Clinical trial NCT02371369
Conditions: Pigmented Villonodular Synovitis Giant Cell Tumors of the Tendon Sheath Tenosynovial Giant Cell Tumor
Keywords: PLX3397 Pexidartinib Colony Stimulating Factor 1 Receptor (CSF-1R) inhibitor
Sponsor: Daiichi Sankyo
Start date: 2015-05-11; Completion date: 2021-04-30
Enrollment: 120 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This is a Phase 3 clinical study, which aims to evaluate the effectiveness of an investigational drug called pexidartinib for the treatment of certain tumors for which surgical removal could cause more harm than good.

The main purpose of this study is to gather information about the investigational drug pexidartinib, which may help to treat tumors of pigmented villonodular synovitis (PVNS) or giant cell tumor of the tendon sheath (GCT-TS).

The study consists of two parts with a follow-up period. In Part 1, eligible study participants will be assigned to receive either pexidartinib or matching placebo for 24 weeks. A number of assessments will be carried out during the course of the study, including physical examinations, blood tests, imaging studies, electrocardiograms, and questionnaires. MRI scans will be used to evaluate the response of the tumors to the treatment. Some subjects, assigned to placebo in Part 1 transitioned to pexidartinib for Part 2.

Then a protocol amendment was written to allow only pexidartinib patients to continue into Part 2. Part 2 is a long-term treatment phase in which all participants receive open-label pexidartinib. There was also a follow-up period added to Part 2.

Detailed description:

Arms: arm 1: Participants received blinded treatment of pexidartinib,1000 mg (5 capsules per day ) for 2 weeks, then 800 mg (4 capsules per day) for 22 weeks arm 2: Participants received blinded treatment of matching placebo (5 capsules per day) for 2 weeks, then matching placebo (4 capsules per day) for 22 weeks arm 3: Participants received pexidartinib in Part 1 and in Part 2 at their prescribed dose arm 4: Participants received placebo in Part 1 and pexidartinib in Part 2 at their prescribed dose
Interventions: intervention 1: Pexidartinib intervention 2: Placebo
Intervention descriptions: intervention 1: Each capsule contains 200 mg of pexidartinib for oral administration intervention 2: Placebo capsule matching pexidartinib capsule for oral administration

Protocol documents:
Prot_SAP_001.pdf: 
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CLINICAL STUDY PROTOCOL 
Protocol Number: 
PLX108-10 
 
 
Title: 
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 (ENLIVEN) 
  
Indication: 
Pigmented villonodular synovitis (PVNS) / giant cell tumor of 
the tendon sheath (GCT-TS) 
 
 
Phase: 
3 
 
 
Sponsor: 
 
Daiichi Sankyo, Inc. 
211 Mount Airy Road 
Basking Ridge, NJ 07920, USA 
 
 
EudraCT Number: 
2014-000148-14 
 
 
Therapeutic Area: 
Antineoplastic agent 
 
 
IND Number: 
117,332 
 
 
Version: 
Superseded Versions: 
10.0, 22 Jan 2020 
9.0, 15 Dec 2017 
8.0, 11 Sep 2017 
7.0, 10 Feb 2017 
6.0, 10 Oct 2016 
5.0, 19 Jul 2016 
4.0, 25 Mar 2016 
 
3.0, 11 Feb 2015  
2.0, 05 Dec 2014 
Original Protocol: 
1.0, 18 Sep 2014 
  
CONFIDENTIALITY STATEMENT 
Information contained in this document is proprietary to Daiichi Sankyo Inc. (DSI). The 
information is provided to you in confidence which is requested under an agreed upon and signed 
Confidentiality and Disclosure Agreement. Do not give this document or any copy of it or reveal 
any proprietary information contained in it to any third party (other than those in your 
organization who are assisting you in this work and are bound by the Confidentiality and 
Disclosure Agreement) without the prior written permission of an authorized representative of 
DSI. 




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TABLE OF CONTENTS 
INVESTIGATOR AGREEMENT...................................................................................................2 
GLOBAL AMENDMENT, PROTOCOL V 10.0 .........................................................................12 
LIST OF ABBREVIATIONS ........................................................................................................13 
PROTOCOL SYNOPSIS ..............................................................................................................16 
1. 
INTRODUCTION AND BACKGROUND INFORMATION .......................................26 
1.1. 
Scientific Background .....................................................................................................26 
1.1.1. 
Pigmented Villonodular Synovitis and Giant Cell Tumors of the Tendon Sheath .........26 
1.1.2. 
Pexidartinib (PLX3397) ..................................................................................................27 
1.2. 
Nonclinical Studies ..........................................................................................................27 
1.3. 
Clinical Experience .........................................................................................................27 
1.3.1. 
Subjects with PVNS/GCT-TS Treated in Study PLX108-01 ..........................................29 
1.4. 
Study Rationale ...............................................................................................................30 
1.4.1. 
Study Purpose ..................................................................................................................31 
1.5. 
Risks and Benefits for Study Subjects .............................................................................32 
1.6. 
Updated Risk Information and Change in Study Conduct ..............................................33 
2. 
STUDY OBJECTIVES AND HYPOTHESIS ................................................................35 
2.1. 
Study Objectives ..............................................................................................................35 
2.2. 
Study Endpoints ...............................................................................................................35 
2.2.1. 
Primary Efficacy Endpoint ..............................................................................................35 
2.2.2. 
Secondary Efficacy Endpoints ........................................................................................37 
2.2.3. 
Additional Endpoints .......................................................................................................39 
2.3. 
Study Hypothesis .............................................................................................................40 
3. 
STUDY DESIGN ............................................................................................................41 
3.1. 
Overall Plan .....................................................................................................................41 
3.2. 
Number of Subjects .........................................................................................................45 
3.3. 
Duration of Study ............................................................................................................45 
4. 
STUDY POPULATION ..................................................................................................46 
4.1. 
Enrollment .......................................................................................................................46 
4.1.1. 
Inclusion Criteria .............................................................................................................46 
4.1.2. 
Exclusion Criteria ............................................................................................................47 
4.2. 
Removal of Subject From Therapy .................................................................................48 


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4.2.1. 
Reasons for Withdrawal/Early Discontinuation ..............................................................48 
4.2.2. 
Withdrawal Procedures ...................................................................................................48 
4.2.3. 
Subject Replacement .......................................................................................................49 
4.3. 
Subject Re-screening Procedures ....................................................................................49 
5. 
TREATMENTS ADMINISTERED ................................................................................50 
5.1. 
Investigational Products ..................................................................................................50 
5.2. 
Study Treatment Administration .....................................................................................50 
5.3. 
Dose Modification Guidelines .........................................................................................51 
5.3.1. 
Renal Impairment ............................................................................................................54 
5.4. 
Concomitant Medications ................................................................................................54 
5.4.1. 
CYP3A and UGT Inhibitors ............................................................................................54 
5.4.2. 
Hormonal Contraceptives ................................................................................................55 
5.4.3. 
Acid-reducing Agents ......................................................................................................55 
5.5. 
Precautions and Restrictions ............................................................................................55 
5.6. 
Blinding and Unblinding .................................................................................................55 
5.6.1. 
Unblinding .......................................................................................................................56 
5.6.1.1. Emergency Unblinding ....................................................................................................56 
5.6.1.2. Unblinding during Part 1 Week 13 to Week 25 for Disease Progression .......................56 
5.6.1.3. Unblinding at the End of Part 1 .......................................................................................57 
5.7. 
Description of Investigational Agents .............................................................................57 
5.8. 
Packaging and Labeling ..................................................................................................58 
5.9. 
Storage, Handling, and Accountability ...........................................................................58 
6. 
STUDY CONDUCT .......................................................................................................60 
6.1. 
Study Personnel and Organizations .................................................................................60 
6.2. 
Recruitment of Subjects ..................................................................................................60 
6.3. 
Treatment Group Assignments ........................................................................................60 
6.4. 
Study Procedures .............................................................................................................60 
6.4.1. 
Demographics and Medical History ................................................................................61 
6.4.2. 
Vital Signs and Subject Weight .......................................................................................61 
6.4.3. 
Physical Examination ......................................................................................................61 
6.4.4. 
Range of Motion Assessment ..........................................................................................61 
6.4.5. 
Electrocardiogram ...........................................................................................................61 
6.4.6. 
Echocardiogram ...............................................................................................................62 


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6.4.7. 
Clinical Laboratory Evaluations ......................................................................................62 
6.4.8. 
Patient Reported Outcome Instruments ...........................................................................64 
6.4.8.1. Most Disturbing Symptom Assessment ..........................................................................64 
6.4.8.2. BPI Worst Pain NRS Item ...............................................................................................64 
6.4.8.3. Worst Stiffness NRS item ...............................................................................................64 
6.4.8.4. PROMIS Physical Function Scale ...................................................................................64 
6.4.8.5. EQ-5D-5L ........................................................................................................................65 
6.4.8.6. Patient Global Impression of Change and Global Rating of Concept Items ...................65 
6.4.9. 
Tumor Imaging ................................................................................................................65 
6.4.10. Surgical Assessment Questionnaire ................................................................................66 
6.4.11. Surgical Data and Outcome Follow-up ...........................................................................66 
6.4.12. Analgesic Use and Analgesic Regimen ...........................................................................66 
6.4.13. Healthcare Resource Use and Productivity .....................................................................67 
6.4.14. Pregnancy Test ................................................................................................................67 
6.4.15. Pharmacodynamic Sampling ...........................................................................................67 
6.4.16. Pharmacokinetic (PK) Sampling .....................................................................................67 
6.4.17. Adverse Events ................................................................................................................68 
6.4.18. Study Treatment Compliance ..........................................................................................68 
6.5. 
Study Procedures .............................................................................................................69 
7. 
STATISTICAL METHODS ...........................................................................................70 
7.1. 
Randomization and Stratification ....................................................................................70 
7.2. 
Analysis Sets ...................................................................................................................70 
7.3. 
Procedures for Handling Missing, Unused, and Spurious Data ......................................70 
7.4. 
General Statistical Considerations ...................................................................................70 
7.5. 
Study Population Data .....................................................................................................71 
7.6. 
Efficacy Analyses ............................................................................................................71 
7.6.1. 
Primary Efficacy Analysis ...............................................................................................71 
7.6.2. 
Secondary Efficacy Analyses ..........................................................................................71 
7.6.3. 
Additional Efficacy Analyses ..........................................................................................73 
7.6.4. 
Subgroup Analyses ..........................................................................................................75 
7.7. 
Pharmacodynamics/Biomarkers ......................................................................................75 
7.8. 
Pharmacogenomic Analysis ............................................................................................75 
7.8.1. 
Genomic or Genetic Banking and Analysis ....................................................................75 


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7.8.1.1. Disclosure of the Results of Genomic or Genetic Analysis ............................................76 
7.8.1.2. Storage and Disposal of Specimens for Genomic or Genetic Banking and 
Analysis ...........................................................................................................................76 
7.9. 
Pharmacokinetics and Exposure–Response Analyses .....................................................76 
7.10. 
Safety Analysis ................................................................................................................76 
7.10.1. Analysis of Treatment-emergent Adverse Events ...........................................................77 
7.10.2. Clinical Laboratory Evaluation Analyses ........................................................................77 
7.10.3. Vital Sign Analyses .........................................................................................................77 
7.10.4. Electrocardiogram Analyses ............................................................................................78 
7.10.5. Echocardiogram Analyses ...............................................................................................78 
7.10.6. Analysis of Physical Examination Findings ....................................................................78 
7.10.7. Concomitant Medication Analyses ..................................................................................78 
7.11. 
Data Monitoring Committee ............................................................................................78 
7.12. 
Sample Size Determination .............................................................................................78 
8. 
ETHICAL CONSIDERATIONS ....................................................................................80 
9. 
SAFETY ASSESSMENT ...............................................................................................81 
9.1. 
Reporting Adverse Events and Serious Adverse Events .................................................81 
9.2. 
Definitions .......................................................................................................................82 
9.2.1. 
Adverse Event .................................................................................................................82 
9.2.2. 
Serious Adverse Event ....................................................................................................82 
9.2.3. 
Adverse Event Severity ...................................................................................................82 
9.2.4. 
Causality Assessment ......................................................................................................83 
9.2.5. 
Action Taken Regarding the Study Treatment ................................................................83 
9.2.6. 
Adverse Event Outcome ..................................................................................................84 
9.2.7. 
Other Action Taken for Event .........................................................................................84 
9.3. 
Serious Adverse Event Reporting Procedure for Investigators .......................................84 
9.3.1. 
Reporting by Investigators ..............................................................................................84 
9.3.2. 
Notifying Regulatory Authorities, Investigators, and Institutional Review 
Boards/Institutional Ethics Committees ..........................................................................85 
9.4. 
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events .............85 
10. 
STUDY ADMINISTRATIVE INFORMATION ............................................................86 
10.1. 
Study Contacts .................................................................................................................86 
10.1.1. Sponsor ............................................................................................................................86 


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10.1.2. Medical Monitor ..............................................................................................................86 
10.1.2.1. Sponsor Medical Monitor ................................................................................................86 
10.1.2.2. Contract Research Organization Medical Monitor ..........................................................86 
10.1.3. SAE Reporting Contact ...................................................................................................86 
11. 
ADMINISTRATIVE REQUIREMENTS .......................................................................87 
11.1. 
Good Clinical Practice .....................................................................................................87 
11.2. 
Data Quality Assurance ...................................................................................................87 
11.3. 
Electronic Case Report Form Completion ......................................................................87 
11.4. 
Data Management ............................................................................................................87 
11.5. 
Study Monitoring .............................................................................................................88 
11.6. 
Subject Information and Informed Consent ....................................................................88 
11.7. 
Subject Confidentiality ....................................................................................................88 
11.8. 
Investigator Compliance ..................................................................................................88 
11.9. 
On-site Audits ..................................................................................................................89 
11.10. 
Investigator and Site Responsibility for Drug Accountability ........................................89 
11.11. 
Product Complaints .........................................................................................................89 
11.12. 
Study Closure ..................................................................................................................89 
11.13. 
Study Documentation and Storage ..................................................................................90 
11.14. 
Record Retention .............................................................................................................90 
11.15. 
Record Keeping ...............................................................................................................91 
12. 
FINANCING AND INSURANCE ..................................................................................92 
12.1. 
Finances ...........................................................................................................................92 
12.2. 
Reimbursement, Indemnity, and Insurance .....................................................................92 
13. 
USE OF INFORMATION ..............................................................................................93 
14. 
REFERENCES ................................................................................................................94 
15. 
APPENDICES .................................................................................................................97 
15.1. 
List of Common CYP3A4 Inhibitors and Inducers .........................................................97 
15.2. 
Detailed Study Procedures by Visit — Part 1 .................................................................97 
15.2.1. Screening (Day –42 to Day –1) .......................................................................................97 
15.2.2. Part 1 – Cycle 1 (Randomization) ...................................................................................99 
15.2.3. Part 1–Cycle 1, Day 1 (P1-C1D1; Week 1) ....................................................................99 
15.2.4. Part 1–Cycle 1, Day 8 (P1-C1D8; Week 2) ± 2 days ....................................................101 
15.2.5. Part 1–Cycle 1, Day 15 (P1-C1D15; Week 3) ± 2 days ................................................101 


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15.2.6. Part 1–Cycle 1, Day 22 (P1-C1D22; Week 4) ± 2 days ................................................101 
15.2.7. Part 1–Cycle 2, Day 1 (P1-C2D1; Week 5) ± 2 days ....................................................102 
15.2.8. Part 1–Cycle 2, Day 8 (P1-C2D8; Week 6) ± 2 days ....................................................102 
15.2.9. Part 1–Cycle 2, Day 15 (P1-C2D15; Week 7) ± 2 days ................................................102 
15.2.10. Part 1–Cycle 2, Day 22 (P1-C2D22; Week 8) ± 2 days ................................................102 
15.2.11. Part 1–Cycle 3, Day 1 (P1-C3D1; Week 9) ± 7 days ....................................................102 
15.2.12. Part 1–Cycle 3, Day 15 (P1-C3D15; Week 11) ± 7 days ..............................................103 
15.2.13. Part 1–Cycle 4, Day 1 (P1-C4D1; Week 13) ± 7 days ..................................................103 
15.2.14. Part 1–Cycle 5, Day 1 (P1-C5D1; Week 17) ± 7 days ..................................................104 
15.2.15. Part 1–Cycle 6, Day 1 (P1-C5D1; Week 21) ± 7 days ..................................................104 
15.2.16. Part 1 Completion visit/Early Termination Visit (Week 25) ± 7 days ..........................105 
15.2.17. Part 1 28 Day Post-Treatment Visit (last dose + 28 days) ± 7 days ..............................106 
15.2.18. Part 1 End-of-Study/12 Week Post-Treatment Visit (12 weeks ± 7 days after the 
last dose) ........................................................................................................................107 
15.3. 
Detailed Study Procedures by Visit — Part 2 ...............................................................108 
15.3.1. Part 2–Cycle 1, Day 1 (P2-C1D1; Week 25) ................................................................108 
15.3.2. Part 2–Cycle 1, Day 8 (P2-C1D8; Week 26) ± 2 days ..................................................109 
15.3.3. Part 2–Cycle 1, Day 15 (P2-C1D15; Week 27) ± 2 days ..............................................109 
15.3.4. Part 2–Cycle 1, Day 22 (P2-C1D22; Week 28) ± 2 days ..............................................110 
15.3.5. Part 2–Cycle 2, Day 1 (P2-C2D1; Week 29) ± 2 days ..................................................110 
15.3.6. Part 2–Cycle 2, Day 8 (P2-C2D8; Week 30) ± 2 days ..................................................110 
15.3.7. Part 2–Cycle 2, Day 15 (P2-C2D15; Week 31) ± 2 days ..............................................111 
15.3.8. Part 2–Cycle 2, Day 22 (P2-C2D22; Week 32) ± 2 days ..............................................111 
15.3.9. Part 2–Cycle 3, Day 1 (P2-C3D1; Week 33) ± 7 days ..................................................111 
15.3.10. Part 2–Cycle 3, Day 15 (P2-C3D15; Week 35) ± 7 days ..............................................111 
15.3.11. Part 2–Cycle 4, Day 1 (P2-C4D1; Week 37) ± 7 days ..................................................111 
15.3.12. Part 2–Cycle 5, Day 1 (P2-C5D1; Week 41) ± 7 days ..................................................112 
15.3.13. Part 2–Cycle 6, Day 1 (P2-C6D1; Week 45) ± 7 days ..................................................112 
15.3.14. Part 2–Cycle 7, Day 1 (P2-C7D1; Week 49) ± 7 days ..................................................113 
15.3.15. Part 2–Cycle 10+, Day 1 (P2-C10+D1; Week 61+) ± 7 days .......................................114 
15.3.16. Post-Treatment Visit (Part 2) .........................................................................................115 
15.3.17. End-of-Study or Early Termination Visit ......................................................................116 
15.4. 
Detailed Study Procedures by Visit — Surgical Outcome ............................................116 


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15.4.1. Four weeks Prior to Surgery ..........................................................................................117 
15.4.2. During or shortly after Surgery .....................................................................................117 
15.4.3. 4 Months (± 2 weeks) after Surgery ..............................................................................117 
15.4.4. 8, 12, 18, and 24 Months (± 2 weeks) after Surgery .....................................................118 
15.5. 
Brief Pain Inventory (BPI) Worst Pain Numeric Rating Scale (NRS) Item .................118 
15.6. 
Worst Stiffness NRS item .............................................................................................118 
15.7. 
PROMIS Physical Function Scale .................................................................................119 
15.8. 
EQ-5D-5L ......................................................................................................................122 
15.9. 
Patient Global Impression of Change and Rating of Concept Items .............................125 
15.10. 
Surgical Assessment Questionnaire ..............................................................................126 
15.11. 
Employment status and productivity questions .............................................................126 
15.12. 
Healthcare  Resource Use Questions .............................................................................128 
15.13. 
Schedule of Events ........................................................................................................130 
 


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LIST OF TABLES 
Table 2.1: Definitions of Response for the Primary Efficacy Endpoint ......................................36 
Table 5.1: Dose Modification Guidelines for Treatment-emergent Toxicities ............................52 
Table 5.2: Additional Liver Evaluation .......................................................................................53 
Table 5.3: Recommended Dosage Reductions for Pexidartinib with Concomitant Use of 
Moderate or Strong CYP3A Inhibitors or UGT Inhibitors .........................................55 
Table 6.1: PK Schedules ..............................................................................................................68 
Table 15.1: Sample Surgical Assessment Questionnaire .............................................................126 
Table 15.2: Schedule of Events – Part 1 (Blinded, Placebo-controlled Phase) ...........................131 
Table 15.3: Schedule of Events – Part 2 (Open-label Phase) ......................................................137 
Table 15.4: Schedule of Events – For Subjects Who Undergo Surgical Resection ....................141 
 


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LIST OF FIGURES 
Figure 3.1: Study Schematic* ........................................................................................................42 
Figure 3.2: Post-treatment Assessments Vary With Reason for Study Withdrawal* ....................44 
 
 


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GLOBAL AMENDMENT, PROTOCOL V 10.0 
Amendment Rationale: 
The main purpose of this amendment is to update the safety information for pexidartinib and to 
revise the dose modification criteria 
Changes to the Protocol: 
Please refer to the comparison document for protocol version 9.0 (dated 15 Dec 2017) vs. 
protocol version 10.0 (dated 22 Jan 2020) for actual changes in-text. The summary of changes 
below is a top-line summary of major changes in the PLX108-10 clinical study protocol 
(Version 10.0) by section. 
DESCRIPTION OF EACH HIGH-LEVEL CHANGE 
1 
Added option of transition to commercial pexidartinib for reason for withdrawal 
from study. 
The following sections of the protocol were updated: 
 Section 4.2.1 (Reasons for Withdrawal/Early Discontinuation) 
2 
Updated dose modification guidelines.  Added additional guidelines for subjects 
with renal impairment. 
The following sections of the protocol were updated: 
 Section 5.3 (Dose Modification Guidelines) 
 Section 5.3.1 (Renal Impairment) 
3 
Updated guidelines for concomitant dosing of CYP3A/UGT inhibitors, hormonal 
contraceptives, and proton-pump inhibitors. 
The following sections of the protocol were updated: 
 Section 5.4.1 (CYP3A and UGT Inhibitors/Inducers) 
 Section 5.4.2 (Hormonal Contraceptives) 
 Section 5.4.3 (Acid-reducing Agents) 
4 
Updated study contacts. 
The following section of the protocol was updated: 
 Section 10.1 (Study Contacts) 


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LIST OF ABBREVIATIONS 
Abbreviation or Term 
Definition/Explanation 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AML 
Acute myeloid leukemia 
AST 
Aspartate aminotransferase 
AUCss 
Area under the time–concentration curve at steady state 
BPI 
Brief Pain Inventory 
Cav 
Average concentration 
CI 
Confidence Interval 
Cmax 
Peak concentration 
CR 
Complete response 
CSF-1 
Colony stimulating factor 1 
CSF1R 
Receptor for Colony stimulating factor 1 
CTCAE 
Common Toxicity Criteria for Adverse Events 
Ctrough 
Minimum concentration 
CVA 
Cerebrovascular accident 
CYP 
Cytochrome P450 
DMC 
Data Monitoring Committee 
DSI 
Daiichi Sankyo, Inc. 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EIU 
Exposure in utero 
EQ-5D-5L 
EuroQol five-dimensional descriptive system 
EU 
European Union 
Flt3 
fms-like tyrosine kinase 3 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GCT-TS 
Giant cell tumor of the tendon sheath 


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Abbreviation or Term 
Definition/Explanation 
GGT 
Gamma-glutamyl transpeptidase 
HCl 
Hydrochloride 
HCRU 
Healthcare resource use 
HCV 
Hepatitis C virus 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
IEC 
Independent ethics committee 
INR 
International normalized ratio 
IRB 
Institutional review board 
ITT 
Intent-to-Treat 
LH 
Luteinizing hormone 
MedDRA 
Medical Dictionary for Drug Regulatory Activities 
Mg 
Milligram 
MMRM 
Mixed models for repeated measurements 
MRI 
Magnetic resonance imaging; magnetic resonance image 
MUGA 
Multi-gated acquisition 
NCI 
National Cancer Institute 
NOAEL 
No Observed Adverse Effect Level 
NRS 
Numeric rating scale 
OTC 
Over-the-counter 
PD 
Progressive disease 
PDy 
Pharmacodynamic(s) 
PGx 
Pharmacogenomic 
PK 
Pharmacokinetic(s) 
PopPK 
Pooled population pharmacokinetic 
PR 
Partial response 
PRO 
Patient-reported outcome 
PROMIS 
Patient-reported Outcomes Measurement Information System 
PT 
Preferred term 
PVNS 
Pigmented villonodular synovitis 
QD 
Once daily 
QTc 
Corrected QT interval  


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Abbreviation or Term 
Definition/Explanation 
QTcF 
Fridericia corrected QT interval  
RAMRIS 
Rheumatoid Arthritis MRI Score 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
Ribonucleic acid 
ROM 
Range of motion 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SAVER 
Serious adverse event report 
SD 
Stable disease 
SOC 
System organ class 
SSD 
Sum of the short-axis dimension 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
TGCT 
Tenosynovial giant cell tumor 
TVS 
Tumor Volume Score 
ULN 
Upper limit of normal 
US 
United States 
WORMS 
Whole Organ MRI Score 


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PROTOCOL SYNOPSIS 
EudraCT No. 
2014-000148-14 
IND 
No. 
117,332 
Protocol 
No. 
PLX108-10 
Investigational 
Product 
Pexidartinib (PLX3397)  
Active Ingredient(s) 
INN 
Pexidartinib 
(PLX3397) 
Study Title 
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 (ENLIVEN) 
Study Phase 
3 
Indication 
Under 
Investigation 
Pigmented villonodular synovitis (PVNS) / giant cell tumor of the tendon 
sheath (GCT-TS), also known as tenosynovial giant cell tumors (TGCT), 
localized and diffuse types, according to the 2013 World Health 
Organization classification system. 
Study 
Objectives 
The primary objective of this study is to compare the response rate of 
pexidartinib 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 PVNS or GCT-TS.  
The secondary efficacy objectives are to evaluate:  (i) patient-reported 
outcomes (PROs), including the Brief Pain Inventory (BPI) Worst Pain 
Numeric Rating Scale (NRS) item, Patient-reported Outcomes 
Measurement Information System (PROMIS) Physical Function Scale, 
and Worst Stiffness NRS item, at Week 25; (ii) response based on 
Tumor Volume Score (TVS) at Week 25; (iii) range of motion (ROM) at 
Week 25; and (iv) duration of response. 
Other objectives are to evaluate:  (i) other measures of efficacy, (ii) 
long-term safety, (iii) pharmacokinetics (PK), and 
(iv) pharmacodynamics (PDy) of pexidartinib in treated subjects. 
Study Design 
This trial is a two-part multi-center Phase 3 study in subjects with 
symptomatic PVNS or GCT-TS for whom surgical resection would be 
associated with potentially worsening functional limitation or severe 
morbidity (locally advanced disease). In Part 1, the double-blind phase, 
eligible candidates will be centrally randomized in a 1:1 ratio to receive 
either pexidartinib or placebo for 24 weeks. Randomization will be 
stratified by US versus non-US sites and by upper extremity vs. lower 
extremity involvement. 
Subjects will take five capsules a day (1000 mg/d pexidartinib or 


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matching placebo) divided into a morning dose of two capsules and an 
evening dose of three capsules for the first 2 weeks in Part 1. Thereafter, 
the dose will be reduced to four capsules a day (800 mg/d pexidartinib or 
matching placebo) divided equally between the morning and evening 
doses. Doses will be taken in the fasting state at approximately the same 
times of the day and approximately 12 hours apart. Each treatment cycle 
is 28 days and subjects will be treated for up to 6 Cycles. Dose 
reductions, interruptions, and re-escalations after previous reductions for 
toxicity are permitted according to pre-specified guidelines. Those 
subjects, whether on pexidartinib or matching placebo, who complete 
Part 1 (ie, complete 24 weeks of dosing and the Week 25 assessments) 
will be eligible to advance to Part 2, a long-term treatment phase where 
all subjects will receive open-label pexidartinib at a maximum starting 
dose of four capsules a day (800 mg/d pexidartinib). Effective 30 Sep 
2016, per study Data Monitoring Committee (DMC) recommendation, 
subjects on placebo are no longer allowed into Part 2 to receive open-
label pexidartinib. 
MRIs will be performed at Week 13 (Cycle 4, Day 1 visit of Part 1) and 
Week 25. For those subjects who undergo surgical resection, an MRI 
will be performed 4 months after surgery. All MRI scans will be 
assessed by central readers blinded to treatment assignment and other 
clinical study data during both Parts 1 and 2 of the study, according to 
procedures outlined in a separate MRI Imaging Charter. The central 
MRI assessment report of progression status will not be provided unless 
the Investigator requests an expedited central review of a scan. 
If disease progression is indicated clinically or by local radiologic 
assessment according to RECIST 1.1 at or after Week 13 but before 
Week 25, the Investigator may request a central review for evaluation of 
disease progression. If a central reading confirms RECIST 1.1-defined 
disease progression, treatment assignment will be unblinded, and 
subjects receiving placebo will be eligible for early entry into Part 2 of 
the study. Effective 30 Sep 2016, subjects receiving placebo will be 
discontinued instead of being eligible to enter Part 2. Subjects receiving 
pexidartinib will be discontinued from the study unless the Investigator 
and the Sponsor’s Medical Monitor judge that the subject would 
potentially benefit from continued treatment with pexidartinib. During 
Parts 1 & 2 of the protocol, the Investigator may request an expedited 
central review of a scan locally assessed as disease progression 
according to RECIST 1.1.  
All subjects in Part 2 will continue to receive open-label pexidartinib 
until all subjects have either reached at least the Week 49 visit (ie, an 
additional 24 weeks of open-label pexidartinib treatment beyond the 
placebo-controlled phase) or withdrawn from the trial. Those subjects 
who complete Part 2 will be eligible to continue for longer efficacy and 


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safety follow-up or to enter a separate protocol to continue receiving 
pexidartinib.  
For statistical analysis of endpoints at the end of Part 1, a clinical data 
cut-off date will be defined for the point when all randomized subjects 
complete or are discontinued from Part 1 with appropriate End of Part 1 
follow-up. All data up to this date will be cleaned. Unblinding of 
database will be performed to facilitate the data analyses, including the 
data from the double-blind Part 1 and available data from Part 2. Such 
unblinding is only intended for the sponsor and the Contract Research 
Organization. Subjects who entered Part 2 may continue to receive open-
label pexidartinib treatment. Updated analysis of Part 2 data only, in the 
form of summary and descriptive statistics, will be performed at the end 
of the trial.  Additional updates between the above-mentioned cut-off 
and end of the trial may also be performed. 
A range-of-motion assessment in the affected joint or tumor location 
will be performed by an independent and blinded third party assessor at 
specified time points. PRO instruments will also be completed at 
specified time points. 
Ongoing safety will be monitored by an independent DMC according to 
a separate charter. 
Subjects who end their study participation early with no radiologic 
disease progression will undergo:  (i) the 28 Day Post-treatment Visit 
assessment with an MRI 28 ± 7 days after their last dose of study 
treatment; and (ii) a final MRI 12 weeks ± 7 days after their last dose of 
study treatment or before any new PVNS therapy, including surgery, 
whichever occurs first (the “Part 1 End-of-Study/12 Week Post-
Treatment Visit”). After completion of the end of Part 1 assessments 
(Part 1 Completion visit/Early Termination visit), subjects who wish to 
continue onto the open label part of this study (Part 2) will be unblinded 
and those on placebo will be discontinued; subjects on pexidartinib in 
Part 1 may continue into Part 2 to continue to receive pexidartinib. 
Subjects who complete Part 2 and choose to enter a separate protocol to 
continue receiving pexidartinib will not have the Post-treatment and 
End-of-Study Visit assessments. Subjects who terminate the study with 
radiologic disease progression will undergo the Post-treatment Visit 
assessment without an MRI 28 ± 7 days after their last dose of study 
treatment or before any new PVNS therapy, including surgery, 
whichever occurs first.  
Subjects are allowed to undergo surgical resection of their tumor after 
the completion of Part 1. For subjects who undergo surgical resection 
within 12 weeks after their last dose of study treatment, they will not 
have the End-of-Study Visit assessments but will follow a separate visit 
schedule after the decision of surgery is made. The surgery is 
recommended to be performed 1-3 weeks after the last dose of study 


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treatment. Details of the surgery and its short and long term outcome 
will be collected. Data collection for the surgery and its outcome may 
continue in a separate protocol.  
Inclusion 
Criteria 
1. Age ≥ 18 years. 
2. A diagnosis of PVNS or GCT-TS (i) that has been histologically 
confirmed either by a pathologist at the treating institution or a 
central pathologist, and (ii) where surgical resection would be 
associated with potentially worsening functional limitation or 
severe morbidity (locally advanced disease), with morbidity 
determined consensually by qualified personnel (eg, two 
surgeons or a multi-disciplinary tumor board). 
3. Measurable disease as defined by RECIST 1.1 (except that a 
minimal size of 2 cm is required), assessed from MRI scans by a 
central radiologist. 
4. Symptomatic disease because of active PVNS or GCT-TS, 
defined as one or more of the following: 
a. a worst pain of at least 4 at any time during the week 
preceding the Screening Visit (based on scale of 0 to 10, with 
10 representing “pain as bad as you can imagine”).  
b. a worst stiffness of at least 4 at any time during the week 
preceding the Screening Visit (based on a scale of 0 to 10, 
with 10 representing “stiffness as bad as you can imagine”). 
5. Stable prescription of analgesic regimen during the 2 weeks prior 
to randomization. 
6. During the 2 weeks prior to randomization, at least 4 of 7 
consecutive days of BPI Worst Pain NRS items and Worst 
Stiffness NRS items completed correctly. 
7. Women of childbearing potential must have a negative serum 
pregnancy test within the14-day period prior to randomization. 
(Where demanded by local regulations, this test may be required 
within 72 hours of randomization.) 
8. Males and females of childbearing potential are permitted in the 
study so long as they consent to avoid getting their partner 
pregnant or becoming pregnant, respectively, by using a highly 
effective contraception method, as described below, throughout 
the study and for up to 90 days after completion.  Highly 
effective methods of contraception include: intra-uterine device 
(nonhormonal or hormonal), bilateral tubal occlusion, vasectomy, 
sexual abstinence, or barrier methods (e.g., condom, diaphragm) 
used in combination with hormonal methods associated with 
inhibition of ovulation. Women of non-childbearing potential 
may be included if they are either surgically sterile or have been 


