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    Clinical Trial Results:
    A Double-blind, Randomized, Placebo-controlled Phase 3 Study of Orally Administered PLX3397 in Subjects with Pigmented Villonodular Synovitis or Giant Cell Tumor of the Tendon Sheath

    Summary
    EudraCT number
    		 2014-000148-14
    Trial protocol
    		 HU   DE   DK   GB   NL   ES   PL   IT  
    Global end of trial date
    30 Apr 2021

    Results information
    Results version number
    		 v2(current)
    This version publication date
    15 May 2022
    First version publication date
    26 Jul 2019
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    New data to add to full data set.

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    PLX108-10
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02371369
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Daiichi Sankyo, Inc.
    Sponsor organisation address
    211 Mount Airy Road, Basking Ridge, NJ, United States, 07920
    Public contact
    Clinical Trial Information, Daiichi Sankyo, Inc., 1 908-992-6400, CTRinfo@dsi.com
    Scientific contact
    Clinical Trial Information, Daiichi Sankyo, Inc., 1 908-992-6400, CTRinfo@dsi.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
    27 Mar 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Mar 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Apr 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to compare the response rate of PLX3397 with that of placebo per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1) at Week 25 in subjects with symptomatic, locally advanced pigmented villonodular synovitis (PVNS) or giant cell tumor of tendon sheath (GCT-TS).
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles of Good Clinical Practice, according to the ICH Harmonised Tripartite Guideline.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 Mar 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 4 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 12
    Country: Number of subjects enrolled
    Canada: 5
    Country: Number of subjects enrolled
    Netherlands: 11
    Country: Number of subjects enrolled
    Poland: 2
    Country: Number of subjects enrolled
    Spain: 8
    Country: Number of subjects enrolled
    United Kingdom: 1
    Country: Number of subjects enrolled
    Denmark: 3
    Country: Number of subjects enrolled
    France: 7
    Country: Number of subjects enrolled
    Germany: 6
    Country: Number of subjects enrolled
    Hungary: 3
    Country: Number of subjects enrolled
    Italy: 17
    Country: Number of subjects enrolled
    United States: 45
    Worldwide total number of subjects
    120
    EEA total number of subjects
    58
    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)
    113
    From 65 to 84 years
    7
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Part 1 was a double-blind, randomized, placebo-controlled study in subjects with symptomatic TGCT for whom surgical resection would be associated with potentially worsening functional limitation or severe morbidity. Part 2 is a long-term treatment phase in which subjects receive open-label pexidartinib.

    Pre-assignment
    Screening details
    		 Subjects were screened for inclusion and exclusion criteria. Screening procedures were performed after consent was obtained and within the 42 days before the first dose of study drug, unless otherwise noted.

    Period 1
    Period 1 title
    Part 1 (randomized phase)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    The pexidartinib and placebo capsules were identical in appearance to maintain the blind during Part 1.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pexidartinib (Part 1)
    Arm description
    		 Subjects randomized to pexidartinib for 24 weeks administered twice a day.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pexidartinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    1000 mg (5 capsules per day) for 2 weeks, then 800 mg (4 capsules per day) for 22 weeks; each capsule contained 200 mg of pexidartinib; oral administration twice a day.

    Arm title
    		 Placebo (Part 1)
    Arm description
    		 Subjects randomized to matching placebo for 24 weeks administered twice a day.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo capsule matching pexidartinib capsule was administered orally (5 capsules per day) for 2 weeks, then matching placebo (4 capsules per day).

    Number of subjects in period 1
    		Pexidartinib (Part 1) Placebo (Part 1)
    Started
    61
    59
    Completed
    52
    48
    Not completed
    9
    11
         Subject noncompliance
    -
    1
         Consent withdrawn by subject
    1
    6
         Physician decision
    -
    3
         Disease progression
    -
    1
         Adverse event, non-fatal
    8
    -
    Period 2
    Period 2 title
    Part 2 (open-label phase)
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Pexidartinib (Parts 1 and 2)
    Arm description
    		 Subjects received pexidartinib in Part 1 and Part 2 at their prescribed dose.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pexidartinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Dose in Part 2 was the pexidartinib dose received at the end of Part 1.

    Arm title
    		 Placebo (Part 1), Crossover Pexidartinib (Part 2)
    Arm description
    		 Subjects received placebo in Part 1 and pexidartinib in Part 2 at their prescribed dose.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pexidartinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Dose in Part 2 was the pexidartinib equivalent dose of placebo at the end of Part 1.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo capsule matching pexidartinib capsule was administered orally (5 capsules per day) for 2 weeks, then matching placebo (4 capsules per day).

    Number of subjects in period 2
    		Pexidartinib (Parts 1 and 2) Placebo (Part 1), Crossover Pexidartinib (Part 2)
    Started
    48
    30
    Completed
    0
    0
    Not completed
    48
    30
         Subject noncompliance
    1
    -
         Physician decision
    1
    2
         Disease progression
    1
    -
         Adverse Event
    6
    5
         Lost to Follow-up
    1
    1
         Subject moved to another DS pexidartinib protocol
    15
    -
         Death
    -
    1
         Not specified
    -
    1
         Subject moved to another DS pexidartinib protocol
    -
    9
         Withdrawal by Subject
    16
    6
         Subject transitioned to commercial supply
    6
    4
         Surgical resection of tumor
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pexidartinib (Part 1)
    Reporting group description
    		 Subjects randomized to pexidartinib for 24 weeks administered twice a day.

    Reporting group title
    Placebo (Part 1)
    Reporting group description
    		 Subjects randomized to matching placebo for 24 weeks administered twice a day.

    Reporting group values
    		 Pexidartinib (Part 1) Placebo (Part 1) Total
    Number of subjects
    		 61 59 120
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 57 56 113
        From 65-84 years
    		 4 3 7
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 44.6 ( 13.2 ) 44.3 ( 13.6 ) -
    Gender categorical
    Units: Subjects
        Female
    		 35 36 71
        Male
    		 26 23 49
    Subject analysis sets

    Subject analysis set title
    All Pexidartinib Treated
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Includes all subjects who received pexidartinib in Part 1 and Part 2 (placebo crossed over to pexidartinib).

    Subject analysis set title
    Pexidartinib Part 1 and Part 2
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received treatment of Pexidartinib,1000 mg (5 capsules per day) for 2 weeks, then 800 mg (4 capsules per day) for 22 weeks and also received Pexidartinib in Part 2 at their prescribed dose. Pexidartinib: Each capsule contains 200 mg of Pexidartinib for oral administration.

    Subject analysis set title
    Placebo Part 1, Pexidartinib Part 2
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received treatment of matching placebo (5 capsules per day) for 2 weeks, then matching placebo (4 capsules per day) for 22 weeks in Part 1 and also received Pexidartinib in Part 2 at their prescribed dose. Placebo: Placebo capsule matching Pexidartinib capsule for oral administration Pexidartinib: Each capsule contains 200 mg of Pexidartinib for oral administration.

    Subject analysis sets values
    		 All Pexidartinib Treated Pexidartinib Part 1 and Part 2 Placebo Part 1, Pexidartinib Part 2
    Number of subjects
    91
    61
    30
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    85
        From 65-84 years
    6
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    45.6 ( 13.2 )
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
    51
        Male
    40

    End points

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    End points reporting groups
    Reporting group title
    Pexidartinib (Part 1)
    Reporting group description
    		 Subjects randomized to pexidartinib for 24 weeks administered twice a day.

    Reporting group title
    Placebo (Part 1)
    Reporting group description
    		 Subjects randomized to matching placebo for 24 weeks administered twice a day.
    Reporting group title
    Pexidartinib (Parts 1 and 2)
    Reporting group description
    		 Subjects received pexidartinib in Part 1 and Part 2 at their prescribed dose.

    Reporting group title
    Placebo (Part 1), Crossover Pexidartinib (Part 2)
    Reporting group description
    		 Subjects received placebo in Part 1 and pexidartinib in Part 2 at their prescribed dose.

    Subject analysis set title
    All Pexidartinib Treated
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Includes all subjects who received pexidartinib in Part 1 and Part 2 (placebo crossed over to pexidartinib).

    Subject analysis set title
    Pexidartinib Part 1 and Part 2
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received treatment of Pexidartinib,1000 mg (5 capsules per day) for 2 weeks, then 800 mg (4 capsules per day) for 22 weeks and also received Pexidartinib in Part 2 at their prescribed dose. Pexidartinib: Each capsule contains 200 mg of Pexidartinib for oral administration.

