A Phase 2, Multicenter, Two-Part, Open-Label Study of Pexidartinib in Adult Subjects With Tenosynovial Giant Cell Tumor in Japan
Phase: PHASE2
Conditions: Tenosynovial Giant Cell Tumor
Sponsor: Daiichi Sankyo Co., Ltd.

 
 
 
CLINICAL STUDY PROTOCOL 
 
A PHASE 2, MULTICENTER, TWO-PART, OPEN-
LABEL STUDY OF PEXIDARTINIB IN ADULT 
SUBJECTS WITH TENOSYNOVIAL GIANT CELL 
TUMOR IN JAPAN 
 
PROTOCOL NUMBER: PL3397-A-J304 
 
 
 
 
VERSION 4.0, 27 Aug 2024 
 
DAIICHI SANKYO, CO. LTD 
3-5-1, Nihonbashi-honcho, Chuo-ku 
Tokyo, 103-8426, Japan 
 
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. 
 

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INVESTIGATOR AGREEMENT 
A PHASE 2, MULTICENTER, TWO-PART, OPEN-LABEL STUDY OF 
PEXIDARTINIB IN ADULT SUBJECTS WITH TENOSYNOVIAL GIANT CELL 
TUMOR IN JAPAN 
Sponsor Approval: 
This clinical study protocol has been reviewed and approved by the Daiichi Sankyo, Co. Ltd 
representative listed below. 
 
 
Print Name 
Signature 
Clinical Science Department 
 
Title 
Date (DD MMM YYYY) 
Investigator’s Signature: 
I have fully discussed the objectives of this study and the contents of this protocol with the 
Sponsor’s representative. 
I understand that information contained in or pertaining to this protocol is confidential and 
should not be disclosed, other than to those directly involved in the execution or the ethical 
review of the study, without written authorization from the Sponsor.  It is, however, 
permissible to provide information to a subject in order to obtain consent. 
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) Guideline for Good Clinical Practice (ICH E6[R2]), 
which has its foundations in the Declaration of Helsinki, and applicable regional regulatory 
requirements. 
I agree to make available to Sponsor personnel, their representatives and relevant regulatory 
authorities, my subjects’ study records in order to verify the data that I have entered into the 
case report forms.  I am aware of my responsibilities as a Principal Investigator as provided 
by the Sponsor. 
I understand that the Sponsor may decide to suspend or prematurely terminate the study at 
any time for whatever reason; such a decision will be communicated to me in writing. 
Conversely, should I decide to withdraw from execution of the study, I will communicate my 
intention immediately in writing to the Sponsor. 
 
 
Print Name 
Signature 
 
 
Title 
Date (DD MMM YYYY) 
PPD
PPD

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DOCUMENT HISTORY 
Version Number 
Version Date 
4.0 
27 Aug 2024 
3.0 
10 Feb 2021 
2.0 
07 Oct 2020 
1.0 
08 Sep 2020 

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SUMMARY OF CHANGES 
Please refer to the comparison document for protocol Version 3.0 (dated 10 Feb 2021) vs. 
protocol Version 4.0 (dated 27 Aug 2024) for actual changes in text.  The summary of changes 
below is a top-line summary of major changes in the current PL3397-A-J304 clinical study 
protocol (Version 4.0) by section. 
Amendment Rationale: 
This protocol amendment is due to the Sponsor's decision to halting enrollment of new 
participants and not proceed with Part 2.  Depending on this decision, the end of study duration 
and the assessment schedule will be changed. 
Section # and Title 
Description of Change 
Brief Rationale 
1.1. Protocol 
Synopsis 
Study Design 
In June 2024, the sponsor decided to halt the enrollment of 
participants after 9 subjects were enrolled in Part 1 and not 
proceed with Part 2.  The safety, PK, and efficacy in Part 2 will 
not be assessed. 
 
Study Duration 
Enrollment was planned to occur over approximately 17 months 
for Part 1 and Part 2, with treatment and follow-up projected to 
continue for approximately 27 months after the last subject was 
enrolled in Part 2. 
Anticipated total duration of the study was planned to be 
approximately 44 months. 
 
In June 2024, the sponsor decided to halt the enrollment of 
participants after 9 subjects were enrolled in Part 1. For the 
subjects receiving the study drug in Part 1 and wish to continue 
receiving it from Protocol Version 4.0 onwards, the study drug 
administration will be allowed to continue until February 2026.  
The study will continue until the overall EOS is reached. 
Due to changes in 
development plans. 
1.2. Study Schema 
In June 2024, the sponsor decided to halt the enrollment of 
participants after 9 subjects were enrolled in Part 1 and not 
proceed with Part 2.  
Due to changes in 
development plans. 
1.3. Schedule of 
Assessments 
Table 1.1  
Table 1.3 
Table 1.1 and Table 1.3 
(Added asterisks for each assessment item below.) 
Biomarker blood sample, Tumor biopsy sample, Range of motion, 
PROMIS Physical Function Scale, BPI Worst Pain NRS, EQ-5D-
5L, Surgical Assessment Questionnaire, Analgesic use 
assessment, Photographic documentation of tumor, Log-term 
follow-up questionnaire 
 
(Added a double asterisk for an assessment item below.) 
MRI of the affected joint 
 
In order to reduce 
the burden on 
subjects, non-
essential efficacy 
assessment items 
will be reduced or 
halted in Part 1. 

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Section # and Title 
Description of Change 
Brief Rationale 
Footnote 
*: Not be performed from Protocol Version 4.0 onwards. 
**: From Protocol Version 4.0 onwards, only local review will be 
performed, and central review will not be performed. 
 