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postmenopausal for ≥ 1 year. Women who have documentation 
of at least 12 months of spontaneous amenorrhea and have an 
follicle-stimulating hormone level > 40 mIU/mL will be 
considered postmenopausal. 
9. Adequate hematologic, hepatic, and renal function, defined by: 
 Absolute neutrophil count ≥ 1.5× 109/L  
 Hemoglobin > 10 g/dL  
 Platelet count ≥ 100 × 109 /L  
 AST/ALT ≤ 1.5× ULN  
 Total bilirubin ≤ 1.5× ULN  
 Serum creatinine ≤ 1.5× ULN 
10. Willingness and ability to complete the BPI Worst Pain NRS 
item, Worst Stiffness NRS item, PROMIS Physical Function 
Scale, and other self-assessment instruments throughout the 
study. 
11. Willingness and ability to use an electronic diary. 
12. Willingness and ability to provide written informed consent prior 
to any study-related procedures and to comply with all study 
requirements. 
Exclusion 
Criteria 
1. Investigational drug use within 28 days of randomization. 
2. Previous use of pexidartinib or any biologic treatment targeting 
colony stimulating factor 1 (CSF-1) or the CSF-1 receptor; 
previous use of oral tyrosine kinase inhibitors, eg, imatinib or 
nilotinib, are allowed. 
3. Active cancer (either concurrent or within the last year of starting 
study treatment) that requires therapy (eg, surgical, 
chemotherapy, or radiation therapy), with the exception of 
adequately treated basal or squamous cell carcinoma of the skin, 
melanoma in-situ, carcinoma in-situ of the cervix or breast, or 
prostate carcinoma with a prostate-specific antigen value <0.2 
ng/mL.  
4. Known metastatic PVNS/GCT-TS. 
5. Active or chronic infection with hepatitis C virus or hepatitis B 
virus or known active or chronic infection with human 
immunodeficiency virus. 
6. Known active tuberculosis. 
7. Significant concomitant arthropathy in the affected joint, serious 
illness, uncontrolled infection, or a medical or psychiatric history 


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that, in the Investigator’s opinion, would likely interfere with a 
candidate’s study participation or the interpretation of his or her 
results. 
8. Women who are breastfeeding. 
9. A screening Fridericia corrected QT interval (QTcF) ≥ 450 ms 
(men) or ≥ 470 ms (women). 
10. MRI contraindications. 
11. History of hypersensitivity to any excipients in the investigational 
product. 
12. Inability to swallow capsules. 
Study Duration 
Each subject will spend a maximum of 6 weeks in screening. Part 1 will 
be a maximum of 24 weeks in duration. Patients for whom disease 
progression is confirmed at or after Week 13 but before Week 25 (by 
independent central radiological evaluation) and are taking placebo are 
eligible for entry into Part 2 early prior to 30 Sep 2016. The duration of 
Part 2 will vary among subjects, as this portion of the trial will continue 
until all subjects in this phase have either completed at least the Week 49 
Visit or withdrawn from the study. The study will end with the last 
subject last visit. Subjects who complete Part 2 will be eligible to 
continue for longer efficacy and safety follow-up or to enter a separate 
protocol to continue receiving pexidartinib until disease progression, 
unacceptable toxicity, or the occurrence of other termination criteria.  
Study Sites & 
Locations 
Approximately 45 study sites internationally across the US, Canada, EU, 
and Australia. 
Planned 
Sample Size 
Approximately 126 subjects across sites globally are planned. 
Test Product, 
Dose, and  
Route of 
Administration 
The study treatment, either pexidartinib or placebo, will be administered 
orally daily in capsule form. Each capsule of pexidartinib will contain 
200 mg of PLX3397 (J-3397-AF in hydroxypropyl methylcellulose 
capsules) or matching placebo. In Part 1, subjects will take five capsules 
a day (1000 mg/d pexidartinib or matching placebo) divided into a 
morning dose of two capsules and an evening dose of three capsules. 
After 2 weeks (P1-C1D15), dosing will be reduced to two capsules in the 
morning and two capsules in the evening (800 mg/d pexidartinib or 
matching placebo). All subjects will begin Part 2 by continuing to take 
the same number of capsules per day of open-label 800 mg/d 
pexidartinib. Doses will be taken in the fasting state (no food for 1 hour 
before and 2 hours after dosing, with a low-fat snack if needed) at 
approximately the same times of the day and approximately 12 hours 
apart. Each treatment cycle is 28 days.  


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The study treatment for home administration during Part 1 will be 
dispensed to the subject for the first time at the Cycle 1, Day 1 visit of 
Part 1, and the study treatment for home administration during Part 2 
will be dispensed to the subject for the first time at the Cycle 1, Day 1 
visit of Part 2. 
Dose 
Modification 
Guidelines 
Reduction or interruption of dosing can be implemented at any time to 
manage intolerable or clinically significant toxicity. Subjects unable to 
tolerate two capsules per day (400 mg/d pexidartinib or matching 
placebo) will be discontinued. Guidelines for dose modification are 
specified in Section 5.3. 
Study 
Assessments 
Efficacy — MRI, range of motion, BPI Worst Pain NRS item, Worst 
Stiffness NRS item, PROMIS Physical Function Scale, EuroQol five-
dimensional descriptive system (EQ-5D-5L), Surgical Assessment 
Questionnaire, major healthcare resource use (HCRU) and productivity, 
analgesic medications. 
Safety — Physical examination, vital signs, 12-lead electrocardiogram 
(ECG), echocardiography, adverse event reports, serum chemistry, 
hematology, coagulation tests, urinalysis, hormone testing (as 
applicable), concomitant medications. 
PK — PK blood samples will be drawn. 
PDy — Plasma samples for pexidartinib PDy markers and for 
exploratory markers of monocyte or macrophage activities. Available 
archival surgical tissue from tumors will be collected and stored for 
exploratory purposes. 
Efficacy 
Endpoints 
Primary efficacy endpoint: 
The proportion of subjects who achieve a complete response (CR) or 
partial response (PR) at the Week 25 visit based on centrally read MRI 
scans and RECIST 1.1. 
 
Secondary efficacy endpoints: 
 Mean change from baseline in range of motion of the affected 
joint, relative to a reference standard for the same joint, at the 
Week 25 visit 
 Proportion of responders based on centrally evaluated MRI 
scans and TVS at the Week 25 visit 
 Mean change from baseline score in the PROMIS Physical 
Function Scale at the Week 25 visit 
 Mean change from baseline score in the Worst Stiffness NRS 
item at the Week 25 visit 


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 Proportion of responders based on the BPI Worst Pain NRS 
item and analgesic use by BPI-30 definition [subject who (i) 
experienced a decrease of at least 30% in the mean BPI Worst 
Pain NRS item and (ii) did not experience a 30% or greater 
increase in narcotic analgesic use compared to baseline] 
 Duration of response (CR or PR) based on MRI and RECIST 
1.1 
 Duration of response (CR or PR) based on MRI and TVS 
 
Additional efficacy endpoints to be analyzed at Week 25, with the 
exception of duration endpoints or otherwise indicated, include: 
 Proportion of responders on the BPI Worst Pain NRS item 
and analgesic use by BPI-2p definition [subject who (i) 
experienced a decrease of at least 2 points in the mean BPI 
Worst Pain NRS item and (ii) did not experience a 30% or 
greater increase in narcotic analgesic use compared to 
baseline] 
 Proportion of responders on the BPI Worst Pain NRS item 
and analgesic use by BPI-50 definition [subject who (i) 
experienced a decrease of at least 50% in the mean BPI Worst 
Pain NRS item and (ii) did not experience a 30 % or greater 
increase in narcotic analgesic use compared to baseline] 
 Proportion of responders on the Worst Stiffness NRS item 
 Proportion of responders on the PROMIS Physical Function 
Scale 
 Mean change from baseline in the BPI Worst Pain NRS item 
 Patient Global Impression of Change item for tumor-related 
stiffness and Patient Global Rating of Concept item for ability 
to carry out every day physical activities.  
 Duration of BPI-based symptom response, analyzed for BPI-
30, BPI-50 and BPI-2p. 
 Results of the Surgical Assessment Questionnaire in Part 1. 
 Response based on the change in the sum of the short-axis 
dimension (SSD) of the tumor on MRI, referred to as 
"modified RECIST 1.1-SSD" 
 Amount of joint/tissue damage (eg, bone erosion, bone 
edema, cartilage loss) assessed on MRI based on adaptations 
of the Rheumatoid Arthritis MRI Score and Whole Organ 
MRI Score 
 Analgesic use expressed as morphine-equivalent doses in Part 


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1 
 EQ-5D-5L parameters in Part 1 
 Major HCRU and productivity in Part 1 
 Duration of response based on MRI and modified RECIST 
1.1-SSD 
 Response based on the most disturbing symptom of pain, 
stiffness, or compromised ability to carry out everyday 
activities 
 Proportion of subjects receiving surgical resection of their 
tumor by 25 weeks, 49 weeks, 73 weeks, and 97 weeks of 
pexidartinib treatment 
PK Analysis 
Plasma–concentration time data for pexidartinib will be summarized by 
visit and time using descriptive statistics. The data from these samples 
will be analyzed using a pooled population pharmacokinetic (PopPK) 
approach using nonlinear mixed effects modeling. PK parameters will 
include apparent clearance and volume of distribution along with transfer 
rate constants such as absorption and elimination rates. Additionally, 
based on post-hoc Bayesian methods, estimates of exposure such as 
Cmax, Ctrough, Cav and AUCss may also be reported 
PDy/Biomarker 
Analysis 
No formal statistical analysis of PDy endpoints will be performed. PDy 
data from each assay will be listed and possible relationships between 
PK and PDy variables may be explored. Any biological activity will be 
described. 
Statistical 
Analyses 
Efficacy analyses will be performed on the intent-to-treat (ITT) Analysis 
Set. For the efficacy analyses, subjects will be included in the treatment 
group to which they were randomized. 
The primary endpoint is the proportion of subjects who achieve a CR or 
PR at the Week 25 Visit based on centrally read MRI scans and RECIST 
1.1. The proportions in the two treatment groups will be compared using 
Fisher’s exact test (two-sided) at the alpha = 0.05 level of significance. 
In addition, the two-sided 95% confidence interval (CI) for the 
difference between the responder proportions in the two treatment 
groups will be provided using the Wilson method. 
The following treatment comparisons at the Week 25 visit are secondary 
efficacy analyses: 
1. Mean change from baseline in range of motion of the affected 
joint, relative to a reference standard for the same joint; 
2. Proportion of responders based on centrally evaluated MRI scans 
and TVS; 


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3. Mean change from baseline in the PROMIS Physical Function 
Scale; 
4. Mean change from baseline in the Worst Stiffness NRS item; 
5. Proportion of responders by BPI Worst Pain NRS item and 
analgesic use by BPI-30 definition. 
These above-listed endpoints will be analyzed using a hierarchical 
(“gatekeeping”) testing procedure. Thus, if the primary analysis is 
statistically significant (p<0.05), then secondary endpoint #1 will be 
analyzed, also based on the use of a two-sided test at the alpha=0.05 
level of significance. If secondary endpoint #1 is statistically significant 
(p<0.05), then the testing procedure will proceed to secondary endpoint 
#2, and so on. If the test for a particular endpoint is not statistically 
significant, the inference for all subsequent endpoints in the hierarchy 
will not be performed. 
Duration of response will also be a secondary efficacy endpoint and will 
be summarized by treatment group using the Kaplan-Meier product limit 
approach. The estimate and 95% CI will be provided for the median and 
the 25th and 75th percentiles. 
All secondary endpoints of mean changes at Week 25 will be analyzed 
using mixed models for repeated measurements. The dependent variable 
will be the change from baseline. Each of these models will include fixed 
effects for treatment group, time point, treatment group-by-time 
interaction, stratification factor of US sites versus non-US sites, and the 
baseline value of the corresponding endpoint as well as the baseline-by-
time interaction. An unstructured variance-covariance matrix will be 
used. Statistical comparisons between groups will be made at the 
specified time point. For secondary endpoints #2 and #5, the proportions 
of responders in the two treatment groups will be compared using 
Fisher’s exact test. 
Safety analyses will be performed on the Safety Analysis Set, and safety 
variables, including treatment-emergent adverse events, laboratory tests, 
vital signs, and ECGs, will be summarized. 
Sample Size Evaluation — The assumed responder rates for the primary 
endpoint are 10% (placebo) and 35% (pexidartinib). Based on the use of 
a two-sided, two-sample comparison of proportions at the alpha=0.05 
level of significance by Fisher’s exact test, a sample size of 126 ITT 
subjects (63 per arm) provides 90% power to detect this magnitude of 
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1. 
INTRODUCTION AND BACKGROUND INFORMATION 
A comprehensive review of pexidartinib (PLX3397) is contained in the Investigator’s Brochure 
(IB). Investigators should review the IB prior to initiating this study. A brief review of 
pexidartinib is provided here.  
1.1. 
Scientific Background 
1.1.1. 
Pigmented Villonodular Synovitis and Giant Cell Tumors of the Tendon Sheath 
Pigmented villonodular synovitis (PVNS) and giant cell tumors of the tendon sheath (GCT-TS) 
are members of a single condition referred to as “tenosynovial giant cell tumour (TGCT), 
localized and diffuse type” and have a common pathogenesis 1. They are rare proliferative 
neoplasms involving the synovium and tendon sheaths that typically present in young and 
middle-aged adults of both sexes. PVNS and GCT-TS are usually monoarticular processes that 
involve the bone, soft tissue, synovium, or tendon sheath of small or large joints. Symptoms 
initially may be minimal due to the slowly progressive nature of the disease, but as the tumor 
mass grows and gradually expands within the fixed confines of the intra-articular space (and 
surrounding tissue); symptoms such as pain, stiffness, swelling, and limitation in range of motion 
(ROM) can become severe and result in marked functional limitation. The diagnosis of PVNS is 
definitively made from pathologic evaluation; however, features highly suggestive of the disease 
may be found on radiologic imaging, including computed tomography and magnetic resonance 
imaging (MRI). 
PVNS and GCT-TS tumors predominantly consist of mononuclear and multinucleated giant 
cells. In both diseases, expansion of the tumor mass appears to be driven by the presence of 
abundant Colony stimulating factor 1 (CSF-1) expressed by a subset of cells within the tumor 
and often associated with genetic translocations linking the collagen 6A3 gene (on 2q35) with 
the CSF-1 gene (on 1p13). The majority of cells in the tumor mass are non-neoplastic 
inflammatory cells that do not express CSF-1 but are attracted to the tumor site because of their 
expression of the receptor, Colony stimulating factor 1 (CSF1R). 
Both PVNS and GCT-TS are rare, with an estimated annual incidence of 1.8 cases per million 
and 9.2 cases per million, respectively, in the US.2  In a review of a Scottish hospital case series, 
Monaghan and coworkers suggested an incidence of 0.2 cases of GCT-TS per 10,000 in the EU.3  
Similarly, Ushijima et al.4  described an incidence of 0.25 cases per 10,000 in Kyushu, Japan, 
while a paired study suggested a PVNS incidence of 0.06 per 10,000.5  Patients are commonly 
diagnosed in their 20s to 50s, and the disease affects men and women equally.2,6 
PVNS and GCT-TS are challenging diseases to manage. The current standard of care is surgical 
resection of the tumor as completely as possible in order to: (1) reduce pain, stiffness, and joint 
destruction caused by the disease process; (2) improve function; and (3) minimize the risk of 
recurrence. Patient outcome following surgery depends on multiple factors, including the 
location and extent of disease, thorough diagnostic evaluation, and the technical skill of the 
surgeon. The overall recurrence rate for patients with focal localized disease is low, ranging from 
0% to 6%; however, in patients with diffuse forms of the disease, recurrence is considerably 
more common, estimated to be in the range of 40%. Diffuse disease carries a significant risk of 


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multiple recurrence, and affected patients often have more extensive involvement and a poorer 
likelihood of success with surgery. Surgical resection may involve removal of major tendons, 
neurovascular structures, or limbs, leading to significant postsurgical morbidity. 
Currently, there are no systemic agents approved for the treatment of PVNS or GCT-TS. 
Products that are being evaluated in PVNS and GCT-TS include: imatinib (Gleevec) 7,8 a multi-
kinase inhibitor that targets Bcr-Abl tyrosine kinase yet also shows activity against CSF1R; 
nilotinib (Tasigna), a second-generation drug based on imatinib 9, a macrophage colony 
stimulating factor antibody; and a humanized monoclonal antibody that targets CSF1R.10 
1.1.2. 
Pexidartinib (PLX3397) 
Pexidartinib is a novel orally active small-molecule tyrosine kinase inhibitor that targets CSF1R, 
Kit (the receptor for stem cell factor), and oncogenic fms-like tyrosine kinase 3 (Flt3), the 
receptor for Flt3 ligand, but remains highly selective versus other kinases. It is hypothesized that 
since PVNS and GCT-TS tumors cause pathology by secreting high levels of CSF-1, 
pexidartinib should oppose disease progression by directly targeting the CSF1R that drives the 
target cells. Inhibition of this pathogenetic pathway should block both the neoplastic cells that 
express CSF-1, which are often in the minority, and the non-neoplastic inflammatory cells that 
comprise most of the tumor mass and do not express CSF-1 but are attracted to the tumor 
because of their expression of CSF1R. 
1.2. 
Nonclinical Studies 
When screened in vitro against a broad panel of 230 kinases, pexidartinib shows potent and 
selective inhibition against its intended targets:  CSF1R, Kit, and activated Flt3. Pexidartinib also 
blocks osteoclast differentiation and cell growth of CSF-1-dependent cell lines. Although 
nonclinical animal models of PVNS are not available, pexidartinib has shown the ability to block 
CSF1R activity in a variety of in vivo models. pexidartinib shows dose-dependent inhibition of 
splenomegaly in an engineered CSF1R-dependent mouse model. In the collagen-induced arthritis 
model, pexidartinib shows substantial efficacy by blocking the activity of macrophages and 
osteoclasts that infiltrate the diseased joints, reduces synovial inflammation and cartilage 
destruction, and reduces clinical scores for joint and digit swelling and redness even with 
treatment of advanced disease. 
Additional detailed information regarding the nonclinical pharmacology and toxicology of 
pexidartinib can be found in the IB.11 
1.3. 
Clinical Experience 
Pexidartinib has been evaluated in multiple clinical studies, three have either been completed or 
have a report in progress: Study PLX108-03, in patients with relapsed or refractory Hodgkin’s 
lymphoma; Study PLX108-04, in recurrent glioblastoma multiforme; and Study PLX108-06, in 
subjects advanced metastatic prostate cancer. In addition, single-dose studies PLX108-11 and 
PLX3397-A-U114 were completed in healthy subjects. Seven ongoing studies are evaluating 
pexidartinib in subjects with advanced incurable solid tumors. These trials focus on PVNS 
(PLX108-01) 12 and PLX108-10), relapsed or refractory acute myeloid leukemia (AML) 
(PLX108-05), combination therapy in advanced incurable solid tumors (PLX108-07, with 
paclitaxel; PLX108-14, with pembrolizumab), in newly diagnosed glioblastoma multiforme 


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(GBM) (PLX108-08, with temozolomide and radiation), and in BRAF-mutated metastatic 
melanoma (PLX108-09, with vemurafenib). All of these studies are open-label and 
uncontrolled.11 
See IB dated 07Dec2015 for total number of subjects exposed and the clinical experiences with 
pexidartinib.11  As of 31-July-2015, 485 subjects have been exposed to pexidartinib. Cumulative 
safety data show the most commonly reported treatment-emergent adverse events (TEAEs) 
(> 10%) treatment-related TEAEs have included fatigue, nausea, decreased appetite, hair color 
changes, diarrhea, AST increased, vomiting, anemia, dysgeusia, ALT increased, and rash. 
Among common treatment-related TEAEs, fatigue, increased AST and ALT, anemia, and rash 
occurred at Grade 3 or higher severity and at a frequency greater than 1%.11  
Serious adverse events (SAEs) that were assessed as subjects who experienced SAEs as judged 
by the study Investigator as possibly or probably related to study drug have been reported across 
all studies. Treatment-related SAEs reported more than once include neutropenia (including 
febrile neutropenia), increased ALT, increased AST, pneumonia, thrombocytopenia, 
dehydration, pyrexia, anemia, hyponatremia, increased INR, decreased neutrophil count, rash, 
and maculo-papular rash.  
A total of 21 deaths (excluding those attributed solely to disease progression) were recorded by 
31 July 2015, which include deaths occurring after study drug discontinuation in the follow-up 
period for assessment of overall survival. The majority of deaths attributed to an AE were 
considered unrelated to study treatment and some were likely related to a complication of their 
underlying malignancy. Death was attributed to pexidartinib treatment by Investigators in 2 
patients: Patient PLX001-06-609 with widely metastatic Erdheim-Chester disease (polyostotic 
sclerosing histiocytosis) died from a cerebrovascular accident (CVA) 504 days after initiating 
treatment with pexidartinib at 1000 mg/day (PLX108-01). The relationship of the CVA to 
pexidartinib was considered by the Sponsor’s Medical Monitor as being unlikely due to lack of 
pharmacologic plausibility (i.e., nonclinical data do not suggest any mechanism for 
thromboembolic events); lack of similar events in the current safety database; and the presence 
of potential underlying predisposing clinical conditions, such as numerous old central nervous 
system infarcts on imaging of the brain, and bilateral internal carotid and middle cerebral artery 
abnormalities of the neck on computerized tomography with contrast. Patient PLX005-07-009 
with AML died from cytokine release syndrome, which was reported as a Serious Adverse 
Reaction (SAR), 31 days after initiating treatment with pexidartinib at 3000 mg/day (PLX108-
05). The fatal SAE of cytokine release syndrome was considered to be partly due to 
differentiation syndrome, a syndrome that can occur in patients manifesting a positive response 
to anti-leukemic therapy. Because this event is considered to occur only in AML patients 
responding to treatment, no additional safety assessments were recommended. 
No safety signals in vital signs, physical examinations, or electrocardiograms (ECGs) (including 
reports of potentially clinically significant QT prolongation) have been identified. At 
pexidartinib doses of ≥ 600 mg/d, transient increases in AST and/or ALT have been observed 
across all clinical studies. In uncontrolled clinical studies of single agent pexidartinib and in 
combination with other anti-cancer agents, bone marrow suppression with leukopenia 
(neutropenia and/or lymphopenia), anemia and thrombocytopenia, either alone or with 
pancytopenia, has been observed. In addition, elevations of liver transaminases and bilirubin 
have also been observed in studies with pexidartinib. 


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The current version of the IB is dated 26Oct2016. 
1.3.1. 
Subjects with PVNS/GCT-TS Treated in Study PLX108-01 
Study PLX108-01, an ongoing open-label uncontrolled dose-escalation study in subjects with 
advanced incurable solid tumors, has provided preliminary data for clinical improvement with 
pexidartinib in a cohort of PVNS/GCT-TS subjects treated in that study’s extension phase. To be 
eligible for the PVNS/GCT-TS cohort, subjects were required to have a histologically confirmed 
diagnosis of inoperable progressive or relapsing PVNS/GCT-TS or have a potentially resectable 
tumor requiring mutilating surgery, and demonstrated progressive disease within the previous 12 
months. Subjects were given pexidartinib at the recommended Phase 2 dose of 1000 mg/d 
administered as a split dose (600 mg in the morning, 400 mg in the evening), and they were to 
continue treatment until tumor progression or unacceptable toxicity. Enrollment is ongoing. 
MRI was performed every two cycles (8 weeks); evaluable scans were assessed by a central 
musculoskeletal radiologist blinded to chronology using a novel Tumor Volume Score (TVS) 
developed specifically for PVNS/GCT-TS. This method was developed for PVNS/GCT-TS and 
used an extension of the 4-point synovitis scale of the well-established and widely used Outcome 
Measures in Rheumatology Clinical Trials Rheumatoid Arthritis MRI Score (RAMRIS) erosion 
scale, originally developed for assessing rheumatoid arthritis of the hands and wrists13, and the 
Whole Organ MRI Score (WORMS)14 originally developed for assessing osteoarthritis. The 
percent change in the TVS is calculated for each post-baseline MRI scan. Responder criteria 
were defined as follows: 
Complete Response (CR): 
Lesion completely gone by the end of the study. 
Partial Response (PR): 
≥ 50% decrease in volume score relative to baseline. 
Progressive Disease (PD): 
≥ 30% increase in volume relative to the lowest score 
during the study whether at baseline or some other visit. 
Stable Disease (SD): 
Does not meet any of the previous criteria based on score 
during the study. 
Subject Characteristics and Tumor Responses 
Twenty-three subjects in this cohort received at least one dose of study treatment. Median 
duration of treatment was 244 days, and the mean duration of treatment was 254 days (range, 15 
to 585 days). Among those who withdrew from the study, reasons for discontinuation were 
subject decision (three subjects), adverse event (two subjects; pain in the non-PVNS extremity 
and fatigue, respectively), noncompliance (one subject), and disease progression (one subject). A 
slight majority was female and most was white. The knee was the most common site of 
involvement. Prior to study enrollment, 18 of the subjects had undergone surgery and four had 
been treated with imatinib or nilotinib. 
As of 30-Jun-2014, an interim analysis data cutoff date, 14 of 23 subjects had a baseline and at 
least one post-baseline MRI that was radiologically evaluable and assessed by central readers 
using a TVS method (Plexxikon; data on file). The radiologically non-evaluable subjects 


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consisted of three subjects with no post-baseline MRI, four subjects with metallic artifact, and 
one subject each with unevaluable tumor or lymph node CT only (metastatic disease). 
Most of the evaluable subjects had a rapid decline in TVS that was maintained over time. Eleven 
(79%) achieved a partial response, and three (21%) experienced stable disease as a best response 
by TVS criteria. None had a complete response or progressive disease. Mean tumor size 
reduction was 61%. While metastatic PVNS/GCT-TS are quite uncommon, one subject with 
metastatic disease was enrolled in the study but was not evaluable by TVS. This subject had 
stable disease for 8 months before progressing at a metastatic focus. From this dataset, this 
subject is the only one who progressed while on therapy. 
All 23 subjects experienced at least one adverse event (AE) considered by the Investigator to be 
possibly or probably related to pexidartinib. The most frequently reported treatment-related AEs 
were hair color changes, fatigue, nausea, decreased appetite, diarrhoea, vomiting, anaemia, rash, 
periorbital edema, and dysgeusia. 11 11 
Treatment-related AEs of Grade ≥ 3 severity was reported in eight subjects:  anemia (one 
subject), neutropenia (one subject), hyponatremia (two subjects), elevated ALT and AST (two 
subject), fatigue (one subject) and diarrhea (one subject). Two subjects experienced three AEs 
that led to hospitalization:  one subject had Grade 3 cholecystitis and Grade 4 hyponatremia, and 
the other had Grade 3 acute renal failure. In the subject with cholecystitis and hyponatremia, the 
cholecystitis was judged as unrelated to treatment while the hyponatremia was judged to be 
treatment related. The events were treated and resolved. This subject left the study because of 
noncompliance. In the subject who experienced acute renal failure, the event occurred in the 
context of an untreated urinary tract infection and dehydration; it was treated, resolved, and 
judged as unrelated to the study treatment. The subject resumed study treatment without incident. 
No subjects in this cohort died during the study. 
Approximately half of the subjects experienced frequent transient increases in AST and/or ALT. 
Most of these elevations were of Grade 1 severity, remained stable or returned to normal with 
continued dosing, and were not considered to be AEs. Three subjects had Grade 3 ALT and/or 
AST elevations that resolved to Grade 1 or less after drug holidays; in two of these three 
subjects, dosing was resumed. One subject had a Grade 2 AST elevation (with a Grade 1 ALT 
elevation) that resolved to Grade 1 or less with continued dosing. In all cases, total bilirubin was 
normal. 
Further details on the clinical experience with pexidartinib can be found in the IB. 11 
1.4. 
Study Rationale 
This study will be conducted in two parts. Part 1 will be a double-blind randomized placebo-
controlled Phase 3 trial in subjects with symptomatic PVNS or GCT-TS for whom surgical 
resection would be associated with potentially worsening functional limitation or severe 
morbidity (locally advanced disease). Eligible candidates will be randomized in a 1:1 ratio to 
receive either pexidartinib or placebo twice daily for 24 weeks. The double-blind and 
randomized design will allow adequate comparison of pexidartinib with a control group. Placebo 
was selected as the control group because there is no existing non-surgical treatment that is 
accepted as standard of care for PVNS/GCT-TS. Surgical treatment cannot be used as a control 
treatment because the patient population includes those for whom surgery is associated with 


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potentially worsening function limitation or severe morbidity. Both the placebo and pexidartinib 
treatment groups will receive the usual supportive standard of care, eg, analgesic medications.  
Subjects will be started with 1000 mg/d pexidartinib or matching placebo, ie five capsules, in 
Part 1. It will be split into a morning dose of two capsules (400 mg pexidartinib or matching 
placebo) and an evening dose of three capsules (600 mg pexidartinib or matching placebo) and 
will be given in the fasting state (no food for 1 hour before and 2 hours after dosing, with a low-
fat snack if needed). Beginning on P1-C1D15, the maximum daily dose will be reduced to four 
capsules (800 mg pexidartinib or matching placebo) if it has not already been reduced to that 
amount or less. When subjects begin Part 2, they will continue taking the same number of 
capsules but of open-label pexidartinib, also split into a morning and an evening dose. Selection 
of the pexidartinib starting dose of 1000 mg/d and the split-dose administration schedule is based 
on data from subjects with solid tumors, including the small cohort of subjects with PVNS who 
received pexidartinib in Study PLX108-01, a Phase 1 trial. In the dose-escalation portion of that 
trial, two subjects receiving 1200 mg/d, administered as a split dose, experienced dose-limiting 
toxicities:  anemia, neutropenia, and syncope in one subject and elevated AST in the other. For 
this reason, 1000 mg/d given as a split dose was selected as the maximum tolerated dose and the 
recommended Phase 2 dose. 
Data from the PVNS cohort in Study PLX108-01, a Phase 1 trial, suggest that some subjects may 
require dose modification. While dose levels at and above 600 mg/d have similar safety profiles, 
subjects who had difficulty tolerating 1000 mg/d as a split dose were able to tolerate 600 or 800 
mg/d. Since approximately half of the PVNS subjects in Study PLX108-01 required a dose 
reduction to at least 800 mg/d within the first 2 cycles (Plexxikon, data on file), in this study 
subjects will be required to reduce their dose, from 1000 mg/d or matching placebo to a 
maintenance dose of 800 mg/d of pexidartinib or matching placebo, beginning on P1-C1D15. A 
dose reduction algorithm will allow subjects to further reduce the dose of pexidartinib or 
matching placebo in increments of one capsule, as needed (Section 5.3). Those unable to tolerate 
pexidartinib 400 mg/d or matching placebo will be discontinued.   
The subjects to be studied in this trial are those with symptomatic nonmetastatic PVNS or 
GCT-TS in whom surgical resection is associated with potentially worsening functional 
limitation or severe morbidity. The use of pexidartinib, a selective kinase inhibitor that targets 
CSF1R (the receptor for colony stimulating factor 1, which is overexpressed in 
PVNS/GCT-TS)15, offers a promising new therapeutic option for patients with this diagnosis 
who would not be adequately treated with surgery, the existing standard of care. 
The 24-week duration of treatment was selected on the basis of the preliminary data from Study 
PLX108-01. Almost all of the decreases in TVS have been observed before the end of C6, ie, 
before the end of 24 weeks of pexidartinib treatment. Accordingly, the duration of Part 1 is 
ethically limited to 24 weeks to keep the placebo-controlled portion as short as possible and 
enable the placebo-treated subjects to receive pexidartinib as soon as possible in Part 2; up to that 
point in the study, the subjects in the placebo arm will be receiving background standard of care. 
1.4.1. 
Study Purpose 
The purpose of this study is to evaluate the efficacy and long-term safety, pharmacokinetics, and 
pharmacodynamics of pexidartinib treatment in subjects with symptomatic PVNS/GCT-TS. The 
primary efficacy endpoint is the proportion of subjects who achieve a complete or partial 