    Subject analysis set title
    Placebo Part 1, Pexidartinib Part 2
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received treatment of matching placebo (5 capsules per day) for 2 weeks, then matching placebo (4 capsules per day) for 22 weeks in Part 1 and also received Pexidartinib in Part 2 at their prescribed dose. Placebo: Placebo capsule matching Pexidartinib capsule for oral administration Pexidartinib: Each capsule contains 200 mg of Pexidartinib for oral administration.

    Primary: Percentage of Subjects With Symptomatic, Locally Advanced Tenosynovial Giant Cell Tumor (TGCT) Achieving Complete or Partial Response to Pexidartinib Compared With That of Placebo per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 at Week 25

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    End point title
    		 Percentage of Subjects With Symptomatic, Locally Advanced Tenosynovial Giant Cell Tumor (TGCT) Achieving Complete or Partial Response to Pexidartinib Compared With That of Placebo per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 at Week 25
    End point description
    Complete (CR) and partial responses (PR) were assessed based on centrally-read magnetic resonance imaging (MRI) scans and Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1). A CR was defined as disappearance of all tumors and a PR was defined as at least a 30% decrease in the sum of diameters of target tumors using the baseline sum diameters as the reference. Best overall response was assessed in the ITT population.
    End point type
    Primary
    End point timeframe
    Week 25
    End point values
    		 Pexidartinib (Part 1) Placebo (Part 1)
    Number of subjects analysed
    61
    59
    Units: Percentage of subjects
    number (not applicable)
        CR
    14.8
    0
        PR
    24.6
    0
        Response (CR or PR)
    39.3
    0
    Statistical analysis title
    		 Pexidartinib vs Placebo
    Statistical analysis description
    Treatment comparison between the pexidartinib and placebo groups at Week 25
    Comparison groups
    Placebo (Part 1) v Pexidartinib (Part 1)
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 < 0.0001
    Method
    		 Fisher's Exact Test
    Confidence interval
    Notes
    [1] - Treatment comparison analysis

    Secondary: Mean Change From Baseline for Range of Motion (ROM) Score in Subjects Receiving Pexidartinib Compared With Those on Placebo Up to Week 25

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    End point title
    		 Mean Change From Baseline for Range of Motion (ROM) Score in Subjects Receiving Pexidartinib Compared With Those on Placebo Up to Week 25
    End point description
    Range of motion (ROM) of the joint was assessed by a qualified, independent, and blinded or third-party assessors at the clinical site. Measurements were recorded in degrees. At baseline, the plane of movement with the smallest relative value (worst) was identified and this plane was used for evaluating the relative change of motion subsequently. Only the plane with the worst impaired ROM at baseline was selected for subsequent analyses. ROM was assessed in the ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 13, Week 25
    End point values
    		 Pexidartinib (Part 1) Placebo (Part 1)
    Number of subjects analysed
    61
    59
    Units: Least square mean change from baseline
    least squares mean (standard error)
        Baseline (N=61, 58)
    62.5 ( 3.2 )
    62.9 ( 2.9 )
        Week 13 (N=52, 53)
    13.0 ( 2.3 )
    4.8 ( 2.6 )
        Week 25 (N=45, 43)
    15.1 ( 2.1 )
    6.2 ( 2.4 )
    Statistical analysis title
    		 Pexidartinib vs Placebo
    Statistical analysis description
    Treatment comparison between the pexidartinib and placebo groups at Week 25
    Comparison groups
    Pexidartinib (Part 1) v Placebo (Part 1)
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 = 0.0043
    Method
    		 Fisher's Exact Test
    Confidence interval
    Notes
    [2] - Treatment comparison analysis

    Secondary: Percentage of Subjects With Symptomatic, Locally Advanced TGCT Achieving Complete or Partial Response Based on Tumor Volume Score (TVS) After Receiving Pexidartinib Compared With Those on Placebo at Week 25

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    End point title
    		 Percentage of Subjects With Symptomatic, Locally Advanced TGCT Achieving Complete or Partial Response Based on Tumor Volume Score (TVS) After Receiving Pexidartinib Compared With Those on Placebo at Week 25
    End point description
    Complete (CR) and partial responses (PR) were assessed using tumor volume score (TVS). A CR was defined as disappearance of all tumors and a PR was defined as at least a 30% decrease in the sum of diameters of target tumors using the baseline sum diameters as the reference. TVS is a semi-quantitative MRI scoring system that describes tumor mass and is based on 10% increments of the estimated volume of the maximally distended synovial cavity or tendon sheath involved. A tumor that is equal in volume to that of a maximally distended synovial cavity or tendon sheath was scored 10; a score of 0 indicated no evidence of tumor. Best overall response was assessed in the ITT population.
    End point type
    Secondary
    End point timeframe
    Week 25
    End point values
    		 Pexidartinib (Part 1) Placebo (Part 1)
    Number of subjects analysed
    61
    59
    Units: Percentage of subjects
    number (not applicable)
        CR
    4.9
    0
        PR
    50.8
    0
        Response (CR or PR)
    55.7
    0
    Statistical analysis title
    		 Pexidartinib vs Placebo
    Statistical analysis description
    Treatment comparison between the pexidartinib and placebo groups at Week 25
    Comparison groups
    Pexidartinib (Part 1) v Placebo (Part 1)
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 < 0.0001
    Method
    		 Fisher's Exact Test
    Confidence interval
    Notes
    [3] - Treatment comparison analysis

    Secondary: Mean Change From Baseline in the Patient-reported Outcomes Measurement Information System (PROMIS) Physical Function Score in Subjects Receiving Pexidartinib Compared With Those on Placebo Up to Week 25

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    End point title
    		 Mean Change From Baseline in the Patient-reported Outcomes Measurement Information System (PROMIS) Physical Function Score in Subjects Receiving Pexidartinib Compared With Those on Placebo Up to Week 25
    End point description
    The Patient-reported Outcomes Measurement Information System (PROMIS) physical function scale was used to assess physical function of the upper and lower limbs. Physical function was assessed in the ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 9, Week 17, Week 25
    End point values
    		 Pexidartinib (Part 1) Placebo (Part 1)
    Number of subjects analysed
    61
    59
    Units: Least square mean change from baseline
    least squares mean (standard error)
        Baseline (N=60, 57)
    37.5 ( 0.6 )
    38.9 ( 0.8 )
        Week 9 (N=38, 41)
    2.8 ( 1.0 )
    -0.4 ( 0.8 )
        Week 17 (N=39, 40)
    3.2 ( 1.1 )
    0.2 ( 1.0 )
        Week 25 (N=38, 31)
    4.1 ( 1.1 )
    -0.9 ( 1.0 )
    Statistical analysis title
    		 Pexidartinib vs Placebo
    Statistical analysis description
    Treatment comparison between the pexidartinib and placebo groups at Week 25
    Comparison groups
    Pexidartinib (Part 1) v Placebo (Part 1)
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 = 0.0019
    Method
    		 Mixed effects model for repeated measure
    Confidence interval
    Notes
    [4] - Treatment comparison analysis

    Secondary: Mean Change From Baseline for Worst Stiffness Numeric Rating Scale Score (NRS) in Subjects Receiving Pexidartinib Compared With Those on Placebo Up to Week 25

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    End point title
    		 Mean Change From Baseline for Worst Stiffness Numeric Rating Scale Score (NRS) in Subjects Receiving Pexidartinib Compared With Those on Placebo Up to Week 25
    End point description
    The Worst Stiffness Numeric Rating Scale (NRS) was a 1-item, self-administered questionnaire assessing the "worst" stiffness in the last 24 hours. The NRS for this item ranged from 0 (no stiffness) to 10 (stiffness as bad as you can imagine). Worst stiffness was assessed in the ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 9, Week 17, Week 25
    End point values
    		 Pexidartinib (Part 1) Placebo (Part 1)
    Number of subjects analysed
    61
    59
    Units: Least square mean change from baseline
    least squares mean (standard error)
        Baseline (N=59, 58)
    5.6 ( 0.2 )
    5.9 ( 0.3 )
        Week 9 (N=30, 38)
    -1.5 ( 0.3 )
    -0.5 ( 0.3 )
        Week 17 (N=37, 30)
    -2.4 ( 0.3 )
    -0.4 ( 0.3 )
        Week 25 (N=33, 35)
    -2.5 ( 0.3 )
    -0.3 ( 0.3 )
    Statistical analysis title
    		 Pexidartinib vs Placebo
    Statistical analysis description
    Treatment comparison between the pexidartinib and placebo groups at Week 25
    Comparison groups
    Placebo (Part 1) v Pexidartinib (Part 1)
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 < 0.0001
    Method
    		 Mixed effects model for repeated measure
    Confidence interval
    Notes
    [5] - Treatment comparison analysis