Table 1.3 
(Added a triple asterisk for an assessment item below.) 
MRI of the affected joint 
 
Footnote 
***: MRI are performed every 24 weeks from Protocol Version 
4.0 onwards. 
3. OBJECTIVES, 
OUTCOME 
MEASURES, AND 
ENDPOINTS 
Table 3.1 
Exploratory Objectives 
Part 1: To evaluate the efficacy of pexidartinib 
Outcome Measure, Endpoints 
The outcome measures planned for assessing the efficacy of the 
primary objectives, the secondary objectives, and the exploratory 
objectives 
Category 
Efficacy 
Due to changes in 
development plans. 
4.1.1. Design 
Overview 
In June 2024, the sponsor decided to halt the enrollment of 
participants after 9 subjects were enrolled in Part 1 and not 
proceed with Part 2. 
Due to changes in 
development plans. 
4.1.4. Duration 
Overall Study 
Duration 
Enrollment was planned to occur over approximately 17 months 
for Part 1 and Part 2, with treatment and follow-up projected to 
continue for approximately 27 months after the last subject was 
enrolled in Part 2. 
Anticipated total duration of the study was planned to be 
approximately 44 months. 
 
In June 2024, the sponsor decided to halt the enrollment of 
participants after 9 subjects were enrolled in Part 1. For the 
subjects receiving the study drug in Part 1 and wish to continue 
receiving it from Protocol Version 4.0 onwards, the study drug 
administration will be allowed to continue until February 2026. 
Due to changes in 
development plans. 
6.7. Prior and 
Concomitant 
Medications 
Prohibited 
Therapies/Products 
Joint aspiration* 
*: Not to be prohibited from Protocol Version 4.0 onwards. 
In order to reduce 
the burden on 
subjects. 
7.1. Discontinuation 
of Study Drug 
During the study, if a subject experiences radiological progression 
documented by central or local 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 Medical 
Monitor or designee to allow the subject to remain in the study. 
Due to completion 
of tumor 
assessment by 
central review. 

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Section # and Title 
Description of Change 
Brief Rationale 
8.3. Efficacy 
Assessments 
Tumor Imaging 
All MRI scans up to Protocol Version 3.0 will be centrally read, 
while MRI scans from Protocol Version 4.0 onwards will not be 
centrally read.  Local evaluation of radiological response, 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 up to Protocol 
Version 3.0 will be read centrally. 
 
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.  While progression 
status will be assessed only by local read from Protocol Version 
4.0 onwards.  The details for MRI scan read are outlined in the 
MRI Procedure Manual. 
Non-essential 
efficacy assessment 
items including the 
central MRI 
assessment will be 
reduced or halted in 
Part 1. 
8.6.1. Biomarker 
Analysis for 
Pharmacodynamics 
(Added an asterisk for a section title) 
*: Sample collection will not be performed from Protocol Version 
4.0 onwards. 
Due to reducing the 
burden on subjects. 
8.6.2. Biomarker 
Analysis for Subject 
Characterization 
(Added an asterisk for a section title) 
*: Sample collection will not be performed from Protocol Version 
4.0 onwards. 
Due to reducing the 
burden on subjects. 
9.1. General 
Statistical 
Considerations 
For all analysis, the Part 1 data at the end of Part 1 will be used. 
The all analysis including the efficacy analysis of the subjects in 
Part 1 was originally planned to be performed at the end of Part 2.  
However, the sponsor decided not to proceed with Part 2. 
Depending on this decision, the Part 1 data will be analyzed at the 
end of Part 1, and the efficacy analysis will be performed as the 
exploratory analysis. 
Due to changes in 
development plans. 
9.2. Statistical 
Hypothesis 
In June 2024, the sponsor decided not to proceed with Part 2.  
Therefore, the statistical hypothesis for Part 2 will not be 
confirmed. 
Due to changes in 
development plans. 
9.5.1. Efficacy 
Analyses 
In June 2024, the sponsor decided not to proceed with Part 2.  
Therefore, the primary efficacy analysis and the secondary 
efficacy analysis will be performed as the exploratory efficacy 
analysis using Part 1 data. 
Due to changes in 
development plans. 
 

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TABLE OF CONTENTS 
INVESTIGATOR AGREEMENT...................................................................................................2 
DOCUMENT HISTORY.................................................................................................................3 
SUMMARY OF CHANGES ...........................................................................................................4 
1. 
PROTOCOL SUMMARY ..............................................................................................13 
1.1. 
Protocol Synopsis ............................................................................................................13 
1.2. 
Study Schema ..................................................................................................................20 
1.3. 
Schedule of Assessments .................................................................................................21 
2. 
INTRODUCTION ...........................................................................................................32 
2.1. 
Background ......................................................................................................................32 
2.1.1. 
Tenosynovial giant cell tumor .........................................................................................32 
2.1.2. 
Pexidartinib (PLX3397) ..................................................................................................33 
2.2. 
Study Rationale ...............................................................................................................33 
2.2.1. 
Study Rationale ...............................................................................................................34 
2.3. 
Benefit and Risk Assessment ..........................................................................................34 
3. 
OBJECTIVES, OUTCOME MEASURES, AND ENDPOINTS ....................................35 
3.1. 
Rationale for Selection of Primary and Key Secondary Endpoints ................................39 
4. 
STUDY DESIGN ............................................................................................................40 
4.1. 
Overall Design .................................................................................................................40 
4.1.1. 
Design Overview .............................................................................................................40 
4.1.2. 
End of Study ....................................................................................................................41 
4.1.3. 
Dose Regimen .................................................................................................................42 
4.1.4. 
Duration ...........................................................................................................................42 
4.2. 
Rationale for Study Design .............................................................................................43 
4.3. 
Justification for Dose .......................................................................................................43 
5. 
STUDY POPULATION ..................................................................................................43 
5.1. 
Inclusion Criteria .............................................................................................................43 
5.2. 
Exclusion Criteria ............................................................................................................44 
5.3. 
Screening Failures, Rescreening, and Subject Replacement ...........................................46 
6. 
STUDY TREATMENT(S) ..............................................................................................47 
6.1. 
Study Drug(s) Description ...............................................................................................47 
6.2. 
Preparation, Handling, Storage, and Accountability for Study Drug(s) ..........................47 

