Multicenter, Single Arm Study of the Efficacy and Safety of Pexidartinib in Adult Subjects With Tenosynovial Giant Cell Tumor
Phase: PHASE3
Conditions: Tenosynovial Giant Cell Tumor
Sponsor: Daiichi Sankyo Co., Ltd.

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 1  
 
 
 
 
 
CLINICAL STUDY PROTOCOL 
MULTICENTER, SINGLE ARM STUDY OF THE 
EFFICACY AND SAFETY OF PEXIDARTINIB IN 
ADULT SUBJECTS WITH TENOSYNOVIAL GIANT 
CELL TUMOR 
 
PL3397-A-A303 
 
 
VERSION 4.0, 29 JAN 2021 
VERSION 3.0, 25 FEB 2020 
VERSION 2.0, 25 NOV 2019 
VERSION 1.1, 31 MAY 2017 
VERSION 1.0, 20 MAY 2016 
 
DAIICHI SANKYO 
 
CONFIDENTIALITY STATEMENT 
Information contained in this document is proprietary to Daiichi Sankyo.  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 
Daiichi Sankyo. 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 3  
PROTOCOL SYNOPSIS 
Protocol Number: 
PL3397-A-A303 
Investigational Product: 
Pexidartinib (PLX3397) 
Active Ingredient/INN: 
Pexidartinib (PLX3397) 
Study Title: 
Multicenter, single arm study of the efficacy and safety of 
pexidartinib in adult subjects with tenosynovial giant cell 
tumor  
Study Phase: 
Phase 3 
Indication Under Investigation: The treatment of adult patients with symptomatic TGCT 
associated with severe morbidity or functional limitations 
and not amenable to improvement with surgery. 
Study Objectives: 
Primary Objective: 
To evaluate the efficacy in the Asian patients with TGCT 
by determining the overall response rate (ORR) of 
pexidartinib based on Response Evaluation Criteria in 
Solid Tumors, version 1.1 (RECIST 1.1) at Week 25 by 
centrally reviewed magnetic resonance imaging (MRI) 
scan. 
Secondary Objectives: 
To evaluate:  
• Response of pexidartinib based on Tumor Volume 
Score (TVS) at Week 25 by centrally reviewed 
MRI scan 
• Range of motion at Week 25 
• Patient-Reported Outcomes Measurement 
Information System (PROMIS) Physical Function 
Scale at Week 25 
• Best overall response of pexidartinib based on 
RECIST 1.1 and TVS by centrally reviewed MRI 
scan 
• Duration of response of pexidartinib based on 
RECIST 1.1 and TVS by centrally reviewed MRI 
scan 
• Safety 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 4  
• Pharmacokinetics (PK) 
Exploratory Objectives: 
To evaluate:   
• ORR of pexidartinib based on RECIST 1.1 at 
Week 25 by locally reviewed MRI scan 
• ORR of pexidartinib based on modified 
RECIST 1.1-sum of the short-axis dimension 
(SSD) at Week 25 by centrally reviewed MRI 
scan 
• EuroQol five-dimensional descriptive system 
(EQ-5D-5L)  
• Best overall response of pexidartinib based on 
RECIST 1.1 by locally reviewed MRI scan 
• Duration of response of pexidartinib based on 
RECIST 1.1 by locally reviewed MRI scan 
• Duration of response of pexidartinib based on 
modified RECIST 1.1-SSD by centrally 
reviewed MRI scan 
• Photographic documentation of tumor size 
change 
• Results of the Surgical Assessment 
Questionnaire 
• Pharmacodynamics (PDy) 
• Long term follow-up of the subject status after 
the end-of-study or early termination visit 
Study Design: 
This is a multicenter, single arm study of pexidartinib 
orally administrated in adult subjects with symptomatic 
TGCT associated with severe morbidity or functional 
limitations and not amenable to improvement with 
surgery.  
Subjects who sign the Informed Consent Form (ICF) and 
meet the eligibility criteria can be enrolled in the study. 
Subjects will take 400 mg twice daily for a total daily 
dose of 800 mg.  Pexidartinib will be administered 
continuously with 28-day treatment cycle until criteria for 
discontinuation are reached. The subjects who complete 
primary endpoint assessments (ie, complete 24 weeks of 
dosing and the Week 25 assessments including MRI) will 
be eligible to continue receiving pexidartinib until disease 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 5  
progression, unacceptable toxicity, the occurrence of 
other termination criteria, or withdrawal from the study. 
Primary, secondary, exploratory endpoints will be 
assessed during the study according to the schedule of 
events. 
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, then the subject 
will be discontinued from the study unless the 
Investigator and Daiichi Sankyo’s Medical Monitor judge 
that the subject would potentially benefit from continued 
treatment with pexidartinib.  
After completion of the end-of-study or early termination 
visit, subject status will be collected every 6 months as a 
long term follow-up at least 2 years. 
Study Duration: 
Each subject will spend a maximum of 6 weeks in 
screening.  All subjects will continue in the study until 
disease progression, unacceptable toxicity, or any of the 
other termination criteria. 
Primary analysis will be performed after the last subject 
completes the Week 25 assessments. 
The duration after the Week 25 assessments will vary 
among subjects, as this portion of the study will continue 
until all subjects have either completed the study drug or 
withdrawn from the study. 
Study Sites and Location: 
Approximately 10 to 15 study sites in China and Taiwan 
Subject Eligibility Criteria: 
Inclusion Criteria: 
Subjects must satisfy all of the following criteria to be 
included in the study: 
1. Age ≥ 18 years (Age ≥ 20 years in Taiwan).  
2. A diagnosis of TGCT (i) that has been 
histologically confirmed by a pathologist and (ii) 
associated with severe morbidity or functional 
limitations and not amenable to improvement with 
surgery determined consensually by qualified 
personnel (eg, 2 surgeons or a multi-disciplinary 
tumor board). 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 6  
3. Measurable disease as defined by RECIST 1.1 
(except that a minimal size of 2 cm is required), 
assessed from MRI scan by a central radiologist. 
4. Stable prescription of analgesic regimen during 
the 2 weeks prior to enrollment. 
5. Women of childbearing potential must have a 
negative serum pregnancy test within the 14-day 
period prior to enrollment (Where demanded by 
local regulations, this test may be required within 
72 hours of enrollment). 
6. 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). Women of 
nonchildbearing 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 a 
follicle-stimulating hormone level > 40 mIU/mL 
will be considered postmenopausal. 
7. Adequate hematologic, hepatic, and renal 
function, defined by: 
• Absolute neutrophil count ≥ 1.5 × 109/L  
• Hemoglobin > 10 g/dL  
• Platelet count ≥ 100 × 109/L  
• Aspartate aminotransferase (AST) and alanine 
aminotransferase (ALT) ≤ 1.0 × upper limit of 
normal (ULN)  
• Total bilirubin and direct bilirubin ≤ 1.0 × 
ULN 
• Alkaline phosphatase  ≤ 1.0 × ULN 
• Creatinine clearance (CLcr) > 15 mL/min 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 7  
8. Willingness and ability to complete the PROMIS 
Physical Function Scale. 
9. Willingness and ability to use a diary. 
10. Willingness and ability to provide written 
informed consent prior to any study-related 
procedures and to comply with all study 
requirements. 
Exclusion Criteria: 
Subjects who meet any of the following criteria will be 
disqualified from entering the study: 
1. Investigational drug/device use within 28 days of 
enrolment. 
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 are allowed (eg, 
imatinib or nilotinib). 
3. Active cancer except for tumor for which a 
subject is enrolled in the study, (either concurrent 
or within the last year of starting study drug) 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 TGCT. 
5. Active or chronic infection with hepatitis C or 
known positive hepatitis B surface antigen, or 
known active or chronic infection with human 
immunodeficiency virus. 
6. Active liver or biliary tract disease  
7. Known active tuberculosis. 
8. Significant concomitant arthropathy in the 
affected joint, serious illness, uncontrolled 
infection, or a medical or psychiatric history that, 
in the Investigator’s opinion, would likely 
interfere with a subject’s study participation or the 
interpretation of his or her results. 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 8  
9. Use of strong Cytochrome P450 (CYP) 3A 
inducers, including St John’s wort, proton pump 
inhibitors (PPIs), and other products known to 
cause hepatotoxicity. 
10. Women who are breastfeeding. 
11. A screening Fridericia corrected QT interval 
(QTcF) ≥ 450 ms (men) or ≥ 470 ms (women). 
12. MRI contraindications. 
13. History of hypersensitivity to any excipients in the 
investigational product. 
14. Inability to swallow capsules. 
Dosage Form, Dose and Route 
of Administration: 
The study drug, pexidartinib will be administered orally 
daily in capsule form.  Each capsule contains 200 mg of 
pexidartinib (J-3397-AF in hypromellose capsules).  
Subjects will take 400 mg twice daily for a total daily 
dose of 800 mg (2 capsules in the morning and 2 capsules 
in the evening).  The study drug must be taken on an 
empty stomach (no food for 1 hour before and 2 hours 
after dosing) at approximately the same time of the day 
with about 12-hour interval.  Pexidartinib will be 
administered continuously with 28-day treatment cycle 
until criteria for discontinuation are reached. 
Dose Modification Guidelines: Reduction or interruption of dosing can be implemented 
at any time to manage intolerable or clinically significant 
toxicity as defined in the protocol.  Permanently 
discontinue pexidartinib in subjects who are unable to 
tolerate 200 mg orally twice daily (400 mg/day 
pexidartinib). 
Study Endpoints: 
Primary Endpoint:  
The proportion of subjects who achieve a complete 
response (CR) or partial response (PR) of pexidartinib 
based on RECIST 1.1 at Week 25 by centrally reviewed 
MRI scan 
Secondary Endpoints: 
• Proportion of subjects who achieve a CR or 
PR of pexidartinib based on TVS at Week 25 
by centrally reviewed MRI scan  

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 9  
• 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 
• Mean change from baseline score in the 
PROMIS Physical Function Scale at the 
Week 25 
• Best overall response (CR or PR) of 
pexidartinib based on RECIST 1.1 and TVS 
by centrally reviewed MRI scan 
• Duration of response (CR or PR) of 
pexidartinib based on RECIST 1.1 and TVS 
by centrally reviewed MRI scan  
• Safety endpoints included the following, but 
not limited to: Treatment-emergent adverse 
events (TEAEs), laboratory tests, vital sign, 
and Electrocardiograms (ECGs) 
• Pharmacokinetics (PK) of pexidartinib and its 
primary metabolite, ZAAD-1006a 
Exploratory Endpoints: 
• Proportion of subjects who achieve a CR or 
PR of pexidartinib based on RECIST 1.1 at 
Week 25 by locally reviewed MRI scan  
• Proportion of subjects who achieve a CR or 
PR of pexidartinib based on modified RECIST 
1.1-SSD at Week 25 by centrally reviewed 
MRI scan 
• Mean change from baseline score in the EQ-
5D-5L at the Week 25 
• Best overall response (CR or PR) of 
pexidartinib based on RECIST 1.1 by locally 
reviewed MRI scan 
• Duration of response (CR or PR) of 
pexidartinib based on RECIST 1.1 by locally 
reviewed MRI scan 
• Duration of response (CR or PR) of 
pexidartinib based on modified RECIST 1.1- 
SSD by centrally reviewed MRI scan 
• Photographic documentation of tumor size 
change 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 10  
• Results of the Surgical Assessment 
Questionnaire 
• PDy of plasma CSF-1 activity 
• Long term subject status after the end-of-study 
or early termination visit 
Planned Sample Size: 
Approximately 35 subjects across multiple sites in China 
and Taiwan. 
Statistical Analyses: 
The primary endpoint is the proportion of subjects who 
achieve a CR or PR of pexidartinib based on RECIST 1.1 
at Week 25 by centrally read MRI scan.   
The estimate of the proportion and 95% exact confidence 
interval (CI) will be provided. 
The proportions and mean changes of the secondary 
endpoints will be summarized.  Duration of responses of 
the secondary efficacy endpoints will be summarized 
descriptively using the Kaplan-Meier method. 
Safety variables, including TEAEs, laboratory tests, vital 
signs, and ECGs, will be summarized. 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 11  
TABLE OF CONTENTS 
INVESTIGATOR AGREEMENT ...................................................................................................... 2 
PROTOCOL SYNOPSIS ..................................................................................................................... 3 
TABLE OF CONTENTS ................................................................................................................... 11 
LIST OF IN-TEXT TABLES ............................................................................................................ 17 
LIST OF IN-TEXT FIGURES........................................................................................................... 18 
LIST OF ABBREVIATIONS ............................................................................................................ 20 
1. 
INTRODUCTION ............................................................................................................... 23 
1.1. 
Scientific Background ......................................................................................................... 23 
1.1.1. 
Tenosynovial giant cell tumor (TGCT) .............................................................................. 23 
1.1.2. 
Pexidartinib (PLX3397) ...................................................................................................... 24 
1.2. 
Nonclinical Studies .............................................................................................................. 24 
1.3. 
Clinical Experience.............................................................................................................. 24 
1.3.1. 
Patients with TGCT Treated in the Phase 1 Study PLX108-01 ....................................... 24 
1.3.2. 
Patients with TGCT Treated in the Phase 3 Study PLX108-10 ....................................... 25 
1.3.3. 
Patients with Solid Tumor Treated in the Phase 1 Study PL3397-A-A103..................... 26 
1.4. 
Study Rationale .................................................................................................................... 26 
1.5. 
Risks and Benefits for Study Subjects ............................................................................... 27 
2. 
STUDY OBJECTIVES AND HYPOTHESIS................................................................... 28 
2.1. 
Study Objectives .................................................................................................................. 28 
2.1.1. 
Primary Objective ................................................................................................................ 28 
2.1.2. 
Secondary Objectives .......................................................................................................... 28 
2.1.3. 
Exploratory Objectives ........................................................................................................ 28 
2.2. 
Study Hypothesis ................................................................................................................. 29 
3. 
STUDY DESIGN ................................................................................................................ 30 
3.1. 
Overall Plan.......................................................................................................................... 30 
3.1.1. 
Duration of Subject Participation ....................................................................................... 31 
3.1.2. 
Study Endpoints ................................................................................................................... 31 
3.1.2.1. Primary Endpoint ................................................................................................................. 31 
3.1.2.2. Secondary Endpoints ........................................................................................................... 31 
3.1.2.3. Exploratory Endpoints ......................................................................................................... 32 
4. 
STUDY POPULATION ..................................................................................................... 33 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 12  
4.1. 
Inclusion Criteria ................................................................................................................. 33 
4.2. 
Exclusion Criteria ................................................................................................................ 34 
4.3. 
Subject Replacement ........................................................................................................... 34 
4.4. 
Subject Re-screening Procedures ....................................................................................... 34 
5. 
STUDY TREATMENT ...................................................................................................... 36 
5.1. 
Assigning Subjects to Treatments and Blinding ................................................................ 36 
5.1.1. 
Treatment Group .................................................................................................................. 36 
5.1.2. 
Method of Treatment Allocation ........................................................................................ 36 
5.1.3. 
Blinding ................................................................................................................................ 36 
5.1.4. 
Emergency Unblinding Procedure ...................................................................................... 36 
5.2. 
Study Drug ........................................................................................................................... 36 
5.2.1. 
Description ........................................................................................................................... 36 
5.2.2. 
Labeling and Packaging ...................................................................................................... 36 
5.2.3. 
Preparation ........................................................................................................................... 36 
5.2.4. 
Administration ..................................................................................................................... 37 
5.2.5. 
Storage .................................................................................................................................. 37 
5.2.6. 
Drug Accountability ............................................................................................................ 37 
5.3. 
Control Treatment ................................................................................................................ 38 
5.4. 
Dose Modification ............................................................................................................... 38 
5.5. 
Method of Assessing Treatment Compliance .................................................................... 41 
5.6. 
Prior and Concomitant Medications ................................................................................... 41 
5.6.1. 
CYP3A inducers .................................................................................................................. 42 
5.6.2. 
CYP3A and UGT inhibitors ................................................................................................ 42 
5.6.3. 
Hormonal Contraceptives .................................................................................................... 42 
5.6.4. 
Acid-reducing Agents .......................................................................................................... 42 
5.7. 
Dosage Modification for Renal Impairment ...................................................................... 43 
5.8. 
Subject Withdrawal/Discontinuation.................................................................................. 43 
5.8.1. 
Reasons for Withdrawal ...................................................................................................... 43 
5.8.2. 
Withdrawal Procedures ....................................................................................................... 43 
5.9. 
Long Term Follow-up ......................................................................................................... 44 
6. 
STUDY PROCEDURES..................................................................................................... 45 
6.1. 
Screening .............................................................................................................................. 45 
6.1.1. 
Screening (Day –42 to Day –1) .......................................................................................... 45 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 13  
6.2. 
Enrollment ............................................................................................................................ 46 
6.2.1. 
Cycle 1 (Enrollment) ........................................................................................................... 46 
6.3. 
Treatment Period.................................................................................................................. 46 
6.3.1. 
Cycle 1, Day 1 (C1D1; Week 1) ......................................................................................... 46 
6.3.2. 
Cycle 1, Day 8 (C1D8 Week 2) ± 2 days ........................................................................... 47 
6.3.3. 
Cycle 1, Day 15 (C1D15 Week 3) ± 2 days ....................................................................... 47 
6.3.4. 
Cycle 1, Day 22 (C1D22; Week 4) ± 2 days ..................................................................... 47 
6.3.5. 
Cycle 2, Day 1 (C2D1; Week 5) ± 2 days .......................................................................... 47 
6.3.6. 
Cycle 2, Day 8 (C2D8; Week 6) ± 2 days .......................................................................... 48 
6.3.7. 
Cycle 2, Day 15 (C2D15; Week 7) ± 2 days ..................................................................... 48 
6.3.8. 
Cycle 2, Day 22 (C2D22; Week 8) ± 2 days ..................................................................... 48 
6.3.9. 
Cycle 3, Day 1 (C3D1; Week 9) ± 7 days .......................................................................... 48 
6.3.10. Cycle 3, Day 15 (C3D15; Week 11) ± 7 days ................................................................... 49 
6.3.11. Cycle 4, Day 1 (C4D1; Week 13) ± 7 days........................................................................ 49 
6.3.12. Cycle 5, Day 1 (C5D1; Week 17) ± 7 days........................................................................ 49 
6.3.13. Cycle 6, Day 1 (C6D1; Week 21) ± 7 days........................................................................ 50 
6.3.14. Cycle 7, Day 1 Visit (C7D1; Week 25) ± 7 days .............................................................. 50 
6.3.15. Cycle 10+, Day 1 (C10+D1; Week 37+) ± 7 days ............................................................ 51 
6.3.16. Post-treatment Visit (last dose + 28 days) ± 7 days .......................................................... 52 
6.3.17. End-of-Study or Early Termination Visit (last dose + 12 weeks) ± 7 days ..................... 52 
6.3.18. Long Term Follow-up (every 6 months after end-of-study or early termination 
visit) ± 2 weeks .................................................................................................................... 53 
7. 
EFFICACY ASSESSMENTS ............................................................................................ 54 
7.1. 
Primary Efficacy Endpoint .................................................................................................. 54 
7.1.1. 
Tumor Imaging .................................................................................................................... 55 
7.2. 
Secondary Efficacy Endpoints ............................................................................................ 56 
7.2.1. 
Range of Motion Assessment ............................................................................................. 57 
7.2.2. 
PROMIS Physical Function Scale ...................................................................................... 57 
7.3. 
Exploratory Efficacy Endpoint ........................................................................................... 57 
7.3.1. 
EuroQol Five-Dimensional Descriptive System................................................................ 58 
7.3.2. 
Photographic Documentation of Tumor size Change ....................................................... 58 
7.3.3. 
Surgical Assessment Questionnaire.................................................................................... 58 
7.4. 
Appropriateness of Selected Efficacy Assessments .......................................................... 58 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 14  
8. 
PHARMACOKINETIC/PHARMACODYNAMIC/ PHARMACOGENOMIC 
ASSESSMENTS.................................................................................................................. 59 
8.1. 
Pharmacodynamic Assessment ........................................................................................... 59 
8.2. 
Pharmacokinetic Assessment .............................................................................................. 59 
9. 
SAFETY EVALUATION AND REPORTING ................................................................ 61 
9.1. 
Adverse Event Collection and Reporting ........................................................................... 61 
9.2. 
Assessment of Safety Endpoint .......................................................................................... 62 
9.3. 
Adverse Events of Special Interest ..................................................................................... 62 
9.3.1. 
Liver enzyme elevations and Bilirubin elevation .............................................................. 62 
9.4. 
Adverse Event ...................................................................................................................... 62 
9.4.1. 
Definition of Adverse Event ............................................................................................... 62 
9.4.2. 
Serious Adverse Event ........................................................................................................ 62 
9.4.3. 
Severity Assessment ............................................................................................................ 63 
9.4.4. 
Causality Assessment .......................................................................................................... 64 
9.4.5. 
Action Taken Regarding Study Drug(s)............................................................................. 64 
9.4.6. 
Other Action Taken for Event............................................................................................. 64 
9.4.7. 
Adverse Event Outcome...................................................................................................... 65 
9.5. 
Adverse Events Reporting–Procedure For Investigators .................................................. 65 
9.6. 
Notifying Regulatory Authorities, Investigators, and Institutional Review 
Board/Ethics Committee ..................................................................................................... 66 
9.7. 
Exposure In Utero During Clinical Studies ....................................................................... 66 
9.8. 
Overdose............................................................................................................................... 66 
9.9. 
Clinical Laboratory Evaluations ......................................................................................... 67 
9.10. 
Pregnancy Test ..................................................................................................................... 68 
9.11. 
Vital Signs ............................................................................................................................ 69 
9.12. 
Electrocardiograms .............................................................................................................. 69 
9.13. 
Examinations ........................................................................................................................ 69 
9.14. 
Safety Monitoring ................................................................................................................ 69 
9.14.1. Safety Monitoring Committee ............................................................................................ 69 
9.14.2. Hepatic Adjudication Committee ....................................................................................... 70 
10. 
STATISTICAL METHODS ............................................................................................... 71 
10.1. 
Analysis Sets ........................................................................................................................ 71 
10.1.1. Enrolled Analysis Set .......................................................................................................... 71 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 15  
10.1.2. Full Analysis Set/Safety Analysis Set ................................................................................ 71 
10.1.3. Per-protocol Analysis Set .................................................................................................... 71 
10.1.4. Pharmacokinetic Analysis Set............................................................................................. 71 
10.1.5. Pharmacokinetic Analysis Set for Noncompartmental Analysis ...................................... 71 
10.2. 
Procedures for Handling Missing, Unused, and Spurious Data ....................................... 71 
10.3. 
General Statistical Considerations ...................................................................................... 71 
10.4. 
Study Population Data ......................................................................................................... 72 
10.5. 
Efficacy Analyses ................................................................................................................ 72 
10.5.1. Primary Efficacy Analyses .................................................................................................. 72 
10.5.2. Secondary Efficacy Analyses.............................................................................................. 72 
10.5.3. Exploratory Efficacy Analyses ........................................................................................... 73 
10.5.4. Subgroup Analyses .............................................................................................................. 73 
10.6. 
Pharmacodynamic/Biomarker Analyses ............................................................................ 73 
10.7. 
Pharmacokinetics and Exposure-Response Analyses ....................................................... 73 
10.7.1. Noncompartmental Pharmacokinetic Analyses ................................................................. 73 
10.7.2. Population Pharmacokinetic Analyses ............................................................................... 74 
10.7.3. Exposure-Response Analyses ............................................................................................. 74 
10.8. 
Safety Analyses.................................................................................................................... 74 
10.8.1. Adverse Event Analyses...................................................................................................... 74 
10.8.2. Clinical Laboratory Evaluation Analyses .......................................................................... 74 
10.8.3. Vital Sign Analyses ............................................................................................................. 75 
10.8.4. Electrocardiogram Analyses ............................................................................................... 75 
10.8.5. Physical Examination Analyses .......................................................................................... 75 
10.8.6. Concomitant Medication Analyses ..................................................................................... 75 
10.9. 
Other Endpoint Analysis ..................................................................................................... 75 
10.10. 
Interim Analyses .................................................................................................................. 75 
10.11. 
Sample Size Determination ................................................................................................. 75 
10.12. 
Statistical Analysis Process ................................................................................................. 76 
11. 
DATA INTEGRITY AND QUALITY ASSURANCE .................................................... 77 
11.1. 
Monitoring and Inspections................................................................................................. 77 
11.2. 
Data Collection .................................................................................................................... 77 
11.3. 
Data Management ................................................................................................................ 78 
11.4. 
Study Documentation and Storage ..................................................................................... 78 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 16  
11.5. 
Record Keeping ................................................................................................................... 78 
12. 
FINANCING AND INSURANCE ..................................................................................... 80 
12.1. 
Finances ................................................................................................................................ 80 
12.2. 
Reimbursement, Indemnity, and Insurance ........................................................................ 80 
13. 
PUBLICATION AND PUBLIC DISCLOSURE OF CLINICAL TRIAL 
INFORMATIONP ............................................................................................................... 81 
14. 
ETHICS AND STUDY ADMINISTRATIVE INFORMATION .................................... 82 
14.1. 
Compliance Statement, Ethics, and Regulatory Compliance ........................................... 82 
14.2. 
Subject Confidentiality ........................................................................................................ 82 
14.3. 
Informed Consent ................................................................................................................ 82 
14.4. 
Regulatory Compliance ....................................................................................................... 83 
14.5. 
Protocol Deviations ............................................................................................................. 84 
14.6. 
Supply of New Information Affecting the Conduct of the Study ..................................... 84 
14.7. 
Protocol Amendments ......................................................................................................... 84 
14.8. 
Study Termination ............................................................................................................... 85 
15. 
REFERENCES .................................................................................................................... 86 
16. 
APPENDICES ..................................................................................................................... 87 
16.1. 
List of Common CYP3A Inhibitors and Inducers ............................................................. 87 
16.2. 
PROMIS Physical Function Scale ...................................................................................... 88 
16.3. 
EuroQol Five-Dimensional Descriptive System................................................................ 92 
16.4. 
Surgical Assessment Questionnaire.................................................................................... 95 
16.5. 
Long Term Follow-up Questionnaire ................................................................................. 96 
16.6. 
Schedule of Assessment ...................................................................................................... 97 
 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 17  
LIST OF IN-TEXT TABLES 
Table 5.1: Dose Modification .......................................................................................................... 39 
Table 5.2: Dose Modification Guidelines for Treatment-emergent Toxicities ............................ 39 
Table 5.3: Additional Liver Evaluation........................................................................................... 40 
Table 5.4: Recommended Dosage Reductions for Pexidartinib for Concomitant Use of 
Moderate and Strong CYP3A Inhibitors or UGT Inhibitors........................................ 42 
Table 7.1: Definitions of Response for the Primary Endpoint ...................................................... 55 
Table 8.1: Pharmacokinetic Schedules ............................................................................................ 59 
Table 16.1: Sample Surgical Assessment Questionnaire ................................................................. 95 
Table 16.2: Sample Long Term Follow-up Questionnaire .............................................................. 96 
Table 16.3: Schedule of Assessment ................................................................................................. 97 
 