    Secondary: Percentage of Participants Who Responded With a Decrease of at Least 30% in the Mean Brief Pain Inventory Worst Pain Numeric Rating Scale Score Among Participants Receiving Pexidartinib Compared With Those on Placebo at Week 25

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    End point title
    		 Percentage of Participants Who Responded With a Decrease of at Least 30% in the Mean Brief Pain Inventory Worst Pain Numeric Rating Scale Score Among Participants Receiving Pexidartinib Compared With Those on Placebo at Week 25
    End point description
    The Brief Pain Inventory (BPI) Worst Pain NRS was a 1-item, self-administered questionnaire assessing the "worst" pain in the last 24 hours. The NRS for this item ranged from 0 (no pain) to 10 (pain as bad as you can imagine). Worst pain was assessed in the ITT population.
    End point type
    Secondary
    End point timeframe
    Week 25
    End point values
    		 Pexidartinib (Part 1) Placebo (Part 1)
    Number of subjects analysed
    61
    59
    Units: Proportion of responders
    number (not applicable)
        Proportion of responders (N=35, 33)
    31.1
    15.3
    No statistical analyses for this end point

    Secondary: Number of Responders to Pexidartinib With and Without Disease Progression

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    End point title
    		 Number of Responders to Pexidartinib With and Without Disease Progression
    End point description
    Duration of response (DOR) is defined as the date of the first recorded response to the first date of documented disease progression. The overall number of responses and the number of subjects with and without disease progression was assessed in the ITT population. The overall number of responses and the number of participants with and without disease progression were assessed in the ITT population, specifically among the Pexidartinib Part 1, Pexidartinib Part 2; Pexidartinib Part 2 only; and All Pexidartinib Treated participants. Participants randomized to Placebo Part 1 only were not analyzed.
    End point type
    Secondary
    End point timeframe
    By Week 96
    End point values
    		 All Pexidartinib Treated Pexidartinib Part 1 and Part 2 Placebo Part 1, Pexidartinib Part 2
    Number of subjects analysed
    91
    61
    30
    Units: Number of responders
    number (not applicable)
        Number of responses
    35
    23
    12
        Week 12 (Day 84); Without disease progression
    35
    23
    12
        Week 12 (Day 84); With disease progression
    0
    0
    0
        Week 24 (Day 168); Without disease progression
    35
    23
    12
        Week 24 (Day 168); With disease progression
    0
    0
    0
        Week 48 (Day 336); Without disease progression
    24
    15
    9
        Week 48 (Day 336); With disease progression
    1
    1
    0
        Week 72 (Day 504); Without disease progression
    12
    9
    3
        Week 72 (Day 504); With disease progression
    1
    1
    0
        Week 96 (Day 672); Without disease progression
    3
    2
    1
        Week 96 (Day 672); With disease progression
    1
    1
    0
    No statistical analyses for this end point

    Secondary: Number of Responders to Pexidartinib With and Without Disease Progression Based on Tumor Volume Score

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    End point title
    		 Number of Responders to Pexidartinib With and Without Disease Progression Based on Tumor Volume Score
    End point description
    TVS is a semi-quantitative MRI scoring system that describes tumor mass and is based on 10% increments of the estimated volume of the maximally distended synovial cavity or tendon sheath involved. A tumor that is equal in volume to that of a maximally distended synovial cavity or tendon sheath was scored 10; a score of 0 indicated no evidence of tumor. The overall number of responses and the number of subjects with and without disease progression was assessed. The overall number of responses and the number of participants with and without disease progression was assessed in the ITT population, specifically among the Pexidartinib Part 1, Pexidartinib Part 2; Pexidartinib Part 2 only; and All Pexidartinib Treated participants. Participants who received Placebo Part 1 only were not analyzed.
    End point type
    Secondary
    End point timeframe
    By Week 120
    End point values
    		 All Pexidartinib Treated Pexidartinib Part 1 and Part 2 Placebo Part 1, Pexidartinib Part 2
    Number of subjects analysed
    91
    61
    30
    Units: Number of responders
    number (not applicable)
        Number of responses
    52
    34
    18
        Week 12 (Day 84); Without disease progression
    51
    33
    18
        Week 12 (Day 84); With disease progression
    0
    0
    0
        Week 24 (Day 168); Without disease progression
    50
    32
    18
        Week 24 (Day 168); With disease progression
    0
    0
    0
        Week 48 (Day 336); Without disease progression
    35
    23
    13
        Week 48 (Day 336); With disease progression
    4
    3
    1
        Week 72 (Day 504); Without disease progression
    16
    13
    3
        Week 72 (Day 504); With disease progression
    4
    3
    1
        Week 96 (Day 672); Without disease progression
    4
    3
    1
        Week 96 (Day 672); With disease progression
    4
    3
    1
        Week 120 (Day 840); Without disease progression
    1
    1
    0
        Week 120 (Day 840); With disease progression
    4
    3
    1
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Reporting Frequent (>=10%) Treatment-Emergent Adverse Events by Preferred Term