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response at the Week 25 visit based on centrally read MRI scans and Response Evaluation 
Criteria in Solid Tumors, v. 1.1 (RECIST 1.1).16 
1.5. 
Risks and Benefits for Study Subjects 
In the Good Laboratory Practice repeat-dose toxicology studies consisting of up to 13 weeks of 
pexidartinib dosing, test article-related adverse effects were noted in testes (testicular 
spermatogonia reduction), ovaries (ovarian follicular degeneration), bone and bone marrow, 
hematology and lymphoid changes; these changes are consistent with the pharmacological 
mechanism of action of pexidartinib. All test article-related findings were partially or fully 
reversible.11  Potential dose-related changes in bone marrow function can be monitored by 
peripheral cell count and differential counts. Because of the effects on reproductive organs, 
subjects will be monitored for changes in luteinizing hormone (LH), follicle-stimulating 
hormone (FSH), and other sex-specific hormone levels. 
Effects on embryofetal development have been observed in both rat and rabbit toxicology studies 
up to 13 weeks. Dose level of 10 mg/kg/day was considered to be the NOAEL for embryofetal 
development when pexidartinib was administered orally by gavage to pregnant Sprague-Dawley 
rats. Dose of 20 mg/kg/day was considered to be the NOAEL for both reproduction in dams and 
embryo/fetal development. It was judged that pexidartinib was teratogenic in rabbits in the 
present study. Subjects in the study will be required to use adequate birth control during the 
study and for 90 days after the last dose of study treatment administered during study 
participation. 
Findings in the nonclinical canine safety pharmacology study suggest that pexidartinib may have 
a negative inotropic effect. Subjects will be monitored for changes in ejection fraction with 
cardiac echocardiograms. 
In clinical evaluation to date, the most common TEAEs of all grades have been fatigue, 
decreased appetite, nausea, vomiting, anemia, hair color depigmentation, and diarrhea. In a 
proportion of all subjects treated with pexidartinib, liver transaminases increased to 
approximately 1.5 × upper limit of normal (ULN) during the first cycle, followed by partial 
resolution during subsequent dosing. In some instances, the increase in liver enzymes may 
require dose hold or modification. Dosing modification guidance is included within the protocol 
for AE monitoring (Section 5.3). Liver function (clinical chemistry), renal function (clinical 
chemistry), and heart electrophysiology (QTc evaluation) will be monitored during this study. 
Based on TEAE reports of increased INR in subjects on warfarin who receive pexidartinib, 
subjects receiving warfarin should be carefully monitored when starting pexidartinib, and 
warfarin doses should be adjusted if an increase in INR is noted. 
More detailed and updated information regarding clinical safety data can be found in the IB.11 
PVNS and GCT-TS are progressive diseases with no ideal or standardized treatments. No 
systemic treatments and no treatments specifically directed to the recently identified 
pathogenetic pathways have been approved for these diseases. Although the standard of care is 
surgery, guidelines and evidence-based data for the timing and extent of surgical intervention are 
lacking.17 Surgical outcomes, even when curative, may result in marked patient morbidity as 
reflected in post-operative pain, limitation in function, and cosmetic disfigurement.18 In extreme 
or recurrent cases, the tumor may be aggressive and require limb amputation.19  The use of 


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pexidartinib, a selective kinase inhibitor that targets CSF1R (which is overexpressed in PVNS 
and GCT-TS)15, offers a promising new therapeutic option for patients with PVNS or GCT-TS. 
In summary, given the acceptable safety profile of the pexidartinib at the selected dose and the 
promising Phase 1 data in subjects with PVNS/GCT-TS, the potential for a positive benefit/risk 
profile is assumed for the Phase 3 study. 
1.6. 
Updated Risk Information and Change in Study Conduct 
During the conduct of this study, updated safety information became available including two 
SAEs in this study consistent with cholestatic liver dysfunction. There were an estimated 80 
subjects who had been exposed to pexidartinib at the time of this finding. The initial case, a 75 
year old woman with few risk factors, experienced hyperbilirubinemia for 2.5 months (ongoing), 
requiring study treatment discontinuation, hospitalization and two liver dialysis procedures. A 
liver biopsy showed cholestasis and ductopenia. The second case, a 52 year old male with few 
risk factors, had grade 4 liver enzyme increase concurrent with hyperbilirubinemia, which 
resolved on study treatment discontinuation without further measures. Both cases were not re-
challenged with the study treatment. 
Five cases of this pattern of liver dysfunction have been observed in other pexidartinib trials, 
both in monotherapy and combination therapy. In total there are now 7 cholestatic/mixed type of 
liver dysfunction cases reported among approximately 550 subjects. In addition to the above 
ENLIVEN study cases, prolonged hyperbilirubinemia (> 8 months, ongoing) occurred in one 
case and two other cases took 2-3 months to resolve. All cases occurred between 14 and 57 days 
of the start of pexidartinib treatment, suggesting a higher risk within the first 8 weeks of 
treatment. Three of the 7 cases had liver biopsy showing cholestasis and ductopenia. More 
detailed and updated information regarding clinical safety data can be found in the IB.11   
In response to the emergence of the two cases of potential cholestatic liver injury, the study Data 
Monitoring Committee (DMC) was requested to review the unblinded safety data related to these 
cases, other safety data from this study, and safety data for similar cases in other studies. The 
DMC recommended safety measures that changed the conduct of this study to enhance the 
protection of subjects. The following measures were implemented effective on 30 Sep 2016: 
1. Enrollment was stopped. No new subjects may start study treatment. Subjects in 
screening and randomized subjects who have not started treatment must be discontinued. 
2. Subjects on placebo in Part 1 are no longer allowed to enter Part 2 to receive open-label 
pexidartinib. After completion of the end of Part 1 assessments (Part 1 Completion 
visit/Early Termination visit), subjects who wish to continue onto the open label part of 
this study (Part 2) will be unblinded and those on placebo will be discontinued; subjects 
on pexidartinib in Part 1 may continue into Part 2 to continue to receive pexidartinib. 
3. Investigators and subjects must be informed of the new safety information and decide 
whether to continue in the study. If, after consultation with the subject, it is deemed to be 
in their best interest to continue treatment, the subject must be re-consented.  
4. The frequency of liver function testing is increased, and gamma-glutamyl transpeptidase 
(GGT) is added to the laboratory panel. 


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Updated hepatic safety risk information as of December 2017; please consult the IB for more 
information. Hepatotoxicity is an important adverse drug reaction. Elevations of liver 
transaminases and bilirubin have been observed in studies with pexidartinib, together with cases 
of drug-induced cholestasis. Cases of cholestasis have been observed in the first 8 weeks and 
have generally resolved with treatment discontinuation; however, some cases have been severe, 
with a protracted course requiring liver dialysis and, in 1 case, transplantation. Hepatotoxicity 
may be fatal. One fatal case with ongoing cholestatic liver injury at the time of death has been 
reported. Monitor patients closely as defined in the protocol. Protocol-defined dose reductions 
and discontinuations of pexidartinib, increased frequency of laboratory monitoring, and reporting 
of findings should be followed. In addition, rechallenge with pexidartinib should not be 
attempted without prior discussion with the Sponsor’s Medical Monitor. 
 


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2. 
STUDY OBJECTIVES AND HYPOTHESIS 
2.1. 
Study Objectives 
The primary objective of this study is to compare the response rate of pexidartinib with that of 
placebo per RECIST 1.1 at Week 25 in subjects with symptomatic, locally advanced PVNS or 
GCT-TS.  
The secondary efficacy objectives are to evaluate:  (i) Patient-reported Outcomes (PROs), 
including the Brief Pain Inventory (BPI) Worst Pain Numeric Rating Scale (NRS) item, Patient-
reported Outcomes Measurement Information System (PROMIS) Physical Function Scale, and 
Worst Stiffness NRS item, at Week 25; (ii) response based on TVS at Week 25; (iii) range of 
motion at Week 25; and (iv) duration of response. 
Other objectives are to evaluate (i) other measures of efficacy, (ii) long-term safety, 
(iii) pharmacokinetics (PK), and (iv) pharmacodynamics (PDy) of pexidartinib in treated 
subjects. 
2.2. 
Study Endpoints 
2.2.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the proportion of subjects who achieve a complete or partial 
response at the Week 25 visit based on centrally read MRI scans and RECIST 1.1. 
The RECIST 1.1 response categories are defined by the following criteria: 
 Complete Response  — Disappearance of all tumors.  
 Partial Response — At least a 30% decrease in the sum of diameters of target 
tumors, taking as reference the baseline sum diameters.  
 Progressive Disease  — At least a 20% increase in the sum of diameters of target 
tumors, using the smallest sum on study as the reference. In addition to the relative 
increase of 20%, the sum must also demonstrate an absolute increase of at least 
5 mm. The appearance of one or more new tumors is also considered progression. 
 Stable Disease — Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD. 
No confirmation (ie, CR or PR at the subsequent MRI assessment) will be required for a CR or 
PR per RECIST 1.1 for a randomized study. Complete and partial response will define response 
for the primary endpoint and additional efficacy analyses. 
Determination of an overall response for each time point is based on the combination of 
responses for target lesions, and the presence or absence of one or more new lesions. For the 
purpose of this protocol and in alignment with RECIST 1.1, determination of the tumor response 
status for each subject in Part 1 with respect to the primary efficacy endpoint is shown in 
Table 2.1. 


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To be considered a response, a tumor must meet the criteria for response and must have 
documented non-progression at Week 25. A tumor that achieves PR at Week 13 followed by 
neither sufficient shrinkage to qualify for CR nor sufficient increase to qualify for PD (ie, non-
CR/non-PD/non-NE) at Week 25 will be considered a responder for the primary efficacy 
endpoint. 
Table 2.1: 
Definitions of Response for the Primary Efficacy Endpoint 
Time Point Response at 
Week 13 
(P1-C4D1 visit) 
Time Point Response at Week 
25 
(Part 1 Completion visit) 
End of Part 1 
Tumor Response Status 
(Primary efficacy endpoint)  
CR or PR 
CR 
Response (CR) 
CR or PR 
PD 
Non-response (PD) 
PR 
non-CR/non-PD/non-NEa 
Response (PR)b 
SD 
CR or PR 
Response (CR or PR) 
SD 
SD 
Non-response (SD) 
SD 
PD 
Non-response (PD)c 
CR, PR, SD, or NE 
NE 
Non-response (NE) 
PD 
Any 
Non-response (PD) 
NE 
CR or PR 
Response (CR or PR) 
NE 
SD or PD 
Non-response (SD or PD) 
CR = complete response; NE = not evaluated or inevaluable; PD = progressive disease; PR = partial response;  
SD = stable disease 
a Neither sufficient shrinkage to qualify for CR nor sufficient increase to qualify for PD, taking as reference the 
nadir at Week 13. 
b A tumor that has achieved the criteria of PR will be considered an ongoing PR until progressive disease is 
objectively documented. 
c To be considered SD, the tumor must achieve the criteria for SD at the Week 25 visit; shorter-duration SD will not 
be considered SD at the end of Part 1. 
For the entire study, centralized review of the scans will be performed by readers blinded to 
treatment assignment and other clinical study data. Scans will be obtained according to the MRI 
Imaging Charter. The imaging charter for this study describes the image acquisition standards 
and methodology to be used as well as the standards for image interpretation.  
RECIST 1.1 has been used as a primary outcome measure in Phase 3 trials of several targeted 
therapies for the treatment of solid tumours (eg, crizotinib for advanced non-small cell lung 
cancer, dabrafenib for BRAF V600 mutation-positive unresectable or metastatic melanoma) and 
is supported by feedback from regulatory agencies for this study. Eisenhauer et al, who proposed 
the revised RECIST guideline (version 1.1), noted the importance of future work in moving from 
anatomic unidirectional assessment of tumour burden to either volumetric anatomical assessment 
or functional assessment with positron emission tomography scan or MRI.16  However, they 
concluded that use of promising newer approaches in these areas would require appropriate 
clinical validation studies. 


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2.2.2. 
Secondary Efficacy Endpoints 
The following evaluations comprise the secondary efficacy endpoints: 
1. Mean change from baseline in range of motion of the affected joint, relative to a 
reference standard for the same joint, at the Week 25 visit 
2. Proportion of responders based on centrally evaluated MRI scans and TVS at the Week 
25 visit 
3. Mean change from baseline score in the PROMIS Physical Function Scale at the Week 
25 visit 
4. Mean change from baseline score in the Worst Stiffness NRS item at the Week 25 visit 
5. Proportion of responders based on the BPI Worst Pain NRS item and analgesic use by 
BPI-30 definition (as defined in Section 7.6.2) 
6. Duration of response (CR or PR) based on MRI and RECIST 1.1 
7. Duration of response (CR or PR) based on MRI and TVS 
The PRO instruments to be used as secondary outcome measures were selected on the basis of a 
process that involved: 
1. A targeted literature review 
2. Discussions with four clinical experts with extensive experience managing PVNS/GCT-
TS 
3. A qualitative study carried out by the Sponsor to identify the key relevant concepts and 
confirm consistency with the literature 
4. Evaluation of a number of symptom instruments that were considered of potential 
relevance and could be adapted for use in assessing symptoms in PVNS/GCT-TS 
Reviews of the literature, input from clinical experts, and subject cognitive debriefing supported 
the content and relevance of the BPI Worst Pain NRS Item. Subjects in the qualitative study 
often reported pain as a common and dominant symptom that varied on a daily basis. For the BPI 
Worst Pain NRS item, subjects are asked to recall their worst pain at the site of their tumor in the 
past 24 hours. The brief recall period of 24 hours could provide information based on daily 
assessment, and the instrument is applicable to any tumor location. Assessments could be 
combined and summarized over a time period longer than 24 hours to yield more accurate 
estimates of subjects’ experiences of pain for weekly periods.  
Selection of stiffness and physical functioning as secondary endpoints was also based on a 
review of the literature, discussions with four clinical experts, and input from subjects with 
PVNS or GCT-TS. Stiffness was mentioned by 16 of the 22 participants (73%), including those 
with upper- and lower-extremity tumors, and specific impacts on functioning were mentioned by 
all participants either in the context of associations with specific symptoms or as a result of 
limitations to range of motion due to the tumors (Plexxikon, data on file).  
Specifically, the PROMIS Physical Functioning items and a Worst Stiffness NRS item were 
selected on the basis of (i) specific recommendations from the clinical experts and (ii) the 


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alignment of the concepts measured by these instruments with the symptom experiences reported 
by subjects with PVNS/ GCT-TS in the qualitative study.  
The PROMIS Physical Functioning items address symptoms of immobility. The first scale is 
applicable to subjects with lower-extremity tumors, and the second scale applies to subjects with 
upper-extremity tumors. Since tumors can be found in either the upper or lower extremities, the 
PROMIS Physical Functioning items provide the opportunity to include measurement of both 
sites in a way that is not possible with other similar instruments (eg, the Western Ontario and 
McMaster Universities Osteoarthritis Index for PVNS and GCT-TS, which only measures 
functioning in the lower extremities).  
Stiffness will be evaluated using a Worst Stiffness NRS item. Similar to the BPI Worst Pain 
item, the Worst Stiffness NRS item uses a 24-hour recall period. Subjects are asked to recall their 
worst stiffness at the site of their tumor in the past 24 hours. Like the BPI Worst Pain item, 
assessments can also be combined and summarized over a longer time period to yield more 
accurate estimates of subjects’ experiences of stiffness for weekly periods. 
TVS is a semi-quantitative MRI scoring system that describes tumor mass and is an extension of 
the 4 point synovitis scale of the well-established and widely used multi-feature score RAMRIS, 
originally developed for rheumatoid arthritis13, and WORMS, originally developed for 
osteoarthritis.14  The extended scale, the TVS, will be based on 10% increments of the estimated 
volume of the maximally distended synovial cavity or tendon sheath involved. Thus, a tumor that 
is equal in volume to that of a maximally distended synovial cavity or tendon sheath will be 
scored 10, whereas a tumor that is 70% of that volume will be scored 7, a tumor that is twice the 
volume of the maximally distended synovial cavity or tendon sheath will be scored 20, and so 
on. A score of “0” means no evidence of tumor. 
Individual subject outcomes by TVS will be classified according to the following criteria 
inspired by RECIST: 
 Complete response: Lesion completely gone. 
 Partial response: ≥ 50% decrease in volume score relative to baseline. 
 Progressive disease: ≥ 30% increase in volume relative to lowest score during the 
study whether at baseline or some other visit. 
 Stable disease: Does not meet any of the prior criteria based on score during study. 
The cutoffs of 50% for PR and +30% for PD were developed in consultation with clinical 
experts. This magnitude of reduction was observed in a majority of evaluable subjects with 
PVNS from the Phase 1 study of pexidartinib (Section 1.3.1). The tumor response status on this 
endpoint in Part 1 is determined in a way similar to that for the primary efficacy endpoint 
(Table 2.1). 
To minimize bias and reduce variability, all MRIs will be read centrally in a blinded manner for 
RECIST 1.1- and TVS-based responses according to the separate MRI Imaging Charter. 
Treatment effects on physical functioning will be assessed by an objective range of motion 
assessment performed by a qualified independent third party such as an orthopedic surgeon or a 
physical therapist blinded to treatment assignment, and when possible, to investigational drug 
name and to study protocol. This assessment uses standard goniometers and has been 


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standardized according to American Medical Association disability criteria.20  Details of this 
analysis are described in Section 7.6.2. 
2.2.3. 
Additional Endpoints 
Additional endpoints to be analyzed at appropriate time points include: 
 The long-term safety of pexidartinib in treated subjects, assessed from physical 
examination findings, vital sign data, 12-lead ECGs, echocardiograms, AEs, serum 
chemistry, hematology, coagulation tests, urinalysis, and hormone testing (as 
applicable) 
 Proportion of responders on the BPI Worst Pain NRS item and analgesic use by 
BPI-2p definition (as defined in Section 7.6.3) 
 Proportion of responders on the BPI Worst Pain NRS item and analgesic use by 
BPI-50  definition (as defined in Section 7.6.3) 
 Proportion of responders on the Worst Stiffness NRS item 
 Proportion of responders on the PROMIS Physical Function Scale 
 Mean change from baseline in the BPI Worst Pain NRS item 
 Patient Global Impression of Change item for tumor-related stiffness and Patient 
Global Rating of Concept item for ability to carry out every day physical activities 
 Duration of BPI-based symptom response, analyzed for BPI-30, BPI-50 and BPI-2p 
 Results of the Surgical Assessment Questionnaire in Part 1 
 Response based on the change in the sum of the short-axis dimension (SSD) of the 
tumor on MRI 
 Proportion of subjects receiving surgical resection of their tumor by 25 weeks, 49 
weeks, 73 weeks, and 97 weeks of pexidartinib treatment 
In addition to standard RECIST 1.1, which is based on the longest unidimensional measurement, 
an exploratory endpoint will be the response based on centrally read MRI and the SSD of the 
tumor, hereafter referred to as “modified RECIST 1.1–SSD.” 
Short-axis measurements will be made perpendicular to a reproducible adjacent landmark such 
as the femoral bone or a tendon, where the tumor dimension appears greatest and yet confidently 
measurable. Measurement of this site will be repeated on the other visits. The tumor response 
status on this endpoint in Part 1 will be determined in a way similar to that for the primary 
endpoint Table 2.1. 
Amount of joint/tissue damage (eg, bone erosion, bone edema, cartilage loss) assessed on MRI 
based on adaptations of the RAMRIS and WORMS: 
Bone erosion will be scored based on the RAMRIS-erosion scale originally developed for 
assessing rheumatoid arthritis of the hands and wrists.13  The scale ranges from 0 to 10 in 10% 
increments of articular bone eroded and is applied to each of the 14 regions in the knee specified 
in WORMS14 or to each articular bone in the ankle/foot or elbow. Articular bone is defined as 
bone within 1 cm of the articular surface. 


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Bone edema and cartilage loss will be scored based on WORMS in the same regions as bone 
erosion assessments. 
 Analgesic use expressed as morphine-equivalent doses in Part 1 
 EuroQol five-dimensional descriptive system (EQ-5D-5L) parameters in Part 1 
 Major healthcare resource use (HCRU) and productivity in Part 1 
 Duration of response based on MRI and modified RECIST 1.1-SSD 
 Response based on the most disturbing symptom of pain, stiffness, or compromised 
ability to carry out everyday activities 
The data from this study will be analyzed using a pooled population pharmacokinetic (PopPK) 
approach using nonlinear mixed effects modeling. PK parameters will include apparent clearance 
and volume of distribution along with transfer rate constants such as absorption and elimination 
rates. Additionally, based on post-hoc Bayesian methods, estimates of exposure such as Cmax, 
Ctrough, Cav and AUCss may also be reported. 
Plasma will be analyzed for pexidartinib PDy markers and for exploratory markers of monocyte 
or macrophage activities, including CSF-1 and adiponectin. When available and consented, 
archival surgical tissue from PVNS or GCT-TS tumors will be collected for exploratory analysis 
related to pexidartinib and/or disease. 
2.3. 
Study Hypothesis 
Pexidartinib is safe and more efficacious than placebo when administered to subjects with 
symptomatic, locally advanced PVNS/GCT-TS. 


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3. 
STUDY DESIGN 
3.1. 
Overall Plan 
This trial is a two-part multi-center Phase 3 study in subjects with symptomatic PVNS or 
GCT-TS for whom surgical resection would be associated with potentially worsening functional 
limitation or severe morbidity (locally advanced disease). In Part 1, the double-blind phase, 
eligible candidates will be centrally randomized in a 1:1 ratio to receive either pexidartinib or 
placebo for 24 weeks. Randomization will be stratified by US versus non-US sites and by upper 
extremity versus lower extremity involvement.  
Study treatment will be administered twice a day, every day. For the first 2 weeks in Part 1, 
subjects will take two capsules in the morning and three capsules in the evening, 1000 mg/d 
pexidartinib or matching placebo. Thereafter, dosing will be reduced to two capsules in the 
morning and two capsules in the evening, 800 mg/d pexidartinib or matching placebo. Subjects 
who had a dose reduction during the first 2 weeks will continue treatment at their reduced dose. 
Each treatment cycle will be 28 days in duration and subjects will be treated for up to 6 Cycles. 
Dose reductions, interruptions, and re-escalations after previous reductions for toxicity are 
permitted according to pre-specified guidelines. Those subjects who complete Part 1 (ie, 
complete 24 weeks of dosing and the Week 25 assessments) will be eligible to advance to Part 2, 
a long-term treatment phase where all subjects will take up to four capsules per day (800 mg/d) 
of open-label pexidartinib. Effective 30 Sep 2016, subjects on placebo are no longer allowed into 
Part 2 to receive open-label pexidartinib. 
MRIs will be performed at Week 13 (Cycle 4, Day 1 visit of Part 1 [P1-C4D1]) and Week 25. If 
disease progression is indicated clinically or by local radiologic assessment according to 
RECIST 1.1 at or after Week 13 but before Week 25, the Investigator may request a central 
review for evaluation of disease progression.  Any disease progression before Week 25 must be 
verified by a central MRI reading. If a central reading confirms RECIST 1.1-defined disease 
progression, treatment assignment will be unblinded, and subjects receiving placebo will be 
eligible for early entry into Part 2 of the study.  Effective 30 Sep 2016, subjects receiving 
placebo will be discontinued instead of being eligible to enter Part 2. Subjects receiving 
pexidartinib will be discontinued from the study unless the Investigator and the Sponsor’s 
Medical Monitor judge that the subject would potentially benefit from continued treatment with 
pexidartinib. For those subjects who undergo surgical resection after Week 25, an MRI will be 
performed 4 months after surgery. 
Part 2 will continue until all subjects have either reached at least the Week 49 visit, ie, an 
additional 24 weeks of study treatment beyond the placebo-controlled phase, or withdrawn from 
the trial (Figure 3.1). As in Part 1, dose reductions, interruptions, and re-escalations after 
previous reductions for toxicity are permitted according to pre-specified guidelines. Subjects 
who complete Part 2 will be eligible to continue pexidartinib treatment for study of longer 
efficacy and safety follow-up assessed per the schedule in Part 2 or to enter a separate protocol to 
continue receiving pexidartinib. 
 


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Figure 3.1: 
Study Schematic* 
 
* Effective 30 Sep 2016, subjects on placebo are no longer allowed into Part 2 to receive open-label pexidartinib. 
All MRI scans will be assessed by central readers blinded to treatment assignment and other 
clinical study data during both Parts 1 and 2 of the study, according to procedures outlined in a 
separate Imaging Independent Review Charter. The MRI report will not be provided in real-time 
unless requested by the Investigator. Results of the baseline MRI scan will be used to qualify a 
candidate. During Part 2, if indicated, Investigators should request confirmation of radiologic 
disease progression by central read. Otherwise, central reads of MRI scans may be performed 
during or after the subject has completed the study. The MRI scan for subjects who undergo 
surgical resection will be performed 4 months after surgery. Details of MRI requirements and 
data collection will be described in the MRI Procedure Manual. 
A range-of-motion assessment in the affected joint or tumor location will be performed by an 
independent and blinded third party assessor at specified time points. The BPI Worst Pain NRS 
item, physical function items from the PROMIS item bank (PROMIS Physical Function Scale), 
and other PRO measures will be administered according to the Study Reference Manual. 
For statistical analysis of endpoints at the end of Part 1, a clinical data cut-off date will be 
defined for the point when all randomized subjects complete or are discontinued from Part 1 with 
appropriate End of Part 1 follow-up. All data up to this date will be cleaned and locked. 
Afterwards, unblinding of database will be performed to facilitate the data analyses, including 
the data from the double-blind Part 1 and available data from Part 2. Such unblinding is only 
intended for the sponsor and the Contract Research Organization. Subjects who entered Part 2 


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may continue to receive open-label pexidartinib treatment. Updated analysis of Part 2 data only, 
in the form of summary and descriptive statistics, will be performed at the end of the 
trial.  Additional updates between the above-mentioned cut-off and end of the trial may also be 
performed. 
The timing and nature of post-treatment assessments are summarized in Figure 3.2. Subjects who 
end their study participation with no documented disease progression will undergo:  (i) the 
28 Day Post-treatment Visit assessment with an MRI 28 ± 7 days after their last dose of study 
treatment; and (ii) a final MRI 12 weeks ± 7 days after their last dose of study treatment or 
before any new PVNS/GCT-TS therapy, including surgery, whichever occurs first (the “Part 1 
End-of-Study/12 Week Post-Treatment”). Subjects who wish to continue onto the open label part 
of this study (Part 2) will be unblinded after completion of the end of Part 1 assessments and 
those on placebo will be discontinued- they will not have the 28 Day Post-treatment and End-of-
Study Visit assessments. The study will end with the last subject last visit. Subjects who 
complete Part 2 and enter a separate protocol to continue receiving pexidartinib will not be 
scheduled for the Post-treatment and End-of-Study Visits. Subjects who terminate the study with 
documented progression will undergo a post-treatment assessment (the 28 Day “Post-treatment 
Visit”; see Section 15.2.17 and Section 15.3.16) without an MRI 28 ± 7 days after their last dose 
of study treatment or before any new PVNS/GCT-TS therapy, including surgery, whichever 
occurs first. 
Subjects are allowed to undergo surgical resection of their tumor after the completion of Part 1. 
For subjects who undergo surgical resection within 12 weeks after their last dose of study 
treatment, they will not have the End-of-Study Visit assessments but will follow a separate visit 
schedule after the decision of surgery is made. The surgery is recommended to be performed 1-3 
weeks after the last dose of study treatment. Details of the surgery and its short and long term 
outcome will be collected. Data collection for the surgery and its outcome may continue in a 
separate protocol. 
 


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Figure 3.2: 
Post-treatment Assessments Vary With Reason for Study Withdrawal* 
 
* Effective 30 Sep 2016, subjects on placebo are no longer allowed into Part 2 to receive open-label pexidartinib. 
Subjects who wish to continue onto the open label part of this study (Part 2) will be unblinded after completion of 
the end of Part 1 assessments and those on placebo will be discontinued- they will not have the 28 Day Post-
treatment and End-of-Study Visit assessments. 


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3.2. 
Number of Subjects 
Approximately 126 subjects across approximately 45 study sites in the US, Canada, EU, and 
Australia are planned. 
3.3. 
Duration of Study 
Each subject will spend approximately 3 to 6 weeks in screening. Part 1 will be 24 weeks in 
duration for all but those who qualify (see Section 3.1) for early entry into Part 2 because of 
disease progression. Effective 30 Sep 2016, subjects on placebo are no longer allowed into Part 2 
to receive open-label pexidartinib. The duration of Part 2 will vary among subjects, as this 
portion of the trial will continue until all subjects either complete 24 weeks of open-label 
treatment or withdraw from the study. The study will end with the last subject last visit. Subjects 
who complete Part 2 without experiencing progression or intolerability, or subjects who undergo 
surgical resection of their tumor after study treatment will be eligible to continue for longer 
efficacy and safety follow-up or to enter a separate protocol to continue receiving pexidartinib or 
for surgical data collection. 


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4. 
STUDY POPULATION 
4.1. 
Enrollment 
All subjects must provide written informed consent. During the consent process, the person 
obtaining consent must inform the subject of all elements of the study. Each subject must sign 
and date an institutional review board (IRB)/independent ethics committee (IEC)-approved 
informed consent form before undergoing any study procedure (including screening procedures 
unless the screening procedure as outlined in the Study Reference Manual is considered standard 
of care and was performed within 42 days of the P1-C1D1 visit). Participation in the study 
begins with signing and dating the informed consent form. A subject will be considered enrolled 
in the study when he or she has met all of the inclusion and exclusion criteria, been deemed 
eligible for study participation, and been randomized. 
4.1.1. 
Inclusion Criteria 
Each subject must meet all of the following criteria to qualify for enrollment: 
1. Age ≥ 18 years. 
2. A diagnosis of PVNS or GCT-TS (i) that has been histologically confirmed either by a 
pathologist at the treating institution or a central pathologist, and (ii) where surgical 
resection would be associated with potentially worsening functional limitation or severe 
morbidity (locally advanced disease), with morbidity determined consensually by 
qualified personnel (eg, two surgeons or a multi-disciplinary tumor board). 
3. Measurable disease as defined by RECIST 1.1 (except that a minimal size of 2 cm is 
required), assessed from MRI scans by a central radiologist.   
4. Symptomatic disease because of active PVNS or GCT-TS, defined as one or more of the 
following: 
a. a worst pain of at least 4 at any time during the week preceding the Screening Visit 
(based on scale of 0 to 10, with 10 representing “pain as bad as you can imagine”).  
b. a worst stiffness of at least 4 at any time during the week preceding the Screening 
Visit (based on a scale of 0 to 10, with 10 representing “stiffness as bad as you can 
imagine”). 
5. Stable prescription of analgesic regimen during the 2 weeks prior to randomization. 
6. During the 2 weeks prior to randomization, at least 4 of 7 consecutive days of BPI Worst 
Pain NRS items and Worst Stiffness NRS items completed correctly.   
7. Women of childbearing potential must have a negative serum pregnancy test within the 
14-day period prior to randomization. (Where demanded by local regulations, this test 
may be required within 72 hours of randomization.) 
8. Males and females of childbearing potential are permitted in the study so long as they 
consent to avoid getting their partner pregnant or becoming pregnant, respectively, by 
using a highly effective contraception method, as described below, throughout the study 
and for up to 90 days after completion.  Highly effective methods of contraception 


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include: intra-uterine device (nonhormonal or hormonal), bilateral tubal occlusion, 
vasectomy, sexual abstinence, or barrier methods (e.g., condom, diaphragm) used in 
combination with hormonal methods associated with inhibition of ovulation. Women of 
non-childbearing potential may be included if they are either surgically sterile or have 
been postmenopausal for ≥ 1 year. Women who have documentation of at least 
12 months of spontaneous amenorrhea and have an FSH level > 40 mIU/mL will be 
considered postmenopausal. 
9. Adequate hematologic, hepatic, and renal function, defined by: 
 Absolute neutrophil count ≥ 1.5 × 109/L  
 Hemoglobin > 10 g/dL  
 Platelet count ≥ 100 × 109/L  
 AST/ALT ≤ 1.5 × ULN  
 Total bilirubin ≤ 1.5 × ULN  
 Serum creatinine ≤ 1.5 × ULN 
10. Willingness and ability to complete the BPI Worst Pain NRS item, Worst Stiffness NRS 
item, PROMIS Physical Function Scale, and other self-assessment instruments 
throughout the study. 
11. Willingness and ability to use an electronic diary. 
12. Willingness and ability to provide written informed consent prior to any study-related 
procedures and to comply with all study requirements. 
4.1.2. 
Exclusion Criteria 
Candidates with any of the following conditions or activities are ineligible for study enrollment: 
1. Investigational drug use within 28 days of randomization. 
2. Previous use of pexidartinib or any biologic treatment targeting CSF-1 or the CSF1R; 
previous use of oral tyrosine kinase inhibitors, eg, imatinib or nilotinib, are allowed. 
3. Active cancer (either concurrent or within the last year of starting study treatment) that 
requires therapy (eg, surgical, chemotherapy, or radiation therapy), with the exception of 
adequately treated basal or squamous cell carcinoma of the skin, melanoma in-situ, 
carcinoma in-situ of the cervix or breast, or prostate carcinoma with a prostate-specific 
antigen value <0.2 ng/mL. 
4. Known metastatic PVNS/GCT-TS. 
5. Active or chronic infection with hepatitis C virus or hepatitis B virus or known active or 
chronic infection with human immunodeficiency virus. 
6. Known active tuberculosis. 
7. Significant concomitant arthropathy in the affected joint, serious illness, uncontrolled 
infection, or a medical or psychiatric history that, in the Investigator’s opinion, would 


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likely interfere with the person’s study participation or the interpretation of his or her 
results. 
8. Women who are breastfeeding. 
9. A screening Fridericia corrected QT interval (QTcF) ≥ 450 ms (men) or ≥ 470 ms 
(women). 
10. MRI contraindications. 
11. History of hypersensitivity to any excipients in the investigational product. 
12. Inability to swallow capsules. 
4.2. 
Removal of Subject From Therapy 
If a subject is withdrawn from the study, the Investigator will complete and report the 
observations as thoroughly as possible up to the date of withdrawal including the date of last 
treatment and the reason for withdrawal. 
If the subject is withdrawn due to an AE, the Investigator will follow the subject until the AE has 
resolved or stabilized. 
Subjects can only be considered for surgical resection after the completion of Part 1.  
If a subject undergoes surgical resection of the tumor after Part 1, the study treatment is 
recommended to be discontinued 1-3 weeks before the surgery. The subject will be followed for 
surgery and its outcome and not considered as discontinued from the study. Data collection for 
the surgery and its outcome may continue in a separate protocol. If a subject undergoes surgical 
resection prior to completion of Part 1, the information about surgery and its outcome will still 
be collected.  
4.2.1. 
Reasons for Withdrawal/Early Discontinuation 
The reasons a subject may discontinue or be withdrawn from the study permanently include but 
are not limited to: 
 AE 
 Protocol violation 
 Disease progression 
 Subject noncompliance 
 Pregnancy 
 Subject request 
 Study termination by the Sponsor or IRB/IEC 
 Subject transition to commercial pexidartinib 
 Investigator decision 
During Part 2, if a subject experiences radiologic progression documented by central read, the 
subject may either be withdrawn from the study or, if the subject is continuing to have clinical 
benefit, the Investigator may consult with the Sponsor’s Medical Monitor or designee to allow 
the subject to remain in the study. 
4.2.2. 
Withdrawal Procedures 
When a subject discontinues or is permanently withdrawn from the study, the Investigator will 
notify the Sponsor and ensure that the procedures listed in the 28 Day “Post-treatment Visit” 
column in the Schedule of Events (Table 15.2 and Table 15.3) are performed 28 ±7 days after the 


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subject’s last dose of study treatment and prior to initiating any new PVNS/GCT-TS therapy, 
including surgery. 
The consequence of a subject’s withdrawal of all consent will be that no new information will be 
collected from that subject and added to the existing data or any database. However, every effort 
will be made to follow all subjects for safety. 
The reason for study withdrawal will be recorded. If a subject discontinues study treatment to 
undergo surgery, information about the type of surgery and its outcome will be collected. 
If a subject discontinues study treatment before the end of Part 1, the end of Part 1 assessments 
(Part 1 Completion visit/Early Termination visit) should be performed at the time of early 
discontinuation (Table 15.2). These subjects will not be unblinded. 
4.2.3. 
Subject Replacement 
Subjects withdrawn from the study will not be replaced. 
4.3. 
Subject Re-screening Procedures 
Re-screening is permitted for any candidate who failed to meet eligibility criteria upon initial 
screening. If rescreened, the candidate will not be given a new subject identification number. The 
initial screening information and the reason why the subject is ineligible for the initial evaluation 
will be recorded on the Screening Log. No data from the initial evaluation will be entered into 
the clinical database for a subject who is rescreened.  However, MRI, ROM and surgical 
assessment may not need to be repeated, following consultation with Sponsor Medical Monitor. 