 
 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 18  
LIST OF IN-TEXT FIGURES 
 
Figure 3.1: Study Schema.................................................................................................................. 31 
 
 
 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 19  
GLOBAL AMENDMENT, PROTOCOL VERSION 4.0 
Amendment Rationale: 
The main purpose of this amendment is to remove Pharmacogenomics (PGx) test in exploratory 
objectives in PL3397-A-A303 study due to HGRAC rejection. 
Changes to the Protocol: 
Please refer to the comparison document for protocol version 3.0 (dated 25 Feb 2020) vs. 
protocol version 4.0 (dated 29 Jan 2021) for actual changes in-text.  The summary of changes 
below is a top-line summary of major changes in the PL3397-A-A303 clinical study protocol 
(Version 4.0) by section. 
DESCRIPTION OF EACH HIGH-LEVEL CHANGE 
1 
Updated INVESTIGATOR AGREEMENT. 
Sponsor Approval name was updated. 
2 
Updated study objectives. 
PGx was removed. 
3 
Updated exploratory endpoints. 
PGx was removed. 
4 
Update LIST OF ABBREVIATIONS 
“HGRAC” was added. 
5 
Updated 6.3.1. Cycle 1, Day 1 (C1D1; Week 1) 
“Blood sampling for PGx analysis” was removed.  
6 
Update 7.1.1. Tumor Imaging 
“Standard operation of the sites” was added. 
7 
Updated 7.3. Exploratory Efficacy Endpoint  
PGx was removed. 
8 
Updated 8. PHARMACOKINETIC/PHARMACODYNAMIC/ 
PHARMACOGENOMIC ASSESSMENTS 
“PGx endpoints” was removed. 
9 
Updated Schedule of Assessment 
PGx was removed. 
 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 20  
LIST OF ABBREVIATIONS 
Abbreviation or Term 
Definition/Explanation 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AMA 
Anti-mitochondrial antibody 
AST 
Aspartate aminotransferase 
AUC6h 
Area under the plasma-concentration-time curve from time 0 h to 6 h  
AUCinf 
Area under the plasma-concentration-time curve from time zero to 
infinity 
BID 
Twice daily 
BP 
Blood pressure 
C1D1 
Cycle 1 Day 1 
CI 
Confidence Interval 
CLcr 
Creatinine clearance 
Cmax 
Peak drug concentration  
CR 
Complete response 
CRO 
Contract Research Organization 
CSF-1 
Colony stimulating factor 1 
CSF1R 
Colony-stimulating factor 1 receptor 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P450 
DS 
Daiichi Sankyo 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture 
EIU 
Exposure in utero 
EQ-5D-5L 
EuroQol five-dimensional descriptive system 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FLT3 
FMS-like tyrosine kinase 3 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GCT-TS 
Giant cell tumor of the tendon sheath 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 21  
Abbreviation or Term 
Definition/Explanation 
GGT 
Gamma-glutamyl transpeptidase 
H2 
histamine 2 
HEAC 
External hepatic adjudication committee 
HGRAC 
Human Genetics Resources Administration of China 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent ethics committee 
INR 
International normalized ratio 
IRB 
Institutional review board 
ITD 
Internal tandem duplication 
KIT 
KIT proto-oncogene receptor tyrosine kinase 
LH 
Luteinizing hormone 
MedDRA 
Medical Dictionary for Drug Regulatory Activities 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
NCI 
National Cancer Institute 
NE 
Not evaluable 
ORR 
Overall response rate 
OTC 
Over-the-counter 
PD 
Progressive disease 
PDy 
Pharmacodynamic(s) 
PK 
Pharmacokinetic 
PopPK 
Population pharmacokinetic 
PPI 
Proton pump inhibitor 
PR 
Partial response 
PRO 
Patient-reported outcomes 
PROMIS 
Patient-reported Outcomes Measurement Information System 
PT 
Preferred term 
PVNS 
Pigmented villonodular synovitis 
QTc 
Corrected QT interval  

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 22  
Abbreviation or Term 
Definition/Explanation 
QTcF 
QT interval using Fridericia’s formula 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
Recommended Phase 2 Dose 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAVER 
Serious Adverse Event Report 
SCF 
Stem cell factor 
SD 
Stable disease 
SMC 
Safety monitoring committee 
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 
Tmax 
Time of maximum observed concentration 
TVS 
Tumor Volume Score 
UGT 
Uridine 5’-diphospho-glucuronosyltransferase 
ULN 
Upper limit of normal 
US 
United States 
WORMS 
Whole organ MRI score 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 23  
1. 
INTRODUCTION 
A comprehensive review of pexidartinib (PLX3397) is contained in the Investigator’s Brochure 
(IB).  Investigators should review the latest IB prior to initiating this study.  A brief review of 
pexidartinib is provided here. 
1.1. 
Scientific Background 
1.1.1. 
Tenosynovial giant cell tumor (TGCT) 
Tenosynovial giant cell tumor (TGCT) is a rare, nonmalignant neoplasm of the synovium, 
bursae, or tendon sheaths, affecting generally young adults (< 40 years of age) of both sexes.1   
Symptoms initially may be minimal due to the slowly progressive nature of the disease.  
However, as the tumor mass grows and gradually expands within the intra- and extra-articular 
space, symptoms such as pain, stiffness, swelling, and reduced range of motion of the affected 
joint can become severe and result in debilitating functional limitations.  The diagnosis of TGCT 
is based on pathologic evaluation; however, features highly suggestive of the disease may be 
found on radiologic imaging (ie, magnetic resonance imaging [MRI]). 
TGCT manifests as localized or diffuse disease.  The localized type (known as giant cell tumor 
of the tendon sheath [GCT-TS]) constitutes 80% to 90% of TGCT cases and is usually a benign 
neoplasm that most commonly occurs in the digits.1,2  Localized TGCT can usually be treated 
effectively with surgery.  The diffuse type (known as pigmented villonodular synovitis [PVNS]) 
constitutes 10% to 20% of cases and is a locally aggressive, nonmalignant neoplasm composed 
of synovial-like mononuclear cells, multinucleate giant cells, foam cells, siderophages, and 
inflammatory cells that may be intra- or extra-articular.  Diffuse TGCT most commonly occurs 
in large joints, particularly the knee, ankle, and hip. 1,2  In the United States (US), the annual 
incidence of new cases is estimated to be ~15,000 for localized TGCT and ~1500 for diffuse 
TGCT.1,3,4   A more recent survey in Denmark provides an incidence of 4.4 per million for 
localized TGCT and 1.2 per million for diffuse TGCT,2 whereas a study in the Netherlands 
reports incidence rates (per million patient-years) of 34 for localized TGCT in the digits, 11 for 
localized disease in other extremities, and 5 for diffuse TGCT.5   
TGCT predominantly consist of mononuclear and multinucleated giant cells.  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 neoplastic cells within the tumor and is often associated with genetic 
translocations, eg, linking the collagen 6A3 gene on chromosomal locus 2q35 with the CSF-1 
gene on chromosomal locus 1p13.6  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 colony-stimulating factor 1 receptor (CSF1R). 
The current standard of care for TGCT is surgical resection of the tumor as completely as 
possible to: (1) reduce pain, stiffness, and joint destruction caused by the disease process; (2) 
improve function; and (3) minimize the risk of recurrence.  However, diffuse disease can be 
challenging to manage surgically.  Patient outcome following surgery depends on multiple 
factors, including the location and extent of the disease.  The overall recurrence rate for patients 
with focal disease is low, ranging from 0% to 6%1; however, in patients with diffuse forms of the 
disease, recurrence is considerably more common, and is estimated to be in the range of 40%.7  
Diffuse disease carries a risk of multiple recurrences, and affected patients often have more 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 24  
extensive involvement and a poorer likelihood of success with surgery.  Surgical resection may 
involve removal of major tendons or neurovascular structures, leading to significant postsurgical 
morbidity.  Limb amputation may be required in severe, recurrent cases.1   
No systemic antitumor agents had been approved for this indication.8  Anti-inflammatory and 
analgesic medications, including opioids, had been commonly used as supportive therapy.  In 
light of the severe morbidity that a patient can experience with this disease, a systemic therapy 
that provides a meaningful clinical benefit is highly needed. 
1.1.2. 
Pexidartinib (PLX3397) 
Pexidartinib is a small molecule tyrosine kinase inhibitor that targets CSF1R, KIT proto-
oncogene receptor tyrosine kinase (KIT), and feline McDonough FMS-like tyrosine kinase 3 
(FLT3) harboring an internal tandem duplication (ITD) mutation.  Pexidartinib inhibited the 
proliferation of cell lines that depend on CSF1R at concentrations below 1 μmol/L.  Ligand-
induced autophosphorylation of CSF1R is also inhibited by pexidartinib.  Pexidartinib has been 
approved in the US for the treatment of TGCT associated with severe morbidity or functional 
limitations and amenable to improvement with surgery. 
1.2. 
Nonclinical Studies 
The effects of pexidartinib on multiple aspects of tumorigenesis have been characterized with in 
vitro and in vivo assays.  The proliferation of cell lines that depend on CSF-1, stem cell factor 
(SCF), or endogenous FLT3-ITD mutation is inhibited at half maximal inhibitory concentration 
values below 1 µmol/L.  Furthermore, CSF-1 induced autophosphorylation of CSF1R and SCF-
induced autophosphorylation of KIT are potently inhibited by pexidartinib.  Finally, the receptor 
activator of NF-kappa B ligand-dependent and CSF-1-dependent differentiation of osteoclast 
precursors is also potently inhibited by pexidartinib.  These in vitro results translate to 
pexidartinib effects in a variety of in vivo models for CSF1R-dependent proliferation, CSF1R-
dependent osteoclast differentiation, FLT3-ITD-dependent tumor growth, and KIT-dependent 
cell proliferation. 
While pharmacologic effects due to the inhibition of CSF1R and KIT are expected, the relative 
selectivity of pexidartinib against other kinases suggests that off-target effects against other 
kinases should be reduced. 
Additional detailed information regarding the nonclinical pharmacology and toxicology of 
pexidartinib can be found in the IB.9   
1.3. 
Clinical Experience 
As of 31 Jul 2018, pexidartinib has been evaluated in 28 company-sponsored clinical studies in 
healthy subjects and in patient populations (cancer and TGCT).  Pexidartinib were administered 
to 645 subjects with cancer or TGCT in company-sponsored clinical studies. 
1.3.1. 
Patients with TGCT Treated in the Phase 1 Study PLX108-01 
This study is evaluating subjects with advanced, incurable, solid tumors in which the target 
kinases are linked to disease pathophysiology.  This study is being conducted in 2 parts: an initial 
dose-escalation part to identify a recommended Phase 2 dose (RP2D), and an extension part to 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 25  
obtain preliminary efficacy data in subjects with selected tumor types.  The dose escalation part 
of the study has been completed and 1000 mg/day, administered as a twice daily (BID) regimen, 
was selected as the maximum tolerated dose (MTD) and RP2D for further evaluation in the 
extension cohorts. 
In the extension phase of the study, as of the 31 March 2017 data cut-off, treatment with 
pexidartinib (1000 mg/day) in the TGCT cohort (2 of 37 subjects) showed a Best Overall 
Response of 62.2% (95% confidence interval [CI]: 42.1%, 75.2%) by investigator assessment 
according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1).  Similar 
efficacy results were observed based upon central MRI review.  Many of the responding subjects 
have been continuing treatment for more than 2 years. 
As of the 31 January 2018 data cut-off, all 39 (100%) subjects experienced at least 1 treatment-
related treatment-emergent adverse event (TEAE), and 35.9% of subjects experienced a Grade  
≥ 3 treatment-related TEAE.  The most frequently occurring treatment-related TEAEs were 
fatigue (74.4%), hair color changes (71.8%), and nausea (56.4%).  The most common Grade ≥ 3 
treatment-related TEAEs were hypophosphatemia (10.3%); alanine aminotransferase (ALT) 
increased (10.3%); aspartate aminotransferase (AST) increased (7.7%); hyponatremia (5.1%); 
and fatigue, diarrhea, anemia, neutropenia, arthritis, and transaminases increased (1 subject 
[2.6%] each).  As of the 03 Mar 2017 data cut-off, in the TGCT cohort of Study PLX108-01, 4 
(10.3%) subjects treated with pexidartinib experienced serious TEAEs.  The serious TEAEs 
reported were cholecystitis, renal cell carcinoma, hyponatremia, neck pain, and renal failure 
acute. No new serious TEAEs or deaths due to adverse events (AEs) were reported between 03 
Mar 2017 and 31 Jan 2018. 
Further details on the clinical experience with pexidartinib can be found in the IB.9  
1.3.2. 
Patients with TGCT Treated in the Phase 3 Study PLX108-10 
This study (PLX108-10) is a 2-part, multicenter, Phase 3 study in subjects with TGCT, for whom 
surgical resection would be associated with potentially worsening functional limitation or severe 
morbidity (locally advanced disease).  In Part 1 (double blind phase), eligible candidates were 
centrally randomized in a 1:1 ratio to receive either pexidartinib or placebo for 24 weeks 
(1000 mg/day [400 mg in the morning and 600 mg in the evening] or placebo for the first 2 
weeks and 800 mg/day [400 mg BID] or placebo for 22 weeks).  Those subjects who complete 
Part 1 (ie, 24 weeks of dosing) were eligible to advance to Part 2, a long-term treatment phase 
where all subjects received open-label pexidartinib at a maximum starting dose of 800 mg/day. 
The primary objective of this study is to compare the response rate of pexidartinib with that of 
placebo at Week 25.  The secondary efficacy objectives are to evaluate 1) range of motion at 
Week 25, 2) response based on TVS at Week 25, 3) patient-reported outcomes (PRO) at 
Week 25, and 4) duration of response. 
PLX108-10 study demonstrated a statistically significant improvement (p < 0.0001) in overall 
response rate (ORR) at Week 25 in the 61 patients randomized to pexidartinib (37.7% [95% CI: 
26.6%, 50.3%]) compared with placebo (0% [95% CI: 0, 6.1%]). 
The rates of the most frequently occurring TEAEs at the 31 Jan 2018 data cut-off per subject 
receiving pexidartinib compared with placebo were hair color changes (74.7% vs 3.4%), AST 
increased (35.2% vs no subjects), ALT increased (28.6% vs 1.7%), dysgeusia (25.3% vs 1.7%), 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 26  
pruritus (22.0% vs 3.4%), rash (20.9% vs 3.4%), periorbital edema (18.7% vs 1.7%), vomiting 
(15.4% vs 5.1%), face edema (15.4% vs 1.7%), edema peripheral (14.3% vs 3.4%), rash maculo-
papular (12.1% vs 1.7%), alkaline phosphatase (ALP) increased (11.0% vs no subjects), and 
lactate dehydrogenase increased (11.0% vs no subjects). For subjects who received pexidartinib 
in Part 1 and/or Part 2, the proportion of subjects reporting TEAEs of Common Terminology 
Criteria for Adverse Events (CTCAE) Grade ≥ 3 considered treatment-related (38.5%) was 
similar to that reported for subjects receiving pexidartinib in Part 1 (37.7%). 
1.3.3. 
Patients with Solid Tumor Treated in the Phase 1 Study PL3397-A-A103 
This is a Phase 1, non-randomized, open-label, multiple-dose study of pexidartinib in Asian 
patients with advanced solid tumors.  The study was conducted in a dose-escalation 3 + 3 design.  
This study comprises 2 dose levels (Cohort 1 and Cohort 2) to assess the safety and tolerability, 
RP2D, pharmacokinetics (PK) and pharmacodynamics (PDy), and preliminary antitumor activity 
of pexidartinib. 
• 
Cohort 1: 600 mg/day (200 mg in the morning and 400 mg in the evening). 
• 
Cohort 2: 1000 mg/day (400 mg in the morning and 600 mg in the evening) for the first 
2 weeks.  Thereafter, the dose will be reduced to 800 mg/day (400 mg in the morning 
and 400 mg in the evening). 
The dose-escalation part of the study showed that daily oral dosing of pexidartinib in 28-day 
cycles was safe and tolerated up to 1000 mg/day in Asian subjects with advanced solid tumors.  
No dose limiting factor was observed and the MTD was determined 1000 mg/day.  The RP2D of 
pexidartinib was determined as 1000 mg/day based on MTD.  Pexidartinib exposure parameters 
increased with increasing dose.  Following multiple-dose administration of pexidartinib, plasma 
concentrations of CSF-1 and adiponectin increased dose-dependently.  Antitumor activity was 
observed in both cohorts.  In Asian subjects with advanced solid tumors, pexidartinib was well-
tolerated, with a safety profile consistent with that previously reported from the first human 
study in US.  
1.4. 
Study Rationale 
The current study will be a multicenter, single arm Phase 3 study in Asian subjects with 
symptomatic TGCT associated with severe morbidity or functional limitations and not amenable 
to improvement with surgery.  The subject population to be studied in this study will be the 
almost same as in the PLX108-10 study. 
The primary endpoint in this study is the proportion of subjects who achieve a complete response 
(CR) or partial response (PR) based on centrally read MRI responder criteria as defined by 
RECIST 1.1 at Week 25, the same as that defined in the PLX108-10 study.  The MRI will be 
assessed at every 12 weeks.  A subject will be considered to have a response if the tumor meets 
the criteria for response and has a documented nonprogression at Week 25.  To minimize bias 
and reduce variability from this single arm study, centralized review of the MRI will be 
performed by the blinded readers.  The Imaging Charter for this study describes the image 
acquisition standards and methodology to be used as well as the standards for image 
interpretation.   