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    End point title
    		 Percentage of Subjects Reporting Frequent (>=10%) Treatment-Emergent Adverse Events by Preferred Term
    End point description
    Treatment-emergent adverse events (TEAEs) were defined as adverse events that started or worsened after the first dose of treatment and within 28 days after the last dose. The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0 was used to grade adverse events. Any Grade and Grade >=3 (severe) TEAEs are reported. TEAEs were coded using MedDRA version 17.1. All safety events were assessed in the Safety Analysis Set.
    End point type
    Secondary
    End point timeframe
    After the first dose of treatment up to 28 days after the last dose
    End point values
    		 Pexidartinib (Part 1) Pexidartinib (Parts 1 and 2) Placebo (Part 1) Placebo (Part 1), Crossover Pexidartinib (Part 2) All Pexidartinib Treated
    Number of subjects analysed
    61
    48
    59
    30
    91
    Units: Percentage of subjects
    number (not applicable)
        Any Hair color changes
    67.2
    73.8
    3.4
    83.3
    76.9
        Grade >=3 Hair color changes
    0
    0
    0
    0
    0
        Any Pruritis
    9.8
    16.4
    3.4
    20.0
    17.6
        Grade >=3 Pruritis
    0
    1.6
    0
    0
    1.1
        Any Rash maculopapular
    9.8
    14.8
    1.7
    10.0
    13.2
        Grade >=3 Rash maculopapular
    0
    1.6
    0
    0
    1.1
        Any Pruritis generalized
    8.2
    8.2
    0
    10.0
    8.8
        Grade >=3 Pruritis generalized
    0
    0
    0
    0
    0
        Any Erythema
    1.6
    3.3
    0
    20.0
    8.8
        Grade >=3 Erythema
    0
    0
    0
    0
    0
        Any Dry skin
    3.3
    6.6
    3.4
    10.0
    7.7
        Grade >=3 Dry skin
    0
    0
    0
    3.3
    1.1
        Any Photosensitivity reaction
    0
    1.6
    0
    10.0
    4.4
        Grade >=3 Photosensitivity reaction
    0
    0
    0
    0
    0
        Any Nausea
    37.7
    44.3
    40.7
    20.0
    36.3
        Grade >=3 Nausea
    0
    0
    0
    0
    0
        Any Diarrhea
    19.7
    26.2
    25.4
    30.0
    27.5
        Grade >=3 Diarrhea
    0
    0
    0
    0
    0
        Any Vomiting
    19.7
    23.0
    5.1
    6.7
    17.6
        Grade >=3 Vomiting
    1.6
    1.6
    0
    0
    1.1
        Any Abdominal Pain
    16.4
    21.3
    10.2
    6.7
    16.5
        Grade >=3 Abdominal Pain
    0
    0
    0
    0
    0
        Any Dry mouth
    9.8
    13.1
    3.4
    13.3
    13.2
        Grade >=3 Dry mouth
    0
    0
    0
    0
    0
        Any Constipation
    11.5
    14.8
    5.1
    10.0
    13.2
        Grade >=3 Constipation
    0
    0
    0
    0
    0
        Any Stomatitis
    6.6
    8.2
    1.7
    10.0
    8.8
        Grade >=3 Stomatitis
    0
    0
    0
    0
    0
        Any Fatigue
    54.1
    55.7
    35.6
    26.7
    46.2
        Grade >=3 Fatigue
    0
    0
    0
    0
    0
        Any Edema peripheral
    13.1
    16.4
    3.4
    20.0
    17.6
        Grade >=3 Edema peripheral
    0
    0
    0
    0
    0
        Any Face edema
    13.1
    14.8
    1.7
    20.0
    16.5
        Grade >=3 Face edema
    0
    1.6
    0
    3.3
    2.2
        Any Asthenia
    9.8
    11.5
    5.1
    20.0
    14.3
        Grade >=3 Asthenia
    0
    0
    0
    0
    0
        Any Pyrexia
    6.6
    8.2
    1.7
    13.3
    9.9
        Grade >=3 Pyrexia
    0
    0
    0
    0
    0
        Any AST increased
    39.3
    44.3
    0
    16.7
    35.2
        Grade >=3 AST increased
    9.8
    9.8
    0
    6.7
    8.8
        Any ALT increased
    27.9
    31.1
    1.7
    23.3
    28.6
        Grade >=3 ALT increased
    9.8
    9.8
    0
    10.0
    9.9
        Any ALP increased
    14.8
    14.8
    0
    3.3
    11.0
        Grade >=3 ALP increased
    6.6
    6.6
    0
    3.3
    5.5
        Any LDH increased
    11.5
    11.5
    0
    10.0
    11.0
        Grade >=3 LDH increased
    1.6
    1.6
    0
    0
    1.1
        Any Weight increased
    3.3
    4.9
    0
    10.0
    6.6
        Grade >=3 Weight increased
    0
    0
    0
    0
    0
        Any Dysgeusia
    24.6
    27.9
    1.7
    23.3
    26.4
        Grade >=3 Dysgeusia
    0
    0
    0
    0
    0
        Any Headache
    19.7
    23.0
    18.6
    20.0
    22.0
        Grade >=3 Headache
    0
    1.6
    0
    0
    1.1
        Any Dizziness
    9.8
    13.1
    15.3
    13.3
    13.2
        Grade >=3 Dizziness
    1.6
    1.6
    0
    0
    1.1
        Any Paresthesia
    1.6
    8.2
    1.7
    10.0
    8.8
        Grade >=3 Paresthesia
    0
    0
    0
    0
    0
        Any Memory impairment
    0
    1.6
    1.7
    10.0
    4.4
        Grade >=3 Memory impairment
    0
    0
    0
    0
    0
        Any Arthralgia
    23.0
    27.9
    25.4
    30.0
    28.6
        Grade >=3 Arthralgia
    3.3
    3.3
    1.7
    0
    2.2
        Any Pain in extremity
    6.6
    9.8
    6.8
    13.3
    11.0
        Grade >=3 Pain in extremity
    0
    0
    1.7
    0
    0
        Any Periorbital edema
    18.0
    24.6
    1.7
    13.3
    20.0
        Grade >=3 Periorbital edema
    1.6
    1.6
    0
    0
    1.1
        Any Eyelid edema
    3.3
    4.9
    0
    10.0
    6.6
        Grade >=3 Eyelid edema
    0
    0
    0
    0
    0
        Any Decreased appetite
    16.4
    18.0
    10.2
    10.0
    15.4
        Grade >=3 Decreased appetite
    0
    0
    0
    0
    0
        Any Hypertension
    14.8
    19.7
    10.2
    30.0
    13.1
        Grade >=3 Hypertension
    4.9
    4.9
    0
    6.7
    5.5
        Any Upper respiratory tract infection
    1.6
    11.5
    0
    3.3
    8.8
        Grade >=3 Upper respiratory tract infection
    0
    0
    0
    0
    0
        Any Cough
    4.9
    6.6
    5.1
    10.0
    7.7
        Grade >=3 Cough
    0
    0
    0
    0
    0
        Any Dyspnea
    1.6
    4.9
    0
    10.0
    7.7
        Grade >=3 Dyspnea
    0
    0
    0
    0
    0
        Any Insomnia
    4.9
    4.9
    3.4
    10.0
    6.6
        Grade >=3 Insomnia
    0
    0
    0
    0
    0
        Any Rash
    14.8
    27.9
    5.1
    23.3
    26.4
        Grade >=3 Rash
    1.6
    1.6
    0
    0
    1.1
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR) Based on RECIST 1.1

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    End point title
    		 Duration of Response (DOR) Based on RECIST 1.1
    End point description
    Duration of response (DOR) based on RECIST 1.1 is defined from the date of the first recorded evidence of response to the first date of documented disease progression. DOR was assessed in the ITR population, specifically among the Pexidartinib Part 1, Pexidartinib Part 2; Pexidartinib Part 2 only. Participants randomized to Placebo Part 1 only were not analyzed. DOR was based on numbers of responders only.
    End point type
    Secondary
    End point timeframe
    Date of first documentation of objective response up to date of first documentation of progressive disease, assessed up to end of study (approximately 71 months)
    End point values
    		 Pexidartinib (Parts 1 and 2) Placebo (Part 1), Crossover Pexidartinib (Part 2)
    Number of subjects analysed
    37 [6]
    18 [7]
    Units: months
        median (confidence interval 95%)
    99.9 (31.01 to 99.9)
    99.9 (39.0 to 99.9)
    Notes
    [6] - 99.9 = NA, median and 95% upper CI not estimable due to insufficient number of events
    [7] - 99.9 = NA, median and 95% upper CI not estimable due to insufficient number of events
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR) Based on Tumor Volume Score (TVS)

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    End point title
    		 Duration of Response (DOR) Based on Tumor Volume Score (TVS)
    End point description
    Duration of response (DOR) based on TVS is defined from the date of the first recorded evidence of response to the first date of documented disease progression. DOR was assessed in the ITT population, specifically among the Pexidartinib Part 1, Pexidartinib Part 2; Pexidartinib Part 2 only. Participants randomized to Placebo Part 1 only were not analyzed. DOR was based on numbers of responders only.
    End point type
    Secondary
    End point timeframe
    Date of first documentation of objective response up to date of first documentation of progressive disease, assessed up to end of study (approximately 71 months)
    End point values
    		 Pexidartinib (Parts 1 and 2) Placebo (Part 1), Crossover Pexidartinib (Part 2)
    Number of subjects analysed
    41 [8]
    21 [9]
    Units: months
        median (confidence interval 95%)
    52.70 (38.60 to 99.9)
    99.9 (99.9 to 99.9)
    Notes
    [8] - 99.9 = NA, 95% CI upper limit was not estimable due to insufficient number of events.
    [9] - 99.9 = NA, median and 95% CIs were not estimable due to insufficient number of events.
    No statistical analyses for this end point

    Other pre-specified: Percentage of Subjects With Symptomatic, Locally Advanced TGCT Achieving Complete or Partial Response to Pexidartinib Compared With That of Placebo per RECIST 1.1 by Week 49

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    End point title
    		 Percentage of Subjects With Symptomatic, Locally Advanced TGCT Achieving Complete or Partial Response to Pexidartinib Compared With That of Placebo per RECIST 1.1 by Week 49
    End point description
    CR and PR were assessed based on centrally-read MRI scans and RECIST 1.1. A CR was defined as disappearance of all tumors and a PR was defined as at least a 30% decrease in the sum of diameters of target tumors using the baseline sum diameters as the reference. Best overall response was assessed in the ITT population.
    End point type
    Other pre-specified
    End point timeframe
    By Week 49
    End point values
    		 All Pexidartinib Treated Pexidartinib Part 1 and Part 2 Placebo Part 1, Pexidartinib Part 2
    Number of subjects analysed
    91
    61
    30
    Units: Percentage of subjects
    number (not applicable)
        CR
    24.2
    24.6
    23.3
        PR
    29.7
    29.5
    30.0
        Response (CR or PR)
    53.8
    54.1
    53.3
    No statistical analyses for this end point