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6.3. 
Measure to Minimize Bias: Randomization and Blinding ..............................................49 
6.4. 
Treatment Compliance ....................................................................................................49 
6.5. 
Guidelines for Dose Modification ...................................................................................49 
6.6. 
Dosage Modification for Renal Impairment ....................................................................52 
6.7. 
Prior and Concomitant Medications ................................................................................53 
7. 
STUDY DRUG DISCONTINUATION AND DISCONTINUATION FROM 
THE STUDY ...................................................................................................................55 
7.1. 
Discontinuation of Study Drug ........................................................................................55 
7.2. 
Subject Withdrawal/Discontinuation from the Study ......................................................56 
7.3. 
Lost to Follow-up ............................................................................................................58 
8. 
STUDY PROCEDURES .................................................................................................59 
8.1. 
Eligibility Assessment .....................................................................................................59 
8.2. 
Enrollment .......................................................................................................................60 
8.3. 
Efficacy Assessments ......................................................................................................60 
8.4. 
Safety Assessments .........................................................................................................64 
8.4.1. 
Adverse Event .................................................................................................................64 
8.4.1.1. Serious Adverse Events Reporting ..................................................................................65 
8.4.1.2. Adverse Events of Special Interest ..................................................................................66 
8.4.2. 
Pregnancy ........................................................................................................................67 
8.4.3. 
Dose-Limiting Toxicities .................................................................................................68 
8.4.4. 
Clinical Laboratory Evaluations ......................................................................................69 
8.4.5. 
Other Safety .....................................................................................................................70 
8.5. 
Pharmacokinetic (PK) Assessment(s) .............................................................................71 
8.6. 
Biomarker Assessments ...................................................................................................72 
8.6.1. 
Biomarker Analysis for Pharmacodynamics ...................................................................72 
8.6.2. 
Biomarker Analysis for Subject Characterization ...........................................................72 
8.6.3. 
Biomarker Analysis Potential for In Vitro Diagnostics / Companion Diagnostics .........73 
8.6.4. 
Additional Biomarker Assessments ................................................................................73 
8.6.5. 
Pharmacogenomic (Inherited Genetic) Analysis .............................................................73 
8.6.5.1. Banking of Specimens for Inherited Genetic Analysis ...................................................73 
9. 
STATISTICAL CONSIDERATIONS ............................................................................75 
9.1. 
General Statistical Considerations ...................................................................................75 
9.2. 
Statistical Hypothesis ......................................................................................................75 

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9.3. 
Sample Size Determination .............................................................................................76 
9.4. 
Population for Analysis Sets ...........................................................................................76 
9.5. 
Statistical Analysis ..........................................................................................................77 
9.5.1. 
Efficacy Analyses ............................................................................................................77 
9.5.1.1. Primary Efficacy Analyses ..............................................................................................77 
9.5.1.2. Secondary Efficacy Analyses ..........................................................................................77 
9.5.1.3. Exploratory Analyses ......................................................................................................78 
9.5.1.4. Multiplicity Adjustment ..................................................................................................79 
9.5.2. 
Safety Analyses ...............................................................................................................79 
9.5.3. 
HEOR Analysis ...............................................................................................................80 
9.5.4. 
Other Analyses ................................................................................................................80 
9.6. 
Interim Analyses ..............................................................................................................81 
10. 
APPENDICES - SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ......................................................................................................82 
10.1. 
Appendix 1 Regulatory and Ethical Considerations .......................................................82 
10.1.1. Regulatory Compliance ...................................................................................................82 
10.1.2. Informed Consent ............................................................................................................83 
10.1.3. Subject Confidentiality ....................................................................................................84 
10.1.4. Data Integrity and Quality Assurance .............................................................................84 
10.1.5. Committees ......................................................................................................................85 
10.1.6. Study Documentation and Storage ..................................................................................86 
10.1.7. Finances ...........................................................................................................................87 
10.1.8. Publication, Public Disclosure Policy, and Data Sharing ................................................87 
10.1.9. Protocol Deviations .........................................................................................................88 
10.1.10. Study and Site Closure ....................................................................................................88 
10.2. 
Appendix 2: Local Laboratory ........................................................................................88 
10.3. 
Appendix 3: Reference Standards ...................................................................................90 
10.3.1. Cockcroft-Gault Equation ...............................................................................................90 
10.3.2. New York Heart Association (NYHA) ...........................................................................90 
10.3.3. CYP3A4 Inhibitors and Inducers ....................................................................................91 
10.3.4. Highly Effective Contraception .......................................................................................92 
10.4. 
Appendix 4: General Information - Adverse Events .......................................................92 
10.4.1. Definition of Adverse Event ............................................................................................92 

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10.4.2. Serious Adverse Event ....................................................................................................93 
10.4.3. Grade Assessment ...........................................................................................................94 
10.4.4. Causality Assessment ......................................................................................................94 
10.4.5. Action Taken Regarding Study Drug(s) ..........................................................................95 
10.4.6. Other Action Taken for Event .........................................................................................95 
10.4.7. Adverse Event Outcome ..................................................................................................95 
10.5. 
Appendix 5: Instructions Related to Severe Acute Respiratory Syndrome 
Coronavirus 2 ..................................................................................................................96 
10.6. 
Appendix 6 Key Data Analysis Requirements ................................................................97 
10.7. 
Appendix 7 Patient Reported Outcomes, Surgical Assessment Questionnaire, 
and Long-Term Follow-up Questionnaire .......................................................................98 
10.7.1. Surgical Assessment Questionnaire ................................................................................98 
10.7.2. Long-Term Follow-up Questionnaire ..............................................................................99 
10.8. 
Appendix 8 Supplement List .........................................................................................100 
11. 
REFERENCES ..............................................................................................................101 
12. 
LIST OF ABBREVIATIONS .......................................................................................103 
 