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5. 
TREATMENTS ADMINISTERED 
5.1. 
Investigational Products 
The study treatment, pexidartinib (PLX3397), is an HCl salt supplied in 200 mg-strength 
immediate-release capsules for oral administration. 
The placebo capsules for this trial have an identical qualitative composition to the PLX3397 HCl 
capsules except no active pharmaceutical ingredient is included. The amount of mannitol is 
increased in the placebo blend to compensate for amount of active ingredient that is not added. 
The placebo and pexidartinib capsules are identical in appearance to maintain the blind during 
Part 1. 
5.2. 
Study Treatment Administration 
Study treatment will only be given to randomized subjects under the supervision of the Principal 
Investigator or identified sub-Investigator(s). The study treatment for home administration 
during Part 1 will be dispensed to the subject for the first time at the P1-C1D1 visit (within 3 
days of randomization), and the study treatment for home administration during Part 2 will be 
dispensed to the subject for the first time at the P2-C1D1 visit. Capsules should be swallowed 
and not crushed, chewed, or dissolved in liquid. In Part 1, subjects will receive either 
pexidartinib or matching placebo capsules. In Part 2, subjects will receive only pexidartinib 
capsules. 
Study treatment administration will begin at the P1-C1D1 visit in the morning. At that visit, 
subjects will be instructed to take five capsules a day for the first 2 weeks; 1000 mg/d 
pexidartinib or matching placebo, this amount will be divided into a morning dose of two 
capsules and an evening dose of three capsules. After 2 weeks (at the P1-C1D15 visit), the dose 
will be reduced to two capsules in the morning and two capsules in the evening, 800 mg/d 
pexidartinib or matching placebo. Subjects who had a dose reduction during the first 2 weeks 
will continue treatment at their reduced dose. Doses should be taken in the fasting state (ie, no 
food for 1 hour before and 2 hours after dose administration). During the fasting period, subjects 
will be permitted to eat a low-fat snack (eg, crackers, toast, tea) if needed. Doses will be taken at 
approximately the same times of the day and approximately 12 hours apart. Each dosing cycle 
will be 28 days. 
For the P1-C1D15 and P2-C1D15 visits and any visit when an ECG will be performed, subjects 
should be told to NOT take their morning dose of study treatment before coming to their study 
visit, which should be scheduled for the morning; instead, they should be told to bring their 
bottle of study treatment to the clinic and take their morning dose upon instruction by the study 
site. The time of dosing will be recorded. Subjects will then take their evening dose at home.  If 
dose administered in the clinic is taken in the afternoon, then the subject should be instructed to 
skip their evening dose for that day. 
For the P2-C1D1 visit (Week 25), subjects should be told to NOT take the morning dose of study 
treatment before their visit and to bring all unused capsules to the clinic for accountability. 
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that visit, taking the same number of capsules per day as they were taking at the end of Part 1, ie, 
a maximum dose of 800 mg/d pexidartinib. 
Between clinic visits, subjects will administer their study treatment at home and record the 
dosing information in the study dosing diary. Missed doses (those generally outside of a ± 2-hour 
dosing window) should be skipped and NOT administered as a double dose at the next dosing 
time point. Subjects who vomit their dose should be instructed NOT to make up that dose. 
Further details on study treatment administration are contained in the separate Pharmacy Manual. 
For subjects who undergo surgical resection of their tumor, study treatment will be discontinued 
before surgery and will not be restarted after surgery. 
5.3. 
Dose Modification Guidelines 
In both Parts 1 and 2, reducing or interrupting the dose for toxicity may take place at any time 
according to the guidelines in Table 5.1 and Table 5.2. Dose reduction/interruption guidelines for 
hematologic and non-hematologic treatment-related TEAEs are based on severity. Dose 
interruptions can be implemented at the discretion of the treating physician to manage intolerable 
or clinically significant toxicity. If a dose interruption is required, study assessments should be 
performed as scheduled, irrespective of the study treatment delay, with the exception of PK 
assessments which should be deferred until treatment is resumed. Interruptions due to toxicity 
lasting >14 d require treatment discontinuation unless the medical monitor approves 
continuation. 
When an odd number of capsules a day are to be taken, the larger number of capsules should be 
taken as the evening dose. For example, 600 mg/d or matching placebo = 3 capsules (1 capsule 
in the morning, 2 capsules in the evening). When an even number of capsules per day is to be 
taken, the morning and evening doses should be the same (eg, 800 mg/d or matching 
placebo = 4 capsules (2 capsules in the morning, 2 capsules in the evening) or 400 mg/d or 
matching placebo = 2 capsules (1 capsule in the morning, 1 capsule in the evening). 
Dose reductions should be applied in increments of 200 mg/d or matching placebo (one capsule), 
with a maximum total reduction of 600 mg/d or matching placebo (ie, a minimum dose of 
400 mg/d or matching placebo). Subjects unable to tolerate 400 mg/d or matching placebo (two 
capsules) will be discontinued. Once dose reduction takes place for toxicity, a dose re-escalation 
is generally not allowed unless approved after discussion with the Sponsor's Medical Monitor or 
designee. 
Dose-modification guidelines for treatment–emergent toxicities as well as guidelines for their  
management are presented Table 5.1 and Table 5.2. These parameters are only a guide and are 
not intended to supersede the clinical judgment of the treating physician.  All adjustments should 
be communicated to the Sponsor’s Medical Monitor or designee.  Rechallenge with a reduced 
dose of pexidartinib may result in a recurrence of increased serum transaminases, bilirubin, or 
ALP.  Monitor liver tests weekly for the first month after rechallenge. 


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Table 5.1: 
Dose Modification Guidelines for Treatment-emergent Toxicities 
Event 
Severity 
Pexidartinib Dosage Modifications 
Hepatoxicity 
Increased ALT 
and/or AST 
>3 to 5 × ULN 
 
Withhold and monitor liver tests weekly. 
 
If AST and ALT ≤3 × ULN within 4 weeks, resume at 
reduced dose. 
 
If AST or ALT not ≤3 × ULN in 4 weeks, permanently 
discontinue pexidartinib. 
>5 to 10 × ULN 
 
Withhold and monitor liver tests twice weekly. 
 
If AST and ALT ≤3 × ULN within 4 weeks, resume at 
reduced dose. 
 
If AST or ALT not ≤3 × ULN in 4 weeks, permanently 
discontinue pexidartinib. 
>10 × ULN 
 
Permanently discontinue pexidartinib. 
 
Monitor liver tests twice weekly until AST or ALT ≤5 × 
ULN, then weekly until ≤3 × ULN. 
Increased ALPa 
and GGT 
ALP >2 × ULN with GGT 
>2 × ULN 
 
Permanently discontinue pexidartinib.  Monitor liver tests 
twice weekly until ALP ≤5 times ULN, then weekly until 
≤2 × ULN. 
Increased 
bilirubin 
TB >ULN to <2 × ULN 
or 
DB >ULN and <1.5 × ULN 
 
Withhold and monitor liver tests twice weekly. 
 
If an alternate cause for increased bilirubin is confirmed and 
bilirubin <ULN within 4 weeks, resume at reduced dose. 
 
If bilirubin not <ULN in 4 weeks, permanently discontinue 
pexidartinib. 
TB ≥2 × ULN 
or 
DB >1.5 × ULN 
 
Permanently discontinue pexidartinib. 
 
Monitor liver tests twice weekly until bilirubin ≤ULN. 
Adverse Reactions or Other Laboratory Abnormalities 
Any 
Severe or intolerable 
 
Withhold until improvement or resolution. 
 
Resume at a reduced dose upon improvement or resolution. 
ALT = alanine aminotransferase; ALP = alkaline phosphatase; AST = aspartate aminotransferase; DB = direct 
bilirubin; GGT = gamma-glutamyl transferase; TB = total bilirubin; ULN = upper limit of normal. 
a Confirm ALP elevations as liver isozyme fraction. 


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Table 5.2: 
Additional Liver Evaluation 
Evaluation 
Comments 
Increase frequency of testing liver chemistries 
to twice per week, including INR, and continue 
until liver chemistries have stabilized, and then 
reduce to weekly until liver chemistries return 
to normal or baseline 
Investigational treatment may be started after 
liver function tests recover to Grade 0 to 1 or 
baseline level, and in consultation with 
Medical Monitor 
Detailed history focusing on medications and 
substances used: alcohol, change in medication 
dosages, new medications added, attention to 
use of acetaminophen, OTC medication use 
and recreational drug use. Check for change in 
diet or use of dietary supplements, with 
particular attention to dose and duration of any 
herbal product 
Suspect medications will be discontinued or 
substituted for if possible 
Detailed medical history and physical exam 
seeking new abnormalities 
Evaluate abnormalities found 
Full serological evaluation for hepatitis A, B, C 
and E (IgG and IgM). Check for autoimmune 
hepatitis with serological laboratory studies 
If viral hepatitis or autoimmune hepatitis 
suggested, have subject evaluated by 
hepatologist 
Liver ultrasound performed to evaluate liver 
and biliary tree 
Evaluate any abnormalities found 
Check history for exposure to chemical agents  
Remove chemical exposure and have subject 
seen by hepatologist 
Obtain hepatology consult if liver function 
continues to rise beyond 14 days 
Contact Medical Monitor 
We request that cases be discussed with the Medical Monitor whenever investigational 
product is being held for liver function test abnormality. 
Ig = Immunoglobulin; INR = international normalized ratio; OTC = over-the-counter. 
For suspected cases of cholestatic liver injury (eg, aminotransferase increase concurrent with 
hyperbilirubinemia, or liver biopsy suggesting cholestasis and/or ductopenia), patients will be 
followed to assess long-term outcome. Additional diagnostic and follow-up procedures might be 
implemented as appropriate to fully assess the event. 


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5.3.1. 
Renal Impairment 
A reduced dose of 600 mg/day (200 mg in the morning and 400 mg in the evening) is 
recommended in study subjects with mild to severe renal impairment (creatinine clearance 
[CLcr] 15 to 89 mL/min estimated by Cockcroft-Gault using actual body weight). 
5.4. 
Concomitant Medications 
During the study, if the use of any concomitant treatment becomes necessary (eg, for treatment 
of an AE), the treatment must be recorded on the source document and electronic Case Report 
Form (eCRF), including the reason for treatment, name of the drug, dosage, route, and date of 
administration. All medications including prescription, over-the-counter (OTC), herbal and other 
nutritional vitamins and/or supplements taken within 28 days of P1-C1D1 will be recorded on 
the eCRF. Analgesic use and analgesic regimen will be recorded as described in Section 6.4.11. 
Subjects enrolled in studies with pexidartinib who are also receiving concomitant warfarin 
should have their anti-coagulation status carefully monitored, especially shortly after initiation of 
pexidartinib, for the potential need to make adjustments in warfarin dosing. In particular, INR 
should be obtained just prior to initiation of pexidartinib, within 1 to 2 weeks after initiation, and 
periodically thereafter. Dose adjustments of warfarin should be made as medically indicated. 
5.4.1. 
CYP3A and UGT Inhibitors 
Although pexidartinib does not appear to inhibit cytochrome P450 (CYP) drug-metabolizing 
enzymes to an important extent, caution is warranted when administering pexidartinib to subjects 
taking drugs that are highly dependent on CYP for metabolism and have a narrow therapeutic 
index. It is not known whether systemic exposure to these medications will increase while 
subjects are receiving pexidartinib. 
Of the five major CYP isoforms, 3A4 (BFC) may be involved in Phase 1 metabolism of 
pexidartinib, with possibly CYP1A2 playing a minor role (see Section 15.1 for a list of common 
CYP3A4 inhibitors and inducers). In general, strong inducers of CYP3A4 should be avoided 
unless clinically necessary. These include anticonvulsants, certain mycin antimicrobials, and 
antiretrovirals. Some common examples include  inducers such as rifampicin, carbamazepine, 
phenytoin, efavirenz, and nevirapine.21 
Avoid concomitant use of pexidartinib with moderate or strong CYP3A inhibitors or UGT 
inhibitors.  If concomitant use with a moderate or strong CYP3A inhibitor or UGT inhibitor 
cannot be avoided, reduce the pexidartinib dose according to the recommendations in Table 5.3. 
If concomitant use of a moderate or strong CYP3A inhibitor or UGT inhibitor is discontinued, 
increase the pexidartinib dose (after 3 plasma half-lives of the moderate or strong CYP3A 
inhibitor or UGT inhibitor) to the dose that was used before starting the inhibitor. 


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Table 5.3: 
Recommended Dosage Reductions for Pexidartinib with Concomitant Use of 
Moderate or Strong CYP3A Inhibitors or UGT Inhibitors 
Current Total Daily Dose 
Modified Total Daily Dose 
Administration of Modified 
Total Daily Dose 
800 mg 
400 mg 
200 mg twice daily 
600 mg 
400 mg 
200 mg twice daily 
400 mg 
200 mg 
200 mg once daily 
5.4.2. 
Hormonal Contraceptives 
Pexidartinib has been indicated to be a moderate CYP3A4 inducer, as concurrent administration 
of pexidartinib decreased the AUCinf of the CYP3A4 substrate midazolam by 57%.  As the 
hormonal contraceptive ethinyl estradiol is a CYP3A4 substrate, there is a potential that exposure 
of ethinyl estradiol may decrease on concurrent administration with pexidartinib.  As 
pexidartinib may cause embryo-fetal harm when administered to a pregnant woman, females of 
reproductive potential should be advised to use an effective, non-hormonal method of 
contraception during treatment with pexidartinib and for 1 month after the last dose.  Males with 
female partners of reproductive potential should be advised to use an effective method of 
contraception during treatment with pexidartinib and for 1 month after the last dose.  Female 
partners of male patients should concurrently use effective contraceptive methods (hormonal or 
non-hormonal). 
5.4.3. 
Acid-reducing Agents 
Avoid the concomitant use of proton pump inhibitors (PPIs) while taking pexidartinib.  As an 
alternative to a PPI, administer pexidartinib 2 hours before or 2 hours after taking a 
locally-acting antacid, or if using a histamine 2 (H2)-receptor antagonist, administer pexidartinib 
at least 2 hours before or 10 hours after taking an H2-receptor antagonist. 
5.5. 
Precautions and Restrictions 
Because pexidartinib is a substrate for CYP3A4/5 and some fruits are CYP3A4/5 inhibitors, 
foods or beverages containing CYP3A4/5 inhibiting fruits (eg, grapefruit, pomelo, star fruit, and 
pomegranate) should be avoided throughout the study. 
5.6. 
Blinding and Unblinding 
Part 1 will be the placebo-controlled double-blind phase of the study where treatment assignment 
will remain unknown to the study subjects, Investigators, study site personnel, safety laboratory 
personnel, central imaging readers, and representatives of Daiichi Sankyo involved in the 
conduct and/or management of the trial. Pexidartinib and placebo capsules will be identical in 
appearance. All study treatment (pexidartinib or placebo) will be labeled with the study number, 
a unique number, and any additional information required in accordance with government 
regulations. Further details are contained in the separate Pharmacy Manual. 


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5.6.1. 
Unblinding 
5.6.1.1. 
Emergency Unblinding 
In the cases of emergency where, in the Investigator’s opinion, immediate unblinding of the 
treatment is necessary in order to evaluate further course of action, the Investigator should access 
the interactive web/voice response system (IXRS) to initiate subject unblinding as follows: 
IXRS Option 04: Emergency Unblinding  
What to enter for each subject: 
 Confirm to continue with unblinding 
 Subject ID 
What the IXRS will provide back to the site: 
 Subject’s randomized treatment arm 
 IXRS transaction confirmation 
The Investigator may also contact the Sponsor’s Medical Monitor or designee for information 
related to pexidartinib adverse effects in making the decision to unblind. (Contact information –
refer to Section 10.1.2.)  It is important to note that, once unblinded, a subject cannot receive 
further study treatment and must discontinue from the study. 
The Investigator should promptly document and report to the Sponsor any unblinding for 
emergency reasons (eg, accidental unblinding, unblinding due to an SAE) of the investigational 
product(s).   
The “Emergency Unblinding” option should not be used for subjects who may need unblinding 
to move into Part 2 after the confirmed disease progression in Part 1. Please see the next section 
for more information. 
5.6.1.2. 
Unblinding during Part 1 Week 13 to Week 25 for Disease Progression 
In addition to the Emergency Unblinding option, if a central reading confirms RECIST 1.1-
defined disease progression at or after Week 13 but before Week 25 visit, treatment assignment 
may be unblinded and potential continuation of a subject to Part 2 of the study will be assessed. 
If an investigator suspects disease progression during this period, an MRI should be submitted to 
the central reader with a request for an expedited read for potential disease progression. The 
investigator should alert the Sponsor and the Clinical Research Organization (Novella Clinical) 
Medical Monitors that the expedited read request has been made. Once the expedited read results 
are received, the investigator should discuss with the Sponsor and Novella Clinical Medical 
Monitors about the decision to unblind. If it is confirmed that the subject’s study treatment 
should be unblinded, the Sponsor or designee will authorise the unblind in the IXRS system. 
Only once the Sponsor authorisation has been logged in IXRS can the site then unblind the 
subject, which will also be done through IXRS: 
IXRS Option 04: Part 1 Week 13 Unblind 
What to enter for each subject: 


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 Confirm to continue with unblinding 
 Subject ID 
What the IXRS will provide back to the site: 
 Subject’s randomized treatment arm 
 IXRS transaction confirmation 
DO NOT USE THE EMERGENCY UNBLIND FUNCTION FOR SUBJECTS WITH 
DISEASE PROGRESSION as they will not be able to receive further treatment and must 
discontinue from the study (as Emergency Unblinding cannot be undone). 
Once in receipt of the unblind information, the site may then choose to continue the subject into 
Part 2 of the study or discontinue the subject from the study. Subjects receiving placebo will be 
eligible for early entry into Part 2 of the study. Effective 30 Sep 2016, subjects receiving placebo 
will be discontinued instead of being eligible to enter Part 2. Subjects receiving pexidartinib will 
be discontinued from the study unless the Investigator and the Sponsor’s Medical Monitor judge 
that the subject would potentially benefit from continued treatment with pexidartinib. 
For statistical analysis of endpoints at the end of Part 1, a clinical data cut-off date will be 
defined for the point when all randomized subjects complete or are discontinued from Part 1 with 
appropriate End of Part 1 follow-up. All data up to this date will be cleaned and locked. 
Afterwards, unblinding of database will be performed to facilitate the data analyses, including 
the data from the double-blind Part 1 and available data from Part 2. Such unblinding is only 
intended for the sponsor and the Contract Research Organization. Subjects who entered Part 2 
may continue to receive open-label pexidartinib treatment. Updated analysis of Part 2 data only, 
in the form of summary and descriptive statistics, will be performed at the end of the 
trial.  Additional updates between the above-mentioned cut-off and end of the trial may also be 
performed. 
5.6.1.3. 
Unblinding at the End of Part 1 
As of 30 Sep 2016, subjects on placebo in Part 1 are no longer allowed to enter Part 2 to receive 
open-label pexidartinib. After completion of the end of Part 1 assessments (Part 1 Completion 
visit/Early Termination visit), subjects who wish to continue onto the open label part of this 
study (Part 2) will be unblinded and those on placebo will be discontinued; subjects on 
pexidartinib in Part 1 may continue into Part 2 to continue to receive pexidartinib. (Detailed 
instructions will be provided separately.) 
5.7. 
Description of Investigational Agents 
Pexidartinib (PLX3397) 
Pexidartinib is an HCl salt with a white to off-white crystalline solid appearance. PLX3397 HCl 
capsules are provided as 200 mg (200 mg free base equivalent) hypromellose capsules for oral 
administration containing the following excipients: Poloxamer 407, mannitol, crospovidone and 
magnesium stearate. Formulation of pexidartinib is J-3397-AF in hydroxypropyl methylcellulose 
capsules. 
Placebo 


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The matching placebo capsules for oral administration contain Poloxamer 407, mannitol, 
crospovidone and magnesium stearate only, with an increased amount of mannitol to adjust for 
the absence of the active pharmaceutical ingredient. 
5.8. 
Packaging and Labeling 
PLX3397-HCl 200 mg capsules and placebo capsules are manufactured, packaged, and labeled 
according to Good Manufacturing Practices and Good Clinical Practices (GCP) at the following 
address: 
 
Catalent Pharma Solutions, Inc. 
10245 Hickman Mills Drive 
Kansas City, MO 64137 
USA 
5.9. 
Storage, Handling, and Accountability 
Study treatment (pexidartinib and placebo) in accordance with this protocol should be stored at 
the sites in a secure controlled facility and only provided to subjects who signed a consent form 
and are participating in the study. The study treatment must be stored at room temperature (do 
not store above 25ºC/77ºF). Excursions are permitted from 15ºC to 30ºC (59ºF to 86ºF), however 
approval for continued use must be obtained from Daiichi Sankyo for excursions <15 ºC or 
≥25ºC (77ºF). Subjects will be instructed to store the study treatment at room temperature out of 
the reach of children or other cohabitants. 
The Food and Drug Administration and other health authorities require accurate and up-to-date 
accounting of the disposition of all study treatment received by the site. Records of study 
treatment disposition required by federal law include the dates and quantities received from the 
Sponsor, the dates and quantities administered to a subject, including the identity of the subject, 
the dates and quantities returned by a subject (if applicable), and the dates and quantities of final 
disposition (ie, dates/quantities that unused study treatment is returned to the Sponsor/designee 
or dates/quantities that unused study treatment is destroyed on-site/off-site as applicable in 
accordance with GCP and site standard operating procedures). For any study treatment that is 
destroyed, destruction details must be documented on accountability and destruction logs and 
include at a minimum the number of bottles and capsules destroyed, batch number (if 
applicable), and the date and method of destruction. Any study treatment accidently or 
deliberately destroyed must be recorded in a timely fashion, including an explanation for the 
destruction in writing. Any discrepancies between the amounts of study treatment dispensed and 
returned must also be explained in writing. 
The Investigator is responsible for the overall accountability and accurate and up-to-date 
documentation/disposition of all unused and used study treatment supplied by the Sponsor. 
Dosage form (ie, capsules) site level accountability documentation is to be included with each 
drug supply return shipment (or other returning facility, such as another depot). This is required 
as part of the receiving records for return shipments. 


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Dosage form (ie, capsules) site level accountability documentation is required as part of the 
disposition records of IP. The dosage form site level accountability documentation should be 
appended to the Certificate of Destruction. 


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6. 
STUDY CONDUCT 
6.1. 
Study Personnel and Organizations 
The contact information for the Sponsor and Novella Clinical Medical Monitor for this study can 
be found in the Study Reference Manual. The contact information for the central imaging reader, 
central and any additional clinical laboratories, the coordinating Investigator for each member 
state/country, and Novella Clinical can be found in the Study Reference Manual. A full list of 
Investigators is available in the Sponsor’s Investigator database. 
6.2. 
Recruitment of Subjects 
Subjects may be recruited from the Investigator’s local practice or referrals from other 
physicians. Any advertisements used for recruitment purposes will be submitted to and reviewed 
by the IRB/IEC. It is not envisioned that prisoners or other populations who might be subject to 
coercion or exploitation will be enrolled into this study. 
6.3. 
Treatment Group Assignments 
Once all screening procedures have been completed and study eligibility has been confirmed, 
subjects will be enrolled in the study and centrally randomized in a 1:1 ratio to receive either 
pexidartinib or placebo twice daily for 24 weeks during Part 1 of the study. Randomization will 
be stratified by US versus non-US sites and by upper extremity versus lower extremity 
involvement. The randomization schedule will be developed by an independent third party 
vendor to ensure that the subject, site personnel, and Sponsor remain blinded to treatment 
assignment. Clinical site staff will obtain investigational medicinal product dispensing 
information by accessing the IXRS. See Study Reference Manual for further details. 
After randomization, the first dose of study treatment (P1-C1D1) should occur within 3 days of 
the randomization date. 
During Part 2 of the study, all subjects will receive open-label pexidartinib. 
6.4. 
Study Procedures 
Study procedures are summarized in Table 15.2 and Table 15.3. Descriptions of the specific 
study procedures are provided in the following subsections, and study procedures are listed by 
visit in Section 15.2. Additional details are provided in the Study Reference Manual, MRI 
Procedure Manual, or Laboratory Manual as applicable. 
Each subject must sign and date an informed consent form before undergoing any study 
procedure (including screening procedures, unless the screening procedure as outlined in the 
Study Reference Manual and is considered standard of care). New safety measures were 
implemented effective on 30 Sept 2016 (see Section 1.6). Investigators and subjects must be 
informed of the new safety information and decide whether to continue in the study. If, after 
consultation with the subject, it is deemed to be in their best interest to continue treatment, the 
subject must be re-consented. 


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Screening procedures are to be performed within the 42 days before the first dose of study 
treatment, unless otherwise noted. 
If a dose interruption is required, study assessments should be performed as scheduled, 
irrespective of the study treatment delay, with the exception of PK assessments which should be 
deferred until the first clinical visit after dosing resumed. 
The last subject last visit defines the end of the study. 
All subjects who complete at least 24 weeks of open-label pexidartinib treatment in Part 2 
without disease progression will be eligible to continue for longer efficacy and safety follow-up 
or to participate in a separate protocol to continue receiving pexidartinib. 
6.4.1. 
Demographics and Medical History 
Subject demographic data such as age, sex, ethnicity (where legally allowed), and race will be 
obtained during the Screening visit. A complete medical history will also be obtained during the 
Screening visit. The medical history will comprise all prior and current medical history, 
including PVNS/GCT-TS treatment history and smoking history. 
6.4.2. 
Vital Signs and Subject Weight 
Vital signs, including systolic/diastolic blood pressure, pulse rate and temperature will be 
measured in accordance with institutional standards and generally should be performed before 
invasive procedures, eg, blood draws. Vital signs and weight will be measured at the indicated 
study visits in the Schedule of Events. 
Height will be measured at the Screening visit only. 
6.4.3. 
Physical Examination 
A physical examination will include the following systems or areas: general appearance; oral 
cavity and neck; cardiothoracic; dermatologic; abdominal; musculoskeletal; and neurological. 
The examination will be performed by a qualified individual such as the Investigator at the study 
visits indicated in the Schedule of Events (Table 15.2 and Table 15.3). 
6.4.4. 
Range of Motion Assessment 
Range of motion of the joint will be assessed by a qualified, independent, and blinded third 
party, such as an orthopedic surgeon or a physical therapist, using goniometers according to a 
standardized method based on American Medical Association disability criteria.20  
Measurements will be recorded in degrees. Details of the measurement procedure for each joint 
will be provided in the Study Reference Manual. 
6.4.5. 
Electrocardiogram 
A standard 12-lead ECG will be obtained at the study visits indicated in the Schedule of Events 
(Table 15.2 and Table 15.3). Subjects should rest in the supine position for at least 5 minutes 
before the ECG recording is started. The ECG recordings must be performed using a standard 
high-quality and high-fidelity electrocardiography machine equipped with computer-based 
interval measurements. For safety monitoring purposes, the ECGs should be reviewed, signed, 
and dated promptly by a qualified physician (or physician’s assistant, nurse practitioner) and any 


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clinically important finding recorded on the appropriate eCRF. The Investigator is responsible 
for interpreting all ECGs. The results may include heart rate, RR interval, PR interval, QRS 
interval, QT interval, and QTcF interval. 
At the visits when ECGs are to be performed, subjects should be told to NOT take the morning 
dose of study treatment; instead, they should be told to bring their bottle of study treatment to the 
clinic and to take the morning dose upon instruction by the site staff. 
6.4.6. 
Echocardiogram 
A resting echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan will be performed at 
the study visits indicated in the Schedule of Events for Part 1 (Table 15.2) and Part 2 
(Table 15.3) of the study to evaluate subjects’ cardiac function throughout study participation. 
(For the purposes of this protocol, “ECHO scan” and “MUGA scan” will be used 
interchangeably.) The choice of whether to perform ECHO or MUGA scanning will be based on 
the preference of the Principal Investigator, but platforms should not be switched during the 
course of a subject’s study participation. Echocardiogram or MUGA scanning should only be 
repeated if more than 3 months have elapsed since the last procedure. Subjects who show a 
reduced ejection fraction relative to baseline at the last visit should be followed until a stable 
ejection fraction is measured by two consecutive tests.  For safety monitoring purposes, the scan 
must be evaluated promptly by a qualified physician (or qualified physician’s assistant or nurse 
practitioner). Clinically important findings, including the ejection fraction, will be recorded on 
the appropriate eCRF. The Investigator is responsible for providing the interpretation of all scan 
findings.   
6.4.7. 
Clinical Laboratory Evaluations 
Clinical laboratory evaluations will be performed centrally at the study visits indicated in the 
Schedule of Events (Table 15.2 and Table 15.3). Collection, processing, labeling, handling, and 
shipment of samples will be outlined in the separate Laboratory Manual. Local laboratory 
evaluations are permitted to facilitate assessment of AEs or support dosing decisions; every 
effort should be taken to submit a sample to the central laboratory at the same time for 
unscheduled samples. 
Clinical laboratory evaluations will be performed as outlined below: 
Blood samples for analysis of the following clinical chemistry, hematologic, coagulation, and 
hormone parameters will be obtained: 
Clinical Chemistry 
 Sodium 
 Total protein  
 Potassium 
 Albumin  
 Chloride 
 Triglycerides* 
 CO2 
 Total cholesterol* 
 Calcium 
 HDL-cholesterol* 


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 Phosphorus 
 LDL-cholesterol* 
 Glucose* 
 Uric acid  
 Blood urea nitrogen 
 Lactate dehydrogenase 
 Creatinine 
 
 * Fasting is recommended but not required. 
Liver Function Tests 
Alkaline phosphatase 
Total bilirubin 
 AST 
 ALT 
 Direct bilirubin 
 GGT 
Hematology 
Red blood cell count 
Hemoglobin 
 White blood cell count with 
differential 
 Hematocrit 
 Platelet count 
 
Hepatitis Panel 
Hepatitis B virus surface antigen test and HCV antibody test 
Coagulation 
Prothrombin time, activated partial thromboplastin time, and INR. 
Hormone Tests 
Females 
Males 
 FSH 
 FSH 
 LH 
 LH 
 Progesterone 
 Testosterone 
 Estradiol 
 
Urinalysis (dipstick and microscopic analysis) 
Urine samples will be obtained for analysis of the following parameters: 
 pH 
 Ketones/acetone  


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 pH 
 Ketones/acetone  
 Protein/albumin 
 Hemoglobin/blood  
 Glucose/sugar 
 Red blood cells, white blood cells, 
epithelial cells, bacteria, casts, 
crystals  
 Nitrites 
6.4.8. 
Patient Reported Outcome Instruments 
Subjects will complete via an electronic diary the BPI Worst Pain NRS item, the Worst Stiffness 
NRS item, the PROMIS Physical Function Scale, the EQ-5D-5L, and the Patient Global Rating 
of Concept item for ability to carry out everyday activities at the indicated study visits in the 
Schedule of Events (Table 15.2 and Table 15.3). In addition, subjects will be given both the BPI 
Worst Pain NRS item and the Worst Stiffness NRS item to complete on an outpatient basis, for 
at least 4 of 7 consecutive days (Day -7 to Day -1) prior to the indicated study visits in the 
Schedule of Events. At the Week 25 visit, subjects will also complete the Patient Global 
Impression of Change item for tumor-related stiffness. 
On study visit days including Screening, subjects will complete instruments prior to any invasive 
procedures and prior to the morning dose. 
6.4.8.1. 
Most Disturbing Symptom Assessment 
Before initiating study treatment, the subject will be asked to identify which symptom of pain, 
stiffness, or compromised ability to carry out everyday activities they find to be most disturbing. 
6.4.8.2. 
BPI Worst Pain NRS Item 
The BPI Worst Pain NRS item is a one-item self-administered questionnaire assessing the 
“worst” pain in the last 24 hours (Section 15.5). The NRS for this item ranges from 0 (“no pain”) 
to 10 (“pain as bad as you can imagine”). 
6.4.8.3. 
Worst Stiffness NRS item 
The Worst Stiffness NRS item is a one-item self-administered questionnaire assessing the 
“worst” stiffness in the last 24 hours (Section 15.6). The NRS for this item ranges from 0 (“no 
stiffness”) to 10 (“stiffness as bad as you can imagine”). 
6.4.8.4. 
PROMIS Physical Function Scale 
Physical function items relevant to the assessment of lower and upper limb function are to be 
selected from the PROMIS physical function item bank (Section 15.7). Items assessing lower 
limb function will be administered to subjects with the lower extremity tumors, and items 
assessing upper limb function will be administered to subjects with upper extremity tumors. The 
results from both sets of items will be combined and analyzed together. 