    Other pre-specified: Mean Change From Baseline for ROM Score in Subjects Receiving Pexidartinib Compared with those on Placebo Up to Week 49

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    End point title
    		 Mean Change From Baseline for ROM Score in Subjects Receiving Pexidartinib Compared with those on Placebo Up to Week 49
    End point description
    Range of motion (ROM) of the joint was assessed by a qualified, independent, and blinded or third-party assessors at the clinical site. Measurements were recorded in degrees. At baseline, the plane of movement with the smallest relative value (worst) was identified and this plane was used for evaluating the relative change of motion subsequently. Only the plane with the worst impaired ROM at baseline was selected for subsequent analyses. ROM was assessed in the ITT population. ROM was assessed in the ITT population.
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 25, Week 49
    End point values
    		 All Pexidartinib Treated Pexidartinib Part 1 and Part 2 Placebo Part 1, Pexidartinib Part 2
    Number of subjects analysed
    91
    61
    30
    Units: Mean change from baseline
    arithmetic mean (standard deviation)
        Baseline (N=61, 30, 91)
    63.8 ( 24.2 )
    62.5 ( 24.8 )
    66.5 ( 22.9 )
        Week 25 (N=45, 24, 69)
    14.8 ( 14.2 )
    15.6 ( 14.9 )
    13.1 ( 12.9 )
        Week 49 (N=33, 22, 55)
    13.4 ( 17.3 )
    14.4 ( 19.5 )
    12.0 ( 13.4 )
    No statistical analyses for this end point

    Other pre-specified: Mean Change From Baseline in the PROMIS Physical Function Score in Subjects Receiving Pexidartinib Compared With Those on Placebo Up to Week 49

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    End point title
    		 Mean Change From Baseline in the PROMIS Physical Function Score in Subjects Receiving Pexidartinib Compared With Those on Placebo Up to Week 49
    End point description
    The PROMIS physical function scale was used to assess physical function of the upper and lower limbs. Physical function was assessed in the ITT population.
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 25, Week 49
    End point values
    		 All Pexidartinib Treated Pexidartinib Part 1 and Part 2 Placebo Part 1, Pexidartinib Part 2
    Number of subjects analysed
    91
    61
    30
    Units: Mean change from baseline
    arithmetic mean (standard deviation)
        Baseline (N=60, 30, 90)
    37.9 ( 5.6 )
    37.5 ( 4.9 )
    38.7 ( 6.9 )
        Week 25 (N=38, 16, 54)
    4.0 ( 5.4 )
    3.6 ( 4.9 )
    4.9 ( 6.3 )
        Week 49 (N=25, 14, 39)
    5.8 ( 5.2 )
    4.7 ( 4.4 )
    7.6 ( 6.3 )
    No statistical analyses for this end point

    Other pre-specified: Mean Change From Baseline for Worst Stiffness Numeric Rating Scale Score in Subjects Receiving Pexidartinib Compared With Those on Placebo Up to Week 49

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    End point title
    		 Mean Change From Baseline for Worst Stiffness Numeric Rating Scale Score in Subjects Receiving Pexidartinib Compared With Those on Placebo Up to Week 49
    End point description
    The Worst Stiffness Numeric Rating Scale (NRS) was a 1-item, self-administered questionnaire assessing the "worst" stiffness in the last 24 hours. The NRS for this item ranged from 0 (no stiffness) to 10 (stiffness as bad as you can imagine). Worst stiffness was assessed in the ITT population.
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 25, Week 49
    End point values
    		 All Pexidartinib Treated Pexidartinib Part 1 and Part 2 Placebo Part 1, Pexidartinib Part 2
    Number of subjects analysed
    91
    61
    30
    Units: Mean change from baseline
    arithmetic mean (standard deviation)
        Baseline (N=59, 26, 85)
    5.6 ( 1.9 )
    5.6 ( 1.7 )
    5.7 ( 2.3 )
        Week 25 (N=33, 18, 51)
    -2.8 ( 2.5 )
    -2.7 ( 2.2 )
    -3.0 ( 3.1 )
        Week 49 (N=22, 10, 32)
    -3.1 ( 2.3 )
    -3.5 ( 1.9 )
    -2.2 ( 2.8 )
    No statistical analyses for this end point

    Other pre-specified: Mean Change From Baseline for Worst Pain NRS in Subjects Receiving Pexidartinib Compared With Those on Placebo by Week 49

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    End point title
    		 Mean Change From Baseline for Worst Pain NRS in Subjects Receiving Pexidartinib Compared With Those on Placebo by Week 49
    End point description
    The Brief Pain Inventory (BPI) Worst Pain NRS was a 1-item, self-administered questionnaire assessing the "worst" pain in the last 24 hours. The NRS for this item ranged from 0 (no pain) to 10 (pain as bad as you can imagine). Worst pain was assessed in the ITT population.
    End point type
    Other pre-specified
    End point timeframe
    By Week 49
    End point values
    		 All Pexidartinib Treated Pexidartinib Part 1 and Part 2 Placebo Part 1, Pexidartinib Part 2
    Number of subjects analysed
    91
    61
    30
    Units: Mean change from baseline
    arithmetic mean (standard deviation)
        Baseline (N=59, 26, 85)
    5.5 ( 1.9 )
    5.6 ( 1.6 )
    5.2 ( 2.5 )
        Week 25 (N=33, 18, 51)
    -2.7 ( 2.5 )
    -2.7 ( 2.2 )
    -2.6 ( 3.1 )
        Week 49 (N=22, 10, 32)
    -3.2 ( 2.3 )
    -3.3 ( 1.7 )
    -2.8 ( 3.4 )
    No statistical analyses for this end point

    Other pre-specified: Percentage of Subjects With Symptomatic, Locally Advanced TGCT Achieving Complete or Partial Response Based on TVS After Receiving Pexidartinib Compared With Those on Placebo by Week 49

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    End point title
    		 Percentage of Subjects With Symptomatic, Locally Advanced TGCT Achieving Complete or Partial Response Based on TVS After Receiving Pexidartinib Compared With Those on Placebo by Week 49
    End point description
    Best overall response (CR or PR) was assessed using tumor volume score (TVS) in the ITT population. TVS is a semi-quantitative MRI scoring system that describes tumor mass and is based on 10% increments of the estimated volume of the maximally distended synovial cavity or tendon sheath involved. A tumor that is equal in volume to that of a maximally distended synovial cavity or tendon sheath was scored 10; a score of 0 indicated no evidence of tumor.
    End point type
    Other pre-specified
    End point timeframe
    By Week 49
    End point values
    		 All Pexidartinib Treated Pexidartinib Part 1 and Part 2 Placebo Part 1, Pexidartinib Part 2
    Number of subjects analysed
    Units: Percentage of subjects
    number (not applicable)
        Best overall response (CR or PR)
    64.8
    63.9
    66.7
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse event were monitored throughout the study from the time the subject signed the informed consent form to 28 days after the final treatment dose.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Pexidartinib (Part 1)
    Reporting group description
    		 Subjects randomized to pexidartinib for 24 weeks administered twice a day.

    Reporting group title
    Placebo (Part 1)
    Reporting group description
    		 Subjects randomized to matching placebo for 24 weeks administered twice a day.

    Reporting group title
    Pexidartinib (Parts 1 and 2)
    Reporting group description
    		 Subjects received pexidartinib in Part 1 and Part 2 at their prescribed dose.

    Reporting group title
    Placebo (Part 1), Crossover Pexidartinib (Part 2)
    Reporting group description
    		 Subjects received placebo in Part 1 and pexidartinib in Part 2 at their prescribed dose.

    Reporting group title
    All Pexidartinib Treated
    Reporting group description
    		 Subjects received pexidartinib in Part 1 and Part 2 (placebo crossed over to pexidartinib).