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LIST OF TABLES 
Table 1.1: Schedule of Assessments (Part 1: from the Screening Period to Cycle 7 Day 
1) .................................................................................................................................21 
Table 1.2: Schedule of Assessments (Part 2: from the Screening Period to Cycle 7 Day 
1) .................................................................................................................................25 
Table 1.3: Schedule of Assessments (Parts 1 and 2: Study drug continuation after Cycle 
7 Day 1) ......................................................................................................................29 
Table 3.1: Description of Objectives, Outcome Measures, and Endpoints .................................35 
Table 6.1: Study Drug Dosing Information .................................................................................47 
Table 6.2: Dose Modification Guidelines ....................................................................................50 
Table 6.3: Dose Modification Guidelines for Treatment-emergent Toxicities ............................50 
Table 6.4: Additional Liver Evaluation .......................................................................................51 
Table 6.5: Recommended Dosage Reductions for Pexidartinib for Concomitant Use of 
Moderate and Strong CYP3A Inhibitors or UGT Inhibitors ......................................53 
Table 8.1: Definitions of Response for the Primary Endpoint.....................................................61 
Table 8.2: Dose-Limiting Toxicities ............................................................................................68 
Table 8.3: Schedule of PK Sample Collection.............................................................................71 
Table 10.1: Clinical Laboratory Tests ...........................................................................................89 
Table 10.2: New York Heart Association classifications ..............................................................90 
Table 10.3: Common CYP3A Inhibitors and Inducers CYP3A4 Inhibitors .................................91 
Table 10.4: Key Data Requirements ..............................................................................................97 
Table 10.5: Sample Surgical Assessment Questionnaire ...............................................................98 
Table 10.6: Sample Long-Term Follow-up Questionnaire ............................................................99 
 

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LIST OF FIGURES 
Figure 1.1: Study Level Flow Diagram .........................................................................................20 
 
 

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Description: BOR as assessed 
by centrally reviewed MRI scan 
based on RECIST 1.1 
Time frame: At the time of the 
primary analysis: After all 
subjects have made the 
Week 25 visit or have 
discontinued from the study, 
whichever occurs first 
disease (PD), and not 
evaluable (NE) recorded as 
the best response based on 
RECIST 1.1 by centrally 
reviewed MRI scan 
Title: BOR based on TVS 
Description: BOR as assessed 
by centrally reviewed MRI scan 
based on TVS 
Time frame: At the time of the 
primary analysis 
BOR is defined as the 
proportion of subjects who 
achieved CR, PR, SD, PD, 
and NE recorded as the 
best response based on 
TVS by centrally reviewed 
MRI scan 
Efficacy 
Title: Duration of response 
(DoR) based on RECIST 1.1 
Description: DoR as assessed 
by centrally reviewed MRI scan 
based on RECIST 1.1 
Time frame: At the time of the 
primary analysis 
DoR is defined as the time 
from the date of the first 
recorded response to the 
first date of documented 
disease progression 
Efficacy 
Title: DoR based on TVS 
Description: DoR as assessed 
by centrally reviewed MRI scan 
based on TVS 
Time frame: At the time of the 
primary analysis 
DoR is defined as the time 
from the date of the first 
recorded response to the 
first date of documented 
disease progression 
Efficacy 
Part 1, Part 2: To 
assess the safety of 
pexidartinib 
Title: Treatment-emergent 
adverse events (TEAEs) and 
other safety parameters during 
the study* 
Description: Descriptive 
statistics of safety endpoints 
Time frame: Continuous 
monitoring and reported at the 
time of each data cut-off 
*Though this is a secondary 
objective, this is a primary 
outcome measure 
Safety evaluation include 
the following, but is not 
limited to: TEAEs, drug 
induced hepatotoxicity, 
laboratory tests, vital 
signs, and 
electrocardiogram (ECG) 
Safety 
Part 1, Part 2: To 
evaluate the PK 
properties of 
pexidartinib 
Title: PK profile 
Description: Plasma 
concentrations and PK 
parameters of pexidartinib and 
ZAAD-1006a 
Time frame: Part 1; C2D1, 
C3D1, and C5D1 (with sparse 
sampling), Part 2; C1D1-C1D2 
and C1D15 (with intensive 
Plasma concentrations and 
PK parameters of 
pexidartinib and ZAAD-
1006a, the major 
metabolite of pexidartinib 
PK 

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 
Creatinine clearance (CLCR) >15 mL/min 
 
If the subject is a female of childbearing potential, she must have a negative serum pregnancy 
test within 14 days before enrollment and must be willing to use highly effective birth control 
with a non-hormonal method of contraception upon enrollment, during the Treatment Period, 
and for 1 month following the last dose of study drug.  A female is considered of childbearing 
potential following menarche and until becoming postmenopausal (no menstrual period for a 
minimum of 12 months and a follicle-stimulating hormone [FSH] level >40 mIU/mL) unless 
permanently sterile (undergone a hysterectomy, bilateral salpingectomy or bilateral 
oophorectomy). 
 
If male, the subject must be surgically sterile or willing to use highly effective birth control 
upon enrollment, during the treatment period, and for 1 month following the last dose of study 
drug. 
 
Male subjects must not freeze or donate sperm starting at Screening and throughout the study 
period, and at least 1 month after the final study drug administration. 
 
Female subjects must not donate, or retrieve for their own use, ova from the time of screening 
and throughout the study treatment period, and for at least 1 month after the final study drug 
administration. 
 
Willingness and ability to undergo tumor biopsy at screening or willingness to provide 
archived tissue samples for assessment of biomarkers 
Key Exclusion Criteria: 
Subjects meeting any exclusion criteria for this study will be excluded from this study.  Below is a list limited to 
the key exclusion criteria: 
 
Inadequate washout period before enrollment, defined as: 
 
Investigational drug/device use within <28 days 
 
Previous use of pexidartinib or any selective treatment targeting colony stimulating factor 1 (CSF-
1) or the colony-stimulating factor 1 receptor (CSF1R); previous use of oral multi-kinase inhibitors 
(eg, imatinib or nilotinib) are allowed. 
 
Active cancer, except for the tumor for which the subject is enrolled in the study, (either 
concurrent or within the last year of starting the 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. 
 
Known metastatic TGCT. 
 
Active, chronic, inactive carrier, or resolved infection hepatitis C or hepatitis B infection, 
except for patients only positive for HBs antibody (HBs antigen negative and HBc antibody 
negative) and with clear prior vaccination.  Or known active or chronic infection with the 
human immunodeficiency virus. 
 
Pre-existing increased serum transaminases; total bilirubin or direct bilirubin (>ULN); or 
active liver or biliary tract disease, including increased ALP. 

