/F06 coarse (Test formulation)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects 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.

    Subject analysis set title
    Part 2 R/F06 fine (Reference formulation)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects 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.

    Subject analysis set title
    Safety Analysis Population for each of Parts 1 and 2
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects who received at least 1 dose of investigational medicinal product (IMP)

    Subject analysis set title
    PK Population for each of Parts 1 and 2
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All subjects who had received at least 1 dose of IMP who satisfied the following criteria for at least one profile: no missing samples or invalid postdose analytical results at critical time points e.g., around the Cmax; no relevant protocol deviations which may have impacted the study objectives with respect to the PK endpoints; no relevant AEs, such as vomiting, which suggested that the dose was not absorbed for a particular subject

    Primary: Area Under the Concentration-Time Curve from Time 0 to Infinity (AUC0-inf) of Entrectinib

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    End point title
    		 Area Under the Concentration-Time Curve from Time 0 to Infinity (AUC0-inf) of Entrectinib [1]
    End point description
    The analysis population included all subjects in Part 1 and Part 2, who received at least one dose of entrectinib. Only subjects for whom data were collected are included in the analysis.
    End point type
    Primary
    End point timeframe
    At pre-defined intervals from study Day 1 to Day 5 of each periods (each period=7 days)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistics was planned to be reported in the endpoint.
    End point values
    		 Part 1 T1/F15 (Test formulation 1) Part 1 T2/F16 (Test formulation 2) Part 1 R/F06 (Reference formulation) Part 2 T/F06 coarse (Test formulation) Part 2 R/F06 fine (Reference formulation)
    Number of subjects analysed
    14
    14
    15
    15
    15
    Units: nmol.h/L
        geometric mean (geometric coefficient of variation)
    41500 ± 38.2
    46600 ± 34.5
    43400 ± 40.9
    9860 ± 64.7
    10100 ± 56.0
    No statistical analyses for this end point

    Primary: AUC0-inf of Entrectinib Active Metabolite M5

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    End point title
    		 AUC0-inf of Entrectinib Active Metabolite M5 [2]
    End point description
    The analysis population included all subjects in Part 1 and Part 2, who received at least one dose of entrectinib. Only subjects for whom data were collected are included in the analysis.
    End point type
    Primary
    End point timeframe
    At pre-defined intervals from study Day 1 to Day 5 of each periods (each period=7 days)
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistics was planned to be reported in the endpoint.
    End point values
    		 Part 1 T1/F15 (Test formulation 1) Part 1 T2/F16 (Test formulation 2) Part 1 R/F06 (Reference formulation) Part 2 T/F06 coarse (Test formulation) Part 2 R/F06 fine (Reference formulation)
    Number of subjects analysed
    7
    2
    5
    9
    9
    Units: nmol.h/L
        geometric mean (geometric coefficient of variation)
    12400 ± 31.1
    12200 ± 20.9
    13600 ± 31.7
    3900 ± 42.8
    3780 ± 28.1
    No statistical analyses for this end point

    Primary: Maximum Plasma Concentration (Cmax) of Entrectinib

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    End point title
    		 Maximum Plasma Concentration (Cmax) of Entrectinib [3]
    End point description
    The analysis population included all subjects in Part 1 and Part 2, who received at least one dose of entrectinib. Only subjects for whom data were collected are included in the analysis.
    End point type
    Primary
    End point timeframe
    At pre-defined intervals from study Day 1 to Day 5 of each periods (each period=7 days)
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistics was planned to be reported in the endpoint.
    End point values
    		 Part 1 T1/F15 (Test formulation 1) Part 1 T2/F16 (Test formulation 2) Part 1 R/F06 (Reference formulation) Part 2 T/F06 coarse (Test formulation) Part 2 R/F06 fine (Reference formulation)
    Number of subjects analysed
    15
    15
    15
    15
    15
    Units: nmol/L
        geometric mean (geometric coefficient of variation)
    1930 ± 24.9
    1940 ± 21.3
    1880 ± 26.1
    494 ± 54.7
    522 ± 33.8
    No statistical analyses for this end point