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 27  
The secondary endpoints are: (i) response based on tumor volume score (TVS) at Week 25; (ii) 
range of motion at Week 25; (iii) Patient-reported Outcomes Measurement Information System 
(PROMIS) Physical Function Scale at Week 25; (iv) best overall response; (v) duration of 
response; (vi) safety; and (vii) PK. 
The endpoint of TVS by the use of central MRI readers will be reinforced for the primary 
imaging endpoint of RECIST 1.1 assessment.  The endpoint of PROMIS assessment or 
improvement of range of motion will reinforce the explanation of clinical benefit from primary 
imaging endpoint. 
1.5. 
Risks and Benefits for Study Subjects 
Pexidartinib has been approved in the US for the treatment of TGCT associated with severe 
morbidity or functional limitations and amenable to improvement with surgery. 
Safety data from nonclinical studies, clinical studies, and non-interventional studies have been 
reviewed.  Liver toxicity is an important identified risk, and both embryo-fetal toxicity and 
fertility toxicity are considered an important potential risk with pexidartinib.  Hepatotoxicity may 
be fatal, and liver transplantation may be required.  The benefit/risk of pexidartinib specific for 
each study population should be assessed in study protocols.  Risk minimization measures, such 
as frequent monitoring during the first 8 weeks of pexidartinib treatment, related to managing 
these risks should be included in all study protocols. 
 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 28  
2. 
STUDY OBJECTIVES AND HYPOTHESIS 
2.1. 
Study Objectives 
The purpose of this study is to evaluate the efficacy and safety of pexidartinib treatment in the 
Asian subjects with symptomatic TGCT associated with severe morbidity or functional 
limitations and not amenable to improvement with surgery.  The primary endpoint of the study is 
the proportion of subjects who achieve a CR or PR of pexidartinib based on RECIST 1.1 at 
Week 25 by centrally reviewed MRI scan. 
2.1.1. 
Primary Objective 
To evaluate the efficacy in the Asian patients with TGCT by determining the ORR of 
pexidartinib based on RECIST 1.1 at Week 25 by centrally reviewed MRI scan. 
2.1.2. 
Secondary Objectives 
To evaluate: 
• Response of pexidartinib based on TVS at Week 25 by centrally reviewed MRI scan 
• Range of motion at Week  25 
• PROMIS Physical Function Scale at Week 25 
• Best overall response of pexidartinib based on RECIST 1.1 by centrally reviewed 
MRI scan 
• Best overall response of pexidartinib based on TVS by centrally reviewed MRI scan 
• Duration of response of pexidartinib based on RECIST 1.1 by centrally reviewed 
MRI scan 
• Duration of response of pexidartinib based on TVS by centrally reviewed MRI scan 
• Safety  
• PK 
2.1.3. 
Exploratory Objectives 
To evaluate:  
• ORR of pexidartinib based on RECIST 1.1 at Week 25 by locally reviewed MRI scan 
• ORR of pexidartinib based on modified RECIST 1.1-sum of the short-axis dimension 
(SSD) at Week 25 by centrally reviewed MRI scan 
• EuroQol five-dimensional descriptive system (EQ-5D-5L) 
• Best overall response of pexidartinib based on RECIST 1.1 by locally reviewed MRI 
scan 
• Duration of response of pexidartinib based on RECIST 1.1 by locally reviewed MRI 
scan 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 29  
• Duration of response of pexidartinib based on modified RECIST 1.1-SSD by 
centrally reviewed MRI scan 
• Photographic documentation of tumor size change 
• Results of the Surgical Assessment Questionnaire 
• PDy 
• Long term follow-up of the subject status after the end-of-study or early termination 
visit 
2.2. 
Study Hypothesis 
Pexidartinib is tolerable and efficacious and shows an acceptable safety profile when 
administered to subjects with symptomatic TGCT associated with severe morbidity or functional 
limitations and not amenable to improvement with surgery. 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 30  
3. 
STUDY DESIGN 
3.1. 
Overall Plan 
This will be a multicenter, single arm study of pexidartinib orally administrated in adult subjects 
with symptomatic TGCT associated with severe morbidity or functional limitations and not 
amenable to improvement with surgery. 
Study drug will be administered twice a day, every day.  Subjects will take 400 mg twice daily 
for a total daily dose of 800 mg (2 capsules in the morning and 2 capsules in the evening).  The 
study drug must be taken on an empty stomach at approximately the same time of the day with 
about 12-hour interval.  The pexidartinib starting dose and treatment regimen in this study are 
based on the rationale of PLX108-10 study and the result of the Study PL3397-A-103. 
The primary endpoint in this study is the proportion of subjects who achieve a CR or PR at the 
Week 25 based on criteria as defined by RECIST 1.1 by centrally reviewed MRI scan, the same 
as defined in the PLX108-10 study.  The MRI will be assessed at every 3 months.  A subject will 
be considered to have a response, if the tumor meets the criteria for response and has a 
documented nonprogression at Week 25.  To minimize bias and reduce variability from this 
single-arm study, centralized review of the MRI image will be performed by blinded readers.  
The Imaging Charter for this study describes the image acquisition standards and methodology to 
be used as well as the standards for image interpretation. 
It is considered that tumor shrinkage is essential to improve symptoms for advanced TGCT 
subjects.  The improvement of symptom will be evaluated with secondary endpoints.  The 
endpoint of TVS by the use of central MRI readers will be reinforced for the primary imaging 
endpoint of RECIST 1.1 assessment.  The endpoint of range of motion or PROMIS will reinforce 
the explanation of clinical benefit from primary imaging endpoint. 
The data of PLX108-01 preliminary results suggests that the use of pexidartinib offers high 
tumor response rate to subjects with this diagnosis who would not be adequately treated with 
surgery, the existing only standard of care.  The use of placebo will be an expected ethical 
limitation to enroll subject with symptomatic and surgical resection associated with potentially 
worsening functional limitation or severe morbidity under the circumstances of rare disease.   
In addition, it is considered that the primary endpoint will assess the durable response of 
6 months by RECIST 1.1 criteria that the primary endpoint for tumor shrinkage in between pre- 
and post-treatment with centralized review of all MRI scans will be conducted and that the study 
will be conducted without the use of placebo.  Moreover, the endpoint of TVS by use of central 
MRI readers will be reinforced for the primary imaging endpoint of RECIST 1.1 assessments.  In 
consideration of the below illustrated aspects, a single arm study without placebo control group 
has been planned. 
After completion of the end-of-study or early termination visit, subject status will be collected 
every 6 months as a long term follow-up at least 2 years. 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 31  
Figure 3.1: 
Study Schema 
 
MRI: magnetic resonance imaging. 
 
3.1.1. 
Duration of Subject Participation 
Each subject will spend a maximum of 6 weeks in screening.  All subjects will continue in the 
study until disease progression, unacceptable toxicity, or any of the other termination criteria. 
(See Section 14.8) 
Primary analysis will be performed after the last subject completes the Week 25 assessments. 
The duration after the Week 25 assessments will vary among subjects, as this portion of the 
study will continue until all subjects have either completed the study drug or withdrawn from the 
study. 
3.1.2. 
Study Endpoints 
3.1.2.1. 
Primary Endpoint 
The primary endpoint is the proportion of subjects who achieve a CR or PR of pexidartinib based 
on RECIST 1.1 at Week 25 by centrally reviewed MRI scan. 
3.1.2.2. 
Secondary Endpoints 
The following evaluations comprise the secondary endpoints: 
• Proportion of subjects who achieve a CR or PR of pexidartinib based on TVS at 
Week 25 by centrally reviewed MRI scan  
• 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 
• Mean change from baseline score in the PROMIS Physical Function Scale at the 
Week 25 
• Best overall response (CR or PR) of pexidartinib based on RECIST 1.1 by centrally 
reviewed MRI scan 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 32  
• Best overall response (CR or PR) of pexidartinib based on TVS by centrally reviewed 
MRI scan 
• Duration of response (CR or PR) of pexidartinib based on RECIST 1.1 by centrally 
reviewed MRI scan  
• Duration of response (CR or PR) of pexidartinib based on TVS by centrally reviewed 
MRI scan  
• Safety endpoints included the following, but not limited to: TEAEs, laboratory tests, 
vital sign, and Electrocardiogram (ECG)s 
• PK of pexidartinib and its primary metabolite, ZAAD-1006a 
3.1.2.3. 
Exploratory Endpoints 
Exploratory endpoints to be analyzed at appropriate time points include: 
• Proportion of subjects who achieve a CR or PR of pexidartinib based on RECIST 1.1 
at Week 25 by locally reviewed MRI scan  
• Proportion of subjects who achieve a CR or PR of pexidartinib based on modified 
RECIST 1.1-SSD at Week 25 by centrally reviewed MRI scan 
• Mean change from baseline score in the EQ-5D-5L at the Week 25 
• Best overall response (CR or PR) of pexidartinib based on RECIST 1.1 by locally 
reviewed MRI scan 
• Duration of response (CR or PR) of pexidartinib based on RECIST 1.1 by locally 
reviewed MRI scan 
• Duration of response (CR or PR) of pexidartinib based on modified RECIST 1.1-SSD 
by centrally reviewed MRI scan 
• Photographic documentation of tumor size change 
• Results of the Surgical Assessment Questionnaire 
• PDy of plasma CSF-1 activity 
• Long term subject status after the end-of study or early termination visit 
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 (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 within 24 weeks of treatment will be 
determined in a way similar to that for the primary endpoint. 
 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 33  
4. 
STUDY POPULATION 
Subjects must sign and date the Informed Consent Form (ICF) provided by the study site before 
any study-specific qualification procedures are conducted. 
4.1. 
Inclusion Criteria 
Subjects must satisfy all of the following criteria to be included in the study: 
1. Age ≥ 18 years (Age ≥ 20 years in Taiwan). 
2. A diagnosis of TGCT (i) that has been histologically confirmed by a pathologist and (ii) 
associated with severe morbidity or functional limitations and not amenable to 
improvement with surgery determined consensually by qualified personnel (eg, 
2 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 scan by a central radiologist. 
4. Stable prescription of analgesic regimen during the 2 weeks prior to enrollment. 
5. Women of childbearing potential must have a negative serum pregnancy test within 
the14-day period prior to enrollment (Where demanded by local regulations, this test may 
be required within 72 hours of enrollment).  
6. 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).  Women of nonchildbearing 
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 a follicle-stimulating hormone level > 40 mIU/mL will 
be considered postmenopausal. 
7. 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 and ALT ≤ 1.0 ×upper limit of normal (ULN) 
• Total bilirubin and direct bilirubin ≤ 1.0 × ULN 
• Alkaline phosphatase  ≤ 1.0 × ULN 
• Creatinine clearance (CLcr) > 15 mL/min 
8. Willingness and ability to complete the PROMIS Physical Function Scale. 
9. Willingness and ability to use a diary. 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 34  
10. Willingness and ability to provide written informed consent prior to any study-related 
procedures and to comply with all study requirements. 
4.2. 
Exclusion Criteria 
Subjects who meet any of the following criteria will be disqualified from entering the study: 
1. Investigational drug/device use within 28 days of enrollment. 
2. Previous use of pexidartinib or any biologic treatment targeting CSF-1 or the CSF1R; 
previous use of oral tyrosine kinase inhibitors are allowed, (eg, imatinib or nilotinib). 
3. Active cancer except for tumor for which a subject is enrolled in the study, (either 
concurrent or within the last year of starting study drug) 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 TGCT. 
5. Active or chronic infection with hepatitis C or known positive hepatitis B surface antigen, 
or known active or chronic infection with human immunodeficiency virus. 
6. Active liver or biliary tract disease.  
7. Known active tuberculosis. 
8. Significant concomitant arthropathy in the affected joint, serious illness, uncontrolled 
infection, or a medical or psychiatric history that, in the Investigator’s opinion, would 
likely interfere with a subject’s study participation or the interpretation of his or her 
results. 
9. Use of strong cytochrome P450 (CYP) 3A inducers, including St John’s wort, proton 
pump inhibitors (PPIs), and other products known to cause hepatotoxicity. 
10. Women who are breastfeeding. 
11. A screening Fridericia corrected QT interval (QTcF) ≥ 450 ms (men) or ≥ 470 ms 
(women). 
12. MRI contraindications. 
13. History of hypersensitivity to any excipients in the investigational product. 
14. Inability to swallow capsules. 
4.3. 
Subject Replacement 
Subjects withdrawn from the study will not be replaced. 
4.4. 
Subject Re-screening Procedures 
Rescreening is permitted for any candidate who failed to meet the eligibility criteria upon initial 
screening.  If rescreened, the candidate will not be given a new subject identification number.  