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1.2. 
Study Schema 
Figure 1.1: 
Study Level Flow Diagram 
 
BID = twice a day; C = cycle; CR = complete response; D = day; DLT = dose-limiting toxicity; MRI = magnetic 
resonance imaging; PK = pharmacokinetics; PR = partial response; ORR = objective response rate; TGCT = 
tenosynovial giant cell tumor; RECIST = response evaluation criteria in solid tumors; Wk = week 
 
In June 2024, the sponsor decided to halt the enrollment of participants after 9 subjects were 
enrolled in Part 1 and not proceed with Part 2.  
 
 

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AE = adverse event; ALT = alanine aminotransferase; AMA = Anti-mitochondrial antibody; AST = aspartate aminotransferase; BPI = brief pain inventory; C = 
cycle; D/d = Day; CQ = chloroquine; ECG = electrocardiogram; End St./Ear. Term. = end of study/early termination; EQ-5D-5L = The five-level version of 
EuroQol five-dimensional questionnaire; FSH = follicle-stimulating hormone; HCQ = hydroxychloroquine; incl. = including; LTFU = long-term follow-up; MRI 
= magnetic resonance imaging; MUGA = multigated acquisition; NRS = numeric rating scale; Pdy = pharmacodynamic(s); PGx = pharmacogenomic(s); PK = 
pharmacokinetic(s); PROMIS = patient-reported outcomes measurement information system; Pt = patient; SARS-CoV-2 = severe acute respiratory syndrome 
coronavirus 2; SCR = screening; TGCT = tenosynovial giant cell tumor; Tx = treatment. 
 
a. 
Procedures performed as part of patient care within the 28-day period before the first dose of the 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 C7D1 applies to patients who are continuing and those who are not continuing the study. 
c. 
28 days after the last study drug administration. Patients who exit the study with radiologic disease progression will undergo their last study 
evaluation at 28 ± 7 days after their last dose of the 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. 
d. Last dosing +12 weeks or before new treatment. Patients who end their study participation with no radiologic disease progression will undergo post-
treatment procedures at 28 ± 7 days after their last dose of the study drug and a final MRI at 12 weeks ± 7 days after their last dose of the 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. 
Every 6 months after the End of Study/Early Termination. 
f. 
Time frame between enrollment and the first dose of the study drug can be up to 3 days prior to C1D1. 
g. Vital signs including blood pressure, pulse rate, and temperature should be performed before any invasive procedures are carried out on the same 
day. 
h. Within 7 days before the enrollment. 
i. 
Before the first dose of the study drug. 
j. 
Weight only. 
k. In the event of early withdrawal, a physical examination is performed at the Post-treatment visit. 
l. 
A standard 12-lead ECG is performed prior to dosing.  Patients should be told not to take their morning dose of the 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 instruction at the site. 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. 
m. Within 72 hours before the first dose of the study drug. 
n. Within 21 days before the first dose of the study drug. 
o. Patients receiving concomitant warfarin should have their anti-coagulation status carefully monitored for any necessary dose adjustments. 
p. Women who are not using hormonal contraception must be tested for levels of FSH, luteinizing hormone (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. 

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q. Women of childbearing potential must have a serum pregnancy test within 14 days before enrollment. 
r. 
Details on blood sampling are found in Section 8.5. 
s. 
A washout period of no less than 14 days is required before restarting pexidartinib. 
t. 
Must be collected during screening. A tumor biopsy that was recently collected may be substituted for the biopsy collected during screening. 
Screening biopsy should only be collected after all other eligibility criteria are met (an archived tissue sample may be acceptable upon 
sponsor’s/designee approval).  A screening biopsy should only be collected after all other eligibility criteria are met. 
u. Optional. 
v. A serum sample should be collected for AMA at screening and when severe hepatotoxicity is observed. 
w. MRI of the affected joint should be performed within 56 days before the first dose of the study drug. 
x. Before any invasive procedures on the same day, PROMIS Physical Function Scale, BPI Worst Pain NRS, and EQ-5D-5L are to be recorded.  
PROMIS Physical Function Scale will be assessed on patients who signed informed consent after the Japanese translated version of PROMIS 
Physical Function Scale is ready. 
y. Subjects will complete the BPI Worst Pain NRS item for seven consecutive days prior to C1D1, C3D1, C5D1, C7D1 and Post-Tx, as well as on the 
day of the study visit. In addition, subjects will complete the BPI Worst Pain NRS item on an outpatient basis prior to the indicated study visits. 
z. 
Subjects will have a diary in which to record all analgesics, including nonsteroidal anti-inflammatory drugs and prescription analgesics, taken from 
the 14-day period before the first dose of the study drug to the Post-treatment visit. 
aa. The morning dose of the study drug should be administered at the site on the indicated days. 
bb. After the patient has provided signed informed consent; Aes are monitored throughout the study via safety assessments, observation, and patient 
reporting. 
cc. If surgical resection of the tumor is performed within the designated time period (28 days for Post-Tx and 12 weeks for End of Study/Early 
Termination) after the last dose of the study drug, details of the surgery and its outcome should be obtained. 
 
*: Not be performed from Protocol Version 4.0 onwards. 
**: From Protocol Version 4.0 onwards, only local review will be performed, and central review will not be performed. 
 