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6.4.8.5. 
EQ-5D-5L 
The EQ-5D-5L is a preference-based general health status or health-related quality of life 
instrument consisting of two parts (Section 15.8). The first part comprises five domains 
(mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) each of which can 
have five levels ranging from no problems through profound difficulties. Accordingly, 3125 
potential health profiles can be generated to which public preferences or utilities are applied. 
These data can subsequently be used in an economic evaluation or cost-utility analysis. The 
second part of the EQ-5D-5L is a Visual Analogue Scale on which the subject rates their current 
health, with 0 representing the “worst health you can imagine” and 100 representing the “best 
health you can imagine.” 
6.4.8.6. 
Patient Global Impression of Change and Global Rating of Concept Items 
A Patient Global Impression of Change item (Section 15.9) assessing tumor-related stiffness will 
be administered at the Part 1 Completion (Week 25) and 28 Day Post-treatment visits. A Patient 
Global Rating of Concept item (Section 15.9) for ability to carry out every day physical activities 
will be administered at defined study visits. Results from these items will be used in exploratory 
analyses to define the magnitude of meaningful change on the Worst Stiffness NRS and 
PROMIS Physical Function Scale, respectively. 
6.4.9. 
Tumor Imaging 
Non-contrast MRI of the affected joint will be performed at the study visits indicated in the 
Schedule of Events (Table 15.2 and Table 15.3). All MRI scans will be centrally read.  Local 
evaluation of radiological response, stable or progressive disease according to RECIST 1.1 will 
be recorded in the eCRF. The central MRI assessment report of progression status will not be 
provided unless requested. The Investigator will follow procedures (including instructions on 
proper imaging technique, and labeling) outlined in a separate MRI Procedure Manual. The 
results of the baseline, centrally read MRI scan will be used to qualify a subject, and all 
subsequent MRI scans will be read centrally in a manner blinded to treatment assignment and 
other clinical trial data at the conclusion of Part 1, the placebo-controlled portion of the study. 
If disease progression is indicated clinically or by local radiologic assessment according to 
RECIST 1.1 at or after Week 13 but before Week 25, the Investigator may request an expedited 
central review for evaluation of disease progression. If a central reading confirms RECIST 1.1-
defined disease progression, treatment assignment will be unblinded, and subjects receiving 
placebo will be eligible for early entry into Part 2 of the study as described in the Study 
Reference Manual. Effective 30 Sep 2016, subjects receiving placebo will be discontinued 
instead of being eligible to enter Part 2. Subjects receiving pexidartinib will be discontinued 
from the study unless the Investigator and the Sponsor’s Medical Monitor judge that the subject 
would potentially benefit from continued treatment with pexidartinib. 
During Part 2, if indicated, Investigators should request confirmation of radiologic disease 
progression by central read. Otherwise, central reading of MRI scans may be performed during 
or after the subject has completed the study. Details for Part 2 MRI scan reads are outlined in the 
MRI Procedure Manual. 
Subjects who terminate the study because of radiologic disease progression will not have a 
follow-up MRI at their Post-treatment visit. 


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6.4.10. 
Surgical Assessment Questionnaire 
The Surgical Assessment Questionnaire (Section 15.10) will be completed by a qualified 
individual (eg, orthopaedic oncologist) to assess the surgical status of the subject at the 
Screening visit and at time points shown in the Schedule of Events. 
6.4.11. 
Surgical Data and Outcome Follow-up 
At or after Week 25 evaluation, subjects may be considered for surgery to remove the tumor. The 
surgery is recommended to be performed 1-3 weeks after the last dose of the study treatment. 
After completion of the end of Part 1 assessments (Part 1 Completion visit/Early Termination 
visit), subjects who wish to continue onto the open label part of this study (Part 2) will be 
unblinded and those on placebo will be discontinued and will not need to have surgical data 
follow-up. 
Detailed information about the surgery will be collected, including but not limited to: 
 Reasons of the surgery 
 Planned surgical procedure and actual surgical procedure performed 
 Surgical margin 
 Copies of surgical report and pathology report, if available 
 Surgery complications such as infection, delayed healing 
Surgically resected tumor samples will be collected for evaluation of study treatment effects on 
tumor cells. 
Before the surgery is performed, the subject should have an additional visit for ROM and PRO 
(pain and stiffness scores, PROMIS questionnaire) evaluation, if these are not done within 6 
weeks prior to the surgery. Subjects do not need to have the End-of-Study visit if a decision has 
been made to have surgical resection of the tumor under study treatment.  
At 4 months (+/- 2 weeks) after the surgery, the subject should have a visit for MRI scan of the 
tumor affected joint, ROM and PRO (pain and stiffness scores, PROMIS questionnaire) 
evaluations. After this visit, the subject should be followed for disease recurrence (defined as the 
need for any new therapeutic intervention of TGCT) at 8, 12, 18 and 24 months after surgery. 
Such follow-up can be performed via phone contact with the subject. 
Subjects who undergo surgery may be rolled into a separate protocol for surgery and its outcome 
data collection. 
6.4.12. 
Analgesic Use and Analgesic Regimen 
Subjects will have an electronic diary in which to record any analgesics, including nonsteroidal 
anti-inflammatory drugs and prescription analgesics, taken during the period before 
investigational product initiation and during the time period when the BPI Worst Pain and Worst 
stiffness Items are scheduled for completion. Subjects must have a stable prescribed analgesic 
regimen during the 2 weeks prior to the first dose of study treatment. During the study, whenever 
possible, the type and dose of long-acting narcotic analgesic and non-narcotic analgesic should 
be kept stable while the dose of short-acting (or rescue) narcotic analgesic might be titrated as 


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needed. Analgesic use will be quantified by multiplying the daily dose unit by the number of 
units taken, averaged by the number of days with available data.22  For subjects who have 
changed narcotic type or if dosages have been changed in subjects concomitantly receiving 
different narcotic types, analgesic use will be calculated following equianalgesic conversion to 
morphine-equivalent doses.23 
Analgesic regimen, both prescription and OTC, will be collected in the eCRF in the same 
manner as other concomitant medications. 
6.4.13. 
Healthcare Resource Use and Productivity 
During Part 1, major HCRU and subject productivity (Section 15.12) will be recorded at 
baseline, selected clinic visits, and at the Completion and 28 Day Post-treatment visits 
(Table 15.2). Questions will be administered to the subject as part of the clinical interview. 
Information will be captured about episodes of hospitalization, including date of admission, date 
of discharge, primary diagnosis at discharge, and days of different levels in inpatient intensity of 
care (Section 15.12). Information on subject employment status will be recorded and, if the 
subject is working, days lost from work because of PVNS/GCT-TS will be assessed 
(Section 15.11). 
6.4.14. 
Pregnancy Test 
For female subjects of child-bearing potential only, a serum pregnancy test (β-human chorionic 
gonadotropin) will be performed at the study visits (centrally for all but local laboratory  is 
allowed at the end of study visit) indicated in the Schedule of Events (Table 15.2 and 
Table 15.3). 
6.4.15. 
Pharmacodynamic Sampling 
Archival surgical tissue from PVNS/GCT-TS tumors (if available) will be obtained at the 
Screening visit (or when available and consented) and will be collected and stored for 
exploratory biomarkers related to pexidartinib and/or disease. Plasma for circulating PDy 
biomarkers will be collected once per day on the same days when PK blood sample(s) are drawn 
(eg, predose) and will be analyzed for markers of pexidartinib exposure and for exploratory 
biomarkers, including CSF-1 and adiponectin. 
Consult the Laboratory Manual for detailed instructions on collection, processing, handling, 
storage, and sample shipment. 
6.4.16. 
Pharmacokinetic (PK) Sampling 
PK sampling will be performed at the study visits indicated in the Schedule of Events for Part 1 
(Table 15.2) and Part 2 (Table 15.3). Each site must choose one of the schedules for each subject 
and must adhere to the selected schedule (Table 6.1) for the duration of the study: 
 


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Table 6.1: 
PK Schedules 
Visit 
Schedule 1 
Schedule 2 
Week1 P1C1D1 
Pre-dose 
Pre-dose 
Week3 P1C1D15 
Pre-dose  
Post-dose: 0.5, 1, 2, 3, 4, and 6 hours 
Pre-dose 
Post-dose: Between 1-3 hours 
Week5 P1C2D1 
 
Random post-dose 
Week9 P1C3D1 
Random post-dose 
Random post-dose 
Week17 P1C5D1 
Random post-dose 
Random post-dose 
Week25 P2C1D1 
Pre-dose 
Pre-dose 
Week27 P2C1D15 
Pre-dose 
Post-dose: 0.5, 1, 2, 3, 4, and 6 hours   
Pre-dose 
Post-dose: Between 1-3 hours 
Week29 P2C2D1 
 
Random post-dose 
Subjects should be told to NOT take the morning dose of study treatment at the P1-C1D15, 
P2-C1D1 (Week 25), and P2-C1D15 visits. Instead, they should be told to bring their bottle of 
study treatment to the clinic and follow dosing instruction by the site staff.  
The exact time of dose administration should be recorded along with the corresponding PK blood 
samplings. The exact time of the three preceding doses should also be recorded. 
Detailed instructions on collection, processing, handling, storage, and sample shipment are 
contained in the separate Laboratory Manual. 
6.4.17. 
Adverse Events 
Adverse events will be monitored throughout the study. Adverse events and SAEs will be 
monitored and recorded in the source documents and eCRFs from the time the subject signs 
informed consent through the subject’s Post-Treatment Visit 28 days (± 7 days) after the last 
dose of study treatment. Adverse events (including clinically significant changes in laboratory 
results, ECHO results, and hormone testing results) should be monitored until they are resolved 
or are determined to be due to a subject’s stable or chronic condition or intercurrent illness(es). If 
an AE remains unresolved at the conclusion of the study, the Investigator should follow the AE 
until s/he deems it to be resolved, stable, or not expected to worsen per medical judgment (eg, 
resolved with sequelae). Definitions, documentation, and reporting of AEs are described in detail 
in Section 9. 
6.4.18. 
Study Treatment Compliance 
At the study visits indicated in the Schedule of Events, blinded pexidartinib or placebo will be 
dispensed to subjects in Part 1, and open-label pexidartinib will be dispensed to subjects in 
Part 2. The appropriate study personnel will document and maintain records of study treatment 
dispensing to each subject and any returns at each study visit. 
Subjects will complete a dosing diary to record the number of capsules/date/time taken during 
each dosing cycle. 


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At each clinic visit, subjects will be assessed for compliance with study treatment administration, 
ie, actual capsules taken / expected capsules taken; so must return all bottles (used/unused) at 
each dispensing visit. 
Further details can be found in the Study Reference Manual. 
6.5. 
Study Procedures 
The Investigator should conduct the study in compliance with the protocol agreed to by Sponsor 
and, if required, by the regulatory authority(ies), and that was given approval/favorable opinion 
by the IRB/IEC. 
A deviation to any protocol procedure, or a waiver to any stated criteria will not be allowed in 
this study except where necessary to eliminate immediate hazard(s) to the subject. Sponsor must 
be notified of all intended or unintended deviations to the protocol (eg, inclusion/exclusion 
criteria, dosing, missed study visits) on an expedited basis. 
The Investigator, or person designated by the Investigator, should document and explain any 
deviation from the approved protocol. 
If a subject was ineligible or received the incorrect dose or investigational treatment and had at 
least one administration of the study treatment, data should be collected for safety purposes, and 
the Sponsor’s Medical Monitor or designee should be informed immediately. 
The Investigator should notify the IRB/IEC of deviations from the protocol in accordance with 
local procedures. 


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7. 
STATISTICAL METHODS 
7.1. 
Randomization and Stratification 
The randomization ratio for Part 1 of the study will be 1:1 for active (pexidartinib) versus 
placebo. Randomization will be stratified by US versus non-US sites and by upper extremity 
versus lower extremity involvement. 
7.2. 
Analysis Sets 
Randomized Analysis Set 
The Randomized Analysis Set consists of all subjects in this study that were randomized. 
ITT Analysis Set 
The Intent-to-treat (ITT) Analysis Set is defined as all randomized subjects, which is the same as 
the Randomized Analysis Set. The primary efficacy analysis as well as all other efficacy 
analyses will be performed in the ITT Analysis Set. Subjects will be included in the treatment 
group to which they were randomized, regardless of the treatment actually received. 
Safety Analysis Set 
The Safety Analysis Set consists of all subjects in the Randomized Analysis Set who received at 
least one dose of study treatment. All safety analyses will be completed in the Safety Analysis 
Set. Subjects will be included in the treatment group based on the actual treatment they received. 
Per-protocol Analysis Set 
The Per-protocol Analysis Set will be defined as subjects in the ITT Analysis Set who did not 
have major eligibility/protocol violations and who are compliant with regard to study treatment 
administration, defined as taking at least 70% of their scheduled dose of study treatment, 
regardless of scheduled dose reduction. 
7.3. 
Procedures for Handling Missing, Unused, and Spurious Data 
For the primary efficacy analysis as well as for all analyses of responder proportion endpoints 
performed on the ITT and Per-protocol Analysis Sets, subjects who do not provide data for the 
responder endpoint will be considered nonresponders, ie, assigned to the less favorable outcome 
for the endpoint. Subjects who discontinue the study before Week 25 and do not have a Week 25 
MRI will be considered nonresponders. Analysis of the endpoints involving range of motion and 
PROs, which are measured at multiple time points, by comparing the central tendency of 
continuous variables between treatment groups (not the responder type of analysis for a binary 
variable), will be performed using mixed models for repeated measurements (MMRM) 
incorporating all available measurements from each subject.24,25,26,27,28 
7.4. 
General Statistical Considerations 
Continuous variables will be summarized by the number of observations, mean, standard 
deviation, median, 25th and 75th percentile, and minimum and maximum values. Categorical 
variables will be summarized using frequency counts and percentages. 


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In general, the baseline value for an efficacy variable, including that for a PRO variable, is the 
last non-missing value before randomization. The baseline value for a safety variable is the last 
non-missing value before the first dose of study treatment. The exceptions are several special 
variables in Part 2, such as the tumor response and duration of response variables evaluated for 
pexidartinib treatment for subjects randomized to placebo in Part 1; in such cases, the baseline 
for Part 2 is defined as the last non-missing value before the first dose in Part 2. Further details 
are contained in the following sections and in the Statistical Analysis Plan (SAP). 
For the primary efficacy endpoint and secondary efficacy endpoints with the exception of 
duration of response, treatment comparison at Week 25 will be performed based on the data 
collected during the visits between baseline and Week 25. Point estimate and accompanying 95% 
confidence interval (CI) will be computed. For duration of response, Kaplan-Meier product limit 
methodology will be utilized to provide estimates, including those for the median and 25th and 
75th percentiles. 
All statistical tests will be 2-sided. Unless otherwise specified, all tests will be carried out at the 
alpha = 0.05 level of significance. 
7.5. 
Study Population Data 
Subject disposition will be summarized for each randomized treatment group and in total for the 
ITT Analysis Set. The total number of subjects for each defined analysis population will also be 
tabulated. The demographic and baseline characteristics will be summarized descriptively for the 
ITT, Per-protocol, and Safety Analysis Sets. Study treatment exposure and study duration will be 
summarized using descriptive statistics by treatment group for the Safety Analysis Set. 
7.6. 
Efficacy Analyses 
7.6.1. 
Primary Efficacy Analysis 
The primary efficacy endpoint is the proportion of subjects who achieve a CR or PR at the 
Week 25 Visit (Table 2.1) based on centrally read MRI scans and RECIST 1.1. The primary 
analysis will be completed using the ITT Analysis Set. The proportions in the two treatment 
groups will be compared using Fisher’s exact test (two-sided) at the alpha = 0.05 level of 
significance. In addition, the two-sided 95% CI for the difference between the responder 
proportions in the two treatment groups will be provided, using the Wilson method.29,30 
As a supportive analysis, mid-p adjustment of Fisher’s exact test will also be performed.31,32 
Additionally, as a sensitivity analysis, the Cochran-Mantel-Haenszel test will also be carried out 
with the strata of US and non-US sites. 
7.6.2. 
Secondary Efficacy Analyses 
Secondary efficacy analyses will include the following treatment comparisons at the Week 25 
visit using the ITT Analysis Set: 
1. Mean change from baseline in range of motion of the affected joint, relative to a 
reference standard for the same joint (as defined below).20 
2. Proportion of responders based on centrally evaluated MRI scans and TVS. 


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3. Mean change from baseline score in the PROMIS Physical Function Scale. 
4. Mean change from baseline score in the Worst Stiffness NRS item. 
5. Proportion of responders based on BPI Worst Pain NRS item and analgesic use (BPI-30, 
as defined below). 
The above-listed endpoints will be analyzed using a hierarchical (“gatekeeping”) testing 
procedure.33  Thus, if the primary analysis of responder rate by RECIST 1.1 is statistically 
significant favoring pexidartinib (p <0.05), then secondary endpoint #1 will be analyzed, also 
based on the use of a two-sided test at the alpha = 0.05 level of significance. If secondary 
endpoint #1 is statistically significant (p <0.05), then the testing procedure will proceed to 
secondary endpoint #2, and so on. If the test for a particular endpoint is not statistically 
significant, the inference for all subsequent endpoints in the hierarchy will not be performed. 
For responder analysis based on the BPI Worst Pain NRS item and analgesic use, a BPI-30 
responder will be defined as a subject who (i) experienced a decrease of at least 30% in the mean 
BPI Worst Pain NRS item and (ii) did not experience a 30% or greater increase in narcotic 
analgesic use, comparing data collected during a 7-day period prior to the current visit for 
responder assessment with baseline values collected prior to the first dose of study treatment. A 
decrease of at least 30% in BPI Worst Pain NRS item has been shown to be clinically 
meaningful in several therapeutic areas.34,35  Subjects who do not provide data for the endpoint 
will be considered to be non-responders. Definition for increase in analgesic use is outlined in 
Section 6.4.11. See SAP for further details. 
The proportion of TVS responders (ie, those who achieve a CR or PR based on TVS criteria) at 
the Week 25 (Part 1 Completion) visit will be analyzed using the same methodology as that used 
for the primary efficacy endpoint (Section 7.6.1). 
Other secondary endpoints will be analyzed using MMRM. The dependent variable will be the 
change from baseline. Each of these models will include fixed effects for treatment group, time 
point, treatment group-by-time interaction, stratification factor of US sites versus non-US sites, 
and the baseline value of the corresponding endpoint as well as the baseline-by-time interaction. 
An unstructured variance-covariance matrix will be used. Statistical comparisons between 
treatment groups will be made at the specified time point. 
For the endpoint of range-of-motion, raw measurements of the affected joint will be performed 
using a goniometer and expressed in degrees (Section 6.4.4). The value for a given joint will be 
normalized to a reference standard, ie, full range-of-motion for the same joint, to provide a 
relative value. The reference standard will be derived from American Medical Association 
disability criteria 20 and are included in the SAP. The change from baseline in relative 
range-of-motion at the Week 13 and Week 25 visits will then be calculated. MMRM will be 
employed to analyze the change from baseline, and a statistical comparison between treatment 
groups will be made for the Week 25 visit. Joint type will also be properly accounted for in the 
model. 
Duration of response will also be analyzed as a secondary endpoint and will be summarized for 
responders based on (i) RECIST 1.1 and (ii) TVS. Duration of response is defined from the date 
of the first recorded response to the first date of documented disease progression. For subjects 
who do not have radiologic progression, the date of the last MRI scan will be censored. The 


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Kaplan-Meier product limit method will be used to compute the estimate and 95% CI of the 
median and 25th and 75th percentiles. The number of responders, the number with subsequent 
disease progression, and the number with censored values will be displayed as well. Within the 
framework of Kaplan-Meier methodology, the estimates for proportions of responders with 
response durations longer than 3, 6, 12, 18, and 24 months will also be provided. 
Duration of response will be summarized for responders in each of the following three groups: 
(A) 
Subjects randomized to receive pexidartinib in Part 1 using data from Part 1 and 
Part 2;  
(B) 
Subjects randomized to receive placebo in Part 1; 
(C) 
Subjects in Part 2 who were randomized to receive placebo in Part 1.  
For Group A, tumor assessment data from both Part 1 and Part 2 will be combined, and the 
baseline assessment will be the one recorded at the Screening visit. For Group B, the duration of 
response will be censored at Week 25 visit if no disease progression was documented, with the 
screening assessment serving as baseline. For Group C, the tumor assessment data in Part 2 will 
be used, with the baseline assessment being the last one before the first dose of pexidartinib in 
Part 2.  
For each of the above three groups, the percentage and 95% CI will be provided for the best 
overall response in the order of CR, PR, SD, PD, and “Inevaluable.” 
The analyses for the primary efficacy endpoint and BPI Worst Pain NRS item associated 
endpoints will also be performed on the Per-protocol Analysis Set as a sensitivity analysis. 
7.6.3. 
Additional Efficacy Analyses 
Additional efficacy endpoints to be analyzed at Week 25, with the exception of duration 
endpoints or otherwise indicated, include: 
 Proportion of responders on the BPI Worst Pain NRS item and analgesic use by 
BPI-2p definition (see below)  
 Proportion of responders on the BPI Worst Pain NRS item and analgesic use by 
BPI-50 (see below) 
 Proportion of responders on the Worst Stiffness NRS item 
 Proportion of responders on the PROMIS Physical Function Scale 
 Mean change from baseline in the BPI Worst Pain NRS item 
 Patient Global Impression of Change item for tumor-related stiffness and Patient 
Global Rating of Concept item for ability to carry out every day physical activities.  
 Duration of BPI-based symptom response, analyzed for BPI-30, BPI-50 and BPI-2p. 
 Results of the Surgical Assessment Questionnaire in Part 1. 
 Response based on the change in the SSD of the tumor on MRI, referred to as 
“modified RECIST 1.1–SSD” 


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 Amount of joint/tissue damage (eg, bone erosion, bone edema, cartilage loss) 
assessed on MRI based on adaptations of the RAMRIS and WORMS 
 Analgesic use expressed as morphine-equivalent doses in Part 122 
 EQ-5D-5L parameters in Part 1 
 Major HCRU and productivity in Part 1 
 Duration of response based on MRI and modified RECIST 1.1-SSD 
 Response based on the most disturbing symptom of pain, stiffness, or compromised 
ability to carry out everyday activities. 
 Proportion of subjects receiving surgical resection of their tumor by 25 weeks, 49 
weeks, 73 weeks, and 97 weeks of pexidartinib treatment 
For responder analysis based on the BPI Worst Pain NRS item and analgesic use, a BPI-2p 
responder will be defined as a subject who (i) experienced a decrease of at least 2 points in the 
mean BPI Worst Pain NRS item and (ii) did not experience a 30% or greater increase in narcotic 
analgesic use, comparing data collected during a 7-day period prior to the current visit for 
responder assessment with baseline values collected prior to the first dose of study treatment. A 
BPI-50 will have the same definition except the subject must experience a decrease of at least 
50% in the mean BPI Worst Pain NRS item. Subjects who do not provide data for the endpoint 
will be considered to be non-responders. Definition for increase in analgesic use is outlined in 
Section 6.4.11. See SAP for further details. 
The endpoints involving the PRO assessments, amount of joint/tissue damage, response based on 
MRI and modified RECIST 1.1-SSD, and duration of response will be analyzed using the same 
methods as those used for the primary and secondary endpoints. 
Duration of BPI symptom response for a responder is the interval from the first time BPI 
symptom response is documented to the first subsequent time point when the BPI symptom 
response is not met. The definition applies to BPI symptom response of BPI-30, BPI-50 and BPI-
2p. Duration of BPI symptom response will be summarized in a way similar to that for duration 
of tumor response by RECIST  1.1. 
For subjects who undergo surgical resection, the surgery-related data will be listed, including 
those collected in the separate protocol, if applicable.  Proportion of subjects receiving surgical 
resection of their tumor by 25 weeks of pexidartinib treatment  will be calculated regardless of 
whether blinded or open-label pexidartinib treatment, or both, was taken.  The numerator is the 
number of subjects having the surgical resection of the tumor within 36 weeks of the first 
treatment of pexidartinib, taking into account the 12 weeks allowable window. The denominator 
is the number of subjects who complete at least 24 weeks of pexidartinib treatment.  Likewise, 
the proportion of subjects receiving surgical resection of their tumor by 49 weeks, 73 weeks, and 
97 weeks of pexidartinib treatment will be calculated similarly. 


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7.6.4. 
Subgroup Analyses 
The primary endpoint and BPI Worst Pain NRS item will be also analyzed in the following 
subgroups of the ITT population: 
 Subjects with disease located in large joints (shoulder, elbow, hip, or knee); 
 Subjects with disease located in small joints (joints other than the shoulder, elbow, 
hip, or knee); 
 Subjects with disease located in the knee; 
 Subjects with GCT-TS type of TGCT; 
 Subjects with PVNS type of TGCT; 
 Subjects with lower extremity tumors; 
 Subjects with upper extremity tumors; 
 Subjects at US sites; 
 Subjects at sites outside of the US; 
 Subjects at sites in the EU region only. 
In each subgroup defined above, the analysis will be carried out using the same type of 
methodology as described for the overall analysis of the corresponding endpoint. These results 
will be considered exploratory because of the multiplicity issue and also smaller sample sizes 
that cannot be pre-specified. For subgroups without an adequate number of subjects, the analysis 
will not be performed. 
7.7. 
Pharmacodynamics/Biomarkers 
Blood samples collected at specified time points will be analyzed for markers of pexidartinib 
exposure and for exploratory biomarkers, including CSF-1 and adiponectin. 
Available and consented archival tissue specimens from PVNS/GCT-TS tumors will be collected 
and stored for exploratory biomarkers related to pexidartinib and/or disease. Plasma will be 
analyzed for markers of pexidartinib exposure and for exploratory biomarkers, including CSF-1 
and adiponectin. No formal statistical analysis of PDy endpoints will be performed. 
Pharmacodynamic data from each assay will be listed and possible relationships between PK and 
PDy variables may be explored. Any biological activity will be described. 
Biomarker data will be summarized using descriptive statistics by treatment and visit. Exposure-
biomarker data will be analyzed graphically and may be modeled if data permit. 
7.8. 
Pharmacogenomic Analysis 
7.8.1. 
Genomic or Genetic Banking and Analysis 
A single blood sample (10 mL) for pharmacogenomics analysis will be collected from each 
subject who consent to this test. Pharmacogenomic sample may also be collected from 
discontinued subjects who provide consent.  Participation in this part of the study is optional for 
all subjects. 


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The following procedures will be used for the long-term preservation (banking) of DNA 
specimens extracted from subjects' blood samples.  Pharmacogenomic samples may be analyzed 
for genes involved in absorption, distribution, metabolism, elimination, safety, and efficacy of 
pexidartinib.  Additionally, samples may be analyzed for genes involved in pexidartinib related 
signaling pathways, or to examine diseases or physiologic processes related to pexidartinib.  
DNA samples will not be immortalized or sold to anyone.  This information may be useful in 
increasing the knowledge of differences among individuals in the way they respond to the study 
drug, as well as helping in the development of new drugs or improvement of existing drugs. 
Specimen shipping and handling details will be included in the laboratory manual. 
7.8.1.1. 
Disclosure of the Results of Genomic or Genetic Analysis 
Because the nature and value of future pharmacogenomic research cannot be known at this time, 
any results obtained from research involving pharmacogenomic samples will not be disclosed to 
the subject or Investigators now or in the future. 
7.8.1.2. 
Storage and Disposal of Specimens for Genomic or Genetic Banking and 
Analysis 
Samples will be retained until exhausted or until the Sponsor requests disposition.  
If the subject withdraws consent, the banked blood samples will be properly and promptly 
disposed of.  However, the data will not be discarded if genetic analysis has been completed 
before the subject withdraws consent. 
7.9. 
Pharmacokinetics and Exposure–Response Analyses 
Plasma–concentration time data for pexidartinib will be summarized by visit and time using 
descriptive statistics. Plasma–concentration data from these samples will be analyzed using a 
PopPK approach using nonlinear mixed effects modeling. Data from Phase 1 studies will be used 
to inform and stabilize the structural PK model and will be pooled with Phase 3 data to assess 
and characterize the inter- and intra-subject variability in PK and to identify significant 
covariates. PK parameters will include apparent clearance and volume of distribution along with 
transfer rate constants such as absorption and elimination rates. Additionally, based on post hoc 
Bayesian methods, estimates of exposure such as Cmax, Ctrough, Cav and AUCss may also be 
reported. 
Exposure–Response 
Bayesian individual exposures of pexidartinib from the PopPK analysis will be used to explore 
relationships between exposure metrics and biomarkers and safety and efficacy endpoints. These 
analyses will be summarized in a separate report. 
7.10. 
Safety Analysis 
The analyses of safety will be performed on the Safety Analysis Set. The summary and display 
of TEAEs will be performed for the following data sets: 
(i) 
Part 1 data for the subjects who received blinded pexidartinib in Part 1; 
(ii) 
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(iii) 
All data from open-label pexidartinib treatment, ie, Part 2 data from all subjects; 
(iv) 
Aggregate pexidartinib data, ie, data from Parts 1 and 2 for the subjects who received 
pexidartinib in Parts 1 and 2 plus Part 2 data for the subjects who received blinded 
placebo in Part 1. 
Terminology from version 19.1 of the Medical Dictionary for Drug Regulatory Activities 
(MedDRA) will be used to assign System Organ Class (SOC) and preferred term (PT) 
classification to AEs and diseases, based on the original terms entered on the eCRF. 
The incidence of TEAEs will be summarized by SOC, PT, relationship to the study treatment, 
and severity for each treatment group. A by-subject listing will be provided for those subjects 
who experience an SAE, including death, or experience an AE associated with early withdrawal 
from the study or study treatment. 
7.10.1. 
Analysis of Treatment-emergent Adverse Events 
TEAEs are AEs that occur, having been absent before the first dose of study treatment, or have 
worsened in severity after the initiating the study treatment. TEAEs will be coded using 
MedDRA and assigned grades based on version 4.0 of the National Cancer Institute’s Common 
Terminology Criteria for Adverse Events (NCI CTCAE). The number and percentage of subjects 
reporting TEAEs will be tabulated by the worst CTCAE grade, SOC, and PT, with a breakdown 
by data set (Section 7.10). Similarly, the number and percentage of subjects reporting treatment-
emergent SAEs will be tabulated, as well as TEAEs leading to discontinuation of study 
treatments. 
A by-subject AE (including treatment-emergent) data listing including but not limited to 
verbatim term, preferred term, system organ class, CTCAE grade, and relationship to study 
treatment will be provided. Deaths, other SAEs, and other significant AEs, including those 
leading to discontinuation of study treatments, will be listed. 
7.10.2. 
Clinical Laboratory Evaluation Analyses 
Descriptive statistics will be provided for the clinical laboratory results by scheduled time of 
evaluation and by treatment group and study part for the Safety Analysis Set, as well as for the 
change from baseline. The baseline value is defined as the last non-missing value before the 
initial administration of study treatment. In addition, mean change from baseline will be 
summarized for the maximum and minimum post-treatment values and the values at the End of 
Treatment visit. 
Abnormal clinical laboratory results will be graded according to NCI CTCAE version 4.0, if 
applicable, and the grade will be presented in a by-subject data listing. A shift table, presenting 
by treatment group the 2-way frequency tabulation for baseline and the worst post-treatment 
value according to the NCI CTCAE grade, will be provided for clinical laboratory tests. 
Abnormal clinical laboratory test results deemed of clinical significance or of Grade 3 or 4 will 
be listed. 
7.10.3. 
Vital Sign Analyses 
Descriptive statistics will be provided for the vital signs measurements by scheduled time of 
evaluation and by treatment group and study part for the Safety Analysis Set, as well as for the 


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change from baseline. The baseline value is defined as the last non-missing value before the 
initial administration of study treatment. In addition, mean change from baseline will be 
presented by treatment group for the maximum and minimum post-treatment values and the 
values at the End of Treatment visit. 
7.10.4. 
Electrocardiogram Analyses 
Descriptive statistics will be provided for the ECG measurements by scheduled time of 
evaluation and by treatment group for the Safety Analysis Set, as well as for the change from 
baseline. The baseline value is defined as the last non-missing value before the initial 
administration of study treatment. In addition, the number and percentage of subjects with ECG 
interval values meeting the criteria will be tabulated (eg, QTc ≤ 450 ms, > 450 to ≤ 480 ms, 
> 480 ms to ≤ 500 ms, and > 500 ms) and QTcF maximum changes from baseline (> 30 and 
> 60 ms) over all post-treatment evaluations will be summarized. ECG data will also be 
presented in the data listings. 
7.10.5. 
Echocardiogram Analyses 
Ejection fraction data will be summarized descriptively, for the Safety Analysis Set, including 
values at baseline and each time point along with mean change from baseline. 
7.10.6. 
Analysis of Physical Examination Findings 
Physical examination data will be listed. 
7.10.7. 
Concomitant Medication Analyses 
Concomitant medications will be coded using the World Health Organization drug dictionary 
(most recent version). Number and percentage of subjects taking concomitant medications will 
be summarized for the Safety Analysis Set by treatment group. 
7.11. 
Data Monitoring Committee 
An independent DMC will be responsible for safeguarding the interests of study subjects, 
assessing the safety of the interventions during the trial, and monitoring the overall conduct of 
the trial. The DMC will also make recommendations about continuing, modifying, or stopping 
the trial. To enhance the integrity of the study, the DMC may also formulate recommendations 
relating to subject selection, recruitment, and management, improving adherence to protocol-
specified regimens and subject retention, and data management and quality control procedures. 
A separate DMC Charter will define the DMC membership, its roles and responsibilities, and the 
process for providing feedback to the Sponsor. 
7.12. 
Sample Size Determination 
For the purpose of sample size evaluation, the assumed rates of responders (subjects achieving a 
CR or PR) for the primary endpoint are 10% (placebo) and 35% (pexidartinib), respectively. 
Based on the use of a 2-sided, two-sample comparison of proportions at the alpha=0.05 level of 
significance by Fisher’s exact test, a sample size of 126 ITT randomized subjects (63 per arm) 


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provides 90% power to detect this magnitude of difference. The sample size was calculated using 
nQuery Advisor 7.0 with the module of two-group Fisher’s exact test of equal proportions. 