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 35  
The initial screening information and the reason why the subject was not eligible for the initial 
evaluation will be recorded on the screening log.  However, MRI, range of motion and surgical 
assessment may not need to be repeated, following consultation with Daiichi Sankyo (DS) 
Medical Monitor. 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 36  
5. 
STUDY TREATMENT 
5.1. 
Assigning Subjects to Treatments and Blinding 
5.1.1. 
Treatment Group  
This is a single arm study.  Eligible subjects will receive 400 mg twice daily for a total daily dose 
of 800 mg (2 capsules in the morning and 2 capsules in the evening).  
Treatment duration of pexidartinib is presented in Section 3.1.1. 
5.1.2. 
Method of Treatment Allocation 
Treatment allocation will not be applied to single arm design.  The study design is described in 
Section 3. 
5.1.3. 
Blinding 
This study is open-label and no blinding will be performed for the study drug.  However, all MRI 
images (scans) will be assessed by central readers blinded to study subject information according 
to procedures outlined in a separate MRI Imaging Charter. 
5.1.4. 
Emergency Unblinding Procedure 
Not applicable. 
5.2. 
Study Drug 
5.2.1. 
Description 
Pexidartinib is a hydrochloride salt with a white to off-white crystalline solid appearance.  
Pexidartinib supplied as a hypromellose capsule formulation J-3397-AF (200 mg free base 
equivalent) for oral administration contains the following excipients: poloxamer 407, mannitol, 
crospovidone, and magnesium stearate.  The Investigator must ensure that the study drug will be 
used only in accordance with the protocol. 
5.2.2. 
Labeling and Packaging 
Pexidartinib will be supplied by DS.  Pexidartinib capsules (200 mg strength) are packaged and 
labeled according to Good Manufacturing Practice and Good Clinical Practice (GCP) at the The 
packaging will be clearly labeled “For Clinical Study Use Only,” and will show the display name 
of the study drug, lot number, storage condition, and other required information in accordance 
with local regulations. 
5.2.3. 
Preparation 
Pexidartinib is an antitumor drug, and as with other potential toxic compounds, caution should be 
exercised when handling pexidartinib.  Specific instructions on preparation and dispensation is 
provided in the Study Pharmacy Manual. 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 37  
5.2.4. 
Administration 
Study drug will only be given to enrolled subjects under the supervision of the principal 
investigator or identified subinvestigator(s).  The study drug for home administration during the 
study will be dispensed to the subject for the first time at the Cycle 1 Day 1 (C1D1) visit (within 
3 days of enrollment).  Capsules must be swallowed and not crushed, chewed, or dissolved in 
liquid.  In this study, subjects will only receive pexidartinib capsules. 
Study drug administration will begin at the C1D1 visit in the morning.  At this visit, subjects will 
be instructed to take 400 mg BID for a total daily dose of 800 mg (2 capsules in the morning and 
2 capsules in the evening) through the study.  The study drug must be taken on an empty 
stomach at approximately the same time of the day with about 12-hour interval.  Each dosing 
cycle will be of 28 days. 
For the C1D15 visit (Week 3) and any visit when an ECG and PK will be performed, subjects 
must be told to NOT take their morning dose of study drug while coming for the study visit, 
which should be scheduled in the morning.  The subject must be instructed to bring their bottle of 
study drug to the site and take their morning dose upon instruction by the study site.  The time of 
dosing must be recorded.  Subjects will then take their evening dose at home.  If dose 
administered at the site is taken in the afternoon, then the subject must be instructed to skip their 
evening dose for that day. 
For the C7D1 visit (Week 25), subjects must be told to NOT take the morning dose of study drug 
before their visit and bring all unused capsules to the site for accountability.  Subjects who 
continue the study will be taking the same number of pexidartinib capsules per day as they will 
be taking at the end of 24 weeks treatment, ie, a maximum dose of 800 mg/day pexidartinib. 
Between site visits, subjects are to administer their study drug at home and record the dosing 
information in the study dosing diary.  Missed doses (those generally outside of a ± 2 hours 
dosing window) must be skipped and NOT administered as a double dose at the next dosing time 
point.  Subjects who vomit their dose must be instructed NOT to make up that dose. 
Further details on study drug administration are present in the Study Pharmacy Manual. 
5.2.5. 
Storage 
The study drug (pexidartinib) must be stored up to 25°C (77°F) in a secure, limited access 
storage area.  Excursion is permitted up to 30°C (86°F). 
If storage conditions are not maintained per specified requirements, then DS or Contract 
Research Organization (CRO) must be contacted.  Subjects are to be instructed to store the study 
drugs at room temperature out of the reach of children or other cohabitants. 
5.2.6. 
Drug Accountability 
When a drug shipment is received, the Investigator or designee are to check the amount and 
condition of the drug, check for appropriate local language on the label, drug expiration date, and 
sign the Receipt of Shipment Form provided. 
In addition, the Investigator or designee shall contact DS as soon as possible if there is a problem 
with the shipment. 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 38  
A Drug Accountability Record will be provided for the study drug.  The record must be kept 
current and must contain the dates and quantities of study drug received; the subject’s 
identification number and/or initials or supply number as applicable, for whom the study drug 
was dispensed; the date and quantity of study drug dispensed and remaining, as well as the 
initials of the dispenser. 
At the end of the study, or as directed, all study drugs (including unused, partially used, or empty 
containers) will be returned to a designee as instructed by DS.  Study drug will be returned only 
after the study monitor has completed a final inventory to verify the quantity to be returned.  The 
return of study drug must be documented and the documentation must be included in the 
shipment.  At the end of the study, a final study drug reconciliation statement must be completed 
by the Investigator or designee and provided to DS. 
All study drug inventory forms must be made available for inspection by DS authorized 
representative or designee and regulatory agency inspectors.  The Investigator or designee is 
responsible for the accountability of all used and unused study supplies at the study site. 
5.3. 
Control Treatment 
Not applicable. 
5.4. 
Dose Modification 
Reducing or interrupting the dose for toxicity may take place at any time during the study 
according to the guidelines in Table 5.1 and Table 5.2.  Dose modification guidelines for 
hematologic and hematologic treatment-related TEAEs are based on severity.  Dose interruptions 
can be implemented at the discretion of the treating Investigator to manage intolerable or 
clinically significant toxicity.  If a dose interruption is required, study assessments must be 
performed as scheduled, irrespective of the study drug delay, with the exception of PK 
assessments which must be deferred until treatment is resumed. 
When an odd number of capsules are taken in a day, the larger number of capsules must be taken 
as the evening dose.  For example, 600 mg/day = 3 capsules (1 capsule in the morning and 
2 capsules in the evening).  When an even number of capsules per day is to be taken, the 
morning and evening doses must be the same (eg, 800 mg/day = 4 capsules [2 capsules in the 
morning and 2 capsules in the evening] or 400 mg/day = 2 capsules [1 capsule in the morning 
and 1 capsule in the evening]). 
Dose reductions must be applied in increments of 200 mg/day (1 capsule), with a maximum total 
reduction of 400 mg/day (ie, a minimum dose of 400 mg/day).  Subjects unable to tolerate 
400 mg/day (2 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 DS’s 
Medical Monitor or designee. 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 39  
Table 5.1: 
Dose Modification 
Dose reduction 
Total daily dose 
Administration of total daily dose 
First 
600 mg 
200 mg in the morning and 400 mg in the evening 
Second 
400 mg 
200 mg twice daily 
 
Dose modification guidelines for treatment-emergent toxicities as well as guidelines for their 
management are presented in Table 5.2.  These parameters are only a guide and are not intended 
to supersede the clinical judgment of the treating Investigator.  All adjustments must be 
communicated to DS’s Medical Monitor or designee.  Additional liver evaluation is presented in 
Table 5.3.  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. 
 
Table 5.2: 
Dose Modification Guidelines for Treatment-emergent Toxicities 
Adverse Reaction 
Severity 
Pexidartinib Dosage Modifications 
Increased ALT 
and/or AST 
Greater than 3 to 
5 times ULN 
• 
Withhold and monitor liver tests weekly. 
• 
If AST and ALT are less than or equal to 3 times 
ULN within 4 weeks, resume at reduced dose. 
• 
If AST or ALT is not less than or equal to 3 times 
ULN in 4 weeks, permanently discontinue 
pexidartinib. 
• 
If AST or ALT is not less than or equal to 3 times 
ULN in 2 weeks, proceed to liver evaluation as 
outlined in Table 5.3  
Greater than 5 to 
10 times ULN 
• 
Withhold and monitor liver tests twice weekly. 
If AST and ALT are less than or equal to 3 times ULN 
within 4 weeks, resume at reduced dose. 
• 
If AST or ALT is not less than or equal to 3 times 
ULN in 4 weeks, permanently discontinue 
pexidartinib. 
• 
If AST or ALT is not less than or equal to 3 times 
ULN in 2 weeks, proceed to liver evaluation as 
outlined in Table 5.3  
Greater than 10 times 
ULN 
• 
Permanently discontinue pexidartinib. 
• 
Monitor liver tests twice weekly until AST or ALT 
is less than or equal to 5 times ULN, then weekly 
until less than or equal to 3 times ULN. 
• 
Proceed to liver evaluation as outlined in Table 5.3  

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 40  
Increased ALP and 
Gamma-glutamyl 
transpeptidase 
(GGT) 
ALP greater than 
2 times ULN with 
GGT greater than 
2 times ULN 
• 
Permanently discontinue pexidartinib.  
• 
Monitor liver tests twice weekly until ALP is less 
than or equal to 5 times ULN, then weekly until 
less than or equal to 2 times ULN. 
• 
Proceed to liver evaluation as outlined in Table 5.3  
Increased bilirubin 
Total bilirubin greater 
than ULN to less than 
2 times ULN  
or  
Direct bilirubin 
greater than ULN and 
less than 1.5 times 
ULN 
• 
Withhold and monitor liver tests twice weekly. 
• 
If an alternate cause for increased bilirubin is 
confirmed and bilirubin is less than ULN within 
4 weeks, resume at reduced dose. 
• 
If bilirubin is not less than ULN in 4 weeks, 
permanently discontinue pexidartinib. 
• 
If bilirubin is not less than ULN in 2 weeks, 
proceed to liver evaluation as outlined in Table 5.3  
Total bilirubin greater 
or equal to 2 times 
ULN  
or  
Direct bilirubin 
greater than 1.5 times 
ULN 
• 
Permanently discontinue pexidartinib. 
• 
Monitor liver tests twice weekly until bilirubin is 
less than or equal to ULN. 
• 
Proceed to liver evaluation as outlined in Table 5.3 
Adverse reactions or 
other laboratory 
abnormalities 
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; GGT = 
gamma-glutamyl transpeptidase; ULN = upper limit of normal  
 
 
Table 5.3: 
Additional Liver Evaluation 
Evaluation 
Instruction 
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. 
Detail medical history and physical examination 
seeking new abnormalities. 
Evaluate any abnormalities found. 
Full serological evaluation for hepatitis A, B, C, D, 
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. 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 41  
Perform liver ultrasound 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 day. 
Contact Medical Monitor. 
Measure AMA. 
Evaluate any abnormalities found. 
Perform liver biopsy to evaluate the pathological 
change (if possible). 
Evaluate any abnormalities found. 
We request that cases be discussed with the Medical Monitor in instances where study drug is being 
held for liver function test abnormalities. 
OTC = over-the-counter; AMA = anti-mitochondrial antibody 
 