    Serious adverse events
    		 Pexidartinib (Part 1) Placebo (Part 1) Pexidartinib (Parts 1 and 2) Placebo (Part 1), Crossover Pexidartinib (Part 2) All Pexidartinib Treated
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 61 (13.11%)
    1 / 59 (1.69%)
    12 / 61 (19.67%)
    9 / 30 (30.00%)
    21 / 91 (23.08%)
         number of deaths (all causes)
    0
    0
    0
    1
    1
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenosquamous carcinoma of the cervix
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    1 / 30 (3.33%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal adenocarcinoma
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    1 / 30 (3.33%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endometrial cancer
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 59 (1.69%)
    0 / 61 (0.00%)
    0 / 30 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    1 / 30 (3.33%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lipoma
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    1 / 30 (3.33%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal cancer stage II
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    1 / 30 (3.33%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Transaminases increased
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    0 / 30 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 59 (0.00%)
    2 / 61 (3.28%)
    0 / 30 (0.00%)
    2 / 91 (2.20%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic enzyme abnormal
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    0 / 30 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    0 / 30 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Joint injury
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    1 / 30 (3.33%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural complication
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    0 / 30 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    1 / 30 (3.33%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    1 / 30 (3.33%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    1 / 30 (3.33%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    1 / 30 (3.33%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Nervous system disorders
    Migraine
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    0 / 30 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    1 / 30 (3.33%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Local swelling
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    1 / 30 (3.33%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    1 / 30 (3.33%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatoxicity
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    0 / 30 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liver disorder
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    0 / 30 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    0 / 30 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    0 / 30 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash papular
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    0 / 30 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    0 / 30 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Neck pain
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    1 / 30 (3.33%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    0 / 30 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spondylolisthesis
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    1 / 30 (3.33%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Hepatitis A
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    0 / 30 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis E
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    0 / 30 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymphangitis
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    1 / 30 (3.33%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    0 / 30 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paronychia
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    0 / 30 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Pexidartinib (Part 1) Placebo (Part 1) Pexidartinib (Parts 1 and 2) Placebo (Part 1), Crossover Pexidartinib (Part 2) All Pexidartinib Treated
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    60 / 61 (98.36%)
    55 / 59 (93.22%)
    61 / 61 (100.00%)
    30 / 30 (100.00%)
    91 / 91 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumor pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    4 / 61 (6.56%)
    4 / 59 (6.78%)
    4 / 61 (6.56%)
    2 / 30 (6.67%)
    6 / 91 (6.59%)
         occurrences all number
    7
    6
    7
    2
    9
    Vascular disorders
    Hypertension
    alternative assessment type: Non-systematic
         subjects affected / exposed
    9 / 61 (14.75%)
    6 / 59 (10.17%)
    14 / 61 (22.95%)
    12 / 30 (40.00%)
    26 / 91 (28.57%)
         occurrences all number
    15
    6
    24
    21
    45
    Hypotension
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    2 / 30 (6.67%)
    2 / 91 (2.20%)
         occurrences all number
    0
    0
    0
    2
    2
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    33 / 61 (54.10%)
    21 / 59 (35.59%)
    35 / 61 (57.38%)
    8 / 30 (26.67%)
    43 / 91 (47.25%)
         occurrences all number
    49
    26
    57
    13
    70
    Face oedema
    alternative assessment type: Non-systematic
         subjects affected / exposed
    8 / 61 (13.11%)
    1 / 59 (1.69%)
    9 / 61 (14.75%)
    6 / 30 (20.00%)
    15 / 91 (16.48%)
         occurrences all number
    8
    1
    11
    13
    24
    Oedema peripheral
    alternative assessment type: Non-systematic
         subjects affected / exposed
    8 / 61 (13.11%)
    2 / 59 (3.39%)
    15 / 61 (24.59%)
    9 / 30 (30.00%)
    24 / 91 (26.37%)
         occurrences all number
    9
    2
    18
    11
    29
    Asthenia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    6 / 61 (9.84%)
    3 / 59 (5.08%)
    9 / 61 (14.75%)
    7 / 30 (23.33%)
    16 / 91 (17.58%)
         occurrences all number
    7
    5
    16
    18
    34
    Pyrexia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    4 / 61 (6.56%)
    1 / 59 (1.69%)
    8 / 61 (13.11%)
    6 / 30 (20.00%)
    14 / 91 (15.38%)
         occurrences all number
    4
    1
    8
    6
    14
    Influenza like illness
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 59 (0.00%)
    5 / 61 (8.20%)
    1 / 30 (3.33%)
    6 / 91 (6.59%)
         occurrences all number
    0
    0
    6
    1
    7
    Chest pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    2 / 30 (6.67%)
    3 / 91 (3.30%)
         occurrences all number
    0
    0
    1
    2
    3
    Malaise
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    2 / 30 (6.67%)
    3 / 91 (3.30%)
         occurrences all number
    0
    0
    1
    3
    4
    Peripheral swelling
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 59 (1.69%)
    0 / 61 (0.00%)
    2 / 30 (6.67%)
    2 / 91 (2.20%)
         occurrences all number
    0
    1
    0
    2
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    3 / 59 (5.08%)
    4 / 61 (6.56%)
    5 / 30 (16.67%)
    9 / 91 (9.89%)
         occurrences all number
    0
    3
    6
    7
    13
    Dyspnoea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 59 (0.00%)
    3 / 61 (4.92%)
    4 / 30 (13.33%)
    7 / 91 (7.69%)
         occurrences all number
    0
    0
    4
    4
    8
    Oropharyngeal pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    2 / 59 (3.39%)
    4 / 61 (6.56%)
    1 / 30 (3.33%)
    5 / 91 (5.49%)
         occurrences all number
    0
    3
    4
    1
    5
    Psychiatric disorders
    Insomnia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    2 / 59 (3.39%)
    4 / 61 (6.56%)
    3 / 30 (10.00%)
    7 / 91 (7.69%)
         occurrences all number
    0
    2
    4
    4
    8
    Anxiety
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 59 (1.69%)
    1 / 61 (1.64%)
    2 / 30 (6.67%)
    3 / 91 (3.30%)
         occurrences all number
    0
    1
    1
    2
    3
    Investigations
    Aspartate aminotransferase increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    24 / 61 (39.34%)
    0 / 59 (0.00%)
    28 / 61 (45.90%)
    6 / 30 (20.00%)
    34 / 91 (37.36%)
         occurrences all number
    48
    0
    63
    11
    74
    Alanine aminotransferase increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    17 / 61 (27.87%)
    1 / 59 (1.69%)
    19 / 61 (31.15%)
    7 / 30 (23.33%)
    26 / 91 (28.57%)
         occurrences all number
    44
    1
    53
    13
    66
    Blood alkaline phosphatase increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    9 / 61 (14.75%)
    0 / 59 (0.00%)
    9 / 61 (14.75%)
    1 / 30 (3.33%)
    10 / 91 (10.99%)
         occurrences all number
    26
    0
    30
    1
    31
    Blood lactate dehydrogenase increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    7 / 61 (11.48%)
    0 / 59 (0.00%)
    7 / 61 (11.48%)
    3 / 30 (10.00%)
    10 / 91 (10.99%)
         occurrences all number
    12
    0
    17
    6
    23
    White blood cell count decreased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 59 (1.69%)
    6 / 61 (9.84%)
    1 / 30 (3.33%)
    7 / 91 (7.69%)
         occurrences all number
    0
    1
    11
    2
    13
    Weight increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 59 (0.00%)
    3 / 61 (4.92%)
    4 / 30 (13.33%)
    7 / 91 (7.69%)
         occurrences all number
    0
    0
    4
    4
    8
    Blood bilirubin increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 59 (1.69%)
    4 / 61 (6.56%)
    1 / 30 (3.33%)
    5 / 91 (5.49%)
         occurrences all number
    0
    2
    8
    1
    9
    Blood creatine phosphokinase increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 59 (0.00%)
    6 / 61 (9.84%)
    4 / 30 (13.33%)
    10 / 91 (10.99%)
         occurrences all number
    0
    0
    16
    27
    43
    Blood triglycerides increased
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    2 / 30 (6.67%)
    3 / 91 (3.30%)
         occurrences all number
    1
    0
    3
    2
    5
    Cardiac disorders
    Bradycardia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    2 / 30 (6.67%)
    2 / 91 (2.20%)
         occurrences all number
    0
    0
    0
    3
    3
    Palpitations
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 59 (0.00%)
    4 / 61 (6.56%)
    0 / 30 (0.00%)
    4 / 91 (4.40%)
         occurrences all number
    2
    0
    5
    0
    5
    Tachycardia
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    2 / 30 (6.67%)
    3 / 91 (3.30%)
         occurrences all number
    0
    0
    3
    2
    5
    Nervous system disorders
    Dysgeusia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    15 / 61 (24.59%)
    1 / 59 (1.69%)
    18 / 61 (29.51%)
    7 / 30 (23.33%)
    25 / 91 (27.47%)
         occurrences all number
    24
    1
    29
    10
    39
    Headache
         subjects affected / exposed
    11 / 61 (18.03%)
    11 / 59 (18.64%)
    15 / 61 (24.59%)
    6 / 30 (20.00%)
    21 / 91 (23.08%)
         occurrences all number
    16
    15
    25
    8
    33
    Dizziness
    alternative assessment type: Non-systematic
         subjects affected / exposed
    6 / 61 (9.84%)
    9 / 59 (15.25%)
    10 / 61 (16.39%)
    5 / 30 (16.67%)
    12 / 91 (13.19%)
         occurrences all number
    7
    12
    14
    5
    16
    Paresthesia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 59 (1.69%)
    6 / 61 (9.84%)
    3 / 30 (10.00%)
    9 / 91 (9.89%)
         occurrences all number
    0
    1
    7
    6
    13
    Memory impairment
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 59 (1.69%)
    2 / 61 (3.28%)
    3 / 30 (10.00%)
    5 / 91 (5.49%)
         occurrences all number
    0
    1
    2
    7
    9