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pharmacokinetic(s); PROMIS = patient-reported outcomes measurement information system; Pt = patient; SARS-CoV-2 = severe acute respiratory syndrome 
coronavirus 2; SCR = screening; 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 the 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 C7D1 applies to patients who are continuing or not continuing the study. 
c. 
28 days after the last study drug administration. Patients who exit the study with radiologic disease progression will undergo their last study 
evaluation at 28 ± 7 days after their last dose of the 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. 
d. Last dosing +12 weeks or before new treatment. Patients who end their study participation with no radiologic disease progression will undergo post-
treatment procedures at 28 ± 7 days after their last dose of the study drug and a final MRI at 12 weeks ± 7 days after their last dose of the 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. 
Every 6 months after the End of Study/Early Termination. 
f. 
Time frame between enrollment and the first dose of the study drug can be up to 3 days prior to C1D1. 
g. Vital signs including blood pressure, pulse rate, and temperature should be performed before any invasive procedures are carried out on the same 
day. 
h. Before the first dose of the study drug. 
i. 
Weight only. 
j. 
In the event of early withdrawal, a physical examination is performed at the Post-treatment visit. 
k. A standard 12-lead ECG is performed prior to dosing.  Patients should be told not to take their morning dose of the 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 instruction at the site. 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. 
l. 
Within 21 days before the first dose of the study drug. 
m. Within 72 hours before the first dose of the study drug. 
n. Hematology only. 
o. Patients receiving concomitant warfarin should have their anti-coagulation status carefully monitored for any necessary dose adjustments. 
p. Women who are not using hormonal contraception must be tested for levels of FSH, luteinizing hormone (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. 
q. Women of childbearing potential must have a serum pregnancy test within 14 days before enrollment. 
r. 
Details on blood sampling are found in Section 8.5. 
s. 
A washout period of no less than 14 days is required before restarting pexidartinib. 

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t. 
Must be collected during screening. A tumor biopsy that was recently collected may be substituted for the biopsy collected during screening (an 
archived tissue sample may be acceptable upon sponsor’s/designee approval). A screening biopsy should only be collected after all other eligibility 
criteria are met. 
u. Optional. 
v. A serum sample should be collected for AMA at screening and when severe hepatotoxicity is observed. 
w. MRI of the affected joint should be performed within 56 days before the first dose of the study drug. 
x. Before any invasive procedures on the same day, PROMIS Physical Function Scale, BPI Worst Pain NRS, and EQ-5D-5L are to be recorded. 
y. Subjects will complete the BPI Worst Pain NRS item for seven consecutive days prior to C1D1, C3D1, C5D1, C7D1 and Post-Tx, as well as on the 
day of the study visit. In addition, subjects will complete the BPI Worst Pain NRS item on an outpatient basis prior to the indicated study visits. 
z. 
Subjects will have a diary in which to record all analgesics, including nonsteroidal anti-inflammatory drugs and prescription analgesics, taken from 
the 14-day period before the first dose of the study drug to the Post-treatment visit. 
aa. The morning dose of the study drug should be administered at the site on the indicated days. 
bb. After the patient has provided signed informed consent; AEs are monitored throughout the study via safety assessments, observation, and patient 
reporting. 
cc. If surgical resection of the tumor is performed within the designated time period (28 days for Post-Tx and 12 weeks for End of Study/Early 
Termination) after the last dose of the study drug, details of the surgery and its outcome should be obtained. 
 
 

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h. Women who are not using hormonal contraception must be tested for levels of FSH, luteinizing hormone (LH), progesterone, and estradiol.  
Hormone testing will not be required for women who have either had an oophorectomy or are post-menopausal. 
i. 
A washout period of no less than 14 days is required before restarting pexidartinib. 
j. 
Optional. 
k. A serum sample should be collected for AMA when severe hepatotoxicity is observed. 
l. 
Before any invasive procedures on the same day, PROMIS Physical Function Scale, BPI Worst Pain NRS, and EQ-5D-5L are to be recorded. 
m. Subjects will complete the BPI Worst Pain NRS item for seven consecutive days prior to the indicated study visits, as well as on the day of the 
study visit. In addition, subjects will complete the BPI Worst Pain NRS item on an outpatient basis prior to the indicated study visits. 
n. If surgical resection of the tumor is performed within the designated time period (28 days for Post-Tx and 12 weeks for End of Study/Early 
Termination) after the last dose of the study drug, details of the surgery and its outcome should be obtained. 
 
*: Not be performed from Protocol Version 4.0 onwards. 
**: From Protocol Version 4.0 onwards, only local review will be performed, and central review will not be performed. 
***: MRI are performed every 24 weeks from Protocol Version 4.0 onwards. 
 

 
 
 
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2. 
INTRODUCTION 
2.1. 
Background 
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. 
2.1.1. 
Tenosynovial giant cell tumor 
Tenosynovial giant cell tumor (TGCT) is a rare, nonmalignant neoplasm of the synovium, 
bursae, or tendon sheaths, generally affecting young adults (<40 years of age) of both sexes.2  
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 (ROM) 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.2,3  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.2,3  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.2,4,5  A more recent survey in Denmark demonstrates an incidence of 4.4 per million 
population for localized TGCT and 1.2 per million population for diffuse TGCT,3 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.6 
TGCT predominantly consists 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), which is 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 1p13.7  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 as complete surgical resection of the tumor 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 in patients with focal disease 
is low, ranging from 0% to 6%2; however, in patients with diffuse forms of the disease, 

 
 
 
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recurrence is considerably more common, and is estimated to be in a range of 40%.8  Diffuse 
disease carries a risk of multiple recurrences, and affected patients often have more extensive 
involvement and a poorer likelihood of success with surgery.  Surgical resection may involve the 
removal of major tendons or neurovascular structures, leading to significant postsurgical 
morbidity.  Limb amputation may be required in severe, recurrent cases.2 
No systemic antitumor agents have been approved for this indication in Japan.9  Anti-
inflammatory and analgesic medications, including opioids, are 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. 
2.1.2. 
Pexidartinib (PLX3397) 
Pexidartinib is a small molecule tyrosine kinase inhibitor that targets CSF1R, KIT proto-
oncogene receptor tyrosine kinase (KIT), and feline McDonough Sarcoma-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 in vitro.  
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 not amenable to improvement with surgery. 
2.2. 
Study Rationale 
Clinical Experience 
PLX108-10 (ENLIVEN Study): Pexidartinib or Placebo in Subjects with Tenosynovial 
Giant Cell Tumor 
The ENLIVEN study was 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 twice a day {BID} or placebo for 22 weeks].  The subjects who 
completed Part 1 (ie, 24 weeks of dosing) were eligible to advance to Part 2, a long-term 
treatment phase where all subjects would receive open-label pexidartinib at a maximum starting 
dose of 800 mg/day. 
The primary objective of this study was to compare the response rate of pexidartinib with that of 
placebo at Week 25.  The secondary efficacy objectives were to evaluate 1) ROM at Week 25, 2) 
response based on tumor volume score (TVS) at Week 25, 3) patient-reported outcomes (PRO) 
at Week 25, and 4) duration of response. 
Study PLX108-10 demonstrated a statistically significant improvement (p < 0.0001) in objective 
response rate (ORR) at Week 25 in the 61 patients randomized to pexidartinib (37.7% [95% 
confidence interval {CI}: 26.6%, 50.3%]) compared with placebo (0% [95% CI: 0, 6.1%]). 
As of the data cut-off date of 31 Jan 2018, frequent treatment-emergent adverse events (TEAEs) 
(>20%) for subjects treated with pexidartinib in Part 1 were hair color changes (pexidartinib arm 
vs placebo arm: 67.2% vs 3.4%); fatigue (54.1% vs 35.6%); AST increased (39.3% vs 0%); 