5.5. 
Method of Assessing Treatment Compliance 
Pexidartinib will be dispensed to subjects at the study visits indicated in the Schedule of 
Assessment.  The appropriate study personnel will document and maintain records of study drug 
dispensed to each subject and any returns at each study visit. 
Subjects will complete a dosing diary to record the number of capsules/date/time the dose was 
taken during each dosing cycle. 
At each site visit, subjects will be assessed for compliance with study drug administration, ie, 
actual capsules taken/expected capsules taken.  The subject must also return all bottles 
(used/unused) at each dispensing visit. 
Further details can be found in each manual. 
5.6. 
Prior and 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 day of C1D1 will be recorded on 
the eCRF.  Analgesic use and analgesic regimen will be recorded. 
Subjects enrolled in studies with pexidartinib and are receiving concomitant warfarin must have 
their anticoagulation status carefully monitored, especially shortly after initiation of pexidartinib, 
for the potential need to make adjustments in warfarin dosing.  In particular, international 
normalized ratio (INR) must be obtained just prior to initiation of pexidartinib, within 1 to 
2 weeks after initiation, and periodically thereafter.  Dose adjustments of warfarin must be made 
as medically indicated. 
Avoid the concomitant use of pexidartinib with other products known to cause hepatotoxicity. 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 42  
5.6.1. 
CYP3A inducers 
Avoid the concomitant use of strong CYP3A inducers, including St John’s wort (see 
Section 16.1 , a list of common CYP3A inhibitors and inducers). 
5.6.2. 
CYP3A and UGT inhibitors 
Avoid concomitant use of pexidartinib with moderate or strong CYP3A inhibitors or UDP-
glucuronosyltransferase (UGT) inhibitors during treatment with pexidartinib.  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 5.4.  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. 
Table 5.4: 
Recommended Dosage Reductions for Pexidartinib for Concomitant Use of 
Moderate and Strong CYP3A Inhibitors or UGT Inhibitors 
Planned Total Daily Dose 
Modified Total Daily Dose 
Administration of  Modified 
Total Daily Dose 
800 mg 
400 mg 
200 mg BID 
600 mg 
400 mg 
200 mg BID 
400 mg 
200 mg 
200 mg once daily 
5.6.3. 
Hormonal Contraceptives 
Pexidartinib has been indicated to be a moderate CYP3A4 inducer, as concurrent administration 
of pexidartinib decreased the area under the plasma-concentration-time curve from time zero to 
infinity (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). 
5.6.4. 
Acid-reducing Agents 
Avoid the concomitant use of 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. 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 43  
5.7. 
Dosage Modification for Renal Impairment 
The recommended dosage of pexidartinib for patients with mild to severe renal impairment 
(CLcr 15 to 89 mL/min estimated by Cockcroft-Gault using actual body weight) is 200 mg in the 
morning and 400 mg in the evening. 
5.8. 
Subject Withdrawal/Discontinuation 
5.8.1. 
Reasons for Withdrawal 
The reason for discontinuation should be recorded for any subject discontinuing from the study. 
The reasons a subject may discontinue or be withdrawn from the study permanently include but 
are not limited to: 
• AE 
• Disease progression 
• Subject request 
• Investigator decision 
• Protocol violation 
• Surgery 
• Subject noncompliance 
• Pregnancy 
• Study termination by DS or institutional review board (IRB)/independent ethics 
committee (IEC) 
During the study, if a subject experiences radiological 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 DS’s Medical Monitor or designee to allow the 
subject to remain in the study. 
5.8.2. 
Withdrawal Procedures 
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 
dose 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. 
All subjects who are withdrawn from the study must complete protocol-specified withdrawal 
procedures. 
When a subject discontinues or is permanently withdrawn from the study, the Investigator will 
notify DS and ensure that the procedures listed in the “post-treatment visit” column in the 
Schedule of Assessment (Table 16.3) are performed 28 ± 7 days after the subject’s last dose of 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 44  
study drug and prior to initiating any new TGCT therapy, including surgery, whichever occurs 
first. 
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 
should be made to follow all subjects for safety. 
The reason for study withdrawal will be recorded.  If a subject discontinues study drug to 
undergo surgery, information about the type of surgery and its outcome must be collected. 
5.9. 
Long Term Follow-up 
After completion of the end-of-study or early termination visit, subject status will be collected by 
telephone contact every 6 months as a long term follow-up at least 2 years from each subject 
who consent. 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 45  
6. 
STUDY PROCEDURES 
Study procedures are listed by visit in the following subsections.  Additional details are provided 
in the MRI Procedure Manual, or Laboratory Manual as applicable. 
Each subject must sign and date an ICF before undergoing any study procedure including 
screening procedures unless the screening procedure is considered standard of care. 
Screening procedures are to be performed within 42 days before the first dose of study drug, 
unless otherwise noted. 
If a dose interruption is required, study assessments must be performed as scheduled, irrespective 
of the study drug delay, with the exception of PK assessments which should be deferred until 
treatment is resumed. 
6.1. 
Screening  
6.1.1. 
Screening (Day –42 to Day –1) 
The following procedures must be performed within the 42-day period before C1D1, unless 
otherwise noted, and the results must be obtained and evaluated for eligibility prior to the C1D1 
visit: 
To be performed before any procedures: 
• Informed consent 
Before any invasive procedures carried out on the same day, the following parameters are to be 
recorded: 
• Vital signs, including blood pressure (BP), pulse rate, and temperature 
• 12-lead ECG 
Other procedures to be performed: 
• Medical history (including TGCT treatment history and smoking history) 
• Demographics, including ethnicity and race 
• Assessment of concomitant medications including analgesics 
• PROMIS Physical Function Scale 
• EQ-5D-5L 
• Surgical Assessment Questionnaire 
• Height and weight 
• Physical examination 
• Clinical laboratory tests: serum chemistry, hematology, liver function, hepatitis panel, 
hormone testing (as applicable) *, serum pregnancy testing (as applicable)** 
• MRI of the affected joint within 56 days prior to C1D1 
• Photographic documentation of tumor 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 46  
• Range of motion assessment of the affected joint 
• AE assessment 
• Serum sample for anti-mitochondrial antibody (AMA) 
* Note: Women who are not using hormonal contraception must be tested for levels 
of follicle-stimulating hormone (FSH), luteinizing hormone (LH), progesterone, and 
estradiol.  Hormone testing will not be required for women who have either had an 
oophorectomy or are postmenopausal.  Men must be tested for levels of LH, FSH, 
and testosterone.  Men whose testosterone level is below baseline at the last study 
visit must 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 enrollment (or, where different regulations apply, within 72 hours of 
enrollment).  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. 
6.2. 
Enrollment 
6.2.1. 
Cycle 1 (Enrollment) 
To be performed after the subject is determined to meet all eligibility criteria: 
• Subject enrollment (can be done up to 3 days prior to C1D1) 
6.3. 
Treatment Period 
6.3.1. 
Cycle 1, Day 1 (C1D1; Week 1) 
Before any invasive procedures, the following parameters are to be recorded: 
• PROMIS Physical Function Scale 
• EQ-5D-5L 
• Vital signs including BP, pulse rate, and temperature 
• 12-lead ECG 
To be performed before the first morning dose of study drug: 
• Assessment of concomitant medications including analgesics 
• Clinical laboratory tests (only need to be done if they were not done within 72 hours 
of Day 1): serum chemistry, hematology, coagulation, hormone testing, liver 
function, and urinalysis 
• Blood sampling for PK and PDy analysis  
• Dispense study drug bottles 
To be performed after the subject is dosed at the site: 
• Record the dose (subject diary, source records, eCRF) 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 47  
• 12-lead ECG to be performed 2 hours ± 10 minutes after dosing 
• AE assessment 
6.3.2. 
Cycle 1, Day 8 (C1D8 Week 2) ± 2 days 
The following parameters are to be recorded: 
• Concomitant medications 
• Clinical laboratory tests: liver function 
• AE assessment  
6.3.3. 
Cycle 1, Day 15 (C1D15 Week 3) ± 2 days 
Before any invasive procedures, the following parameters are to be recorded: 
• Vital signs, including BP, pulse rate, and temperature 
• 12-lead ECG 
To be performed before the morning dose: 
• Assessment of concomitant medications including analgesics  
• Treatment compliance assessment 
• Clinical laboratory tests: liver function, hematology 
• Blood sampling for PK and PDy analysis 
To be performed after the subject is dosed at the site: 
• Record of the dose (subject diary, source records, eCRF) 
• Blood sampling for PK analysis at various postdose time points (see Section 8.2) 
• 12-lead ECG to be performed 2 hours ± 10 minutes after dosing 
• AE assessment 
6.3.4. 
Cycle 1, Day 22 (C1D22; Week 4) ± 2 days 
The following parameters are to be recorded: 
• Concomitant medications 
• Clinical laboratory tests: liver function  
• AE assessment  
6.3.5. 
Cycle 2, Day 1 (C2D1; Week 5) ± 2 days 
Before any invasive procedures, the following parameters are to be recorded: 
• Vital signs including BP, pulse rate, and temperature 
Other procedures to be performed: 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 48  
• Treatment compliance assessment 
• Assessment of concomitant medications including analgesics 
• Physical examination 
• Clinical laboratory tests: serum chemistry, hematology, liver function, serum 
pregnancy testing (as applicable) 
• Blood sampling for PK and PDy analysis (see Section 8.2) 
• Dispensation of study drug bottles  
• AE assessment 
6.3.6. 
Cycle 2, Day 8 (C2D8; Week 6) ± 2 days 
The following parameters are to be recorded: 
• Concomitant medications 
• Clinical laboratory tests: liver function 
• AE assessment 
6.3.7. 
Cycle 2, Day 15 (C2D15; Week 7) ± 2 days 
The following parameters are to be recorded: 
• Concomitant medications 
• Clinical laboratory tests: liver function 
• AE assessment 
6.3.8. 
Cycle 2, Day 22 (C2D22; Week 8) ± 2 days 
The following parameters are to be recorded: 
• Concomitant medications 
• Clinical laboratory tests: liver function 
• AE assessment 
6.3.9. 
Cycle 3, Day 1 (C3D1; Week 9) ± 7 days 
Before any invasive procedures, the following parameters are to be recorded: 
• PROMIS Physical Function Scale 
• EQ-5D-5L 
• Vital signs including BP, pulse rate, and temperature 
Other procedures to be performed: 
• Treatment compliance assessment 
• Assessment of concomitant medications including analgesics 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 49  
• Clinical laboratory tests: serum chemistry, hematology, liver function, serum 
pregnancy testing (as applicable) 
• Random postdose blood sampling for PK and PDy analysis 
• Dispensation of study drug bottles 
• AE assessment 
6.3.10. 
Cycle 3, Day 15 (C3D15; Week 11) ± 7 days 
The following parameters are to be recorded: 
• Concomitant medications 
• Clinical laboratory tests: liver function 
• AE assessment 
6.3.11. 
Cycle 4, Day 1 (C4D1; Week 13) ± 7 days 
Before any invasive procedures, the following parameters are to be recorded: 
• Vital signs, including BP, pulse rate, and temperature 
To be performed within (±) 7 days of the visit: 
• Treatment compliance assessment 
• Assessment of concomitant medications including analgesics 
• Physical examination 
• 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 
• Photographic documentation of tumor 
• Range-of-motion assessment of the affected joint 
Other procedures to be performed: 
• Clinical laboratory tests: serum chemistry, hematology, liver function, serum 
pregnancy testing (as applicable), and urinalysis 
• Dispensation of study drug bottles 
• AE assessment 
6.3.12. 
Cycle 5, Day 1 (C5D1; Week 17) ± 7 days 
Before any invasive procedures, the following parameters are to be recorded: 
• PROMIS Physical Function Scale 
• EQ-5D-5L 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 50  
• Vital signs including BP, pulse rate, and temperature 
Other procedures to be performed: 
• Treatment compliance assessment 
• Assessment of concomitant medications including analgesics 
• Clinical laboratory tests: serum chemistry, hematology, liver function, serum 
pregnancy testing (as applicable) 
• Random postdose blood sampling for PK and PDy analysis 
• Dispensation of study drug bottles 
• AE assessment 
6.3.13. 
Cycle 6, Day 1 (C6D1; Week 21) ± 7 days 
Before any invasive procedures, the following parameters are to be recorded: 
• Vital signs including BP, pulse rate, and temperature 
Other procedures to be performed: 
• Treatment compliance assessment 
• Assessment of concomitant medications including analgesics 
• Clinical laboratory tests: serum chemistry, hematology, liver function, serum 
pregnancy testing (if applicable) 
• Dispensation of study drug bottles 
• AE assessment 
6.3.14. 
Cycle 7, Day 1 Visit (C7D1; Week 25) ± 7 days 
Before any invasive procedures, the following procedures have to be performed: 
• PROMIS Physical Function Scale 
• EQ-5D-5L 
• Vital signs including BP, pulse rate, and temperature 
• 12-lead ECG 
To be performed within (±) 7 days of the visit: 
• Treatment compliance assessment 
• Assessment of concomitant medications including analgesics 
• Surgical Assessment Questionnaire 
• Weight 
• Physical examination 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 51  
• 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 
• Photographic documentation of tumor 
• Range-of-motion assessment of the affected joint 
Other procedures to be performed: 
• Clinical laboratory tests: serum chemistry, hematology, coagulation, liver function, 
hormone testing, serum pregnancy testing (as applicable), and urinalysis 
• AE assessment 
The following procedures will be performed as part of the C7D1visit if the subject will continue 
the study: 
After the subject is dosed at the site: 
• Record the dose (subject diary, source records, eCRF) 
• Dispensation of study drug bottles 
6.3.15. 
Cycle 10+, Day 1 (C10+D1; Week 37+) ± 7 days 
To be performed at C10+D1 ± 7 day and every 12 weeks thereafter (eg, C13, C16, C19). 
Before any invasive procedures, the following parameters are to be recorded: 
• PROMIS Physical Function Scale 
• EQ-5D-5L 
• Vital signs, including BP, pulse rate, and temperature 
To be performed within (±) 7 days of the visit: 
• Physical examination 
• Treatment compliance assessment 
• Assessment of  concomitant medications, including analgesics 
• 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 
• Photographic documentation of tumor 
• Range-of-motion assessment of the affected joint 
To be performed other procedures: 
• Clinical laboratory tests: serum chemistry, hematology, liver function, serum 
pregnancy testing (if applicable) 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 52  
• Dispensation of study drug bottles  
• AE assessment 
6.3.16. 
Post-treatment Visit (last dose + 28 days) ± 7 days 
To be performed at 28 ± 7 days after the last dose of study drug.  
Before any invasive procedures, the following parameters are to be recorded: 
• PROMIS Physical Function Scale 
• EQ-5D-5L 
• Vital signs including BP, pulse rate, and temperature 
• 12-lead ECG 
The following procedures are to be performed within (±) 7 days of this visit: 
• Assessment of concomitant medications including analgesics 
• Surgical Assessment Questionnaire 
• Weight 
• Physical examination 
• 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) 
• Photographic documentation of tumor 
• Third-party range-of-motion assessment of the affected joint 
Other procedures to be performed: 
• Clinical laboratory tests: serum chemistry, hematology, coagulation, liver function, 
hormone testing, serum pregnancy testing (if applicable), and urinalysis 
• If surgical resection of the tumor is performed within 28 days after the last dose of 
study drug, obtain details and outcome of the surgery 
• AE assessment 
• For subjects terminating the study because of progression, document if they plan to 
undergo any new TGCT therapy, including surgery, during the 28 days period 
(± 7 days) after their last dose of study drug 
6.3.17. 
End-of-Study or Early Termination Visit (last dose + 12 weeks) ± 7 days 
This visit is scheduled 12 weeks ± 7 days after the last dose of study drug or before any new 
TGCT therapy, including surgery, whichever occurs first.  It is scheduled for subjects who 
withdraw from the study for reasons other than progression. 
• Concomitant medications 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 53  
• If surgical resection of the tumor is performed within 12 weeks after the last dose of 
study drug, obtain details and outcome of the surgery 
• MRI of the affected joint (with local assessment of progression status) is to be 
performed within (±) 7 days of the visit 
• Photographic documentation of tumor 
• Assess if the subject plans to begin any new TGCT therapy, including surgery 
• Clinical laboratory tests: serum pregnancy testing (if applicable) 
• AE assessment 
• Terminate the subject from the study 
6.3.18. 
Long Term Follow-up (every 6 months after end-of-study or early termination 
visit) ± 2 weeks 
After completion of the end-of-study or early termination visit, the long term follow-up will be 
performed every 6 months by telephone contact. The questionnaire is provided in Section 16.5.  
• Subject status 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 54  
7. 
EFFICACY ASSESSMENTS 
Subjects will be assessed for the efficacy endpoints listed in Section 3.1.2 
7.1. 
Primary Efficacy Endpoint 
The primary endpoint will be the proportion of subjects who achieve a CR or PR of pexidartinib 
based on RECIST 1.1 at Week 25 by centrally reviewed MRI scan. 
The RECIST 1.1 response categories are defined by the following criteria: 
• Complete Response (CR) — Disappearance of all tumors. 
• Partial Response (PR) — At least a 30% decrease in the sum of diameters of target 
tumors, taking as reference the baseline sum diameters. 
• Progressive Disease (PD) — 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 (SD) — Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD. 
CR and PR 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 within 24 weeks treatment with respect to the primary efficacy endpoint is 
shown in Table 7.1. 
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/not evaluable [NE]) at Week 25 will be considered a responder for the primary 
efficacy endpoint. 
 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 55  
Table 7.1: 
Definitions of Response for the Primary Endpoint 
Time Point Response at 
Week 13 
(C4D1 visit) 
Time Point Response at 
Week 25 
(C7D1visit) 
Tumor Response Status 
(Primary efficacy endpoint)  
CR or PR 
CR 
Response (CR) 
CR or PR 
PD 
Nonresponse (PD) 
PR 
non-CR/non-PD/non-NE a 
Response (PR)b 
SD 
CR or PR 
Response (CR or PR) 
SD 
SD 
Nonresponse (SD) 
SD 
PD 
Nonresponse (PD)c 
CR, PR, SD, or NE 
NE 
Nonresponse (NE) 
PD 
Any 
Nonresponse (PD) 
NE 
CR or PR 
Response (CR or PR) 
NE 
SD or PD 
Nonresponse (SD or PD) 
CR = complete response; NE = not evaluable; 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 Week 24. 
 
For the entire study, centralized review of the MRI scans will be performed by readers blinded to 
study subject information according to procedures outlined in a separate MRI Imaging Charter.  
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. 
7.1.1. 
Tumor Imaging 
MRI (Noncontrast or follow the standard operation of the sites) of the affected joint will be 
performed at the study visits indicated in the Schedule of Assessment (Table 16.3).  All MRI 
scans will be centrally read.  Local evaluation of radiological response, stable disease (SD) or PD 
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. 
If disease progression is indicated clinically or by local radiological 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 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 56  
disease progression, subject will be discontinued from the study unless the Investigator and the 
DS’s Medical Monitor judge that the subject would potentially benefit from continued treatment 
with pexidartinib. 
During the study, if indicated, Investigators should request confirmation of radiological 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 MRI scan reads are outlined in the MRI 
Procedure Manual. 
Subjects who terminate the study because of radiological disease progression will NOT have a 
follow-up MRI at their post-treatment visit. 
7.2. 
Secondary Efficacy Endpoints 
The following evaluations comprise the secondary endpoints: 
• Proportion of subjects who achieve a CR or PR of pexidartinib based on TVS at 
Week 25 by centrally reviewed MRI scan  
• 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 
• Mean change from baseline score in the PROMIS Physical Function Scale at the 
Week 25 
• Best overall response (CR or PR) of pexidartinib based on RECIST 1.1 and TVS by 
centrally reviewed MRI scan 
• Duration of response (CR or PR) of pexidartinib based on RECIST 1.1 and TVS by 
centrally reviewed MRI scan   
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 multifeature score 
(Rheumatoid Arthritis MRI Score), originally developed for rheumatoid arthritis10 and whole-
organ MRI score (WORMS), originally developed for osteoarthritis.11  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 1.1: 
• Complete response: Lesion completely gone. 
• PR: ≥ 50% decrease in volume score relative to baseline. 
• PD: ≥ 30% increase in volume relative to lowest score during the study whether at 
baseline or some other visit. In the case of limited residual disease, the increase in 
tumor volume must also be unequivocally larger. 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 57  
• SD: 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 
TGCT from the Phase 1 of pexidartinib (Section 1.3.1).  The tumor response status on this 
endpoint within 24 weeks treatment is determined in a way similar to that for the primary 
efficacy endpoint (Table 7.1).  To minimize bias and reduce variability, MRIs for primary 
endpoint and secondary endpoints 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 function will be assessed by an objective range of motion 
assessment performed by a qualified assessor, such as an orthopedic surgeon or a physical 
therapist blinded and when possible, to study drug name and to study protocol.  This assessment 
uses standard goniometers and has been standardized according to American Medical 
Association disability criteria.12  Details of this analysis are described in Section 10.5. 
The PROMIS Physical Functioning items addresses 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 provides 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 TGCT, which only measures functioning in the 
lower extremities). 
7.2.1. 
Range of Motion Assessment 
Range of motion will be assessed by a qualified assessor, such as an orthopedic surgeon or a 
physical therapist, using goniometers according to a standardized method based on American 
Medical Association disability criteria.12   Measurements will be recorded in degrees.  Details of 
the measurement procedure for each joint will be provided in the manual. 
7.2.2. 
PROMIS Physical Function Scale 
At the Week 25 visit, subjects will complete via the PROMIS Physical Function Scale at the 
indicated study visits in the Schedule of Assessment (Table 16.3). 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 16.2).  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. 
7.3. 
Exploratory Efficacy Endpoint 
Exploratory efficacy endpoints to be analyzed at appropriate time points include: 
• Proportion of subjects who achieve a CR or PR of pexidartinib based on RECIST 1.1 
at Week 25 by locally reviewed MRI scan  
• Proportion of subjects who achieve a CR or PR of pexidartinib based on modified 
RECIST 1.1-SSD at Week 25 by centrally reviewed MRI scan 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 58  
• Mean change from baseline score in the EQ-5D-5L at the Week 25 
• Best overall response (CR or PR) of pexidartinib based on RECIST 1.1 by locally 
reviewed MRI scan 
• Duration of response (CR or PR) of pexidartinib based on RECIST 1.1 by locally 
reviewed MRI scan 
• Duration of response (CR or PR) of pexidartinib based on modified RECIST 1.1-SSD 
by centrally reviewed MRI scan 
• Photographic documentation of tumor size change 
• Results of the Surgical Assessment Questionnaire 
• PDy of plasma CSF-1 activity 
• Long term subject status after the end-of-study or early termination visit 
7.3.1. 
EuroQol Five-Dimensional Descriptive System 
At the Week 25 visit, subjects will complete via the EQ-5D-5L at the indicated study visits in 
the Schedule of Assessment (Table 16.3).  
The EQ-5D-5L is a preference-based general health status or health-related quality of life 
instrument consisting of two parts.  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.” 
7.3.2. 
Photographic Documentation of Tumor size Change 
The photographic documentation will be collected to assess the tumor size change by photo if 
applicable. 
7.3.3. 
Surgical Assessment Questionnaire 
The surgical assessment questionnaire (Section 16.4) 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 Assessment. 
7.4. 
Appropriateness of Selected Efficacy Assessments 
The appropriateness of selected efficacy endpoints is described in Section 7.1 and Section 7.2.  
 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 59  
8. 
PHARMACOKINETIC/PHARMACODYNAMIC/ 
PHARMACOGENOMIC ASSESSMENTS 
Subjects will be assessed for the PK and PDy endpoints. 
8.1. 
Pharmacodynamic Assessment 
Plasma for PDy biomarker (CSF-1 activity) 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. 
Detailed instructions on collection, processing, handling, storage, and sample shipment is 
provided in the Laboratory Manual. 
8.2. 
Pharmacokinetic Assessment 
PK sampling will be performed at the study visits indicated in the Schedule of Assessment 
(Table 16.3).  Each site must choose one of the schedules for each subject and must adhere to the 
selected schedule (Table 8.1) for the duration of the study: 
 
Table 8.1: 
Pharmacokinetic Schedules 
Visit 
Schedule 1 
Schedule 2 
Week 1 C1D1 
Predose 
Predose 
Week 3 C1D15 
Predose  
0.5 h postdose (± 10 min)  
1 h postdose (± 15 min)  
2 h postdose (± 15 min)  
4 h postdose (± 20 min)  
6 h postdose (± 20 min) 
Predose 
Postdose: Between 1 h and 3 h 
Week 5 C2D1 
Random postdose 
Random postdose 
Week 9 C3D1 
Random postdose 
Random postdose 
Week 17 C5D1 
Random postdose 
Random postdose 
h = hour(s); min = minute(s) 
 