    Neuropathy peripheral
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 59 (0.00%)
    4 / 61 (6.56%)
    1 / 30 (3.33%)
    5 / 91 (5.49%)
         occurrences all number
    0
    0
    5
    1
    6
    Hypoaesthesia
         subjects affected / exposed
    1 / 61 (1.64%)
    2 / 59 (3.39%)
    1 / 61 (1.64%)
    3 / 30 (10.00%)
    4 / 91 (4.40%)
         occurrences all number
    1
    2
    1
    5
    6
    Sciatica
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 59 (1.69%)
    0 / 61 (0.00%)
    2 / 30 (6.67%)
    2 / 91 (2.20%)
         occurrences all number
    0
    1
    0
    2
    2
    Blood and lymphatic system disorders
    Anaemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 61 (4.92%)
    1 / 59 (1.69%)
    7 / 61 (11.48%)
    1 / 30 (3.33%)
    8 / 91 (8.79%)
         occurrences all number
    3
    2
    12
    1
    13
    Neutropenia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 61 (4.92%)
    0 / 59 (0.00%)
    4 / 61 (6.56%)
    2 / 30 (6.67%)
    6 / 91 (6.59%)
         occurrences all number
    3
    0
    13
    3
    16
    Leukopenia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 59 (0.00%)
    4 / 61 (6.56%)
    2 / 30 (6.67%)
    6 / 91 (6.59%)
         occurrences all number
    2
    0
    7
    10
    17
    Thrombocytopenia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 59 (0.00%)
    2 / 61 (3.28%)
    2 / 30 (6.67%)
    4 / 91 (4.40%)
         occurrences all number
    2
    0
    2
    5
    7
    Ear and labyrinth disorders
    Tinnitus
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 59 (0.00%)
    2 / 61 (3.28%)
    3 / 30 (10.00%)
    5 / 91 (5.49%)
         occurrences all number
    1
    0
    2
    6
    8
    Vertigo
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 59 (0.00%)
    4 / 61 (6.56%)
    4 / 30 (13.33%)
    8 / 91 (8.79%)
         occurrences all number
    1
    0
    4
    4
    8
    Eye disorders
    Periorbital edema
    alternative assessment type: Non-systematic
         subjects affected / exposed
    11 / 61 (18.03%)
    1 / 59 (1.69%)
    17 / 61 (27.87%)
    5 / 30 (16.67%)
    22 / 91 (24.18%)
         occurrences all number
    13
    1
    23
    6
    29
    Eye oedema
    alternative assessment type: Non-systematic
         subjects affected / exposed
    6 / 61 (9.84%)
    2 / 59 (3.39%)
    6 / 61 (9.84%)
    0 / 30 (0.00%)
    6 / 91 (6.59%)
         occurrences all number
    6
    2
    6
    0
    6
    Eyelid oedema
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 59 (0.00%)
    3 / 61 (4.92%)
    3 / 30 (10.00%)
    6 / 91 (6.59%)
         occurrences all number
    0
    0
    5
    4
    9
    Vision blurred
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 59 (0.00%)
    5 / 61 (8.20%)
    2 / 30 (6.67%)
    7 / 91 (7.69%)
         occurrences all number
    0
    0
    5
    3
    8
    Lacrimation increased
         subjects affected / exposed
    3 / 61 (4.92%)
    0 / 59 (0.00%)
    4 / 61 (6.56%)
    1 / 30 (3.33%)
    5 / 91 (5.49%)
         occurrences all number
    3
    0
    4
    1
    5
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    23 / 61 (37.70%)
    24 / 59 (40.68%)
    28 / 61 (45.90%)
    7 / 30 (23.33%)
    35 / 91 (38.46%)
         occurrences all number
    40
    27
    66
    10
    76
    Diarrhea
         subjects affected / exposed
    13 / 61 (21.31%)
    15 / 59 (25.42%)
    19 / 61 (31.15%)
    10 / 30 (33.33%)
    29 / 91 (31.87%)
         occurrences all number
    17
    18
    34
    23
    57
    Vomiting
         subjects affected / exposed
    12 / 61 (19.67%)
    3 / 59 (5.08%)
    16 / 61 (26.23%)
    3 / 30 (10.00%)
    19 / 91 (20.88%)
         occurrences all number
    16
    3
    23
    3
    26
    Abdominal pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    10 / 61 (16.39%)
    6 / 59 (10.17%)
    13 / 61 (21.31%)
    3 / 30 (10.00%)
    16 / 91 (17.58%)
         occurrences all number
    12
    8
    15
    3
    18
    Constipation
    alternative assessment type: Non-systematic
         subjects affected / exposed
    7 / 61 (11.48%)
    3 / 59 (5.08%)
    10 / 61 (16.39%)
    3 / 30 (10.00%)
    13 / 91 (14.29%)
         occurrences all number
    8
    3
    13
    5
    18
    Dry mouth
    alternative assessment type: Non-systematic
         subjects affected / exposed
    6 / 61 (9.84%)
    2 / 59 (3.39%)
    8 / 61 (13.11%)
    4 / 30 (13.33%)
    12 / 91 (13.19%)
         occurrences all number
    6
    2
    10
    4
    14
    Stomatitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    4 / 61 (6.56%)
    1 / 59 (1.69%)
    5 / 61 (8.20%)
    3 / 30 (10.00%)
    8 / 91 (8.79%)
         occurrences all number
    4
    2
    5
    5
    10
    Abdominal pain upper
         subjects affected / exposed
    0 / 61 (0.00%)
    4 / 59 (6.78%)
    3 / 61 (4.92%)
    2 / 30 (6.67%)
    5 / 91 (5.49%)
         occurrences all number
    0
    4
    3
    2
    5
    Skin and subcutaneous tissue disorders
    Hair color changes
    alternative assessment type: Non-systematic
         subjects affected / exposed
    41 / 61 (67.21%)
    2 / 59 (3.39%)
    44 / 61 (72.13%)
    25 / 30 (83.33%)
    69 / 91 (75.82%)
         occurrences all number
    46
    2
    53
    39
    92
    Pruritis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    10 / 61 (16.39%)
    2 / 59 (3.39%)
    10 / 61 (16.39%)
    9 / 30 (30.00%)
    19 / 91 (20.88%)
         occurrences all number
    11
    2
    10
    15
    25
    Rash
    alternative assessment type: Non-systematic
         subjects affected / exposed
    8 / 61 (13.11%)
    3 / 59 (5.08%)
    17 / 61 (27.87%)
    8 / 30 (26.67%)
    25 / 91 (27.47%)
         occurrences all number
    9
    4
    28
    13
    41
    Rash maculo-papular
    alternative assessment type: Non-systematic
         subjects affected / exposed
    6 / 61 (9.84%)
    1 / 59 (1.69%)
    10 / 61 (16.39%)
    4 / 30 (13.33%)
    14 / 91 (15.38%)
         occurrences all number
    8
    1
    17
    5
    22
    Erythema
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 59 (0.00%)
    2 / 61 (3.28%)
    6 / 30 (20.00%)
    8 / 91 (8.79%)
         occurrences all number
    0
    0
    3
    10
    13
    Pruritis generalized
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 59 (0.00%)
    6 / 61 (9.84%)
    5 / 30 (16.67%)
    11 / 91 (12.09%)
         occurrences all number
    0
    0
    7
    5
    12
    Dry skin
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    2 / 59 (3.39%)
    5 / 61 (8.20%)
    3 / 30 (10.00%)
    8 / 91 (8.79%)
         occurrences all number
    0
    2
    6
    4
    10
    Alopecia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 59 (0.00%)
    4 / 61 (6.56%)
    2 / 30 (6.67%)
    6 / 91 (6.59%)
         occurrences all number
    0
    0
    4
    2
    6
    Skin hypopigmentation
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 59 (1.69%)
    5 / 61 (8.20%)
    1 / 30 (3.33%)
    6 / 91 (6.59%)
         occurrences all number
    0
    1
    7
    1
    8
    Photosensitivity reaction
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 59 (0.00%)
    3 / 61 (4.92%)
    3 / 30 (10.00%)
    6 / 91 (6.59%)
         occurrences all number
    0
    0
    3
    4
    7
    Rash pruritic
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 59 (1.69%)
    1 / 61 (1.64%)
    2 / 30 (6.67%)
    3 / 91 (3.30%)
         occurrences all number
    0
    1
    1
    3
    4
    Dermatitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    2 / 30 (6.67%)
    2 / 91 (2.20%)
         occurrences all number
    0
    0
    0
    3
    3
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 61 (0.00%)
    2 / 59 (3.39%)
    0 / 61 (0.00%)
    2 / 30 (6.67%)
    2 / 91 (2.20%)
         occurrences all number
    0
    2
    0
    2
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    14 / 61 (22.95%)
    15 / 59 (25.42%)
    19 / 61 (31.15%)
    15 / 30 (50.00%)
    34 / 91 (37.36%)
         occurrences all number
    17
    18
    29
    33
    62
    Pain in extremity
    alternative assessment type: Non-systematic
         subjects affected / exposed
    4 / 61 (6.56%)
    3 / 59 (5.08%)
    9 / 61 (14.75%)
    6 / 30 (20.00%)
    15 / 91 (16.48%)
         occurrences all number
    6
    3
    11
    17
    28
    Back pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 59 (0.00%)
    6 / 61 (9.84%)
    4 / 30 (13.33%)
    10 / 91 (10.99%)
         occurrences all number
    0
    0
    7
    8
    15
    Muscle spasms
         subjects affected / exposed
    2 / 61 (3.28%)
    1 / 59 (1.69%)
    4 / 61 (6.56%)
    1 / 30 (3.33%)
    5 / 91 (5.49%)
         occurrences all number
    2
    1
    6
    1
    7
    Myalgia
         subjects affected / exposed
    1 / 61 (1.64%)
    2 / 59 (3.39%)
    2 / 61 (3.28%)
    4 / 30 (13.33%)
    6 / 91 (6.59%)
         occurrences all number
    1
    2
    2
    7
    9
    Infections and infestations
    Nasopharyngitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    4 / 61 (6.56%)
    3 / 59 (5.08%)
    5 / 61 (8.20%)
    2 / 30 (6.67%)
    7 / 91 (7.69%)
         occurrences all number
    5
    3
    7
    2
    9
    Upper respiratory tract infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 59 (0.00%)
    8 / 61 (13.11%)
    2 / 30 (6.67%)
    10 / 91 (10.99%)
         occurrences all number
    0
    0
    11
    2
    13
    Sinusitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 59 (0.00%)
    5 / 61 (8.20%)
    1 / 30 (3.33%)
    6 / 91 (6.59%)
         occurrences all number
    0
    0
    9
    1
    10
    Cellulitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    3 / 30 (10.00%)
    4 / 91 (4.40%)
         occurrences all number
    0
    0
    1
    3
    4
    Cystitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 59 (1.69%)
    0 / 61 (0.00%)
    2 / 30 (6.67%)
    2 / 91 (2.20%)
         occurrences all number
    0
    1
    0
    3
    3
    Herpes zoster
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    2 / 30 (6.67%)
    2 / 91 (2.20%)
         occurrences all number
    0
    0
    0
    2
    2
    Influenza
         subjects affected / exposed
    0 / 61 (0.00%)
    2 / 59 (3.39%)
    2 / 61 (3.28%)
    4 / 30 (13.33%)
    6 / 91 (6.59%)
         occurrences all number
    0
    2
    3
    5
    8
    Urinary tract infection
         subjects affected / exposed
    0 / 61 (0.00%)
    4 / 59 (6.78%)
    2 / 61 (3.28%)
    2 / 30 (6.67%)
    4 / 91 (4.40%)
         occurrences all number
    0
    5
    2
    6
    8
    Metabolism and nutrition disorders
    Decreased appetite
    alternative assessment type: Non-systematic
         subjects affected / exposed
    10 / 61 (16.39%)
    6 / 59 (10.17%)
    11 / 61 (18.03%)
    3 / 30 (10.00%)
    14 / 91 (15.38%)
         occurrences all number
    13
    6
    15
    4
    19
    Hypercholesterolemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    5 / 61 (8.20%)
    0 / 59 (0.00%)
    7 / 61 (11.48%)
    4 / 30 (13.33%)
    11 / 91 (12.09%)
         occurrences all number
    8
    0
    20
    7
    27
    Fluid retention
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 59 (0.00%)
    3 / 61 (4.92%)
    2 / 30 (6.67%)
    5 / 91 (5.49%)
         occurrences all number
    0
    0
    6
    5
    11
    Hyperglycemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 59 (1.69%)
    1 / 61 (1.64%)
    2 / 30 (6.67%)
    3 / 91 (3.30%)
         occurrences all number
    0
    1
    1
    2
    3
    Hypertriglyceridaemia
         subjects affected / exposed
    0 / 61 (0.00%)
    4 / 59 (6.78%)
    2 / 61 (3.28%)
    2 / 30 (6.67%)
    4 / 91 (4.40%)
         occurrences all number
    0
    5
    4
    3
    7
    Hypophosphataemia
         subjects affected / exposed
    3 / 61 (4.92%)
    1 / 59 (1.69%)
    3 / 61 (4.92%)
    2 / 30 (6.67%)
    5 / 91 (5.49%)
         occurrences all number
    3
    1
    6
    3
    9