 
 
 
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nausea (37.7% vs 40.7%); ALT increased (27.9% vs 1.7%); dysgeusia (24.6% vs 1.7%); 
arthralgia (23.0% vs 25.4%).  Generally, the frequency of TEAEs in pexidartinib-treated subjects 
in Part 1 and Part 2 was only slightly greater than the frequency in Part 1 only, demonstrating 
that few new TEAEs occurred with long-term pexidartinib treatment.  Most TEAEs occurred in 
the first 12 weeks of pexidartinib treatment.  Please refer to the most recent IB for additional 
information.10 
2.2.1. 
Study Rationale 
The principal data supporting the efficacy of pexidartinib in TGCT have been indicated in the 
phase 3 study (Study PLX108-10 [ENLIVEN], N = 120) conducted in the US, Canada, European 
countries, and Australia.  Pexidartinib was approved for adult patients with symptomatic TGCT 
associated with severe morbidity or functional limitations and not amenable to improvement with 
surgery by the US Food and Drug Administration (FDA) on 2 August 2019. 
No systemic antitumor agents are approved for TGCT in Japan. A systemic therapy that provides 
a meaningful clinical benefit for TGCT patients is highly needed.  
Similar safety, pharmacokinetics (PK), and efficacy as the ENLIVEN study can be expected in 
this Japan phase 2 study because there are no differences between the study populations of 
TGCT subjects in the ENLIVEN study and this Japanese phase 2 study in terms of extrinsic 
factors such as disease definition, diagnosis, medical practice and therapeutic approach. 
Regarding intrinsic ethnic factors, there is currently no evidence to indicate that the populations 
are not similar.  Pexidartinib has the potential to offer a treatment option for TGCT patients in 
Japan. 
2.3. 
Benefit and Risk Assessment 
Pexidartinib has been approved in the US for the treatment of TGCT associated with severe 
morbidity or functional limitations and not amenable to improvement with surgery. 
Safety data from nonclinical studies, clinical studies, and non-interventional studies have been 
reviewed.  Hepatotoxicity is an important identified risk, and both embryo-fetal toxicity and 
fertility toxicity are considered an important potential risk with pexidartinib.  In repeated dose 
toxicity studies in rats and dogs, male rats and dogs displayed testicular toxicity.  Following a 
16-week recovery period, testicular toxicity persisted in rats and partially recovered in dogs, but 
did not fully recover.  Serious and prolonged hepatotoxicity with ductopenia and/or cholestasis 
has been observed in subjects treated with pexidartinib.  Cases of cholestasis have been observed 
in the first 8 weeks and have generally resolved with treatment discontinuation, but in some 
cases have been severe, with a protracted course requiring liver dialysis and, in 1 case, 
transplantation.  Hepatotoxicity may be fatal.  One fatal case with ongoing cholestatic liver 
injury at the time of death has been reported.  The mechanism of cholestatic hepatotoxicity is 
unknown, and its occurrence cannot be predicted.  Protocol-defined dose reductions and 
discontinuations of pexidartinib, increased frequency of laboratory monitoring, and reporting of 
findings should be followed.  In addition, rechallenge with pexidartinib should not be attempted.  
Risk minimization measures, such as frequent monitoring during the first 8 weeks of pexidartinib 
treatment related to managing these risks, should be conducted.  Please refer to the most recent 
IB for additional information.10 

 
 
 
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generation sequencing; NE = not evaluable; NRS = numeric rating scale; ORR = objective response rate; PD = 
progressive disease; PGx = pharmacogenomics; PK= pharmacokinetics; PR = partial response; PRO = patient-
reported outcomes; PROMIS = patient-reported outcomes measurement information system; RECIST= response 
evaluation criteria in solid tumors; ROM = range of motion; SD = stable disease; SSD = sum of the short-axis 
dimension; TEAE = treatment-emergent adverse event; TVS = tumor volume score 
 
3.1. 
Rationale for Selection of Primary and Key Secondary Endpoints 
The primary endpoint of Part 1 will be the dose-limiting toxicities (DLTs) evaluation and PK 
profiles to evaluate the tolerability and PK of pexidartinib in Japanese subjects. 
The primary endpoint of Part 2 will be the ORR, defined as the proportion of subjects who 
achieve a complete response (CR) or partial response (PR) based on Response Evaluation 
Criteria in Solid Tumors Version 1.1 (RECIST 1.1) and assessed by centrally reviewed MRI 
scan.  Confirmation will not be required for CR or PR.11  The ORR is a direct measure of the 
drug antitumor activity.  Since ORR is directly attributable to the drug effect, it is an appropriate 
measure of efficacy in studies without a comparator.12  The efficacy of pexidartinib in TGCT 
was evaluated with same primary endpoint in the ENLIVEN study. 
The study hypotheses of Part 2 is that the ORR of the primary endpoint exceeds the ORR of 5% 
of the placebo arm in the ENLIVEN study. The assumed ORR of the primary endpoint is 37.7% 
of the pexidartinib arm in the ENLIVEN study. 
It is considered that tumor shrinkage is essential to improve symptoms of advanced TGCT 
subjects.  The improvement of symptoms will be evaluated with secondary endpoints.  The 
endpoint of TVS using central MRI readers will be reinforced for the primary imaging endpoint 
of RECIST 1.1 assessment.  The endpoint of ROM, the Patient-Reported Outcomes 
Measurement Information System (PROMIS) Physical Function Scale, the Brief Pain Inventory 
(BPI) Worst Pain Numeric Rating Scale (NRS) Item will reinforce the explanation of clinical 
benefit from the primary imaging endpoint. 