Subjects must be told to NOT take the morning dose of study drug at the C1D15 visit.  Instead, 
they must be told to bring their bottle of study drug to the site and follow dosing instruction by 
the site staff. 
The exact time of dose administration must be recorded along with the corresponding PK blood 
samplings.  The exact time of the doses should also be recorded. 
Blood samples of approximately 3 mL for PK analyses will be collected at the time points 
specified in Table 8.1. 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 60  
The PK analyses will be performed on the PK analysis set (see Section 10.7).  Detailed 
instructions on collection, processing, handling, storage, and sample shipment are provided in the 
Laboratory Manual. 
 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 61  
9. 
SAFETY EVALUATION AND REPORTING 
9.1. 
Adverse Event Collection and Reporting 
All AEs (see Section 9.4.1 for definitions) occurring after the subject signs the ICF and through 
the post-treatment visit (28 ± 7 days after the last dose of study drug), 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 AEs and serious adverse events (SAEs) are to be reported according to the procedures in 
Section 9.5. 
All clinical laboratory results, vital signs, hormone testing results and ECG results or findings 
should be appraised by the Investigator to determine their clinical significance.  Isolated 
abnormal clinical laboratory results, hormone testing results, vital sign findings, or ECG findings 
(ie, not part of a reported diagnosis) should be reported as AEs if they are symptomatic, lead to 
study drug discontinuation, dose reduction, require corrective treatment, or constitute an AE in 
the Investigator’s clinical judgment. 
At each visit, the Investigator will determine whether any AEs have occurred by evaluating the 
subject.  AEs 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 9.4.1.  The Investigator’s assessment must be clearly documented in the site’s source 
documentation with the Investigator’s signature. 
Always report the diagnosis as the AE or SAE term.  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.  Preplanned (prior to signing the ICF) 
procedures or treatments requiring hospitalization for preexisting conditions that do not worsen 
in severity should not be reported as SAEs (see Section 9.4.2 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.  In addition, any serious untoward event that may occur subsequent to the reporting 
period that the Investigator assesses as related to study drug must also be reported and managed 
as an SAE. 
The Investigator must 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, the events will be followed up until resolution or until they become 
clinically not relevant. 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 62  
9.2. 
Assessment of Safety Endpoint 
Safety endpoints include physical examination, vital signs, 12-lead ECG, AE reports, serum 
chemistry, hematology, coagulation tests, urinalysis, hormone testing (as applicable), and 
concomitant medications.  All TEAEs will be graded according to the National Cancer Institute-
Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. 
9.3. 
Adverse Events of Special Interest 
9.3.1. 
Liver enzyme elevations and Bilirubin elevation 
• Elevation of ALT and/or AST greater than 3 × ULN 
• Elevation of ALP greater than 2 × ULN with elevation of GGT greater than 2 × ULN 
• Elevation of total bilirubin greater than ULN 
• Elevation of direct bilirubin greater than ULN 
• Combined elevations of aminotransferases and bilirubin, either serious or nonserious 
and whether or not causally related, meeting the laboratory criteria of a potential Hy’s 
Law (ALT or AST ≥ 3 × ULN and total bilirubin > 2 × ULN) that may occur 
simultaneously or at different time points during the study   
If the subject meet the criteria described in Table 5.2 due to liver enzyme abnormalities, the 
subject will have additional clinical and laboratory evaluations as described in Section 5.4 in 
order to determine the cause and severity of the potential liver injury. 
9.4. 
Adverse Event 
9.4.1. 
Definition of Adverse Event 
An AE is any untoward medical occurrence in a patient administered pharmaceutical product and 
that 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 (International Council for 
Harmonisation [ICH] E2A Guideline.  Clinical Safety Data Management: Definitions and 
Standards for Expedited Reporting, Oct 1994).13 
It is the responsibility of Investigators, based on their knowledge and experience, to determine 
those circumstances or abnormal laboratory findings which should be considered as AEs. 
9.4.2. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death, 
• Is life-threatening, 
• Requires inpatient hospitalization or prolongation of existing hospitalization, 
• Results in persistent or significant disability/incapacity, 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 63  
• Is a congenital anomaly/birth defect, or 
• Is an important medical event. 
Note: The term “life-threatening” in the definition of “serious” refers to an event in which the 
patient 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 (ICH E2A Guideline.  Clinical 
Safety Data Management: Definitions and Standards for Expedited Reporting, Oct 1994).13  
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:  
• Procedures are not AEs or SAEs, but the reason for the procedure may be an AE or 
SAE. 
• Preplanned (prior to signing the ICF) procedures or treatments requiring 
hospitalizations for preexisting conditions that do not worsen in severity are not 
SAEs. 
9.4.3. 
Severity Assessment  
All AEs will be graded (1 to 5; see below) according to the latest NCI-CTCAE, for each episode. 
• 
Grade 1: Mild → awareness of sign or symptom, but easily tolerated, ie, does not 
interfere with subject’s usual function 
• 
Grade 2: Moderate → discomfort enough to cause interference with usual activity 
• 
Grade 3: Severe → incapacitating with inability to work or do usual activity, ie, interferes 
significantly with subject’s usual function 
• 
Grade 4: Life-threatening or disabling AE → urgent intervention indicated 
• 
Grade 5: Death related to AE 
The NCI-CTCAE guidelines do not allow certain grades for certain AEs.  For example, pain can 
be Grade 1 to 3 only (ie, cannot be life-threatening or fatal), whereas sepsis can only be Grade 4 
or 5 (ie, can only be life-threatening or fatal).  In addition, alopecia can only be Grade 1 or 2.  
The NCI-CTCAE guidelines should be followed closely. 
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 grade may or may not be assessed as serious 
based on the seriousness criteria. 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 64  
9.4.4. 
Causality Assessment 
The Investigator should assess causal relationship between an AE and the study drug on the basis 
of his/her clinical judgment and the following definitions.  The causality assessment must be 
made based on the available information and can be updated as new information becomes 
available. 
• Related: 
− The AE follows a reasonable temporal sequence from study drug administration, 
and cannot be reasonably explained by the subject’s clinical state or other factors 
(eg, disease under study, concurrent diseases, and concomitant medications). 
or 
− The AE follows a reasonable temporal sequence from study drug administration, 
and is a known reaction to the drug under study or its chemical group, or is 
predicted by known pharmacology. 
• Not Related: 
− The AE does not follow a reasonable sequence from study drug administration, or 
can be reasonably explained by the subject’s clinical state or other factors (eg, 
disease under study, concurrent diseases, and concomitant medications). 
9.4.5. 
Action Taken Regarding Study Drug(s) 
• Dose Not Changed: No change in study drug dosage was made. 
• Drug Withdrawn: The study drug was permanently stopped. 
• Dose Reduced: The dosage of study drug was reduced. 
• Drug Interrupted: The study drug was temporarily stopped. 
• Dose Increased: The dosage of study drug was increased. 
• Not Applicable: Subject died, study treatment had been completed prior to 
reaction/event, or reaction/event occurred prior to start of treatment. 
9.4.6. 
Other Action Taken for Event 
• None 
− No treatment was required. 
• Medication required 
− Prescription and/or OTC medication was required to treat the AE. 
• Hospitalization or prolongation of hospitalization required 
− Hospitalization was required or prolonged because of the AE, whether or not 
medication was required. 
• Other 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 65  
9.4.7. 
Adverse Event Outcome 
• Recovered/Resolved 
− The subject fully recovered from the AE with no residual effect observed. 
• Recovered/Resolved with Sequelae 
− The residual effects of the AE are still present and observable. 
− Document sequelae/residual effects. 
• Not Recovered/Not Resolved 
− The AE itself is still present and observable. 
• Fatal 
− Fatal should be used when death is a direct outcome of the AE. 
• Unknown 
9.5. 
Adverse Events Reporting–Procedure For Investigators 
All AEs and SAEs will be reported in the eCRF. 
The following types of events should be reported by the Investigator on the SAE form of eCRF 
or on a Serious Adverse Event Report (SAVER) Form in case of eCRF downtime within 
24 hours of awareness: 
• SAEs (see Section 9.4.2) 
• Adverse Event of Special Interest (see Section 9.3) 
− Elevation of ALT and/or AST greater than 3 × ULN 
− Elevation of ALP greater than 2 × ULN with elevation of GGT greater than 
2 × ULN 
− Elevation of total bilirubin greater than ULN 
− Elevation of direct bilirubin greater than ULN 
− Combined elevations of aminotransferases and bilirubin, either serious or 
nonserious and whether or not causally related, meeting the laboratory criteria of 
a potential Hy’s Law (ALT or AST ≥ 3 × ULN and total bilirubin > 2 × ULN) 
that may occur simultaneously or at different time points during the study   
• Overdose (see Section 9.8) 
All events (serious and nonserious) must be reported along with the Investigator’s assessment of 
the event’s seriousness, severity, and causality to the study drug.  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 state whether an autopsy was or will be performed, and include the results if available.  

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 66  
Source documents (including medical reports) will be retained at the study site and should not be 
submitted to DS for SAE reporting purpose. 
Urgent safety queries must be followed up and addressed promptly.  Follow-up information and 
response to nonurgent safety queries should be combined for reporting to provide the most 
complete data possible within each follow-up. 
Please call the local SAE Hotline (see medical monitoring plan) or your study monitor for any 
questions on SAE reporting. 
9.6. 
Notifying Regulatory Authorities, Investigators, and Institutional 
Review Board/Ethics Committee 
DS and/or designee will inform Investigators, IRBs/IECs, and regulatory authorities of any 
suspected unexpected serious adverse reactions (SUSARs) occurring in other study sites or other 
DS studies of the investigational product, as appropriate per local reporting requirements.  DS 
and/or designee will comply with any additional local safety reporting requirements. 
In the China, upon receipt of DS’s notification of SUSARs that occurred with the investigational 
product, unless delegated to DS, it is the Investigator’s responsibility to inform the IRB 
according to reporting guideline of the IRBs. 
9.7. 
Exposure In Utero During Clinical Studies 
DS must be notified of any female subject or any male subject whose female partner becomes 
pregnant while receiving or within 90 days of discontinuing the study drug.  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 and complete the EIU Reporting Form with complete pregnancy outcome 
information, including normal delivery and induced abortion.  The adverse pregnancy outcome, 
either serious or nonserious, should be reported in accordance with study procedures.  If the 
outcome of pregnancy meets the criteria for immediate classification as an SAE (ie, postpartum 
complications, spontaneous or induced abortion, stillbirth, neonatal death, or congenital 
anomaly, including that in an aborted fetus), the Investigator should follow the procedures for 
reporting SAEs outlined in Section 9.5.  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) must be 
completed with the subject’s enrollment number, initials, and date of birth, and details regarding 
the female partner should be entered in the narrative section. 
9.8. 
Overdose 
Overdose, defined as the accidental or intentional administration of any dose of pexidartinib that 
is considered both excessive and medically important.  All occurrences of overdose must be 
reported to (CRO or Sponsor) within 24 hours of awareness.  Overdose could be reported via 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 67  
[SAVER/overdose] form or eCRF.  An “excessive and medically important” overdose includes 
any overdose in which either a SAE, a non-SAE, or no AE occurs and is considered by the 
Investigator as clinically relevant, i.e. poses an actual or potential risk to the subject.  Details of 
the overdose including pexidartinib dosage, clinical course, associated AEs, and outcome must 
be captured in the Narrative form of the eCRF within electronic data capture (EDC). 
9.9. 
Clinical Laboratory Evaluations 
Clinical laboratory evaluations will be performed in local laboratory at the study visits indicated 
in the Schedule of Assessment (Table 16.3).  For clinical laboratory parameters, the reference 
range of the institution that performs the measurement will be used. 
Clinical laboratory evaluations will be performed as outlined below: 
Blood samples for analysis of the following clinical chemistry, hematologic, coagulation, and 
hormone testing will be obtained: 
Clinical Chemistry 
• 
Sodium 
• 
Total protein  
• 
Potassium 
• 
Albumin  
• 
Chloride 
• 
Triglycerides* 
• 
CO2 
• 
Total cholesterol* 
• 
Calcium 
• 
HDL-cholesterol* 
• 
Phosphorus 
• 
LDL-cholesterol* 
• 
Glucose* 
• 
Uric acid  
• 
Blood urea nitrogen 
• 
Lactate dehydrogenase 
• 
Creatinine (creatinine clearance)** 
 
CO2 = Carbon dioxide; HDL = high density lipoprotein; LDL = low density lipoprotein  
* Fasting is recommended but not required. 
**CLcr will be calculated using following formula (Cockcroft-Gault). 
CLcr = {((140 – age) × weight (kg))/(72 × serum creatinine (mg/dl))} (× 0.85 if female). 
 
Liver function Tests 
• 
Alkaline phosphatase 
• 
Total bilirubin 
• 
AST 
• 
Direct bilirubin 
• 
ALT 
• 
GGT 
ALT = alanine aminotransferase; AST = aspartate aminotransferase. ; GGT = gamma-glutamyl transpeptidase. 
 
Hematology 
• 
Red blood cell count 
• 
Hemoglobin 
• 
White blood cell count with 
differential 
• 
Hematocrit 
• 
Platelet count 
 
 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 68  
Hepatitis Panel 
Hepatitis B virus surface antigen test and hepatitis C virus antibody test 
 
Coagulation 
Prothrombin time, activated partial thromboplastin time, and INR 
 
Hormone Testing 
Females 
Males 
• FSH 
• FSH 
• LH 
• LH 
• Progesterone 
• Testosterone 
• Estradiol 
 
FSH = follicle stimulating hormone; LH = luteinizing hormone 
 
Urinalysis (dipstick and microscopic analysis) 
Urine samples will be obtained for analysis of the following parameters: 
• pH 
• Ketones/acetone  
• Protein/albumin 
• Hemoglobin/blood  
• Glucose/sugar 
• Red blood cells, white blood 
cells, epithelial cells, bacteria, 
casts, crystals  
• Nitrites 
 
Others 
Serum sample must be collected for AMA at Screening and once severe hepatotoxicity is 
observed (Section 5.4). 
9.10. 
Pregnancy Test 
For women of childbearing potential only, a serum pregnancy test (β-human chorionic 
gonadotropin) will be performed at the study visits indicated in the Schedule of Assessment 
(Table 16.3). 
For postmenopausal subjects (no childbearing potential, as indicated by an elapse of at least 
12 months after the last menstruation) or female subjects who have no possibility of pregnancy 
due to sterilization surgery, etc. the pregnancy test will not be required. 
Female subjects who have been amenorrheic for 12 months or longer due to medical reasons 
other than sterilization surgery (eg, effect of medication) will be regarded as women of 
childbearing potential and are required to undergo the pregnancy test. 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 69  
9.11. 
Vital Signs  
Vital signs, including systolic/diastolic BP, pulse rate and temperature will be measured in 
accordance with institutional standards and generally must be performed before any invasive 
procedures, eg, blood withdraws.  Vital signs and weight will be measured at the study visits 
mentioned in the Schedule of Assessment (Table 16.3).  Height will be measured at the 
Screenings visit only. 
BP and pulse rate will be measured after the subject has rested in a recumbent position for 
5 minutes or more. 
Information will be entered in the eCRF on whether or not measured, date of measurement, and 
measurement results. 
9.12. 
Electrocardiograms 
A standard 12-lead ECG will be obtained at the study visits indicated in the Schedule of 
Assessment (Table 16.3). 
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 must be reviewed, signed, and dated promptly by a qualified 
Investigator (or Investigator’s assistant, nurse practitioner) and any clinically important finding 
must be recorded on the appropriate eCRF.  The Investigator is responsible for interpreting all 
ECGs.  The results will include heart rate, RR interval, PR interval, QRS interval, QT interval, 
and QTcF interval. 
At the visits when ECGs are to be performed, subjects must be told NOT to take the morning 
dose of study drug; instead, they must be told to bring their bottle of study drug to the site and 
take the morning dose upon instruction by the site staff. 
Whether or not measurement is performed, date performed, results, and findings for the 
parameters will be recorded in the eCRF. 
9.13. 
Examinations 
The examination will be performed by a qualified individual such as the Investigator at the study 
visits indicated in the Schedule of Assessment (Table 16.3). 
Physical examination findings will be used to evaluate the following systems or areas: general 
appearance, oral cavity and neck, cardiothoracic, dermatologic, abdominal, musculoskeletal, and 
neurological. 
9.14. 
Safety Monitoring 
9.14.1. 
Safety Monitoring Committee 
A safety monitoring committee (SMC) to assess liver toxicity will be established and will be 
responsible for safeguarding the interests of study subjects, assessing the safety of the 
interventions during the study, and monitoring the overall conduct of the study.  The SMC will 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 70  
also evaluate progress of the study and other relevant information, and make recommendations 
about continuing, modifying, or stopping the study.  A separate SMC Charter will define the 
SMC membership, its roles and responsibilities, and the process for providing feedback to the 
DS. 
9.14.2. 
Hepatic Adjudication Committee 
An external hepatic adjudication committee (HEAC) is used for evaluating hepatic AEs for this 
study.  Details on the membership, responsibilities, and working procedures of the external 
HEAC will be described in the separate charter.  This additional data collection will cover a 
more in-depth, relevant medical history, diagnostic evaluation, treatment, and outcome of the 
event.  Adjudication of hepatic events will be based on evaluation of eCRFs and source 
documents, including, but not limited to, liver ultrasound, other imaging of the liver, and liver 
biopsy. 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 71  
10. 
STATISTICAL METHODS  
10.1. 
Analysis Sets 
10.1.1. 
Enrolled Analysis Set 
The enrolled analysis set will include all subjects who sign the ICF and are enrolled in the study. 
10.1.2. 
Full Analysis Set/Safety Analysis Set 
The Full analysis set (FAS)/safety analysis set will include all subjects who received at least 
1 dose of pexidartinib. 
10.1.3. 
Per-protocol Analysis Set 
Not Applicable. 
10.1.4. 
Pharmacokinetic Analysis Set 
The PK analysis set will include all subjects in the enrolled analysis set who received at least 
1 dose of pexidartinib and had measurable plasma concentrations of pexidartinib. 
10.1.5. 
Pharmacokinetic Analysis Set for Noncompartmental Analysis 
The PK analysis set for noncompartmental analysis will include all subjects in the PK analysis 
set who chose Schedule 1 in clinical sites. 
10.2. 
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 FAS, 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 do not have the Week 25 MRI assessment, for example, those who discontinue the study 
without Week 25 assessment will be considered nonresponders. 
10.3. 
General Statistical Considerations 
The data cutoff for the primary analysis will occur after all subjects have either discontinued the 
study or completed at least Week 25 assessments. 
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. 
Assessments of change from baseline to post-treatment or the ratio of post-treatment to baseline 
will include only those subjects with both baseline and post-treatment measurements.  The last 
nonmissing value of a variable taken before the first dose of study drug will be used as the 
baseline value, unless otherwise specified.  In general, missing or dropout data will not be 
imputed for the purpose of data analysis, unless otherwise specified. 
For the primary efficacy endpoint and secondary efficacy endpoints with the exception of 
duration of response, point estimate and accompanying 95% CI will be computed.  For duration 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 72  
of response, Kaplan-Meier product limit methodology will be utilized to provide estimates, 
including those for the median and 25th and 75th percentiles. 
10.4. 
Study Population Data 
Subject disposition will be summarized for subjects in the enrolled 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 FAS/safety analysis sets.  
Study drug exposure and study duration will be summarized using descriptive statistics for the 
safety analysis set. 
10.5. 
Efficacy Analyses 
10.5.1. 
Primary Efficacy Analyses 
The primary endpoint will be the proportion of subjects who achieve a CR or PR of pexidartinib 
based on RECIST 1.1 at Week 25 by centrally reviewed MRI scan (see Section 7.1).  The 
primary analysis will be completed using the FAS.  The estimate of the proportion and two-sided 
95% CI based on Clopper-Pearson method will be provided.   
10.5.2. 
Secondary Efficacy Analyses 
The secondary efficacy endpoints to be analyzed at Week 25 include: 
• Proportion of subjects who achieve a CR or PR of pexidartinib based on TVS at 
Week 25 by centrally reviewed MRI scan  
• 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 
• Mean change from baseline score in the PROMIS Physical Function Scale at the 
Week 25 
Subjects who do not provide data for the endpoint will be considered to be non-responders 
(TVS). 
The estimate of the proportion of TVS responders (ie, those who achieve a CR or PR based on 
TVS criteria) and 95% CI at Week 25 will be calculated. 
Other secondary endpoints will be also summarized with point estimates and 95% CIs. 
For the endpoint of range-of-motion, raw measurements of the affected joint will be performed 
using a goniometer and expressed in degrees (Section 7.2.1).  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.12   
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 radiological progression, the duration of response will be censored.  The 
Kaplan-Meier product limit method will be used to compute the estimate and 95%CI of the 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 73  
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. 
The percentage and 95% CI will be provided for the best overall response in the order of CR, PR, 
SD, PD, and NE. 
10.5.3. 
Exploratory Efficacy Analyses 
Exploratory efficacy endpoints to be analyzed at Week 25, with the exception of duration 
endpoints or otherwise indicated, include: 
• Results of the Surgical Assessment Questionnaire 
• Response based on the change in the SSD of the tumor on MRI 
• Duration of response based on MRI and modified RECIST 1.1-SSD 
• Mean change from baseline score in the EQ-5D-5L at Week 25 
• Summary of the long term subject status during the follow-up period 
10.5.4. 
Subgroup Analyses 
The primary endpoint will be also analyzed in the following subgroups of the FAS: 
• Subjects with disease located in large joints (shoulder, elbow, hip, or knee) 
• Subjects with disease located in the knee 
• Subjects with lower extremity tumors 
• Subjects with upper extremity tumors 
• Subjects at sites in China 
• Subjects at sites in Taiwan 
10.6. 
Pharmacodynamic/Biomarker Analyses 
Plasma will be analyzed for PDy marker, CSF-1 activity.  No formal statistical analysis of PDy 
endpoint will be performed.  Pharmacodynamic data from each assay will be listed and 
biological activity will be described.  Blood sample collected at specified time points will be 
analyzed for genes possibly related to efficacy and safety of pexidartinib. 
10.7. 
Pharmacokinetics and Exposure-Response Analyses 
10.7.1. 
Noncompartmental Pharmacokinetic Analyses 
The PK analyses will be performed on the PK analysis set.  Plasma-concentration time data for 
pexidartinib and ZAAD-1006a will be summarized by visit and time using descriptive statistics. 
Plasma-concentration data of pexidartinib and ZAAD-1006a on C1D15 (Week 3) will be 
analyzed for the PK analysis set for noncompartmental analysis using standard 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 74  
noncompartmental methods.  Primary PK parameters are area under the plasma-concentration-
time curve from time 0 h to 6 h (AUC6h), peak drug concentration (Cmax), and time of 
maximum observed concentration (Tmax).  The PK parameters of pexidartinib will be listed for 
each subject and summarized using descriptive statistics. 
10.7.2. 
Population Pharmacokinetic Analyses 
Plasma-concentration data from these samples will be analyzed using a population 
pharmacokinetic (PopPK) approach using nonlinear mixed effects modeling by pooled with 
other studies data to assess and characterize the inter- and intra-subject variability in PK and to 
identify significant covariates.  These results will be analyzed and reported separately from the 
clinical study results. 
10.7.3. 
Exposure-Response Analyses 
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. 
10.8. 
Safety Analyses 
The analyses of safety will be performed on the safety analysis set.  The summary and display of 
TEAEs will be performed. 
Terminology 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 in the eCRF. 
The incidence of TEAEs will be summarized by SOC, PT, relationship to the study drug, 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 drug. 
10.8.1. 
Adverse Event Analyses 
TEAEs are AEs that occur, having been absent before the first dose of study drug, or have 
worsened in severity after the initiating the study drug.  TEAEs will be coded using MedDRA 
and assigned grades based on NCI-CTCAE version 5.0.  The number and percentage of subjects 
reporting TEAEs will be tabulated by the worst CTCAE grade, SOC, and PT.  Similarly, the 
number and percentage of subjects reporting treatment-emergent SAEs will be tabulated, as well 
as TEAEs leading to discontinuation of study drug. 
A by-subject AE (including treatment-emergent) data listing including but not limited to 
verbatim term, SOC, PT, CTCAE grade, and relationship to study drug will be provided.  
Deaths, other SAEs, and other significant AEs, including those leading to discontinuation of 
study drug, will be listed. 
10.8.2. 
Clinical Laboratory Evaluation Analyses 
Descriptive statistics will be provided for the clinical laboratory results by scheduled time of 
evaluation for the safety analysis set, as well as for the change from baseline.  In addition, mean 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 75  
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 5.0, if 
applicable, and the grade will be presented in a by-subject data listing.  A shift table, presenting 
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. 
10.8.3. 
Vital Sign Analyses 
Descriptive statistics will be provided for the vital signs measurements by scheduled time of 
evaluation for the safety analysis set, as well as for the change from baseline.  In addition, mean 
change from baseline will be presented for the maximum and minimum post-treatment values 
and the values at the end of treatment visit. 
10.8.4. 
Electrocardiogram Analyses 
Descriptive statistics will be provided for the ECG measurements by scheduled time of 
evaluation for the safety analysis set, as well as for the change from baseline.  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. 
10.8.5. 
Physical Examination Analyses 
Physical examination data will be listed. 
10.8.6. 
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. 
10.9. 
Other Endpoint Analysis 
Not applicable. 
10.10. 
Interim Analyses 
No formal interim analysis is planned. 
10.11. 
Sample Size Determination 
Planned sample size is approximately 35 subjects.  The 95% CIs for some ORR values based on 
35 subjects are as follows: 
N 
Number of responders 
ORR 
95% CI 
35 
9 
25.7% 
(12.5%, 43.3%) 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 76  
35 
10 
28.6% 
(14.6%, 46.3%) 
35 
11 
31.4% 
(16.9%, 49.3%) 
35 
12 
34.3% 
(19.1%, 52.2%) 
35 
13 
37.1% 
(21.5%, 55.1%) 
35 
14 
40.0% 
(23.9%, 57.9%) 
35 
15 
42.9% 
(26.3%, 60.6%) 
35 
16 
45.7% 
(28.8%, 63.4%) 
 
