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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
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

Collapse all Expand all

Trial information

Top of page

Sponsor protocol code

PLX108-10

ISRCTN number

-

US NCT number

NCT02371369

WHO universal trial number (UTN)

-

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

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

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

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

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

Top of page

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.

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 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.

Are arms mutually exclusive

Yes

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.

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 title

Part 2 (open-label phase)

Is this the baseline period?

No

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

No

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.

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

Top of page

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 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

Top of page

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

Top of page

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

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

Top of page

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 )

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

Top of page

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

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

Top of page

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 )

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

Top of page

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 )

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

Top of page

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

Top of page

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

Top of page

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

Top of page

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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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 name

MedDRA

Dictionary version

17.1

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

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Were there any global substantial amendments to the protocol? Yes

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.

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 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.

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