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8. 
ETHICAL CONSIDERATIONS 
This study will be conducted in accordance with ethical principles founded in the Declaration of 
Helsinki and in compliance with the protocol, GCP, and applicable regulatory requirements 
(including International Conference on Harmonisation [ICH] guidelines). The IRB/IEC will 
review all appropriate study documentation in order to safeguard the rights, safety and well-
being of the subjects. The study will only be conducted at sites where IRB/IEC approval has 
been obtained. The protocol, IB, informed consent form, advertisements (if applicable), written 
information given to the subjects (including diary cards and PRO instruments), safety updates, 
annual progress reports, and any revisions to these documents will be provided to the IRB/IEC 
by the Investigator or the Sponsor, as allowable by local regulations. 


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9. 
SAFETY ASSESSMENT 
9.1. 
Reporting Adverse Events and Serious Adverse Events 
All AEs occurring after the subject signs the informed consent form and through the Post-
Treatment Visit (28 ± 7 days after the last dose of study treatment), whether observed by the 
Investigator or reported by the subject, will be recorded on the AE eCRF page. Medical 
conditions (including laboratory values/vital signs that are out of range) that were diagnosed or 
known to exist prior to informed consent will be recorded as part of medical history. All SAEs 
are to be reported according to the procedures in Section 9.3 (SAE Reporting-Procedure for 
Investigators). 
Always report diagnosis as the AE or SAE term(s). When a diagnosis is unavailable, report the 
primary sign or symptom as the AE or SAE term with additional details included in the narrative 
until the diagnosis becomes available. 
If the signs and symptoms are distinct and do not suggest a common diagnosis, report them as 
individual entries of AE or SAE. For events that are serious due to hospitalization, the reason for 
hospitalization must be reported as the SAE (diagnosis or symptom requiring hospitalization). A 
procedure is not an AE or SAE, but the reason for the procedure may be an AE or SAE. Pre-
planned (prior to signing the informed consent form) procedure or treatment requiring 
hospitalization for pre-existing conditions that do not worsen in severity should not be reported 
as SAEs (see Section 9.2 for definitions). For deaths, the underlying or immediate cause of death 
should always be reported as an SAE. Disease progression is a study endpoint and, consequently, 
should not be reported as an AE/SAE. However, when a subject dies from disease progression 
with no other immediate causes, “disease progression” should be reported as an SAE. In 
addition, any serious untoward event that may occur subsequent to the reporting period that the 
Investigator assesses as related to study treatment should also be reported and managed as an 
SAE. 
At each visit, the Investigator will determine whether any AEs have occurred by evaluating the 
subject. Adverse events may be directly observed, reported spontaneously by the subject or by 
questioning the subject at each study visit. Subjects should be questioned in a general way, 
without asking about the occurrence of any specific symptoms. The Investigator must assess all 
AEs to determine seriousness, severity, and causality, in accordance with the definitions in 
Section 9.2. The Investigator’s assessment must be clearly documented in the site’s source 
documentation with the Investigator’s signature. All laboratory values must be appraised by the 
Investigator as to clinical significance. All abnormal laboratory values considered clinically 
significant by the Investigator must be recorded as an adverse event on the eCRF, and if serious, 
report as an SAE following the procedures in Section 9.3. 
The Investigator should follow subjects with AEs until the event has resolved or the condition 
has stabilized. In case of unresolved AEs, including significant abnormal laboratory values at the 
end of study assessment, these events will be followed up until resolution or until they become 
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9.2. 
Definitions 
9.2.1. 
Adverse Event 
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding, for example), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product.36 
It is the responsibility of Investigators, based on their knowledge and experience, to determine 
those circumstances or abnormal laboratory findings that should be considered AEs. 
9.2.2. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose that: 
 Results in death; 
 Is life-threatening; 
 Requires inpatient hospitalization or prolongation of existing hospitalization; 
 Results in persistent or significant disability/incapacity; 
 Is a congenital anomaly or birth defect; 
 Is an important medical event. 
Note: The term “life-threatening” in the definition of “serious” refers to an event in which the 
subject was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe.36  
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may require 
intervention to prevent one of the other outcomes listed in the definition above. Examples 
include allergic bronchospasm, convulsions, and blood dyscrasias or development of drug 
dependency or drug abuse. 
Note: 
 A procedure is not an AE or SAE, but the reason for the procedure may be an AE or 
SAE. 
 Pre-planned (prior to signing the informed consent form) procedures or treatment 
requiring hospitalizations for pre-existing conditions which do not worsen in severity 
are not SAEs. 
9.2.3. 
Adverse Event Severity 
All AEs will be graded (1 to 5; see below) according to the latest NCI CTCAE: 
 Grade 1 — Mild. 


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 Grade 2 — Moderate. 
 Grade 3 — Severe. 
 Grade 4 — Life-threatening consequences; urgent intervention indicated. 
 Grade 5 — Death related to the AE. 
Severity vs. Seriousness 
Severity is used to describe the intensity of a specific event while the event itself, however, may 
be of relatively minor medical significance (such as severe headache). This is not the same as 
“seriousness,” which is based on subject/event outcome at the time of the event. For example, the 
NCI CTCAE Grade 4 (life-threatening consequences; urgent intervention indicated) is assessed 
based on unique clinical descriptions of severity for each AE, and these criteria may be different 
from those used for the assessment of AE seriousness. An AE assessed as Grade 4 based on the 
NCI CTCAE grades may or may not be assessed as serious based on the seriousness criteria. 
9.2.4. 
Causality Assessment 
The Investigator should assess causal relationship between an adverse event and the study 
treatment on the basis or his/her clinical judgment and the following definitions. The causality 
assessment should be made based on the available information and can be updated as new 
information becomes available. 
 Related: 
o The AE follows a reasonable temporal sequence from study treatment 
administration, and cannot be reasonably explained by the subject’s clinical 
state or other factors (eg, disease under study, concurrent diseases, and 
concomitant medications). 
o The AE follows a reasonable temporal sequence from study treatment 
administration, and is a known reaction to the drug under study or its chemical 
group, or is predicted by known pharmacology. 
 Not Related: 
o The AE does not follow a reasonable sequence from study product 
administration, or can be reasonably explained by the subject’s clinical state 
or other factors (eg, disease under study, concurrent diseases, and concomitant 
medications). 
9.2.5. 
Action Taken Regarding the Study Treatment 
 1 = Dose Not Changed:  No change in study treatment dosage was made. 
 2 = Drug Withdrawn:  The study product was permanently stopped. 
 3 = Dose Reduced:  The dosage of study product was reduced. 
 4 = Drug Interrupted:  The study product was temporarily stopped. 
 5 = Dose Increased:  The dosage of study product was increased. 


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9.2.6. 
Adverse Event Outcome 
 1 = Recovered/Resolved 
o The subject fully recovered from the adverse event with no residual effect 
observed. 
 2 = Recovered/Resolved with Sequelae 
o The residual effects of the adverse event are still present and observable. 
o Include sequelae/residual effects. 
 3 = Not Recovered/Not Resolved 
o The adverse event itself is still present and observable. 
 4 = Fatal 
9.2.7. 
Other Action Taken for Event 
 1 = None. 
o No treatment was required. 
 2 = Medication required. 
o Prescription and/or OTC medication was required to treat the adverse event. 
 3 = Hospitalization or prolongation of hospitalization required. 
o Hospitalization was required or prolonged because of the adverse event, 
whether or not medication was required. 
 4 = Other. 
9.3. 
Serious Adverse Event Reporting Procedure for Investigators 
9.3.1. 
Reporting by Investigators 
All AEs and SAEs will be reported in the eCRF. 
The following types of events should also be reported on the Daiichi Sankyo Serious Adverse 
Event Report (SAVER) Form within 24 hours of awareness: 
 SAEs (Section 9.2.2) 
 Hepatic events meeting combination abnormalities [ALT or AST ≥ 3 × ULN with 
simultaneous total bilirubin ≥ 2 × ULN] (potential Hy’s Law case), both serious and 
non-serious 
All AEs (serious and non-serious) must be reported with Investigator’s assessment of the event’s 
seriousness, severity, and causality to the blinded study treatment. A detailed narrative 
summarizing the course of the event, including its evaluation, treatment, and outcome should be 
provided. Specific or estimated dates of event onset, treatment, and resolution should be included 
when available. Medical history, concomitant medications, and laboratory data that are relevant 
to the event should also be summarized in the narrative. For fatal events, the narrative should 


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state whether an autopsy was or will be performed, and include the results if available. Source 
documents will be retained in site’s files and should not be submitted to the Sponsor for SAE 
reporting purposes. 
Urgent safety queries must be followed up and addressed promptly. Follow-up information and 
response to non-urgent safety queries should be combined for reporting via eCRF to provide the 
most complete data possible within each follow-up. 
Please call the local SAE Hotline or your study monitor for any questions on SAE reporting (see 
Section 10.1.2.2). 
9.3.2. 
Notifying Regulatory Authorities, Investigators, and Institutional Review 
Boards/Institutional Ethics Committees 
The Sponsor and/or designee will inform Investigators, IRBs/IECs, and regulatory authorities of 
any suspected unexpected serious adverse reactions (SUSARs) occurring in other study centers 
or other Daiichi Sankyo studies of the investigational product, as appropriate per local reporting 
requirements. 
In the US, upon receipt of the Sponsor’s notification of SUSARs that occurred with the 
investigational product, unless delegated to the Sponsor, it is the Investigator’s responsibility to 
inform the IRB per the Sponsor’s instruction. 
In the European Economic Area member states, it is the Sponsor’s responsibility to report 
SUSARs to all IECs. 
9.4. 
Procedures for Reporting Drug Exposure During Pregnancy and 
Birth Events 
The Sponsor must be notified of any female subject or any male subject whose female partner 
who becomes pregnant while receiving or within 90 days of discontinuing the study treatment. 
Reporting after follow-up visit or early termination is done voluntarily by the Investigator. 
Although pregnancy is not technically an AE, all pregnancies must be followed to conclusion to 
determine their outcome. This information is important for both drug safety and public health 
concerns. It is the responsibility of the Investigator or designee to report any pregnancy in a 
female subject or a male subject’s female partner using the Exposure In Utero (EIU) Reporting 
Form. Please contact your study monitor to receive the EIU Reporting Form upon learning of a 
pregnancy. The Investigator should make every effort to follow the subject until completion of 
the pregnancy. If the outcome of the pregnancy meets the criteria for immediate classification as 
an SAE (ie, post-partum complications, spontaneous abortion, stillbirth, neonatal death, or 
congenital anomaly, including that in an aborted fetus), the Investigator should follow the 
procedures for reporting SAEs as outlined in Section 9.3. For reports of pregnancy in the female 
partner of a male subject, the EIU Reporting Form (or SAE form if associated with an adverse 
outcome) should be completed with the subject’s randomization number, initials, and date of 
birth, and details regarding the female partner should be entered in the narrative section. 


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10. 
STUDY ADMINISTRATIVE INFORMATION 
10.1. 
Study Contacts 
10.1.1. 
Sponsor 
Daiichi Sankyo, Inc. 
211 Mount Airy Road 
Basking Ridge, NJ 07920, USA 
 
10.1.2. 
Medical Monitor 
10.1.2.1. Sponsor Medical Monitor 
 
Senior Director, Global Oncology R&D 
 
10.1.2.2. Contract Research Organization Medical Monitor 
 
IQVIA 
All Regions Except Europe Medical Monitor 
 
Pivotal 
EU Medical Monitor 
10.1.3. 
SAE Reporting Contact 
The Investigator will ensure that the SAE reporting form is completed and e-mailed/eFaxed to 
the following address within 24 hours of learning of the occurrence of any SAE: 
Novella Clinical Safety Management Group 
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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11. 
ADMINISTRATIVE REQUIREMENTS 
11.1. 
Good Clinical Practice 
The study will be conducted in accordance with the ICH Guideline for GCP and the appropriate 
regulatory requirement(s). The Investigator will be thoroughly familiar with the appropriate use 
of the study treatment as described in the protocol and the IB. 
11.2. 
Data Quality Assurance 
The Investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each study subject. 
Study data will be entered into an eCRF by site personnel using a secure, validated web-based 
electronic data capture (EDC) application. The Sponsor will have access to all data upon entry in 
the EDC application. 
Study monitors will discuss instances of missing or uninterpretable data with the Investigator 
and/or designee for resolution. Any changes to study data will be made to the eCRF and 
documented via an electronic audit trail associated with the affected eCRF. 
11.3. 
Electronic Case Report Form Completion 
The Sponsor or Sponsor’s designee will provide the study sites with secure access to and training 
on the EDC application, sufficient to permit site personnel to enter or correct information in the 
eCRFs for the subjects for which they are responsible. 
eCRFs will be completed for each study subject. It is the Investigator’s responsibility to ensure 
the accuracy, completeness, clarity, and timeliness of the data reported in the subject’s eCRF. 
The Investigator, or designated representative, should complete the eCRF as specified in the 
eCRF Completion Guidelines. 
The audit trail entry will show the user’s identification information, and the date and time of the 
correction. The Investigator must provide through the EDC application formal approval of all the 
information in the eCRFs and changes to the eCRFs to endorse the final submitted data for the 
subjects for which he or she is responsible. 
The Sponsor or a designee will retain the eCRF data and corresponding audit trails. A copy of 
the final archival eCRF in the form of a compact disk or other electronic media will be placed in 
the Investigator’s study file. 
11.4. 
Data Management 
Each subject will be identified in the database by a unique subject identifier as defined by the 
Sponsor. 
To ensure the quality of clinical data across all subjects and sites, a Clinical Data Management 
review will be performed on subject data according to specifications given to the Sponsor or 
Sponsor designee. Data will be vetted both electronically and manually for eCRFs, and the data 
will be electronically vetted by programmed data rules within the application. Queries generated 


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by rules and raised by reviewers will be generated within the EDC application. During this 
review, subject data will be checked for consistency, omissions, and any apparent discrepancies. 
Data received from external sources such as central laboratories will be reconciled to the clinical 
database. 
Serious adverse events in the clinical database will be reconciled with the safety database. All 
AEs will be coded using MedDRA. 
11.5. 
Study Monitoring 
Monitoring and auditing procedures developed or approved by the Sponsor will be followed, in 
order to comply with GCP guidelines. 
All information recorded on the eCRFs for this study must be consistent with the subject’s 
source documentation. During the course of the study, the study monitor will make study site 
visits to review protocol compliance, verify eCRFs against source documentation, assess drug 
accountability, and ensure that the study is being conducted according to pertinent regulatory 
requirements. The review of medical records will be performed in a manner to ensure that 
subject confidentiality is maintained. 
11.6. 
Subject Information and Informed Consent 
After the study has been fully explained, written informed consent will be obtained from either 
the subject or his/her guardian or legal representative prior to study participation. The method of 
obtaining and documenting the informed consent and the contents of the consent must comply 
with ICH-GCP and all applicable regulatory requirement(s). 
11.7. 
Subject Confidentiality 
In order to maintain subject privacy, all eCRFs, study treatment accountability records, study 
reports and communications will identify the subject by initials where permitted and/or by the 
assigned subject number. The subject’s confidentiality will be maintained and will not be made 
publicly available to the extent permitted by the applicable laws and regulations. 
11.8. 
Investigator Compliance 
The Investigator will conduct the trial in compliance with the protocol provided by the Sponsor, 
and given approval/favorable opinion by the IRB/IEC and the appropriate regulatory authority 
(ies). Modifications to the protocol are not be made without agreement of both the Investigator 
and the Sponsor. Changes to the protocol will require written IRB/IEC approval/favorable 
opinion prior to implementation, except when the modification is needed to eliminate an 
immediate hazard(s) to subjects. The Sponsor or a designee will submit all protocol 
modifications to the appropriate regulatory authority (ies) in accordance with the governing 
regulations. 
When immediate deviation from the protocol is required to eliminate an immediate hazard(s) to 
subjects, the Investigator will contact the Sponsor or a designee if circumstances permit, to 
discuss the planned course of action. Any departures from the protocol must be documented. 


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11.9. 
On-site Audits 
Regulatory authorities, the IEC/IRB, and/or the Sponsor or its designee(s) may request access to 
all source documents, eCRFs, and other study documentation for on-site audit or inspection. 
Direct access to these documents must be guaranteed by the Investigator, who must provide 
support at all times for these activities. 
11.10. 
Investigator and Site Responsibility for Drug Accountability 
Accountability for the study treatment at the trial site is the responsibility of the Investigator. 
Drug accountability records including the study treatment’s delivery date to the site, inventory at 
the site, use by each subject, and amount returned to the Sponsor or a designee (or disposal of the 
study treatment, if approved by the Sponsor) will be maintained by the clinical site. The Sponsor 
or its designee will review drug accountability at the site on an ongoing basis. 
All material containing study treatment will be treated and disposed of as hazardous waste in 
accordance with governing regulations. 
Also see Section 5.9 for specific details. 
11.11. 
Product Complaints 
A product complaint is any dissatisfaction with a product that may be attributed to the identity, 
quality, durability, reliability, or safety of the product. Individuals who identify a potential 
product complaint situation should immediately report the event. Whenever possible, the 
associated product should be maintained in accordance with the label instructions pending 
further guidance from a quality representative from the Sponsor. 
For product complaints, refer to the Study Pharmacy Manual for instructions and details. 
11.12. 
Study Closure 
Within 90 days of the end of the study the Sponsor will notify the competent authorities and the 
IRBs/IECs in all member states where the study is being carried out that the study has ended. 
Within 1 year of the end of the study, a summary of the clinical trial results will be submitted to 
the competent authorities and IRBs/IECs in all member states involved in the study. 
Study participation by individual sites or the entire study may be prematurely terminated, if in 
the opinion of the Investigator or the Sponsor, there is sufficient reasonable cause. Written 
notification documenting the reason for study termination will be provided to the Investigator or 
the Sponsor by the terminating party. 
Circumstances that may warrant termination include, but are not limited to: 
 Determination of unexpected, significant, or unacceptable risk to subjects 
 Failure to enter subjects at an acceptable rate 
 Insufficient adherence to protocol requirements 
 Insufficient, incomplete, and/or unevaluable data 
 Plans to modify, suspend or discontinue the development of the study treatment 


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Should the study be closed prematurely, the site will no longer be able to access the EDC 
application, will not have a right to use the EDC application, and will cease using the password 
or access materials once their participation in the study has concluded. In the event that any 
access devices for the EDC application have been provided, these will be returned to the Sponsor 
or designee once the site’s participation in the study has concluded. 
Within 15 business days of premature closure, the Sponsor must notify the competent authorities 
and IRBs/IECs of any member state where the study is being conducted, providing the reasons 
for study closure. 
11.13. 
Study Documentation and Storage 
The Investigator will maintain a Signature List of appropriately qualified persons to whom 
he/she has delegated study duties. All persons authorized to make entries and/or corrections on 
eCRFs will be included on the Signature List. 
Source documents are original documents, data, and records from which the subject’s eCRF data 
are obtained. These include but are not limited to hospital records, clinical and office charts, 
laboratory and pharmacy records, diaries, microfiches, X-rays, and correspondence. eCRF 
entries may be considered source data if the eCRF is the site of the original recording (ie, there is 
no other written or electronic record of data). 
The Investigator and study staff are responsible for maintaining a comprehensive and centralized 
filing system (Trial Master File) of all study-related (essential) documentation, suitable for 
inspection at any time by representatives from the Sponsor and/or applicable regulatory 
authorities. Essential documents include: 
 Subject files containing completed copy of eCRFs, informed consents, and supporting 
copies of source documentation (if kept). 
 Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of relevant essential documents required prior to commencing a clinical study, 
and all correspondence to and from the IEC/IRB and the Sponsor. 
 Records related to the investigational product(s) including acknowledgment of receipt 
at site, accountability records and final reconciliation and applicable correspondence. 
In addition, all original source documents supporting entries in the eCRFs must be maintained 
and be readily available. 
11.14. 
Record Retention 
All essential documentation will be retained by the Investigator until at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 2 years have lapsed since the 
formal discontinuation of clinical development of the investigational product. These documents 
should be retained for a longer period, however, if required by the applicable regulatory 
requirements or by an agreement with the Sponsor. It is the responsibility of the Sponsor to 
inform the Investigator/institution as to when these documents no longer need to be retained. 


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No study document should be destroyed without prior written agreement between Sponsor and 
the Investigator. Should the Investigator wish to assign the study records to another party or 
move them to another location, he/she must notify Sponsor in writing of the new responsible 
person and/or the new location. 
11.15. 
Record Keeping 
Records of subjects, source documents, monitoring visit logs, data correction forms, eCRFs, 
inventory of study product, regulatory documents (eg, protocol and amendments, IRB/IEC 
correspondence and approvals, approved and signed informed consent forms, Investigator’s 
Agreement, clinical supplies receipts, distribution and return records), and other sponsor 
correspondence pertaining to the study must be kept in appropriate study files at the site. Source 
documents include all recordings and observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical study. These 
records will be retained in a secure file for the period required by the institution or site policy. 
Prior to transfer or destruction of these records, the Sponsor must be notified in writing and be 
given the opportunity to further store such records. 


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12. 
FINANCING AND INSURANCE 
12.1. 
Finances 
Prior to starting the study, the Principal Investigator and/or institution will sign a clinical study 
agreement with the Sponsor. This agreement will include the financial information agreed upon 
by the parties. 
12.2. 
Reimbursement, Indemnity, and Insurance 
Reimbursement, indemnity and insurance shall be addressed in a separate agreement on terms 
agreed upon by the parties. 


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13. 
USE OF INFORMATION 
All information regarding pexidartinib supplied by the Sponsor to the Investigator is privileged 
and confidential information. The Investigator agrees to use this information to accomplish the 
study and will not use it for other purposes without consent from the Sponsor. It is understood 
that there is an obligation to provide the Sponsor with complete data obtained during the study. 
The information obtained from the clinical study will be used toward the development of 
pexidartinib and may be disclosed to regulatory authority(ies), other Investigators, corporate 
partners, public databases (eg, ClinicalTrials.gov, EU Clinical Trial Register), or consultants as 
required. 
Upon completion of the clinical study and evaluation of results by the Sponsor, the hospital or 
institution and/or Investigator may publish or disclose the clinical trial results pursuant to the 
terms contained in the applicable Clinical Trial Agreement. 
It is anticipated that the results of this study will be presented at scientific meetings and/or 
published in a peer-reviewed scientific or medical journal. A Publications Group comprised of 
Sponsor employees and study Investigators will be formed to oversee the publication of the study 
results that will reflect the experience of all participating study centers. Subsequently, individual 
Investigators may publish results from the study in compliance with their agreements with the 
Sponsor. 
A prepublication manuscript or abstract is to be provided to the Sponsor a minimum of 30 days 
prior to the intended submission date of the manuscript or abstract to a publisher. Within 30 days 
after receipt by the Sponsor of the notification, the Sponsor shall inform the sites whether it has 
objections to the publication for reasons including, but not limited to, those defined below: 
 If patentable subject matter is disclosed, the publication shall be delayed for a period 
not to exceed 90 days from the Sponsor’s receipt of the proposed publication to allow 
time for the filing of patent applications covering patentable subject matter. 
 If confidential information is contained in any proposed publication or public 
disclosure, such confidential information will be removed at the Sponsor’s request. 


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14. 
REFERENCES 
1. Fletcher CDM, Bridge JA, Hogendoorn P, Mertens F. WHO Classification of Tumours of 
Soft Tissue and Bone, Fourth Edition. Lyon: IARC Press, 2013. 
2. Myers BW, Masi AT. Pigmented villonodular synovitis and tenosynovitis: a clinical 
epidemiologic study of 166 cases and literature review. Medicine. 1980;(59):223–38. 
3. Monaghan H, Salter DM, Al-Nafussi A. Giant cell tumour of tendon sheath (localized 
nodular tenosynovitis):  clinicopathological features of 71 cases. J Clin Pathol 
2001;(54):404–7. 
4. Ushijima M, Hashimoto H, Tsuneyoshi M, Enjoji M. Giant cell tumor of the tendon 
sheath (nodular tenosynovitis). A study of 207 cases to compare the large joint group 
with the common digit group. Cancer. 1986;57(4):875–84. 
5. Ushijima M, Hashimoto H, Tsuneyoshi M, Enjoji M. Pigmented villonodular synovitis. A 
clinicopathologic study of 52 cases. Acta Pathol Jpn. 1986;36(3):317–26. 
6. Rao AS, Vigorita VJ. Pigmented villonodular synovitis (giant-cell tumor of the tendon 
sheath and synovial membrane): A review of eighty-one cases. J Bone Joint Surg Am. 
1984;66:76–94. 
7. Blay J-Y, El Sayadi H, Thiesse P, and Garret J. Letter to the editor:  Complete response 
to imatinib in relapsing pigmented villonodular synovitis/tenosynovial giant cell tumor 
(PVNS/TGCT). Ann Oncol. 2008;19:821–2. 
8. Cassier PA, Gelderblom H, Stacchiotti S, et al. Efficacy of imatinib mesylate for the 
treatment of locally advanced and/or metastatic tenosynovial giant cell tumor/pigmented 
villonodular synovitis. Cancer. 2012;118(6):1649–55. 
9. Gelderblom H, Pérol D, Chevreau C, et al. An open-label international multicentric phase 
II study of nilotinib in progressive pigmented villo-nodular synovitis (PVNS) not 
amenable to a conservative surgical treatment. J Clin Oncol. 2013;31(suppl 15S):10516.  
[2013 American Society of Clinical Oncology (ASCO) Annual Meeting, Abstract 
#10516.] 
10. Cassier PA, Italiano A, Gomez-Roca CA, et al. CSF1R inhibition with emactuzumab in 
locally advanced diffuse-type tenosynovial giant cell tumours of the soft tissue: a dose-
escalation and dose-expansion phase 1 study. Lancet Oncol. 2015;16(8):949-56. 
11. PLX3397 Investigator’s Brochure, v.7. Berkeley, CA:  Plexxikon Inc. Dec 2015. 
12. Tap WD, Wainberg ZA, Anthony SP, et al Structure-Guided Blockade of CSF1R Kinase 
in Tenosynovial Giant-Cell Tumor. N Engl J Med 2015;373:428-437. 
13. Ostergaard M, Peterfy C, Conaghan P, et al. OMERACT Rheumatoid Arthritis Magnetic 
Resonance Imaging Studies. Core set of MRI acquisitions, joint pathology definitions, 
and the OMERACT RA-MRI scoring system. J Rheumatol. 2003;30(6):1385–6. 
14. Peterfy C, Guermazi A, Zaim S, et al. Whole-Organ Magnetic Resonance Imaging Score 
(WORMS) of the knee in osteoarthritis. Osteoarthritis Cartilage. 2004;12(3):177–90. 


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15. West RB, Rubin BP, Miller MA, et al. A landscape effect in tenosynovial giant-cell 
tumor from activation of CSF1 expression by a translocation in a minority of tumor cells. 
Proc Natl Acad Sci USA. 2006;103(3):690–5. 
16. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). 
Eur J Cancer. 2009;45:228–47. 
17. van der Heijden L, Gibbons CL, Dijkstra PD, et al. The management of diffuse-type giant 
cell tumour (pigmented villonodular synovitis) and giant cell tumour of tendon sheath 
(nodular tenosynovitis). J Bone Joint Surg Br. 2012;94(7):882–8. 
18. van der Heijden L, Gibbons CL, Hassan AB, et al. A multidisciplinary approach to giant 
cell tumors of tendon sheath and synovium: A critical appraisal of literature and 
treatment proposal. J Surg Oncol. 2013;107(4):433–45. 
19. O’Sullivan B, Cummings B, Catton C, et al. Outcome following radiation treatment for 
high-risk pigmented villonodular synovitis. Int J Radiat Oncol Biol Phys. 1995;32:777–
86. 
20. Gerhardt JJ, Cocchiarella L, Lea RD. The Practical Guide to Range of Motion 
Assessment. Chicago, IL. Amer Med Assoc Press; 2002. 
21. Flockhart, DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana 
University School of Medicine [2009]. Available from: 
http://medicine.iupui.edu/clinpharm/ddis/main-table/. Accessed October 22, 2014. 
22. Basch, Ethan, Autio, Karen A, Smith, Matthew R, et al, Effects of Cabozantinib on Pain 
and Narcotic Use in Patients with Castration-resistant Prostate Cancer: Results from a 
Phase 2 Nonrandomized Expansion Cohort, Eur Urol (2014), 
http://dx.doi.org/10.1016/j.eururo.2014.02.013.  
23. The Management of Postoperative Pain Working Group. VHA/DoD clinical practice 
guidelines for the management of postoperative pain. version 1.2. Washington, DC:  
Veterans Health Administration, Department of Defense; 2002. p. 44–5. 
24. Milliken, G.A.; Johnson D.E. The Analysis of Messy Data. In Vol. I: Designed 
Experiments. Chapman & Hall: New York; 1992. 
25. Little R J A., Rubin D B. Statistical Analysis with Missing Data. 2nd ed. New York: 
Wiley; 2002. 
26. Mallinckrodt C H, Clark W S, David S R. Accounting for dropout bias using mixed-
effects models. J of Biopharm Statist. 2001; 11: 9–21. 
27. Siddiqui, O., Hung, H. M., O’Neil, R. MMRM versus LOCF: A comprehensive 
comparison based on simulation study and 25 NDA data sets. J of Biopharm Statist. 
2009;.19: 227–46. 
28. Siddiqui, O. MMRM versus MI in Dealing with Missing Data—A Comparison Based on 
25 NDA Data Sets, J of Biopharm Statist. 2011; 21(3): 423-36. 
29. Wilson, EB: Probable Inference, the Law of Succession, and Statistical Inference. J of the 
Amer Statist Assoc. 1927;22: 209. 


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30. Newcombe, RG: Interval Estimation for the Difference Between Independent 
Proportions: Comparison of Eleven Methods. Statis in Med. 1998;17: 873–90. 
31. Lancaster HO. Significance tests in discrete distributions. J Am Statist Assoc. 
1961;294(56):223–34. 
32. Lydersen S, Fagerland MW, Laake P. Recommended tests for association in 2 x 2 tables. 
Statist Med. 2009;28:1159–75. 
33. Westfall PH, Krishen A. Optimally weighted, fixed sequence and gatekeeper multiple 
testing procedures. J Statist Plan Infer. 2001;99(1):25–40. 
34. Dworkin RH, Turk DC, Wyrwich KW, et al. Interpreting the Clinical Importance of 
Treatment Outcomes in Chronic Pain Clinical Trials: IMMPACT Recommendations. J 
Pain. 2008; 9(2): 105-21. 
35. Farrara JT, Young Jr. JP, LaMoreaux L, et al. Clinical importance of changes in chronic 
pain intensity measured on an 11-point numerical pain rating scale. Pain. 2001; 94(2): 
149–58. 
36. International Conference on Harmonisation of Technical Requirements for Registration 
of Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guidelines. Clinical 
Safety Data Management: Definitions and Standards for Expedited Reporting E2A. 
Current Step 4 Revision. 27 October 1994. Available from: 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E2A/
Step4/E2A_Guideline.pdf. Accessed November 4, 2014. 
 