10.12. 
Statistical Analysis Process 
The clinical study will be analyzed by DS or its agent/CRO followed by this protocol, and 
statistical analysis plan (SAP) which will demonstrate all methodologies and displays/shells for 
statistical analyses. 
The SAP will provide the statistical methods and definitions for the analysis of the efficacy and 
safety data, as well as describe the approaches to be taken for summarizing other clinical study 
information such as subject disposition, demographic and baseline characteristics, study drug 
exposure, and prior and concomitant medications.  The SAP will also include a description of 
how missing, unused, and spurious data will be addressed. 
To preserve the integrity of the statistical analysis and clinical study conclusions, the SAP will be 
finalized prior to database lock. 
All statistical analyses will be performed using SAS® Version 9.2 or higher (SAS Institute, Cary, 
NC 27513). 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 77  
11. 
DATA INTEGRITY AND QUALITY ASSURANCE 
The Investigator/investigational study sites will permit study-related monitoring, audits, IRB 
review, and regulatory inspections by providing direct access to the source data/documents.  
Direct access includes permission to examine, analyze, verify, and reproduce any records and 
reports that are important to the evaluation of a clinical study. 
11.1. 
Monitoring and Inspections 
DS/CRO monitor and regulatory authority inspectors are responsible for contacting and visiting 
the Investigator for the purpose of inspecting the facilities and, upon request, inspecting the 
various records of the study (eg, CRFs, source data, and other pertinent documents). 
The verification of adherence to the protocol; completeness, accuracy, and consistency of the 
data; and adherence to ICH GCP and local regulations on the conduct of clinical research will be 
accomplished through a combination of onsite visits by the monitor and review of study data 
remotely.  The frequency of the monitoring visit will vary based on the activity at each study 
site.  The monitor is responsible for inspecting the eCRFs and ensuring completeness of the 
study essential documents.  The monitor should have access to subject’s medical records and 
other study-related records needed to verify the entries on the eCRFs.  Detailed information is 
provided in the monitoring plan. 
The monitor will communicate any deviations from the protocol, Standard Operating Procedures, 
GCP and applicable regulations to the Investigator and will ensure that appropriate action (s) 
designed to prevent recurrence of the detected deviations is taken and documented. 
The Investigator agrees to cooperate with the monitor to ensure that any problems detected in the 
course of these monitoring visits are addressed to the satisfaction of DS and documented. 
In accordance with ICH GCP and the DS’s audit plans, this study site may be selected for audit 
by representatives from DS.  Audit of study site facilities (eg, pharmacy, drug storage areas, 
laboratories) and review of study related records will occur in order to evaluate the study conduct 
and compliance with the protocol, ICH GCP, and applicable regulatory requirements.  The 
Investigator should respond to audit findings.  In the event that a regulatory authority informs the 
Investigator that it intends to conduct an inspection, DS shall be notified immediately. 
11.2. 
Data Collection 
DS or its 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 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 78  
the information in the eCRFs and changes to the eCRFs to endorse the final submitted data for 
the subject for which he or she is responsible. 
DS 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 Trial 
Master file. 
11.3. 
Data Management 
Each subject will be identified in the database by a unique subject identifier as defined by DS. 
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 DS or DS 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 by 
rules and raised by reviewers will be generated within the EDC application.  During this review, 
subject data will be checked for consistency, completeness, and any apparent discrepancies. 
Data received from external sources such as central laboratories will be reconciled to the clinical 
database. 
SAE in the clinical database will be reconciled with the safety database.  All AEs will be coded 
using MedDRA. 
11.4. 
Study Documentation and Storage 
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). 
Records of subjects, source documents, monitoring visit logs, data correction forms, eCRFs, 
inventory of study drug, regulatory documents (eg, protocol and amendments, IRB/EC 
correspondence and approvals, approved and signed ICFs, Investigator’s Agreement, clinical 
supplies receipts, distribution and return records), and other DS correspondence pertaining to the 
study must be kept in appropriate study files at the study site (Trial Master File).  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 study site 
policy.  Prior to transfer or destruction of these records, DS must be notified in writing and be 
given the opportunity to further store such records. 
11.5. 
Record Keeping 
The Investigator and study staff are responsible for maintaining a comprehensive and centralized 
filing system (Trial Master File) of all study-related (essential) documentation.  These documents 
should be suitable for inspection at any time by representatives from DS and/or applicable 
regulatory authorities.  Essential documents contained in the Trial Master File include: 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 79  
• Subject files containing completed eCRFs, ICFs, and supporting copies of source 
documentation (if kept). 
• Study files containing the protocol with all amendments, IB, copies of relevant 
essential documents required prior to commencing a clinical study, and all 
correspondence to and from the IRB/EC and DS. 
• Records related to the study drug(s) including acknowledgment of receipt at study 
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. 
All study related essential documentation will be retained by the Investigator until at least 3 
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 3 years have lapsed 
since the formal discontinuation of clinical development of the investigational drug.  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. 
Subject's medical files should be retained in accordance with applicable legislation and in 
accordance with the maximum period of time permitted by the hospital, institution, or private 
practice. 
No study document should be destroyed without prior written agreement between DS 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 DS in writing of the new responsible person and/or 
the new location. 
 
 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 80  
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 DS/CRO.  This agreement will include the financial information agreed upon by 
the parties. 
12.2. 
Reimbursement, Indemnity, and Insurance 
DS provides insurance for study subjects to make available compensation in case of study-
related injury. 
Reimbursement, indemnity and insurance shall be addressed in a separate agreement on terms 
agreed upon by the parties. 
 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 81  
13. 
PUBLICATION AND PUBLIC DISCLOSURE OF CLINICAL 
TRIAL INFORMATIONP 
DS is committed to meeting the highest standards of publication and public disclosure of 
information arising from clinical trials sponsored by the company.  We will comply with US, 
EU, and Japanese policies for public disclosure of the clinical trial protocol and clinical trial 
results, and for sharing of clinical trial data.  We follow the principles set forward in “Good 
Publication Practice for Communicating Company-Sponsored Medical Research (GPP3)”, and 
publications will adhere to the “Recommendations for the Conduct, Reporting, Editing, and 
Publication of Scholarly Work in Medical Journals” established by the International Council of 
Medical Journal Editors (ICMJE).   
In order to ensure that we are in compliance with the public disclosure policies and the ICMJE 
recommendations, and to protect proprietary information generated during the study, all 
publications (manuscripts, abstracts, or other public disclosure) based on data generated in this 
study must be accepted, reviewed, and approved in writing by the sponsor prior to submission. 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 82  
14. 
ETHICS AND STUDY ADMINISTRATIVE INFORMATION 
14.1. 
Compliance Statement, Ethics, and Regulatory Compliance 
This study will be conducted in compliance with the protocol, the ethical principles that have 
their origin in the Declaration of Helsinki, ICH consolidated Guideline E6 for GCP 
(CPMP/ICH/135/95), and applicable regulatory requirement(s). 
14.2. 
Subject Confidentiality 
The Investigators and DS will preserve the confidentiality of all subjects taking part in the study, 
in accordance with GCP and local regulations. 
The Investigator must ensure that the subject’s anonymity is maintained.  On the eCRFs or other 
documents submitted to DS or the CRO, subjects should be identified by a unique subject 
identifier as designated by DS.  Documents that are not for submission to DS or the CRO (eg, 
signed ICF) should be kept in strict confidence by the Investigator. 
In compliance with ICH GCP Guidelines, it is required that the Investigator and institution 
permit authorized representatives of the company, of the regulatory agency(s), and the IRB/IEC 
direct access to review the subject’s original medical records for verification of study-related 
procedures and data.  The Investigator is obligated to inform the subject that his/her study-related 
records will be reviewed by the above named representatives without violating the 
confidentiality of the subject. 
14.3. 
Informed Consent  
Before a subject’s participation in the study, it is the Investigator’s responsibility to obtain freely 
given consent, in writing, from the subject after adequate explanation of the aims, methods, 
anticipated benefits, and potential hazards of the study and before any protocol-specific 
procedures or any study drugs are administered.  Subjects must be given the opportunity to ask 
questions and receive satisfactory answers to their inquiries, and must have adequate time to 
decide whether or not to participate in the study.  The written ICF should be prepared in the local 
language(s) of the potential subject population. 
In obtaining and documenting informed consent, the Investigator must comply with the 
applicable regulatory requirements, and must adhere to GCP and to the ethical principles that 
have their origin in the Declaration of Helsinki.  The consent form and any revision(s) must be 
approved by the IEC or IRB prior to being provided to potential subjects. 
The subject’s written informed consent must be documented in the subject’s medical records.  
The ICF must be signed and personally dated by the subject and by the person who conducted 
the informed consent discussion (not necessarily the Investigator).  The original signed ICF must 
be retained in accordance with institutional policy, and a copy of the signed consent form must 
be provided to the subject.  The date and time (if applicable) that informed consent was given 
must be recorded on the eCRF. 
If the subject cannot read, then according to ICH GCP Guideline (Section 4.8.9), an impartial 
witness must be present during the entire informed consent discussion.  This witness must sign 
the ICF after the subject has consented to the subject’s participation and, if possible, signed the 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 83  
ICF.  By signing the ICF, the witness attests that the information in the ICF and any other written 
information was adequately explained to and apparently understood by the subject and that 
informed consent was freely given by the subject. 
Suggested model text for the ICF for the study and any applicable subparts (genomic, PK, etc.) 
are provided in the DS’s ICF template for the Investigator to prepare the documents to be used at 
his or her study site.  Updates to applicable forms will be communicated via letter from DS. 
14.4. 
Regulatory Compliance 
The study protocol, subject ICF, the IB, any written instructions to be given to the subject, 
available safety information, subject recruitment procedures (eg, advertisements), information 
about payments and compensation available to the subjects, and documentation evidencing the 
Investigator’s qualifications should be submitted to the EC or IRB for ethical review and 
approval according to local regulations, prior to the study start.  The written approval must 
identify all documents reviewed by name and version. 
Changes in the conduct of the study or planned analysis will be documented in a protocol 
amendment and/or the SAP. 
The Sponsor will appoint a Coordinating Investigator.  Among other possible duties, the 
Coordinating Investigator will be responsible for reviewing and approving the Final Clinical 
Study Report and testifying to the accuracy of the description of the study conduct.  Because the 
Coordinating Investigator should have personal knowledge of the conduct of the study, he or she 
will normally be chosen from among those Investigators who have enrolled and treated at least 
one subject.   However, where an Investigator has special knowledge of the field or of the trial, 
the Coordinating Investigator can be chosen prior to enrolment of the first subject.   In all cases, 
the Coordinating Investigator must be chosen prior to locking the database.   
The Investigator and/or DS must submit and, where necessary, obtain approval from the EC or 
IRB for all subsequent protocol amendments and changes to the ICF.  The Investigator must 
notify the EC or IRB of deviations from the protocol or SAEs occurring at the study site and 
other AE reports received from DS or CRO, in accordance with local procedures. 
As required by local regulations, the DS’s local Regulatory Affairs group or representative to 
whom this responsibility has been delegated will ensure all legal aspects are covered, and 
approval from the appropriate regulatory bodies obtained, prior to study initiation.  If changes to 
the initial protocol and other relevant study documents are made, this representative will also 
ensure that any revised documents required for submission are submitted to regulatory 
authorities and implementation of these changes happen only after the approval by the relevant 
regulatory bodies. 
In the event of any prohibition or restriction imposed (eg, clinical hold) by an applicable 
Regulatory Authorities in any area of the world, or if the Investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of the study drug, DS 
must be informed immediately. 
In addition, the Investigator will inform DS immediately of any urgent safety measures taken by 
the Investigator to protect the study subjects against any immediate hazard, and of any 
suspected/actual serious GCP non-compliance that the Investigator becomes aware of. 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 84  
14.5. 
Protocol Deviations 
The Investigator must conduct the study in compliance with the protocol agreed to by DS and, if 
required, by the regulatory authorities, 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.  DS 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 study treatment, and had at least one 
administration of the study drug, for example, data should be collected for safety purposes, and 
the DS’s medical monitor or designee should be informed immediately. 
The Investigator must notify the IRB/IEC of deviations from the protocol in accordance with 
local procedures. 
14.6. 
Supply of New Information Affecting the Conduct of the Study 
When new information becomes available that may adversely affect the safety of subjects or the 
conduct of the study, DS will inform all Investigators involved in the clinical study, IECs/IRBs, 
and regulatory authorities of such information, and when needed, will amend the protocol and/or 
subject information. 
The Investigator must immediately inform the subject whenever new information becomes 
available that may be relevant to the subject’s consent or may influence the subject’s willingness 
to continue participation in the study.  The communication must be documented on medical 
records, for example, and it must be confirmed whether the subject is willing to remain in the 
study. 
If the subject information is revised, it must be re-approved by the IEC/IRB.  The Investigator 
must obtain written informed consent to continue participation with the revised written 
information even if subjects were already informed of the relevant information.  The Investigator 
or other responsible personnel who provided the explanations and the subject must sign and date 
the revised ICF. 
14.7. 
Protocol Amendments 
Any amendments to the study protocol that seem to be appropriate as the study progresses will 
be communicated to the Investigator by DS or the CRO.  Also, DS will ensure the timely 
submission of amendments to regulatory authorities.  
A protocol amendment will affect study conduct at all study sites in all regions of the world.  
Such amendments will be incorporated into a revised protocol document.  Changes made by such 
amendments will be documented in a Summary of Changes document.  These protocol 
amendments will undergo the same review and approval process as the original protocol.  