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Dec 2014
    Clarified treatment procedures (e.g. maximum number of cycles) of pexidartinib, revised inclusion and exclusion criteria, modified sample size, updated treatment composition, and clarified dose modification guidelines.
    11 Feb 2015
    Revised inclusion criteria, clarified blinding/unblinding procedures, updated list of participating countries, clarified location of Schedule of Events, updated medical monitor, and updated assessment methods.
    25 Mar 2016
    Updated formulation of pexidartinib, clarified inclusion and exclusion criteria, revised study assessments, clarified study procedures, and updated efficacy endpoints and dose modification guidelines.
    19 Jul 2016
    Revised study procedures and statistical analyses, updated efficacy endpoints, and clarified unblinding procedures.
    10 Oct 2016
    Updated Risk Information and Change in Study Conduct section and new safety data and measures were included.
    10 Feb 2017
    Clarified study inclusion and exclusion criteria, updated methods for pharmacogenomics analysis, clarified criteria of completion for assessments, clarified study procedures for subjects who complete Part 2, and updated MedDRA version reference.
    11 Sep 2017
    Sequential hierarchy of the secondary efficacy endpoints was changed and the medical monitor was updated.
    15 Dec 2017
    Updated safety data for pexidartinib and revised the criteria for pexidartinib dose modification.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    30 Sep 2016
    Enrollment was stopped; no new subjects were permitted to start the study drug. Subjects on placebo in Part 1 were no longer allowed to enter Part 2 to receive open-label pexidartinib. After Part 1 was completed, subjects who wished to continue onto the open-label part of the study (Part 2) were unblinded and those on placebo were discontinued. Investigators and subjects were informed of the new safety information and decided whether to continue in the study. The frequency of liver function testing was increased and gamma-glutamyl transpeptidase was added to the laboratory panel. These changes were implemented in the protocol version 6.0 dated 10 Oct 2016.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Enrollment was stopped on 30 Sep 2016; no new subjects received the study drug. After Part 1, those who wished to continue were un-blinded; those on placebo were discontinued.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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