    Primary: Cmax of Entrectinib Active Metabolite M5

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    End point title
    		 Cmax of Entrectinib Active Metabolite M5 [4]
    End point description
    The analysis population included all subjects in Part 1 and Part 2, who received at least one dose of entrectinib. Only subjects for whom data were collected are included in the analysis.
    End point type
    Primary
    End point timeframe
    At pre-defined intervals from study Day 1 to Day 5 of each periods (each period=7 days)
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistics was planned to be reported in the endpoint.
    End point values
    		 Part 1 T1/F15 (Test formulation 1) Part 1 T2/F16 (Test formulation 2) Part 1 R/F06 (Reference formulation) Part 2 T/F06 coarse (Test formulation) Part 2 R/F06 fine (Reference formulation)
    Number of subjects analysed
    15
    15
    15
    15
    15
    Units: nmol/L
        geometric mean (geometric coefficient of variation)
    398 ± 32.2
    325 ± 32.3
    360 ± 30.1
    100 ± 63.2
    113 ± 42.4
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Treatment-Emergent Adverse Events (TEAEs)

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    End point title
    		 Percentage of Subjects with Treatment-Emergent Adverse Events (TEAEs)
    End point description
    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. The analysis population included all subjects in Part 1 and Part 2, who received at least one dose of entrectinib.
    End point type
    Secondary
    End point timeframe
    From Day -1 to Day 5 of each periods (each period=7 days)
    End point values
    		 Part 1 T1/F15 (Test formulation 1) Part 1 T2/F16 (Test formulation 2) Part 1 R/F06 (Reference formulation) Part 2 T/F06 coarse (Test formulation) Part 2 R/F06 fine (Reference formulation)
    Number of subjects analysed
    15
    15
    15
    16
    16
    Units: Percentage of Subjects
        number (not applicable)
    100
    93.3
    100
    31.3
    37.5
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day -1 through Day 5 of each period in both Part 1 and Part 2 (one period=7 days)
    Adverse event reporting additional description
    The analysis population included all subjects in Part 1 and Part 2, who received at least one dose of entrectinib.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Part 1 T1/F15 (Test formulation 1)
    Reporting group description
    		 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.

    Reporting group title
    Part 1 T2/F16 (Test formulation 2)
    Reporting group description
    		 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.

    Reporting group title
    Part 2 T/F06 coarse (Test formulation)
    Reporting group description
    		 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.

    Reporting group title
    Part 1 R/F06 (Reference formulation)
    Reporting group description
    		 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.

    Reporting group title
    Part 2 R/F06 fine (Reference formulation)
    Reporting group description
    		 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.

    Serious adverse events
    		 Part 1 T1/F15 (Test formulation 1) Part 1 T2/F16 (Test formulation 2) Part 2 T/F06 coarse (Test formulation) Part 1 R/F06 (Reference formulation) Part 2 R/F06 fine (Reference formulation)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Part 1 T1/F15 (Test formulation 1) Part 1 T2/F16 (Test formulation 2) Part 2 T/F06 coarse (Test formulation) Part 1 R/F06 (Reference formulation) Part 2 R/F06 fine (Reference formulation)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 15 (100.00%)
    14 / 15 (93.33%)
    5 / 16 (31.25%)
    15 / 15 (100.00%)
    6 / 16 (37.50%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    0
    1
    Dysgeusia
         subjects affected / exposed
    2 / 15 (13.33%)
    2 / 15 (13.33%)
    2 / 16 (12.50%)
    4 / 15 (26.67%)
    0 / 16 (0.00%)
         occurrences all number
    2
    2
    2
    4
    0
    Headache
         subjects affected / exposed
    3 / 15 (20.00%)
    1 / 15 (6.67%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    2 / 16 (12.50%)
         occurrences all number
    3
    1
    0
    0
    2
    Paraesthesia
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Somnolence
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    1
    Taste disorder
         subjects affected / exposed
    2 / 15 (13.33%)
    1 / 15 (6.67%)
    0 / 16 (0.00%)
    2 / 15 (13.33%)
    0 / 16 (0.00%)
         occurrences all number
    2
    1
    0
    2
    0
    Tension headache
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    Diarrhoea
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Hyperaesthesia teeth
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Hypoaesthesia oral
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Lip dry
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    1
    Paraesthesia oral
         subjects affected / exposed
    13 / 15 (86.67%)
    11 / 15 (73.33%)
    2 / 16 (12.50%)
    14 / 15 (93.33%)
    1 / 16 (6.25%)
         occurrences all number
    13
    11
    2
    14
    1
    Toothache
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 15 (0.00%)
    3 / 15 (20.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    Back pain
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    3 / 15 (20.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    3
    0
    Myalgia
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 15 (6.67%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Pain in extremity
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 15 (6.67%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Pain in jaw
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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