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15. 
APPENDICES 
15.1. 
List of Common CYP3A4 Inhibitors and Inducers 
Strong Inhibitors 
 
Strong Inducers 
Protease inhibitors 
 
Anticonvulsants, mood stabilizers 
 
 Ritonavir 
 
 
 Phenytoin 
 
 Indinavir 
 
 
 Carbamazepine 
 
 Nelfinavir 
 
 
 Oxcarbazepine 
Macrolide antibiotics 
 
Non-nucleoside reverse transcriptase inhibitors 
 
 Erythromycin   
 
 Efavirenz 
 
 Telithromycin 
 
 Nevirapine 
 
 Clarithromycin 
 
 Etravirine   
Azole antifungals 
 
Phenobarbital (barbiturate) 
 
 Fluconazole 
 
Rifampicin (bactericidal) 
 
 Ketoconazole 
 
Modafinil (stimulant) 
 
 Itraconazole 
 
Hyperforin (constituent of St. John’s Wort) 
Chloramphenicol (antibiotic)  
 
Cyproterone (antiandrogen, progestin) 
Nefazodone (antidepressant) 
 
 
Bergamottin (constituent of grapefruit juice)    
 
Aprepitant (antiemetic)   
 
 
Verapamil (calcium channel blocker)   
 
 
Source: Flockhart, DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of 
Medicine [2009]. Available from: http://medicine.iupui.edu/clinpharm/ddis/main-table/. Accessed October 22, 2014. 
15.2. 
Detailed Study Procedures by Visit — Part 1 
15.2.1. 
Screening (Day –42 to Day –1) 
Procedures performed as part of patient care within the 42-day period before the first dose of 
study treatment may be used for screening purposes if they conform to protocol requirements and 


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standards. All screening test results must be reviewed prior to dosing to assess the study 
candidate’s eligibility for inclusion. 
The following procedures must be performed within the 42-day period before P1-C1D1, unless 
otherwise noted, and the results must be obtained and evaluated for eligibility prior to the 
P1-C1D1 visit: 
To be performed before any other procedures: 
 Informed consent. 
To be performed before any invasive procedures carried out on the same day: 
 Vital signs, including blood pressure, pulse rate, and oral temperature; 
 12-lead ECG. 
Other procedures to be performed: 
 Medical history (including PVNS/GCT-TS treatment history and smoking history); 
 Demographics, including ethnicity and race; 
 Concomitant medications; 
 BPI Worst Pain NRS item 
o This assessment is performed at the Screening Visit only. The recall period 
will be the preceding week. The subject’s response must be documented in the 
medical notes; 
 Worst Stiffness NRS item 
o This assessment is performed at the Screening Visit only. The recall period 
will be the preceding week. The subject’s response must be documented in the 
medical notes; 
 PROMIS Physical Function Scale 
 Height and weight; 
 Physical examination; 
 AE assessment; 
 Clinical laboratory tests — serum chemistry, hematology, liver function, hepatitis 
panel, hormone testing (as applicable), serum pregnancy testing (as applicable). 
Note: Women who are not using hormonal contraception will be tested for levels of 
FSH, LH, progesterone, and estradiol. Hormone testing will not be required for 
women who have either had an oophorectomy or are post-menopausal. Men will be 
tested for levels of LH, FSH, and testosterone. Men whose testosterone level is below 
baseline at the last study visit should be followed until their level has stabilized or 
returned to baseline. 
Note: Women of childbearing potential must have a serum pregnancy test within 14 
days of randomization (or, where different regulations apply, within 72 hours of 


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randomization). (Women who have documentation of at least 12 months of 
spontaneous amenorrhea and have an FSH level > 40 mIU/mL will be considered 
postmenopausal and need not undergo pregnancy testing.) 
 ECHO or MUGA scanning; 
 MRI of the affected joint within 56 days of P1-C1D1; 
 Third-party blinded range-of-motion assessment of the affected joint;  
 Dispense subject diary for recording daily BPI Worst Pain NRS, Worst Stiffness NRS 
and analgesic use during the 2-week period prior to P1-C1D1; 
 Surgical Assessment Questionnaire. 
To be performed any time during or after the Screening visit: 
 Obtain archival tumor tissue. 
15.2.2. 
Part 1 – Cycle 1 (Randomization) 
To be performed after the subject is determined to meet all eligibility criteria: 
 Subject randomization (time frame between randomization and first dose of study 
treatment can be up to 3 days prior to P1-C1D1). 
15.2.3. 
Part 1–Cycle 1, Day 1 (P1-C1D1; Week 1) 
To be performed before any invasive procedures: 
 Vital signs, including blood pressure, pulse rate, and oral temperature; 
 12-lead ECG; 
 PRO instruments, in the following order: 
o BPI Worst Pain NRS Item; 
o Worst Stiffness NRS item; 
o PROMIS Physical Function Scale; 
o Patient Global Rating of Concept item for carrying out every day physical 
activities; 
o EQ-5D-5L 
To be performed before the first morning dose of study treatment: 
 Review of outpatient PRO instruments; 
 AE assessment; 
 Concomitant medications; 
 Analgesic use assessment; 
 Most disturbing symptom assessment; 
 HCRU and productivity; 


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 Clinical laboratory tests (only need to be done if they were not done within 72h of 
Day 1) — serum chemistry, hematology, coagulation, hormone levels, liver function, 
urinalysis; 
 Blood sampling for PK and PDy analysis;  
 Dispense study treatment bottles. 


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Subject is dosed in clinic. 
To be performed after dosing: 
 Record the dose (subject diary, source records, eCRF); 
To be performed 2 hours ± 10 minutes after dosing: 
 12-lead ECG.  
15.2.4. 
Part 1–Cycle 1, Day 8 (P1-C1D8; Week 2) ± 2 days 
 Clinical laboratory tests — liver function; 
 AE assessment; 
 Concomitant medications. 
15.2.5. 
Part 1–Cycle 1, Day 15 (P1-C1D15; Week 3) ± 2 days 
To be performed before any invasive procedures: 
 Vital signs, including blood pressure, pulse rate, and oral temperature; 
 12-lead ECG. 
To be performed before the morning dose: 
 AE assessment; 
 Concomitant medications, including analgesics; 
 Treatment compliance assessment; 
 Clinical laboratory tests — liver function, hematology; 
 Blood sampling for PK and PDy analysis; 
Subject is dosed in clinic. 
To be performed after the morning dose: 
 Record the dose (subject diary, source records, eCRF); 
 Re-dispense study treatment bottles; 
 Blood sampling for PK analysis at various post-dose time points (see Section 6.4.16). 
To be performed 2 hours ± 10 minutes after dosing: 
 12-lead ECG. 
15.2.6. 
Part 1–Cycle 1, Day 22 (P1-C1D22; Week 4) ± 2 days 
 Clinical laboratory tests — liver function; 
 AE assessment; 
 Concomitant medications. 


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15.2.7. 
Part 1–Cycle 2, Day 1 (P1-C2D1; Week 5) ± 2 days 
To be performed before any invasive procedures: 
 Vital signs, including blood pressure, pulse rate, and oral temperature; 
 AE assessment; 
 Concomitant medications, including analgesics; 
 HCRU and productivity; 
 Treatment compliance assessment. 
Other procedures to be performed: 
 Physical examination; 
 Clinical laboratory tests — serum chemistry, hematology, liver function, serum 
pregnancy testing (as applicable); 
 Blood sampling for PK and PDy analysis; 
 Dispense study treatment bottles 
15.2.8. 
Part 1–Cycle 2, Day 8 (P1-C2D8; Week 6) ± 2 days 
To be performed before any invasive procedures: 
 Clinical laboratory tests — liver function; 
 AE assessment. 
 Concomitant medications. 
15.2.9. 
Part 1–Cycle 2, Day 15 (P1-C2D15; Week 7) ± 2 days 
 Clinical laboratory tests — liver function; 
 AE assessment; 
 Concomitant medications. 
15.2.10. 
Part 1–Cycle 2, Day 22 (P1-C2D22; Week 8) ± 2 days 
To be performed before any invasive procedures: 
 Clinical laboratory tests — liver function; 
 AE assessment. 
 Concomitant medications. 
15.2.11. 
Part 1–Cycle 3, Day 1 (P1-C3D1; Week 9) ± 7 days 
To be performed before any invasive procedures: 
 Vital signs, including blood pressure, pulse rate, and oral temperature; 
 PRO instruments, in the following order: 


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o BPI Worst Pain NRS item; 
o Worst Stiffness NRS item; 
o PROMIS Physical Function Scale 
o Patient Global Rating of Concept item for carrying out every day physical 
activities; 
o EQ-5D-5L. 
Other procedures to be performed: 
 Review outpatient PRO instruments; 
 AE assessment; 
 Concomitant medications, including analgesics; 
 HCRU and productivity; 
 Treatment compliance assessment; 
 Clinical laboratory tests — serum chemistry, hematology, liver function, serum 
pregnancy testing (as applicable); 
 Random post-dose blood sampling for PK and PDy analysis; 
 Dispense study treatment bottles. 
 Analgesic use assessment. 
15.2.12. 
Part 1–Cycle 3, Day 15 (P1-C3D15; Week 11) ± 7 days 
To be performed before any invasive procedures: 
 Clinical laboratory tests — liver function; 
 AE assessment. 
 Concomitant medications. 
15.2.13. 
Part 1–Cycle 4, Day 1 (P1-C4D1; Week 13) ± 7 days 
To be performed within (±) 7 days of the visit: 
 ECHO or MUGA scanning; 
 MRI of the affected joint (with local assessment of progression status). The 
Investigator may request a centrally read blinded MRI to confirm progression, eg, if a 
subject’s mid-study clinical profile or local radiological assessment indicates 
progression; 
 Third-party blinded range-of-motion assessment of the affected joint. 
To be performed before any invasive procedures: 
 Vital signs, including blood pressure, pulse rate, and oral temperature. 
Other procedures to be performed: 


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 Dispense study treatment bottles; 
 AE assessment; 
 Concomitant medications, including analgesics; 
 HCRU and productivity; 
 Treatment compliance assessment; 
 Physical examination; 
 Clinical laboratory tests — serum chemistry, hematology, liver function, serum 
pregnancy testing (as applicable), and urinalysis. 
15.2.14. 
Part 1–Cycle 5, Day 1 (P1-C5D1; Week 17) ± 7 days 
To be performed before any invasive procedures: 
 Vital signs, including blood pressure, pulse rate, and oral temperature; 
 PRO instruments, in the following order: 
o BPI Worst Pain NRS Item; 
o Worst Stiffness NRS item; 
o PROMIS Physical Function Scale; 
o Patient Global Rating of Concept item for carrying out every day physical 
activities; 
o EQ-5D-5L. 
Other procedures to be performed: 
 Dispense study treatment bottles; 
 Analgesic use assessment; 
 Review outpatient PRO instruments; 
 AE assessment; 
 Concomitant medications, including analgesics; 
 HCRU and productivity; 
 Treatment compliance assessment; 
 Random post-dose blood sampling for PK and PDy analysis; 
 Clinical laboratory tests — serum chemistry, hematology, liver function, serum 
pregnancy testing (as applicable).  
15.2.15. 
Part 1–Cycle 6, Day 1 (P1-C5D1; Week 21) ± 7 days 
To be performed before any invasive procedures: 
 Vital signs, including blood pressure, pulse rate, and oral temperature; 


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Other procedures to be performed: 
 Dispense study treatment bottles; 
 AE assessment; 
 Concomitant medications, including analgesics; 
 HCRU and productivity; 
 Treatment compliance assessment; 
 Clinical laboratory tests — serum chemistry, hematology, liver function, serum 
pregnancy testing (as applicable). 
15.2.16. 
Part 1 Completion visit/Early Termination Visit (Week 25) ± 7 days 
For subjects continuing to Part 2, see Section 15.3.1 instead.  
To be performed within the 7-day period before the visit: 
 ECHO or MUGA scanning; 
 MRI of the affected joint (with local assessment of progression status); 
 Third-party blinded range-of-motion assessment of affected joint. 
To be performed before any invasive procedures: 
 Vital signs, including blood pressure, pulse rate, and oral temperature; 
 12-lead ECG. 
 PRO instruments, in the following order: 
o BPI Worst Pain NRS Item; 
o Worst Stiffness NRS item; 
o PROMIS Physical Function Scale; 
o Patient Global Rating of Concept item for carrying out every day physical 
activities; 
o EQ-5D-5L; 
o Patient Global Impression of Change item for tumor-related stiffness. 
Other procedures to be performed: 
 Review outpatient PRO instruments; 
 AE assessment; 
 Concomitant medications, including analgesics; 
 HCRU and productivity. 
 Treatment compliance assessment; 
 Analgesic use assessment; 


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 Weight; 
 Physical examination; 
 Clinical laboratory tests — serum chemistry, hematology, coagulation, liver function, 
hormone levels, serum pregnancy testing (as applicable), urinalysis; 
 Surgical Assessment Questionnaire. 
 For subjects who undergo surgical resection of the tumor within 12 weeks of the last 
dose of study treatment, refer to Section 15.4 for collection of surgery related data. If 
a subject has surgery within 4 weeks of the last dose, the subject does not need to 
have the 28 Day Post-Treatment Visit evaluations. However, if a subject has surgery 
after 4 weeks of the last dose, the subject should have the 28 Day Post-Treatment 
Visit evaluations. None of these subjects need to have the End-of-Study Visit.  
As of 30 Sep 2016, subjects who wish to continue onto the open label part of this study (Part 2) 
will be unblinded after completion of the end of Part 1 assessments (Part 1 Completion 
visit/Early Termination visit) and those on placebo will be discontinued; subjects on pexidartinib 
in Part 1 may continue into Part 2 to continue to receive pexidartinib. Subjects who discontinue 
Part 1 early, should complete the end of Part 1 assessments (Part 1 Completion visit/Early 
Termination) at or before the time of their last treatment (MRI or range of motion assessments do 
not need to be repeated, if completed in the previous 28 days). 
15.2.17. 
Part 1 28 Day Post-Treatment Visit (last dose + 28 days) ± 7 days 
As of 30 Sep 2016, subjects who wish to continue onto the open label part of this study (Part 2) 
will be unblinded after completion of the end of Part 1 assessments (Part 1 Completion 
visit/Early Termination visit) and those on placebo will be discontinued and will not need to 
complete the Part 1 28 Day Post-Treatment Visit and associated procedures. 
This visit is scheduled 28 ± 7 days after the last dose of study treatment.  
To be performed within (±) 7 days of the visit: 
 MRI of the affected joint (for subjects who withdraw from the study for reasons other 
than progression; local assessment of progression status will be recorded); 
 Third-party blinded range-of-motion assessment of the affected joint. 
To be performed before any invasive procedures: 
 Vital signs, including blood pressure, pulse rate, and oral temperature; 
 12-lead ECG; 
 PRO instruments, in the following order: 
 BPI Worst Pain NRS item; 
 Worst Stiffness NRS item; 
 PROMIS Physical Function Scale; 
 Patient Global Rating of Concept item for carrying out every day physical 
activities; 


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 EQ-5D-5L; 
 Patient Global Impression of Change item for tumor-related stiffness. 
Other procedures to be performed: 
 Review outpatient PRO instruments; 
 AE assessment; 
 Concomitant medications, including analgesics; 
 HCRU and productivity; 
 Analgesic use assessment; 
 Weight; 
 Physical examination; 
 ECHO or MUGA scanning (only if > 3 months have elapsed since the previous scan); 
 Clinical laboratory tests — serum chemistry, hematology, coagulation, liver function, 
hormone levels, serum pregnancy testing (if applicable), urinalysis; 
 Surgical Assessment Questionnaire. 
 For subjects terminating the study because of progression, document if they plan to 
undergo any new PVNS/GCT-TS therapy, including surgery, during the 28-day 
period (± 7 days) after their last dose of study treatment. 
 For subjects who undergo surgical resection of the tumor within 12 weeks of the last 
dose of study treatment, refer to Section 15.4 for collection of surgery related data. 
15.2.18. 
Part 1 End-of-Study/12 Week Post-Treatment Visit (12 weeks ± 7 days after the 
last dose) 
As of 30 Sep 2016, subjects who wish to continue onto the open label part of this study (Part 2) 
will be unblinded after completion of the end of Part 1 assessments (Part 1 Completion 
visit/Early Termination visit) and those on placebo will be discontinued and will not need to 
complete the Part 1 End-of-study/12 Week Post-Treatment Visit and associated procedures. 
This visit is scheduled 12 weeks ± 7 days after the last dose of study treatment or before any new 
PVNS/GCT-TS therapy, including surgery, whichever occurs first. It is scheduled for subjects 
who withdraw from the study for reasons other than progression.  


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To be performed within (±) 7 days of the visit: 
 MRI of the affected joint (with local assessment of progression status) 
Other procedures to be performed: 
 Clinical laboratory tests — serum pregnancy testing (if applicable); 
 AE assessment; 
 Concomitant medications; 
 Ask the subject if s/he plans to begin any new PVNS/GCT-TS therapy, including 
surgery. For subjects who undergo surgical resection of the tumor within 12 weeks of 
the last dose of study treatment, refer to Section 15.4 for collection of surgery related 
data.  
 For other subjects, terminate the subject from the study. 
15.3. 
Detailed Study Procedures by Visit — Part 2 
If the subject is known to have been on pexidartinib treatment in Part 1, then visits and 
associated procedures are only required on Day 1 of each cycle in Part 2. 
15.3.1. 
Part 2–Cycle 1, Day 1 (P2-C1D1; Week 25) 
For subjects continuing to Part 2, the P2-C1D1 visit will serve as both the Part 1 Completion 
visit and the first visit of Part 2. Some procedures for both visits can occur on the same day. 
The following procedures are performed as part of the P1-Completion visit. 
To be performed within the 7-day period before the P2-C1D1 visit: 
 ECHO or MUGA scanning; 
 MRI of the affected joint (with local assessment of progression status). The 
Investigator may request a centrally read MRI to confirm progression, eg, if a 
subject’s mid-study clinical profile or local radiological assessment indicates 
progression. 
 Third-party blinded range-of-motion assessment of the affected joint. 
To be performed before any invasive procedures: 
 Vital signs, including blood pressure, pulse rate, and oral temperature; 
 PRO instruments, in the following order: 
o BPI Worst Pain NRS item; 
o Worst Stiffness NRS item; 
o PROMIS Physical Function Scale; 
o EQ-5D-5L.  
To be performed before dosing at the P2-C1D1 visit: 
 Review outpatient PRO instruments; 


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 AE assessment; 
 Concomitant medications, including analgesics; 
 Treatment compliance assessment; 
 Analgesic use assessment. 
 Weight; 
 Physical examination; 
 Clinical laboratory tests - serum chemistry, hematology, coagulation, liver function, 
hormone levels, serum pregnancy testing (as applicable), urinalysis. 
Note: Women who are not using hormonal contraception will be tested for levels of 
FSH, LH, progesterone, and estradiol. Hormone testing will not be required for 
women who have either had an oophorectomy or are post-menopausal. Men will be 
tested for levels of LH, FSH, and testosterone. Men whose testosterone level is below 
baseline at the last study visit should be followed until their level has stabilized or 
returned to baseline.  
 Surgical Assessment Questionnaire. 
The following procedures will be performed as part of the P2-C1D1visit. 
To be performed before dosing: 
 Blood sampling for PK and PDy analysis 
Subject is dosed in clinic. 
To be performed after dosing: 
 Record the dose (subject diary, source records, eCRF); 
 Dispense study treatment bottles. 
To be performed 2 hours ± 10 minutes after dosing: 
 12-lead ECG. 
15.3.2. 
Part 2–Cycle 1, Day 8 (P2-C1D8; Week 26) ± 2 days 
 Clinical laboratory tests — liver function; 
 AE assessment; 
 Concomitant medications. 
15.3.3. 
Part 2–Cycle 1, Day 15 (P2-C1D15; Week 27) ± 2 days 
To be performed before any invasive procedures: 
 Vital signs, including blood pressure, pulse rate, and oral temperature; 
 12-lead ECG. 
To be performed before the morning dose: 


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 Blood sampling for PK and PDy analysis; 
 Clinical laboratory tests — hematology, liver function; 
Subject is dosed in clinic. 
To be performed after the morning dose: 
 Record the dosing (subject diary, source records, eCRF); 
 Blood sampling for PK analysis at various post-dose time points (see Section 6.4.16 
for details). 
To be performed 2 hours ± 10 minutes after dosing: 
 12-lead ECG. 
Other procedures to be performed: 
 AE assessment; 
 Concomitant medications, including analgesics; 
 Treatment compliance assessment; 
15.3.4. 
Part 2–Cycle 1, Day 22 (P2-C1D22; Week 28) ± 2 days 
 Clinical laboratory tests:  liver function; 
 AE assessment; 
 Concomitant medications. 
15.3.5. 
Part 2–Cycle 2, Day 1 (P2-C2D1; Week 29) ± 2 days 
To be performed before any invasive procedures: 
 Vital signs, including blood pressure, pulse rate, and oral temperature. 
Other procedures to be performed: 
 Dispense study treatment bottles; 
 AE assessment; 
 Concomitant medications, including analgesics; 
 Treatment compliance assessment; 
 Random post-dose blood sampling for PK and PDy analysis; 
 Clinical laboratory tests - serum chemistry, hematology, liver function; serum 
pregnancy testing (if applicable); 
 Physical examination. 
15.3.6. 
Part 2–Cycle 2, Day 8 (P2-C2D8; Week 30) ± 2 days 
 Clinical laboratory tests — liver function; 


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 AE assessment. 
 Concomitant medications. 
15.3.7. 
Part 2–Cycle 2, Day 15 (P2-C2D15; Week 31) ± 2 days 
 Clinical laboratory tests — liver function; 
 AE assessment; 
 Concomitant medications. 
15.3.8. 
Part 2–Cycle 2, Day 22 (P2-C2D22; Week 32) ± 2 days 
To be performed before any invasive procedures: 
 Clinical laboratory tests — liver function; 
 AE assessment. 
 Concomitant medications. 
15.3.9. 
Part 2–Cycle 3, Day 1 (P2-C3D1; Week 33) ± 7 days 
To be performed before any invasive procedures: 
 Vital signs, including blood pressure, pulse rate, and oral temperature. 
Other procedures to be performed: 
 AE assessment; 
 Concomitant medications, including analgesics; 
 Treatment compliance assessment; 
 Clinical laboratory tests — serum chemistry, hematology, liver function; serum 
pregnancy testing (if applicable); 
 Dispense study treatment bottles. 
15.3.10. 
Part 2–Cycle 3, Day 15 (P2-C3D15; Week 35) ± 7 days 
To be performed before any invasive procedures: 
 Clinical laboratory tests — liver function; 
 AE assessment. 
 Concomitant medications. 
15.3.11. 
Part 2–Cycle 4, Day 1 (P2-C4D1; Week 37) ± 7 days 
To be performed within (±) 7 days of the visit: 
 ECHO or MUGA scanning; 
 MRI of the affected joint (with local assessment of progression status); 


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 Third-party blinded range-of-motion assessment of the affected joint; 
To be performed before any invasive procedures: 
 Vital signs, including blood pressure, pulse rate, and oral temperature; 
 PRO instruments, in the following order: 
 BPI Worst Pain NRS Item 
 Worst Stiffness NRS item 
 PROMIS Physical Function Scale 
 EQ-5D-5L 
Other procedures to be performed: 
 Dispense study treatment bottles. 
 Review outpatient PRO instruments; 
 AE assessment; 
 Concomitant medications, including analgesics; 
 Treatment compliance assessment; 
 Physical examination; 
 Clinical laboratory tests — serum chemistry, hematology, liver function, serum 
pregnancy testing (if applicable), urinalysis; 
 Analgesic use assessment. 
15.3.12. 
Part 2–Cycle 5, Day 1 (P2-C5D1; Week 41) ± 7 days 
To be performed before any invasive procedures: 
 Vital signs, including blood pressure, pulse rate, and oral temperature. 
Other procedures to be performed: 
 Dispense study treatment bottles; 
 AE assessment; 
 Concomitant medications, including analgesics; 
 Treatment compliance assessment; 
 Clinical laboratory tests — serum chemistry, hematology, liver function, serum 
pregnancy testing (if applicable). 
15.3.13. 
Part 2–Cycle 6, Day 1 (P2-C6D1; Week 45) ± 7 days 
To be performed before any invasive procedures: 
 Vital signs, including blood pressure, pulse rate, and oral temperature. 


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Other procedures to be performed: 
 Dispense study treatment bottles; 
 AE assessment; 
 Concomitant medications, including analgesics; 
 Treatment compliance assessment; 
 Clinical laboratory tests — serum chemistry, hematology, liver function, serum 
pregnancy testing (if applicable); 
15.3.14. 
Part 2–Cycle 7, Day 1 (P2-C7D1; Week 49) ± 7 days  
To be performed within (±) 7 days of the visit: 
 ECHO or MUGA scanning; 
 MRI of the affected joint (with local assessment of progression status); 
 Third-party blinded range-of-motion assessment of the affected joint. 
To be performed before any invasive procedures: 
 Vital signs, including blood pressure, pulse rate, and oral temperature; 
 12-lead ECG (performed every 24 weeks from this point forward, ie, P2-C13D1, P2-
C19D1, etc.); 
 PRO instruments, in the following order: 
o BPI Worst Pain NRS Item 
o Worst Stiffness NRS item 
o PROMIS Physical Function Scale 
o EQ-5D-5L 
To be performed before dosing: 
 Blood sampling for hormone levels (performed every 24 weeks from this point 
forward, ie, P2-C13D1, P2-C19D1, etc.); 
 Dispense study treatment bottles. 
Subject is dosed in clinic. 
To be performed after the morning dose: 
 Record the dose (subject diary, source records, eCRF); 
Other procedures to be performed: 
 Review outpatient PRO instruments; 
 AE assessment; 
 Concomitant medications, including analgesics; 


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 Treatment compliance assessment; 
 Physical examination; 
 Clinical laboratory tests — serum chemistry, hematology, liver function, serum 
pregnancy testing (if applicable); 
 Analgesic use assessment; 
 Surgical Assessment Questionnaire. 
 For subjects who undergo surgical resection of the tumor within 12 weeks of the last 
dose of study treatment, refer to Section 15.4 for collection of surgery related data. If 
a subject has surgery within 4 weeks of the last dose, the subject does not need to 
have the Post-Treatment Visit evaluations.  However, if a subject has surgery after 4 
weeks of the last dose, the subject should have the Post-Treatment Visit evaluations. 
None of these subjects need to have the End-of-Study Visit. 
15.3.15. 
Part 2–Cycle 10+, Day 1 (P2-C10+D1; Week 61+) ± 7 days  
The procedures described below are performed at P2-C10D1 ± 7 days and every 12 weeks 
thereafter (eg, P2-C13, P2-C16). 
To be performed within (±) 7 days of the visit: 
 MRI of the affected joint (with local assessment of progression status); 
 Third-party blinded range-of-motion assessment of the affected joint. 
To be performed before any invasive procedures: 
 Vital signs, including blood pressure, pulse rate, and oral temperature; 
 PRO instruments, in the following order: 
o BPI Worst Pain NRS Item 
o Worst Stiffness NRS item 
o PROMIS Physical Function Scale 
o EQ-5D-5L 
Other procedures to be performed: 
 Dispense study treatment bottles. 
 Review outpatient PRO instruments; 
 AE assessment; 
 Concomitant medications, including analgesics; 
 Treatment compliance assessment; 
 Physical examination; 
 Clinical laboratory tests — serum chemistry, hematology, liver function, serum 
pregnancy testing (if applicable); 


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 Analgesic use assessment; 
15.3.16. 
Post-Treatment Visit (Part 2) 
The Post-treatment Visit is scheduled 28 ± 7 days after the last dose of study treatment. 
To be performed within (±) 7 days of the visit: 
 MRI of the affected joint (with local assessment of progression status); 
 Third-party blinded range-of-motion assessment of the affected joint. 
To be performed before any invasive procedures: 
 Vital signs, including blood pressure, pulse rate, and oral temperature; 
 12-lead ECG; 
 PRO instruments (if not done within the last 30 days), in the following order: 
o BPI Worst Pain NRS Item 
o Worst Stiffness NRS item 
o PROMIS Physical Function Scale 
o EQ-5D-5L 


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Other procedures to be performed: 
 Review outpatient PRO instruments; 
 AE assessment; 
 Concomitant medications, including analgesics; 
 Treatment compliance assessment; 
 Analgesic use assessment; 
 Weight; 
 Physical examination; 
 ECHO or MUGA scanning (only if >3 months have elapsed since the previous scan); 
 Clinical laboratory tests — serum chemistry, hematology, coagulation, liver function, 
hormone levels, serum pregnancy testing (as applicable), urinalysis; 
 Surgical Assessment Questionnaire; 
 For subjects terminating the study because of progression, document if they plan to 
undergo any new PVNS/GCT-TS therapy, including surgery, during the 28-day 
period (± 7 days) after their last dose of study treatment.  
 For subjects who undergo surgical resection of the tumor within 12 weeks of the last 
dose of study treatment, refer to Section 15.4 for collection of surgery related data.  
15.3.17. 
End-of-Study or Early Termination Visit 
The End-of-Study/Early Termination Visit is scheduled 12 weeks ± 7 days after the last dose of 
study treatment or before any new PVNS/GCT-TS therapy, including surgery, whichever occurs 
first.  
To be performed within (±) 7 days of the visit: 
 MRI of the affected joint (with local assessment of progression status); 
Other procedures to be performed: 
 Clinical laboratory tests - serum pregnancy testing (if applicable); 
 AE assessment; 
 Concomitant medications; 
 Ask the subject if s/he has begun any new PVNS/GCT-TS therapy, including surgery; 
For subjects who undergo surgical resection of the tumor within 12 weeks of the last 
dose of study treatment, refer to Section 15.4 for collection of surgery related data. 
 For other subjects, terminate the subject from the study. 
15.4. 
Detailed Study Procedures by Visit — Surgical Outcome 
For subjects who undergo surgical resection of the tumor within 12 weeks of the last dose of 
study treatment, they will remain on the study and follow a different study visit schedule to 


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obtain data on the surgical procedure and its outcome. There is no need to have the End-of-Study 
visit. 
If a subject has surgery within 4 weeks of the last dose of study treatment, the subject does not 
need to have the Post-Treatment Visit evaluations per Section 15.2 and Section 15.3, but will 
need to have the safety lab tests (blood chemistry, hematology, liver function tests, coagulation 
tests, urinalysis, and serum pregnancy test) and an ECG performed at least 7 days after the last 
dose of study treatment, but prior to surgery. 
If a subject has surgery after 4 weeks of the last dose of study treatment, the subject should have 
the Post-Treatment Visit evaluations per Section 15.2 and Section 15.3. 
15.4.1. 
Four weeks Prior to Surgery 
For subjects undergoing surgical resection, the following procedures are performed within the 4-
week period before surgery: 
 MRI of the affected joint (Only perform if not done within 12 weeks prior to the 
surgery) 
 Third-party blinded range-of-motion assessment of the affected joint. 
 PRO instruments, in the following order: 
o BPI Worst Pain NRS item; 
o Worst Stiffness NRS item; 
o PROMIS Physical Function Scale; 
 Collection of SAEs (Note: hospitalization for the surgery is not considered as SAE) 
 Reasons for surgery 
15.4.2. 
During or shortly after Surgery 
 Surgical procedures and findings 
 Tumor sample submission 
 Collection of SAEs 
15.4.3. 
4 Months (± 2 weeks) after Surgery 
 MRI of the affected joint 
 Third-party blinded range-of-motion assessment of the affected joint. 
 PRO instruments, in the following order: 
o BPI Worst Pain NRS item; 
o Worst Stiffness NRS item; 
 Collection of SAEs (Note: hospitalization for the surgery is not considered as SAE) 
 Disease Recurrence 


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15.4.4. 
8, 12, 18, and 24 Months (± 2 weeks) after Surgery 
 Disease Recurrence 
 No End-of-Study visit is required, however an End of Study eCRF will be completed 
at this time 
15.5. 
Brief Pain Inventory (BPI) Worst Pain Numeric Rating Scale (NRS) 
Item 
The following question asks about pain at the site of your tumor. 
 