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 85  
A local protocol amendment will affect study conduct at a particular study site(s) and/or in a 
particular region/country.  DS approval of local amendments will be clearly documented. 
A protocol amendment may be implemented after it has been approved by the IRB/IEC and by 
regulatory authorities where appropriate, unless immediate implementation of the change is 
necessary for subject safety. 
14.8. 
Study Termination 
The study may be terminated at any time by the IRB, DS, or regulatory agencies as part of their 
duty is to ensure that the research subjects are protected. 
DS reserves the right to temporarily suspend or prematurely discontinue this study either at a 
single study site or at all study sites at any time for reasons including, but not limited to, safety or 
ethical issues or severe noncompliance.  If DS determines such action is needed, then DS will 
discuss this with the Investigator (including the reasons for taking such action) at that time.  
When feasible, DS will provide prior notification to the Investigator of the impending action 
prior to its taking effect. 
DS will promptly inform all other Investigators and/or study sites conducting the study if the 
study is suspended or terminated for safety reasons, and will also inform the regulatory 
authorities of the suspension or termination of the study and the reasons for the action.  If 
required by applicable regulations, the Investigator must inform the IRB promptly and provide 
the reasons for the suspension or termination. 
If the study is prematurely discontinued, all study data must be returned to DS.  In addition, 
arrangements will be made for return of all unused study drugs in accordance with the DS’s 
applicable procedures for the study. 
Financial compensation to the Investigators and/or institutions will be in accordance with the 
agreement established between the Investigator and DS. 
 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 86  
15. 
REFERENCES 
1. Mastboom MJL, Verspoor FGM, Gelderblom H, et al. Limb amputation after multiple 
treatments of tenosynovial giant cell tumor: series of 4 Dutch cases. Case Rep Orthop 
2017. 2017:7402570. 
2. Ehrenstein V, Andersen SL, Qazi I, et al. Tenosynovial giant cell tumor: incidence, 
prevalence, patient characteristics, and recurrence. A registry-based cohort study in 
Denmark. J Rheum. 2017; 44(10):1476-83. 
3. Myers BW, Masi AT. Pigmented villonodular synovitis and tenosynovitis: a clinical 
epidemiologic study of 166 cases and literature review. Medicine. 1980; 59(3):223-38. 
4. US Census Bureau. Projected Population by Single Year of Age, Sex, Race, and Hispanic 
Origin for the United States: 2016 to 2060. Available at: 
https://www.census.gov/data/datasets/2017/demo/popproj/2017-popproj.html. Accessed 
March 25, 2019.  
5. Mastboom MJL, Verspoor FGM, Verschoor AJ, et al. Higher incidence rates than 
previously known in tenosynovial giant cell tumors. A nationwide study in The 
Netherlands. Acta Orthopaedica. 2017; 88(6):688-94. 
6. Molena B, Sfriso P, Oliviero F, et al. Synovial colony-stimulating factor-1 mRNA 
expression in diffuse pigmented villonodular synovitis. Clin Exp Rheumatol. 2011; 
29:547-50. 
7. Palmerini E, Staals EL, Maki RG, et al. Tenosynovial giant cell tumor/pigmented 
villonodular synovitis: outcome of 294 patients before the era of kinase inhibitors. Eur J 
Cancer. 2015; 51:210-17. 
8. Brahmi M, Vinceneux A, Cassier P. Current systemic treatment options for tenosynovial 
giant cell Tumor/pigmented villonodular Synovitis: targeting the CSF1/CSF1R Axis. 
Curr Treat Options in Oncol. 2016; 17(10):1-9. 
9. PEXIDARTINIB Investigator’s Brochure. Version 10.0, 19 DEC 2018. 
10. 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. 
11. Peterfy CG, 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. 
12. Gerhardt JJ, Cocchiarella L, Lea RD. The Practical Guide to Range of Motion 
Assessment. Chicago, IL. Amer Med Assoc Press; 2002. 
13. 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. 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 87  
16. 
APPENDICES 
16.1. 
List of Common CYP3A Inhibitors and Inducers  
 
Strong Inhibitors 
Moderate inhibitors 
Strong Inducers 
• Boceprevir 
• Aprepitant 
• Carbamazepine 
• Clarithromycin 
• Ciprofloxacin 
• Enzalutamide 
• Cobicistat 
• Conivaptan 
• Mitotane 
• Danoprevir and ritonavir  
• Crizotinib 
• Phenytoin 
• Elvitegravir and ritonavir 
• Cyclosporine 
• Rifampin 
• Grapefruit juice 
• Diltiazem 
• St. John’s wort 
• Idelalisib 
• Dronedarone 
• Apalutamide 
• Indinavir and ritonavir 
• Erythromycin 
 
• Itraconazole 
• Fluconazole 
 
• Ketoconazole 
• Fluvoxamine 
 
• Lopinavir and ritonavir 
• Imatinib 
 
• Nefazodone 
• Tofisopam 
 
• Nelfinavir 
• Verapamil 
 
• Paritaprevir and ritonavir 
and (ombitasvir and/or 
dasabuvir) 
 
 
• Posaconazole 
 
 
• Ritonavir 
 
 
• Saquinavir and ritonavir 
 
 
• Telaprevir 
 
 
• Telithromycin 
 
 
• Tipranavir and ritonavir 
 
 
• Troleandomycin 
 
 
• Voriconazole 
 
 
Source: Food and Drug Administration (FDA) web site: Drug Development and Drug Interactions: Table of 
Substrates, Inhibitors and Inducers (3 Dec 2019). Available from: https://www.fda.gov/drugs/drug-interactions-
labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers 
 
 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 92  
16.3. 
EuroQol Five-Dimensional Descriptive System 
 
 
 
 
Health Questionnaire 
 
 
English version 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 
English © 2009 EuroQol Group. EQ-5D™ is a trade mark of the EuroQol Group

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 93  
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 
English © 2009 EuroQol Group. EQ-5D™ is a trade mark of the EuroQol Group 
 

 
 
 
Protocol PL3397-A-A303 
Version 4.0, 29JAN2021 
Proprietary and Confidential 
Page 95  
16.4. 
Surgical Assessment Questionnaire 
Table 16.1: 
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 
 

 
Proprietary and Confidential 
Page 96 
16.5. 
Long Term Follow-up Questionnaire 
Table 16.2: 
Sample Long Term Follow-up Questionnaire 
Question 
Response 
Did TGCT worsen or recur after study 
treatment discontinuation? 
・ No 
・ Yes  
A) Symptoms worse or recurred:  Yes / No / Unknown 
B) Functional Impairment worse or recurred:  Yes / No / Unknown 
C) Radiographic progression:  Yes / No / Unknown 
・ Other, describe (lost to follow-up, death, etc): __________ 
Was/were MRI performed >3 months after 
study treatment discontinuation? 
・ No 
・ Unknown 
・ Yes: Date of assessment:  _____________,   
Result:  CR, PR, SD, PD, NE 
(repeating to enter each MRI until PD or other TGCT intervention) 
Was there surgery for TGCT >3 months after 
study treatment discontinuation? 
・ No 
・ Yes: Date of first surgery after discontinuation:  _______, 
Reason for surgery:  ___ Resection___ Other, describe:  _______ 
Was systemic anti-tumor therapy for TGCT 
given after study treatment discontinuation? 
・ No 
・ Yes: Date of first treatment:  _______, Agent:  ________________ 
Was radiotherapy for TGCT given after study 
treatment discontinuation? 
・ No 
・ Yes: Date of radiotherapy:  _____________ 
CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease; NE = not evaluable. 
 
 

 
Proprietary and Confidential 
Page 97 
16.6. 
Schedule of Assessment 
Table 16.3: 
Schedule of Assessment 
Schedule of Assessment (Completion of study at Week 25, day before C7D1) 
Procedure 
Day 
-42 to 
-1a 
C1D1 
C1D8 
± 2d 
C1D15 
± 2d 
C1D22 
± 2d 
C2D1 
± 2d 
C2D8 
± 2d 
C2D15 
± 2d 
C2D22 
± 2d 
C3D1 
± 7d 
C3D15 
± 7d 
C4D1 
± 7d 
C5D1 
± 7d 
C6D1 
± 7d 
C7D1b 
± 7d 
Post Tc 
± 7d  
End St/Ear. 
Term. ± 7d 
Long term 
follow-up 
± 14d 
Screen a  
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 d 
Every 6 
month 
after End 
St/Ear. 
Term 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics & 
medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height, weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xe 
Xe 
 
 
Vital signs, incl. 
BP, pulse rate, 
temperaturef 
X 
X 
 
X 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
Physical 
examinationg 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
X 
 
 
ECGh 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
Chemistry, 
hematology  
X 
X 
 
Xi 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
Liver tests j 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Urinalysis 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
 
 
Hepatitis panel 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation tests k 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
Hormone testingl 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
PROMIS Physical 
Function Scale  
X 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
X 
 
 
EQ-5D-5L 
X 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
X 
 
 
MRI of the 
affected jointm 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
 
Photographic 
documentation of 
tumor 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
 

 
Proprietary and Confidential 
Page 98 
Procedure 
Day 
-42 to 
-1a 
C1D1 
C1D8 
± 2d 
C1D15 
± 2d 
C1D22 
± 2d 
C2D1 
± 2d 
C2D8 
± 2d 
C2D15 
± 2d 
C2D22 
± 2d 
C3D1 
± 7d 
C3D15 
± 7d 
C4D1 
± 7d 
C5D1 
± 7d 
C6D1 
± 7d 
C7D1b 
± 7d 
Post Tc 
± 7d  
End St/Ear. 
Term. ± 7d 
Long term 
follow-up 
± 14d 
Screen a  
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 d 
Every 6 
month 
after End 
St/Ear. 
Term 
Range of motion 
assessment n 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
 
 
Serum pregnancy 
test 
Xo 
 
 
 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
PK, PDy blood 
samplingp 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
Surgical 
Assessment 
Questionnaire 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
Analgesic use 
assessment  
Xq 
X 
 
X 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
Dispense study Tx 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
 
 
 
Study drug dosing 
at siter 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
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 
 
Adverse events s 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Collection of 
surgical datat 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
AMAu 
X 
X 
 
 
Subject statusv 
 
 
 
X 
 
AE = adverse event; ALT = alanine aminotransferase; AMA = Anti-mitochondrial antibody; AST = aspartate aminotransferase; BP = blood pressure; C = cycle; D/d = Day; ECG = electrocardiogram; End 
St./Ear. Term. = End-of-Study/Early Termination; FSH = follicle-stimulating hormone; GGT = gamma-glutamyl transferase; incl. = including; LD = last dose; MRI = magnetic resonance imaging; PDy = 
pharmacodynamic; PK = pharmacokinetic; PROMIS = Patient-reported Outcomes Measurement Information System; Pt = patient; TGCT = tenosynovial giant cell tumor; Tx = treatment. 
a  
Procedures performed as part of patient care within the 42-day period before the first dose of study drug 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. 
b 
The Cycle 7, Day 1 visit (C7D1) applies to patients who are continuing or not continuing the study. 
c 
Patients who exit the study with radiologic disease progression will undergo their last study evaluation 28 ± 7 days after their last dose of study drug and before any new TGCT therapy, including 
surgery, whichever occurs first.  Any planned new TGCT therapy, including the type of surgical procedure, will be recorded.  Patients who withdraw from the study with radiologic progression do not 
undergo an End of Study/Early Termination MRI. 

 
Proprietary and Confidential 
Page 99 
d 
Patients who end their study participation with no radiologic disease progression will undergo post-treatment procedures 28 ± 7 days after their last dose of study drug and a final MRI 12 weeks ± 7 days 
after their last dose of study drug or before any new TGCT therapy, including surgery, whichever occurs first. The latter MRI need not be performed if new TGCT therapy starts within 4 weeks of the 
Post-treatment visit.  Before or at the End-of-Study/Early Termination visit, plans for any new TGCT therapy will be obtained. 
e 
Weight only. 
f 
Vital signs should be performed before any invasive procedures are carried out on the same day. 
g 
In the event of early withdrawal, a physical examination is performed at the Post-treatment visit. 
h 
A standard 12-lead ECG is performed prior to dosing.  Patients should be told not to take their morning dose of study drug at home on days when an ECG is performed; instead, they should bring their 
study drug bottle to the site and take their morning dose upon site instruction. At the C1D1 and C1D15 visits only, the ECG is performed before and 2 hours after dosing. The ECG before dosing should 
be performed before any invasive procedures are carried out on the same day. The 2 hour post-dose ECG should begin within ± 10 minutes of the 2 hour post-dose time point. 
i 
Hematology only. 
j 
Alkaline phosphatase, ALT, AST, total and direct bilirubin, and GGT should be assessed at Screening, weekly for the first 8 weeks (until C3D1) and every 2 weeks for the next month (C3D15 and 
C4D1), then every month thereafter.  
k 
Patients receiving concomitant warfarin should have their anti-coagulation status carefully monitored for any necessary dose adjustments (see Section 5.6). 
l 
Women who are not using hormonal contraception must 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 must be tested for levels of LH, FSH, and testosterone. Men whose testosterone level is below baseline at the last study visit must be followed until their 
level has stabilized or returned to baseline. 
m MRI of the affected joint should be performed within 56 days prior to C1D1. The Investigator may request a centrally read blinded MRI to confirm progression, eg, if a subject’s mid-study clinical 
profile or local radiologic assessment indicates progression. 
n 
A range of motion assessment in the affected joint will be performed by a qualified assessor. 
o 
Women of childbearing potential must have a serum pregnancy test within 14 days of enrollment (or, where different regulations apply, within 72 hours of enrollment).  (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). 
p 
Details on blood sampling are found in Table 8.1  (PK) and Section 8.1 (PDy). 
q 
A diary of analgesic use must be kept for the 7-day period before the first dose of study drug. 
r 
The morning dose of study drug should be administered at the site on the days indicated. 
s 
After the patient provides signed informed consent; AEs are monitored throughout the study via safety assessments, observation, and patient reporting (see Section 9.5). 
t 
If surgical resection of the tumor is performed within the designated time period (28 days for Post-Tx and 12 weeks for End St/Ear Term) after the last dose of study drug, details of the surgery and its 
outcome should be obtained. 
u     Serum sample should be collected for AMA at screening and once severe hepatotoxicity is observed (Section 5.4). 
v 
Subject status will be collected by telephone contact every 6 months from each subject who consent. 
 

 
Proprietary and Confidential 
Page 100 
Schedule of Assessment (Study drug continuation after Week 25) 
Procedure 
C10+D1 
± 7da 
Post Tx  
± 7b 
End St/Ear. Term. ± 7d 
Long term follow-up 
± 14d 
Week 37+ 
LD+28d 
LD+12 Week 
/ < new Tx c 
Every 6 month after End 
St/Ear. Term 
Weight 
 
X 
 
 
Vital signs, incl. BP, pulse rate, temperatured 
X 
X 
 
 
Physical examinatione 
X 
X 
 
 
ECGf 
 
X 
 
 
Chemistry, hematology  
X 
X 
 
 
Liver tests g 
X 
X 
 
 
Urinalysis 
 
X 
 
 
Coagulation tests h 
 
X 
 
 
Hormone testingi  
 
X 
 
 
PROMIS Physical Function Scale 
X 
X 
 
 
EQ-5D-5L 
X 
X 
 
 
MRI of the affected jointj 
X 
X 
X 
 
Photographic documentation of tumor 
X 
X 
X 
 
Range of motion assessment k 
X 
X 
 
 
Serum pregnancy test 
X 
X 
X 
 
Surgical Assessment Questionnaire 
 
X 
 
 
Analgesic use assessment  
X 
X 
 
 
Dispense study Tx 
X 
 
 
 
Tx compliance assessment 
X 
 
 
 
Concomitant medications 
X 
X 
X 
 
Adverse events 
X 
X 
X 
 
Collection of surgical datal 
 
X 
X 
 
AMAm 
X 
 
 
Subject statusn 
 
 
X 

 
Proprietary and Confidential 
Page 101 
AE = adverse event; ALT = alanine aminotransferase; AMA = Anti-mitochondrial antibody; AST = aspartate aminotransferase; BP = blood pressure; C = cycle; D/d = Day; ECG = electrocardiogram; 
End St./Ear. Term. = End-of-Study/Early Termination; FSH = follicle-stimulating hormone; incl. = including; LD = last dose; MRI = magnetic resonance imaging; PROMIS = Patient-reported 
Outcomes Measurement Information System; Pt = patient; TCGT = tenosynovial giant cell tumor; Tx = treatment. 
a 
The procedures are performed at C10+D1 and every 12 weeks thereafter (eg, C13, C16, C19). 
b 
Patients who exit the study with radiological disease progression will undergo their last study evaluation 28 ± 7 days after their last dose of study drug and before any new TGCT therapy, including 
surgery, whichever occurs first.  Any planned new TGCT therapy, including the type of surgical procedure, will be recorded.  Patients who withdraw from the study with radiological progression do 
not undergo an End of Study/Early Termination MRI. 
c 
Patients who end their study participation with no radiological disease progression will undergo post-treatment procedures 28 ± 7 days after their last dose of study drug and a final MRI 12 weeks ± 
7 days after their last dose of study drug or before any new TGCT therapy, including surgery, whichever occurs first. The latter MRI need not be performed if new TGCT therapy starts within 
4 weeks of the Post-treatment visit.  Before or at the End-of-Study/Early Termination visit, plans for any new TGCT therapy will be obtained.  
d 
Vital signs should be performed before any invasive procedures are carried out on the same day. 
e 
In the event of early withdrawal, a physical examination is performed at the Post-treatment visit. 
f 
A standard 12-lead ECG is performed prior to dosing.  Patients should be told not to take their morning dose of study drug at home on days when an ECG is performed; instead, they should bring 
their study drug bottle to the site and take their morning dose upon site instruction.  
g 
Alkaline phosphatase, ALT, AST, total and direct bilirubin, and GGT should be assessed on Day 1 of every 3 cycles thereafter.  
h 
Patients receiving concomitant warfarin should have their anti-coagulation status carefully monitored for any necessary dose adjustments (see Section 5.6). 
i 
Women who are not using hormonal contraception must 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.   
j 
The Investigator may request a centrally read blinded MRI to confirm progression, eg, if asubject’s mid-study clinical profile or local radiologic assessment indicates progression. 
k 
A range of motion assessment in the affected joint will be performed by a qualified assessor. 
l 
If surgical resection of the tumor is performed within the designated time period (28 days for Post-Tx and 12 weeks for End St/Ear Term) after the last dose of study drug, details of the surgery and 
its outcome should be obtained. 
m Serum sample should be collected for AMA once severe hepatotoxicity is observed (Section 5.4). 
n 
Subject status will be collected by telephone contact every 6 months from each subject who consent.