15.6. 
Worst Stiffness NRS item 
The following question asks about stiffness at the site of your tumor. 
 
 








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15.8. 
EQ-5D-5L 
 
 
 
Health Questionnaire 
 
 
English version for the USA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 
USA (English) © 2009 EuroQol Group. EQ-5D™ is a trade mark of the EuroQol Group 


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Under each heading, please check the ONE box that best describes your health TODAY 
 
MOBILITY 
I have no problems walking   
 
 
 
 
I have slight problems walking  
 
 
 
 
I have moderate problems walking 
  
 
 
 
I have severe problems walking 
  
 
 
 
I am unable to walk 
 
 
 
 
 
 
 
SELF-CARE 
I have no problems washing or dressing myself  
 
 
I have slight problems washing or dressing myself   
 
I have moderate problems washing or dressing myself  
 
I have severe problems washing or dressing myself  
 
I am unable to wash or dress myself  
 
 
 
 
USUAL ACTIVITIES (eg work, study, housework,  
family or leisure activities) 
I have no problems doing my usual activities  
 
 
I have slight problems doing my usual activities  
 
 
I have moderate problems doing my usual activities  
 
I have severe problems doing my usual activities  
 
 
I am unable to do my usual activities  
 
 
 
 
PAIN / DISCOMFORT 
I have no pain or discomfort   
 
 
 
 
I have slight pain or discomfort  
 
 
 
 
I have moderate pain or discomfort   
 
 
 
I have severe pain or discomfort  
 
 
 
 
I have extreme pain or discomfort  
 
 
 
 
 
ANXIETY / DEPRESSION 
I am not anxious or depressed  
 
 
 
 
I am slightly anxious or depressed   
 
 
 
I am moderately anxious or depressed  
 
 
 
I am severely anxious or depressed   
 
 
 
I am extremely anxious or depressed  
 
 
 
 
 
 
 
 
 
 
 
 
2 
USA (English) © 2009 EuroQol Group. EQ-5D™ is a trade mark of the EuroQol Group 




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15.9. 
Patient Global Impression of Change and Rating of Concept Items 
Patient Global Rating of Concept – Physical Functioning 
Please rate your tumor-related physical functioning. Please focus on your ability to carry out 
your everyday physical activities, such as walking, climbing stairs, or carrying groceries. 
How much has your tumor limited your physical functioning today? 
 Not at all 
 
 A little 
 
 Somewhat 
 
 Severely 
 
 Extremely 
 
 
Patient Global Impression of Change in Symptoms – Stiffness 
Please rate the change in your stiffness at the site of your tumor today compared to your 
stiffness at the site of your tumor before you received treatment at the start of the study. 
 Much improved  
 Moderately improved  
 A little improved  
 No change  
 A little worse  
 Moderately worse 
 Much worse  
 


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15.10. 
Surgical Assessment Questionnaire 
Table 15.1: 
Sample Surgical Assessment Questionnaire 
Question 
Response 
Expected probability of a complete resection with 
no microscopic residual tumor: 
High  
Medium  
Low 
None 
Expected postoperative morbidity: 
None 
Mild 
Moderate 
Severe 
Complexity of surgical procedure: 
Low 
Medium 
High 
Operative risk due to other medical conditions: 
Low 
Medium 
High 
Pre-Operative Assessment Not Done 
15.11. 
Employment status and productivity questions 
Please choose one of the following which best describes your current work situation. 
□   Employed 
□   Self-employed 
□   Unemployed 
□   Student 
□   Retired 
□   Other, please specify: __________ 
If employed, self-employed or unemployed, which of the following best describes your current 
work situation? 
□   I am working full time for pay 
□   I am only working part-time for pay because of my tumour 
□   I am only working part-time for pay for reasons not related to my tumour 
□   I am not working for pay because of my tumour 
□   I am not working for pay for reasons not related to my tumour 


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If you are working, in the past 4 weeks, on average, how many days per week did you miss from 
work due to your tumour? 
Include time when you were late getting to work, when you left work early, and time spent for 
doctors’ visits and hospitalizations. 
 
                Days (Please record to the nearest half day. If none, record 0.) 


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15.12. 
Healthcare  Resource Use Questions 
1. Has the subject been hospitalized in the past 4 weeks? 
□   Yes 
□   No 
If Yes, 
1a. What was the date of admission?    ___/___/____ (DD/MM/YYYY) 
 
1b. What was the date of discharge?    ___/___/____ (DD/MM/YYYY) 
 
1c. Was the hospitalization related to the subject’s tumour? 
□   Yes 
□   No 
 
1d. What was the reason/diagnosis for hospitalization? 
Specify: __________ 
 
1e. What was the nature of the hospitalization? (Please tick one) 
□   Urgent/ Emergency 
□   Scheduled/Planned 
□   Prolongation of existing hospitalization 
 
1f. Number of days spent in general ward: __________ 
 
1g. Number of days spent in intensive care unit (ICU) 
(or equivalent units, e.g. cardiac care or high dependency unit): __________ 
 
1h. Did the subject have any additional hospitalizations in the past 4 weeks? 
□   Yes 
□   No 
If Yes, repeat questions 1a to 1g. If No, proceed to question 2. 
 


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2. Did the subject have any Accident & Emergency (emergency room) visits that did not result in 
hospitalization in the past 4 weeks? 
Number of visits: __________ (If none, record 0) 
 
2a. For each A&E (ER) visit record the following: 
Was the visit related to the subject’s tumour? 
□   Yes 
□   No 
 


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15.13. 
Schedule of Events 


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Table 15.2: 
Schedule of Events – Part 1 (Blinded, Placebo-controlled Phase) 
Procedurea 
Day 
-42 to -
1b 
P1- 
C1D1 
P1- 
C1D8 
± 2d  
P1- 
C1D15 
± 2d 
P1- 
C1D22 
± 2d 
P1- 
C2D1 
± 2d 
P1- 
C2D8 
± 2d 
P1- 
C2D15 
± 2d  
P1- 
C2D22 
± 2d 
P1- 
C3D1 
± 7d 
P1- 
C3D15 
± 7d 
P1- 
C4D1 
± 7d 
P1- 
C5D1 
± 7d 
P1- 
C6D1 
± 7d 
P1 
Compl./
Early 
Termc 
± 7d 
P1- 
28 Day 
Post Tx
d 
± 7d  
P1 End 
St/12 
Week 
post- 
Tx ± 7d 
 
Screen
b 
Week 
1 
Week 
2 
Week 
3 
Week 
4 
Week 
5 
Week 
6 
Week 
7 
Week 
8 
Week 
9 
Week 
11 
Week 
13 
Week 
17 
Week 
21 
Week 25 
LD+28d 
LD+12 
Week 
/ < new 
Tx e 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demog. & 
medical 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height, 
weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xf 
Xf 
 
Vital signs, 
incl. BP, 
pulse, temp. 
Xg 
X 
 
X 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
 
Physical 
examinationh 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
X 
 
ECGi 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
ECHO or 
MUGA 
scanningj 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Xk 
 
Chemistry, 
hematology 
X 
X 
 
Xl 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
 
Liver 
function tests
m 
X 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
 
Urinalysis 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
 
Hepatitis 
panel 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation 
testsn 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 


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Procedurea 
Day 
-42 to -
1b 
P1- 
C1D1 
P1- 
C1D8 
± 2d  
P1- 
C1D15 
± 2d 
P1- 
C1D22 
± 2d 
P1- 
C2D1 
± 2d 
P1- 
C2D8 
± 2d 
P1- 
C2D15 
± 2d  
P1- 
C2D22 
± 2d 
P1- 
C3D1 
± 7d 
P1- 
C3D15 
± 7d 
P1- 
C4D1 
± 7d 
P1- 
C5D1 
± 7d 
P1- 
C6D1 
± 7d 
P1 
Compl./
Early 
Termc 
± 7d 
P1- 
28 Day 
Post Tx
d 
± 7d  
P1 End 
St/12 
Week 
post- 
Tx ± 7d 
 
Screen
b 
Week 
1 
Week 
2 
Week 
3 
Week 
4 
Week 
5 
Week 
6 
Week 
7 
Week 
8 
Week 
9 
Week 
11 
Week 
13 
Week 
17 
Week 
21 
Week 25 
LD+28d 
LD+12 
Week 
/ < new 
Tx e 
Hormone 
testingo 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
BPI Worst 
Pain NRSp, q 
X 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
X 
 
Worst 
Stiffness 
NRS itemp,q 
X 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
X 
 
Most 
disturbing Sx 
assessment 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PROMIS 
Physical 
Function 
Scalep 
X 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
X 
 
Global 
Rating of 
Concept item 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
X 
 
EQ-5D-5L 
instrumentp 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
X 
 
Review 
completed 
outpatient 
PROs 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
X 
 
Pt. Global 
Impress. of 
Change item 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
MRI of the 
affected joint
r 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 


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Procedurea 
Day 
-42 to -
1b 
P1- 
C1D1 
P1- 
C1D8 
± 2d  
P1- 
C1D15 
± 2d 
P1- 
C1D22 
± 2d 
P1- 
C2D1 
± 2d 
P1- 
C2D8 
± 2d 
P1- 
C2D15 
± 2d  
P1- 
C2D22 
± 2d 
P1- 
C3D1 
± 7d 
P1- 
C3D15 
± 7d 
P1- 
C4D1 
± 7d 
P1- 
C5D1 
± 7d 
P1- 
C6D1 
± 7d 
P1 
Compl./
Early 
Termc 
± 7d 
P1- 
28 Day 
Post Tx
d 
± 7d  
P1 End 
St/12 
Week 
post- 
Tx ± 7d 
 
Screen
b 
Week 
1 
Week 
2 
Week 
3 
Week 
4 
Week 
5 
Week 
6 
Week 
7 
Week 
8 
Week 
9 
Week 
11 
Week 
13 
Week 
17 
Week 
21 
Week 25 
LD+28d 
LD+12 
Week 
/ < new 
Tx e 
Range-of-
motion 
assessments 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
 
Serum 
pregnancy 
testt 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
Archival 
tumor tissueu 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK, PDy 
blood 
samplingv 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
Analgesic 
use 
assessment 
Xw 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
X 
 
Subject 
randomizatio
n 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense 
study Tx 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
X 
X 
 
 
 
In-clinic 
study Tx 
dosingx 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Tx 
dosingy 
 
—— Twice daily dosing through Week 24y —— 
 
 
 
Tx 
compliance 
assessment 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
 
 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Procedurea 
Day 
-42 to -
1b 
P1- 
C1D1 
P1- 
C1D8 
± 2d  
P1- 
C1D15 
± 2d 
P1- 
C1D22 
± 2d 
P1- 
C2D1 
± 2d 
P1- 
C2D8 
± 2d 
P1- 
C2D15 
± 2d  
P1- 
C2D22 
± 2d 
P1- 
C3D1 
± 7d 
P1- 
C3D15 
± 7d 
P1- 
C4D1 
± 7d 
P1- 
C5D1 
± 7d 
P1- 
C6D1 
± 7d 
P1 
Compl./
Early 
Termc 
± 7d 
P1- 
28 Day 
Post Tx
d 
± 7d  
P1 End 
St/12 
Week 
post- 
Tx ± 7d 
 
Screen
b 
Week 
1 
Week 
2 
Week 
3 
Week 
4 
Week 
5 
Week 
6 
Week 
7 
Week 
8 
Week 
9 
Week 
11 
Week 
13 
Week 
17 
Week 
21 
Week 25 
LD+28d 
LD+12 
Week 
/ < new 
Tx e 
Adverse 
eventsz 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Surgical 
Assessment 
Questionnair
e 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Collection of 
surgical data
aa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xaa 
Xaa 
Xaa 
HCRU & 
productivity 
assessment 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
 
PGx blood 
samplingbb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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 AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BP = blood pressure; BPI = Brief Pain Inventory; C = cycle; Compl  = Completion; D/d = Day; Demog. = 
demographics; ECG = electrocardiogram; ECHO = echocardiography; End St./12 Week post Tx. = End-of-Study/12 Week Post-Treatment; EQ-5D-5L =EuroQol five-dimensional descriptive system; 
FSH = follicle-stimulating hormone; GCT-TS = giant cell tumor of the tendon sheath; GGT = gamma-glutamyl transpeptidase; HCRU = healthcare resource use; incl. = including; LD = last dose; LH 
= luteinizing hormone; MRI = magnetic resonance imaging; MUGA = multi-gated acquisition; NRS = numeric rating scale; P = Part; PDy = pharmacodynamic; PGx = pharmacogenomic; PK = 
pharmacokinetic; PRO = patient-reported outcome; PROMIS = Patient-reported Outcomes Measurement Information System; Pt = patient; PVNS = pigmented villonodular synovitis; Screen = 
Screening; Sx = symptom; temp. = temperature; Tx = treatment; Week = week 
 
a Effective 30 Sep 2016, subjects who wish to continue onto the open label part of this study (Part 2) will be unblinded after completion of the end of Part 1 assessments (Part 1 Completion visit/Early 
Termination visit) and those on placebo will be discontinued and will not have the 28 Day Post-treatment and End-of-Study Visit assessments. 
b Procedures performed as part of patient care within the 42-day period before the first dose of study treatment may be used for screening purposes if they conform to protocol requirements and 
standards. All screening test results must be reviewed prior to dosing to assess the study candidate’s eligibility for inclusion. 
c The Part 1 Completion visit applies to subjects who are not continuing into Part 2. Those continuing into Part 2 will instead have the assessments indicated at P2-C1D1 (see Table 15.3). Effective 
30 Sep 2016, subjects who wish to continue onto the open label part of this study (Part 2) will be unblinded after completion of the end of Part 1 assessments (Part 1 Completion visit/Early 
Termination visit) and those on placebo will be discontinued; subjects on pexidartinib in Part 1 may continue into Part 2 to continue to receive pexidartinib. Subjects who discontinue Part 1 early, 
should complete the end of Part 1 assessments (Part 1 Completion visit/Early Termination) at or before the time of their last treatment (MRI or range of motion assessments do not need to be repeated, 
if completed in the previous 28 days). 
d As of 30 Sep 2016, subjects who wish to continue onto the open label part of this study (Part 2) will be unblinded after completion of the end of Part 1 assessments (Part 1 Completion visit/Early 
Termination visit) and those on placebo will be discontinued and will not need to complete the Part 1 28 Day Post-Treatment Visit and associated procedures. Subjects who exit the study with 
radiologic disease progression will undergo their last study evaluation 28 ± 7 days after their last dose of study treatment or before any new PVNS therapy, including surgery, whichever occurs first. 
Any planned new PVNS therapy, including the type of surgical procedure, will be recorded. Subjects who withdraw from the study with radiologic progression do not undergo a Part 1 End-of-
Study/12 Week Post-Treatment MRI. 
e Subjects who end their study participation with no radiologic disease progression will undergo post-treatment procedures 28 ± 7 days after their last dose of study treatment and a final MRI 12 weeks 
± 7 days after their last dose of study treatment or before any new PVNS therapy, including surgery, whichever occurs first. The latter MRI need not be performed if new PVNS therapy starts within 4 
weeks of the 28 Day Post-treatment Visit. Before or at the Part 1 End-of-Study/12 Week Post-Treatment Visit, plans for any new PVNS therapy will be obtained. (see Footnote aa) As of 30 Sep 2016, 
subjects who wish to continue onto the open label part of this study (Part 2) will be unblinded after completion of the end of Part 1 assessments (Part 1 Completion visit/Early Termination visit) and 
those on placebo will be discontinued and will not have the 28 Day Post-treatment and End-of-Study Visit assessments. 
f Weight only. 
g Vital signs should be performed before any invasive procedures are carried out on the same day. 
h In the event of early withdrawal or if the subject completes Part 1 but does not enter Part 2, a physical examination is performed at the 28 Day Post-treatment Visit. 
i A standard 12-lead ECG is performed prior to dosing. Subjects should be told not to take their morning dose of study treatment at home on days when an ECG is performed; instead, they should bring 
their study treatment bottle to the clinic and take their morning dose upon site instruction. At the P1-C1D1 and P1-C1D15 visits only, the ECG is performed before and 2 hours after dosing. The 2 
hour post-dose ECG should begin within 10 minutes of the 2 hour post-dose time point. 
j ECHO or MUGA scanning is chosen by Investigator preference. However, the same imaging platform must be used throughout the study.  
k ECHO or MUGA scanning should only be repeated if more than 3 months have elapsed since the last procedure. Subjects who show a reduced ejection fraction relative to baseline at the last visit 
should be followed until a stable ejection fraction is measured by two consecutive tests. 
l Hematology only. 
m Alkaline phosphatase, ALT, AST, total and direct bilirubin, and GGT should be assessed at screening, weekly during P1-C1 beginning on Day 1, weekly during P1-C2 beginning on Day 1, biweekly 
during P1-C3 beginning on Day 1, and on Day 1 of every cycle thereafter. More frequent monitoring is required in the case of increased liver function tests (see Section 5.3). 
n Subjects receiving concomitant warfarin should have their anti-coagulation status carefully monitored for any necessary dose adjustments (see Section 5.3). 
o Women who are not using hormonal contraception will be tested for levels of FSH, LH, progesterone, and estradiol. Hormone testing will not be required for women who have either had an 
oophorectomy or are post-menopausal. Men will be tested for levels of LH, FSH, and testosterone. Men whose testosterone level is below baseline at the last study visit should be followed until their 
level has stabilized or returned to baseline. 
p Subjects should record responses to the BPI Worst Pain NRS item, Worst Stiffness NRS item, PROMIS Physical Function Scale, and EQ-5D-5L in the eDiary before any invasive procedures. (NOTE: 
at the Screening Visit only, the recall period will be the preceding week for the BPI Worst Pain NRS item and Worst Stiffness NRS item. The subject’s response must be documented in the medical 
notes.) 
q Subjects should be reminded to complete the BPI Worst Pain NRS item and the Worst Stiffness NRS item, at least 4 of 7 consecutive days for 2 weeks prior to randomization, and prior to Day 1 of 
P1-C1, P1-C3, and P1-C5 and before the Part 1 Completion Visit (Week 25). In the event of early withdrawal or if the subject completes Part 1 but does not enter Part 2, this item will be completed 
prior to the 28 Day Post-treatment Visit. 
r The Investigator may request a centrally read blinded MRI to confirm progression, eg, if a subject’s mid-study clinical profile or local radiological assessment indicates progression. 


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s A range-of-motion assessment in the affected joint or tumor location will be performed by a blinded independent third party assessor. 
t Women of childbearing potential must have a serum pregnancy test within 14 days of randomization (or, where different regulations apply, within 72 hours of randomization). (Women who have 
documentation of at least 12 months of spontaneous amenorrhea and have an FSH level > 40 mIU/mL will be considered postmenopausal and need not undergo pregnancy testing.) 
u Archival surgical tissue from PVNS/GCT-TS tumors should be obtained at screening (or whenever available) for biomarker assessment. 
v Details on blood sampling are found in Section 6.4.16 (PK) and Section 6.4.15 (PDy). 
w A diary of analgesic use must be kept for the 2-week period before the first dose of study treatment. 
x The morning dose of study treatment should be administered in the clinic on the days indicated; P1-C1D1 should be within 3 days after randomization. 
y Dose administration by the subject at home. See Section 3.1 for dose reduction as of P1-C1D15. Subjects should take their last dose of study treatment the evening before their scheduled Part 1 
Completion Visit (Week 25). 
z After the subject provides signed informed consent; AEs are monitored throughout the study via safety assessments, observation, and subject reporting (see Section 6.4.17). 
aa If surgical resection of the tumor is performed within 12 weeks after the last dose of study treatment, details of the surgery and its outcome should be obtained (see Table 15.4). After completion of the 
end of Part 1 assessments (Part 1 Completion visit/Early Termination visit), subjects who wish to continue onto the open label part of this study (Part 2) will be unblinded and those on placebo will be 
discontinued and will not need to have surgical data follow-up. 
bb The pharmacogenomics blood sample is optional. If taken, it should only be taken once as soon as reasonably possible after the subject has signed the consent form. 


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Table 15.3: 
Schedule of Events – Part 2 (Open-label Phase) 
 
P2- 
C1D1a 
P2- 
C1D8 
± 2d  
P2- 
C1D1
5 
± 2d 
P2- 
C1D22 
± 2d  
P2- 
C2D1 
± 2d 
P2- 
C2D8 
± 2d 
P2- 
C2D1
5 
± 2d  
P2- 
C2D22 
± 2d 
P2- 
C3D1 
± 7d 
P2- 
C3D1
5 
± 7d 
P2- 
C4D1 
± 7d 
P2- 
C5D1 
± 7d 
P2- 
C6D1 
± 7d 
P2- 
C7D1 
± 7d 
P2- 
C10+D1b 
± 7d 
P2-Post 
Txc 
± 7d 
End St./ 
Ear. 
Term. ± 
7d 
Procedured 
Week 
25 
Week  
26 
Week 
27 
Week 
28 
Week 
29 
Week 
30 
Week 
31 
Week 
32 
Week 
33 
Week 
35 
Week 
37 
Week 
41 
Week 
45 
Week 
49 
Week 
61+ 
LD  
+ 28d 
LD + 12 
Week/ < 
new Txe 
Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Vital signs, 
incl. BP, 
pulse, temp. 
X 
 
X 
 
X 
 
 
 
X 
 
X 
Xf 
Xf 
Xf 
Xf 
Xf 
 
Physical 
examination 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
X 
Xf 
 
ECG 
Xg 
 
Xg 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
ECHO or 
MUGA 
scanning 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
Xh 
 
Chemistry, 
hematology 
X 
 
Xi 
 
X 
 
 
 
X 
 
Xf 
Xf 
Xf 
Xf 
Xf 
Xf 
 
Liver 
function 
testsj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
Coagulation 
testsk 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Hormone 
testingl  
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
BPI Worst 
Pain NRS 
item 
X 
 
 
 
 
 
 
 
 
 
Xf,m 
 
 
Xf,m 
Xf,m 
Xf,m 
 
Worst 
Stiffness 
NRS item 
X 
 
 
 
 
 
 
 
 
 
Xf,m 
 
 
Xf,m 
Xf,m 
Xf,m 
 


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P2- 
C1D1a 
P2- 
C1D8 
± 2d  
P2- 
C1D1
5 
± 2d 
P2- 
C1D22 
± 2d  
P2- 
C2D1 
± 2d 
P2- 
C2D8 
± 2d 
P2- 
C2D1
5 
± 2d  
P2- 
C2D22 
± 2d 
P2- 
C3D1 
± 7d 
P2- 
C3D1
5 
± 7d 
P2- 
C4D1 
± 7d 
P2- 
C5D1 
± 7d 
P2- 
C6D1 
± 7d 
P2- 
C7D1 
± 7d 
P2- 
C10+D1b 
± 7d 
P2-Post 
Txc 
± 7d 
End St./ 
Ear. 
Term. ± 
7d 
Procedured 
Week 
25 
Week  
26 
Week 
27 
Week 
28 
Week 
29 
Week 
30 
Week 
31 
Week 
32 
Week 
33 
Week 
35 
Week 
37 
Week 
41 
Week 
45 
Week 
49 
Week 
61+ 
LD  
+ 28d 
LD + 12 
Week/ < 
new Txe 
PROMIS 
Physical 
Function 
Scale 
X 
 
 
 
 
 
 
 
 
 
Xf 
 
 
Xf 
Xf 
Xf 
 
EQ-5D-5L 
instrument 
X 
 
 
 
 
 
 
 
 
 
Xf 
 
 
Xf 
Xf 
Xf 
 
Review 
completed 
outpatient 
PROs 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
 
MRI of the 
affected joint
n 
X 
 
 
 
 
 
 
 
 
 
Xf 
 
 
Xf 
Xf 
Xf 
Xo 
Range-of-
motion 
assessmentp 
X 
 
 
 
 
 
 
 
 
 
Xf 
 
 
Xf 
Xf 
Xf 
 
Serum 
pregnancy 
test 
X 
 
 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
PK, PDy 
blood 
samplingq 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Analgesic 
use 
assessment 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
 
Dispense 
pexidartinib 
X 
 
 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
In-clinic 
pexidartinib 
dosingr 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Pexidartinib 
dosings 
X 
—— Twice daily dosings —— 
 
 


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P2- 
C1D1a 
P2- 
C1D8 
± 2d  
P2- 
C1D1
5 
± 2d 
P2- 
C1D22 
± 2d  
P2- 
C2D1 
± 2d 
P2- 
C2D8 
± 2d 
P2- 
C2D1
5 
± 2d  
P2- 
C2D22 
± 2d 
P2- 
C3D1 
± 7d 
P2- 
C3D1
5 
± 7d 
P2- 
C4D1 
± 7d 
P2- 
C5D1 
± 7d 
P2- 
C6D1 
± 7d 
P2- 
C7D1 
± 7d 
P2- 
C10+D1b 
± 7d 
P2-Post 
Txc 
± 7d 
End St./ 
Ear. 
Term. ± 
7d 
Procedured 
Week 
25 
Week  
26 
Week 
27 
Week 
28 
Week 
29 
Week 
30 
Week 
31 
Week 
32 
Week 
33 
Week 
35 
Week 
37 
Week 
41 
Week 
45 
Week 
49 
Week 
61+ 
LD  
+ 28d 
LD + 12 
Week/ < 
new Txe 
Tx 
compliance 
assessment 
X 
 
X 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse 
eventst 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Surgical 
Assessment 
Questionnair
e 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
Collection of 
surgical data
u 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xu 
 
Xu  
Xu 
PGx blood 
samplingv 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BP = blood pressure; BPI = Brief Pain Inventory; C = cycle; D/d = Day; ECG = electrocardiogram; ECHO = 
echocardiography; End St./Ear. Term. = End-of-Study/Early Termination; EQ-5D-5L =EuroQol five-dimensional descriptive system; FSH = follicle-stimulating hormone; GGT = gamma-glutamyl 
transpeptidase; incl. = including; LD = last dose; LH = luteinizing hormone; MRI = magnetic resonance imaging; MUGA = multi-gated acquisition; NRS = numeric rating scale; P = Part; PDy = 
pharmacodynamic; PGx = pharmacogenomic; PK = pharmacokinetic; PRO = patient-reported outcome; PROMIS = Patient-reported Outcomes Measurement Information System; PVNS = pigmented 
villonodular synovitis; temp. = temperature; Tx = treatment; Week = week 
a The Part 1 Completion (Week 25) Visit will serve as the first visit of Part 2 and will be designated as P2-C1D1. All procedures listed for this visit are for reference only and will already have been 
conducted at the Part 1 Completion (Week 25) Visit except for the following, which should be performed at this visit:  (i) administering the morning dose of pexidartinib; (ii) dispensing the dosing 
diary; (iii) 2-hour post-dose ECG; and (iv) dispensing the analgesic use diary. 
b Starting with P2-C10 (Week 61), subjects will return to the clinic every 12 weeks (ie, P2-C13, P2-C16, etc.) to undergo the procedures indicated. 
c If the subject withdraws before completing Part 2 or completes Part 2 but declines to continue treatment for study of longer efficacy and safety follow-up or in the separate continuation study, the post-
treatment procedures should be completed 28 ± 7 days after the last dose of study treatment and before initiating any new PVNS therapy, including surgery. Subjects who complete Part 2 without 
experiencing progression or intolerability, or subjects who undergo surgical resection of their tumor after study treatment will be eligible to continue for longer efficacy and safety follow-up or to enter 
a separate protocol to continue receiving pexidartinib or for surgical data collection.. Subjects who enter the separate protocol will not undergo Post-treatment and End-of-Study Visits. 
d Effective 30 Sep 2016, subjects who wish to continue onto the open label part of this study (Part 2) will be unblinded after completion of the end of Part 1 assessments (Part 1 Completion visit/Early 
Termination visit) and those on placebo will be discontinued; subjects on pexidartinib in Part 1 may continue into Part 2 to continue to receive pexidartinib. If the patient is known to have been on 
pexidartinib treatment in Part 1, then visits and associated procedures are only required on Day 1 of each cycle in Part 2. 
e The End-of-Study/Early Termination MRI need not be performed if new PVNS therapy begins within 4 weeks of the Post-treatment Visit. Before or at the End-of-Study/Early Termination Visit, plans 
for any new PVNS therapy will be obtained. Details of any surgical treatment will be obtained per Footnote u. 
f A physical examination by study staff, MRI, blinded range-of-motion assessment of the joint location by a third-party examiner not otherwise affiliated with the trial, and administration of the PRO 
instruments are performed at all of the indicated visits including the P2-C4D1 visit, every 12 weeks thereafter (ie, P2-C7D1, P2-C10D1, etc.), and at the Post-treatment Visit. Vital sign assessment, 


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clinical laboratory studies (chemistry, hematology), and PK/PDy blood sampling will be performed at all of the indicated visits, including the P2-C4D1 visit, every 12 weeks thereafter (ie, P2-C7D1, 
P2-C10D1, etc.), P2-C5D1, and P2-C6D1. [NOTE:  On study visit days, the PRO instruments, including the EQ-5D-5L, should be administered before performing any invasive procedures.] 
g A standard 12-lead ECG is performed 2 hours after dosing at the P2-C1D1 visit and before and 2 hours after dosing at the P2-C1D15 visit. The 2-hour post-dose ECG measurements should begin 
within 10 minutes of the 2 hour post-dose time point. Thereafter, the ECG and blood draw for hormone testing is performed before dosing at the C13D1 visit, every 24 weeks thereafter (ie, C19D1, 
C25D1, etc.), and at the Post-treatment Visit. 
h ECHO or MUGA scanning should only be repeated if more than 3 months have elapsed since the last procedure. Subjects who show a reduced ejection fraction relative to baseline at the last visit 
should be followed until a stable ejection fraction is measured by two consecutive tests. 
i Hematology only. 
j Alkaline phosphatase, ALT, AST, total and direct bilirubin, and GGT should be assessed weekly during P2-C1 beginning on Day 1, weekly during P2-C2 beginning on Day 1, biweekly during P2-C3 
beginning on Day 1, and on Day 1 of every cycle thereafter. More frequent monitoring is required in the case of increased liver function tests (see Section 5.3).  
k Subjects receiving concomitant warfarin should have their anti-coagulation status carefully monitored for any necessary dose adjustments (see Section 5.3) . 
l Women who are not using hormonal contraception will be tested for levels of FSH, LH, progesterone, and estradiol. Hormone testing will not be required for women who have either had an 
oophorectomy or are post-menopausal. Men will be tested for levels of LH, FSH, and testosterone. Men whose testosterone level is below baseline at the last study visit should be followed until their 
level has stabilized or returned to baseline. 
m Subjects should be reminded to complete the BPI Worst Pain NRS item and Worst Stiffness NRS item for at least 4 of 7 consecutive days  prior to Day 1 of P2-C4, P2-C7, P2-C10, and before the 
Post-treatment Visit. 
n The investigator may request a centrally read MRI to confirm progression as detailed in the Imaging Charter. 
o For subjects who discontinue the study before completing Part 2 or complete Part 2 but decline to continue treatment for study of longer efficacy and safety follow-up or to enter the separate 
continuation study for reasons other than progression, the end-of-study or early termination MRI should be completed 12 weeks ± 7 days after the last dose of study treatment or before starting any 
new PVNS therapy, including surgery, whichever occurs first. Subjects who withdraw from the study with progression do not undergo an End-of-Study/Early Termination MRI. 
p A range-of-motion assessment in the affected joint or tumor location will be performed by a blinded independent third party assessor. 
q Details on blood sampling are found in Section 6.4.16 (PK) and Section 6.4.15 (PDy). 
r The morning dose of pexidartinib should be administered in the clinic at all of the indicated time points. 
s Dose administration by the subject at home. 
t AEs are monitored throughout the study via safety assessments, observation, and subject reporting (see Section 6.4.17). 
u If surgical resection of the tumor is performed within 12 weeks after the last dose of study treatment, details of the surgery and its outcome should be obtained (see Table 15.4). 
v The pharmacogenomic blood sample is optional. If taken, it should only be taken once as soon as reasonably possible after the subject has signed the consent form. 
 


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Table 15.4: 
Schedule of Events – For Subjects Who Undergo Surgical Resection 
 
Follow Up Visit 1 
 
Follow Up Visit 2 
Follow Up 
Contact 1 
Follow Up Contact 
2 
Follow Up Contact 
3 
Follow Up Contact 
4 
Procedurea 
Within 4 Weeks 
prior to  Surgery 
During or Shortly 
after Surgery 
4 months (+/- 2 
weeks) after 
Surgery 
8 months (+/- 2 
weeks) after 
Surgery 
12 months (+/- 2 
weeks) after 
Surgery 
18 months (+/- 2 
weeks) after 
Surgery 
24 months (+/- 2 
weeks) after 
Surgery 
BPI Worst Pain NRS 
Xb 
 
X 
 
 
 
 
Worst Stiffness NRS item 
Xb 
 
X 
 
 
 
 
PROMIS Physical Function 
Scale 
Xb 
 
X 
 
 
 
 
MRI of the affected joint 
Xc 
 
X 
 
 
 
 
Range-of-motion assessment 
Xb 
 
X 
 
 
 
 
Reasons of Surgery 
Xb 
 
 
 
 
 
 
Blood Chemistry, Hematology 
Xd 
 
 
 
 
 
 
Liver function tests 
Xd 
 
 
 
 
 
 
Coagulation tests 
Xd 
 
 
 
 
 
 
Urinalysis 
Xd 
 
 
 
 
 
 
Serum pregnancy test 
Xd 
 
 
 
 
 
 
ECG 
Xd 
 
 
 
 
 
 
Surgical Procedure and 
Findingse 
 
X 
 
 
 
 
 
Surgical Complications 
 
 
X 
 
 
 
 
Tumor Sample Submission 
 
X 
 
 
 
 
 
Collection of serious adverse 
events 
X  
 
X 
 
 
 
 
Disease Recurrencef 
 
 
X 
X 
X 
X 
X 
End of Study CRF Completion 
 
 
 
 
 
 
X 
PGx blood samplingg 
 
 
 
 
 
 
 
 BPI = Brief Pain Inventory; CRF = Case report form; ECG = electrocardiogram; MRI = magnetic resonance imaging; NRS = numeric rating scale; PGx = pharmacogenomic; PROMIS = Patient-
reported Outcomes Measurement Information System; TGCT = tenosynovial giant cell tumor 
a If a subject has surgery within 4 weeks of the last dose of study treatment, the subject does not need to have the Post-Treatment Visit evaluations (in Table 15.2 and Table 15.3), but will need to have 
the safety lab tests (blood chemistry, hematology, liver function tests, coagulation tests, urinalysis, and serum pregnancy test) and an ECG performed at least 7 days after the last dose of study 
treatment, but prior to surgery. However, if a subject has surgery after 4 weeks of the last dose of study treatment, the subject should have the Post-Treatment Visit evaluations (in Table 15.2 and 
Table 15 3). None of these subjects need to have the End-of-Study Visit (in Table 15.2 and Table 15.3). 


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b Only perform if not done within 4 weeks prior to the surgery. 
c Only perform if not done within 12 weeks prior to the surgery. 
d Only for subjects who have surgery within 4 weeks of the last dose of study treatment. 
e Including planned surgical procedure and actual surgical procedure performed, surgical margin, copies of surgical report and pathology report, if available . 
f Disease recurrence is defined as the need for any new therapeutic intervention of TGCT. Such follow-up can be performed via phone contact with the subject. 
g The pharmacogenomic blood sample is optional. If taken, it should only be taken once as soon as reasonably possible after the subject has signed the consent form.