 
 
 
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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a phase 2, multicenter, two-part, open-label, single-arm study, conducted in Japan, which 
is aimed to evaluate the tolerability, safety, efficacy, and PK of pexidartinib in adult subjects 
with symptomatic TGCT associated with severe morbidity or functional limitation and not 
amenable to improvement with surgery.  It is planned to conduct this study at approximately 5 
study sites located in Japan.  The subject population is described in Section 5. 
The study start date is the date when the first subject has signed informed consent.  A subject is 
eligible to be enrolled into the interventional phase of the study when the Investigator or 
designee has determined that all inclusion and exclusion criteria have been satisfied, including 
having obtained written informed consent. 
Enrollment is defined as the timepoint at which the Investigator has obtained the subject 
identifier (SID) in the interactive response technology (IRT) and the study drug has been 
assigned. 
4.1.1. 
Design Overview 
This study consists of 2 parts: In Part 1, the tolerability and PK of pexidartinib 800 mg/day 
(400 mg BID) given on an empty stomach will be evaluated to determine the initiation of Part 2, 
and in Part 2, the efficacy, safety and PK of pexidartinib 800 mg/day given on an empty stomach 
will be evaluated.   
Part 1: 
Three or six eligible subjects will be enrolled in Part 1.  Part 1 will be divided into 3 periods: 
Screening Period, Treatment Period, and Follow-up Period (which includes the Long-term 
Follow-up [LTFU]):   
At the beginning of the Screening Period subjects sign the informed consent form (ICF).  During 
the 28-day Screening Period, subjects’ eligibility will be confirmed.  They will undergo medical 
history evaluation, physical examination, vital sign determination, laboratory assessments, and 
electrocardiogram (ECG), echocardiogram (ECHO) or multigated acquisition (MUGA) scan. 
The Treatment Period starts on Cycle 1 Day 1 (C1D1) and continues until a subject permanently 
discontinues pexidartinib (Section 7.1).  During the Treatment Period, pexidartinib will be 
administered at 400 mg once (2 capsules in the morning) on C1D1 to evaluate the PK profile for 
24 hours.  From C1D2 and after, pexidartinib will be administered at 400 mg BID (2 capsules in 
the morning and 2 capsules in the evening).  Pexidartinib must be administered on an empty 
stomach (at least 1 hour before or 2 hours after a meal or snack), at approximately the same 
times of the day, and approximately 12 hours apart.  Subjects will be hospitalized from C1D1 to 
C1D2 in Part 1 to allow for careful safety monitoring.  Discharge will be decided at the 
Investigator’s discretion. The Investigator should examine the subject carefully before deciding 
to discharge. The study site should educate the subject about an emergency contact. Additional 
safety assessments should be conducted as needed, at the Investigator’s discretion.  The second 
subject should start dosing at least 24 hours after the initial dosing of the first subject. 

 
 
 
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After study treatment is discontinued, subjects will be followed for 28 ± 7 days for safety.  
Subjects will then enter LTFU for collection of information on subsequent treatment.   
The subject population is described in Section 5. 
Evaluation of tolerability is based on review of all DLT-evaluable subjects who have received 
pexidartinib and have either completed the minimum safety evaluation requirements over the 
DLT evaluation period (28 days) or have experienced a DLT during the DLT evaluation period.  
If a DLT is observed in 1 of 3 subjects, at least 6 subjects in total will be treated in Part 1.  If a 
DLT is observed in 0 of 3 subjects or l of 6 subjects in Part 1, Part 2 will be initiated.  If a DLT is 
observed in ≥2 of 3 subjects or ≥2 of 6 subjects in Part 1, the safety monitoring committee 
(SMC) will discuss whether more subjects should be added to Part 1.  Transition to Part 2 will be 
considered based on review of the tolerability, available safety and PK data from Part 1 including 
subjects who are not considered to be DLT-evaluable subjects for any other reason than a DLT. 
Part 2: 
Part 2 will begin after completing evaluation of tolerability and PK in Part 1.  Fifteen eligible 
subjects will be enrolled in Part 2.  Part 2 will be divided into 3 periods: Screening Period, 
Treatment Period, and Follow-up Period (which includes the LTFU):   
At the beginning of the Screening Period subjects sign the ICF.  During the 42-day Screening 
Period, subjects’ eligibility will be confirmed.  They will undergo medical history evaluation, 
physical examination, vital sign determination, laboratory assessments, and ECG, ECHO or 
MUGA scan. 
During the Treatment Period, pexidartinib will be administered at 400 mg once (2 capsules in the 
morning) on C1D1 to evaluate the PK profile for 24 hours.  From C1D2 and after, pexidartinib 
will be administered at 400 mg BID (2 capsules in the morning and 2 capsules in the evening).  
Pexidartinib must be administered on an empty stomach (at least 1 hour before or 2 hours after a 
meal or snack), at approximately the same times of the day, and approximately 12 hours apart.  
The Treatment Period starts on C1D1 and continues until a subject permanently discontinues 
pexidartinib (Section 7.1).   
After study treatment is discontinued, subjects will be followed for 28 ± 7 days for safety.  
Subjects will then enter LTFU for collection of information on subsequent treatment. 
 
In June 2024, the sponsor decided to halt the enrollment of participants after 9 subjects were 
enrolled in Part 1 and not proceed with Part 2.  
4.1.2. 
End of Study 
The primary completion date is the date when all enrolled subjects have completed the 
predetermined duration of treatment (ie, the date when all DLT-evaluable subjects have either 
completed minimum safety evaluation requirements over the DLT evaluation period [28 days] or 
have experienced a DLT during the DLT evaluation period for Part 1, Week 25 for Part 2) or 
have discontinued the study.  This date is used as the cut-off date for the analysis of the primary 
endpoint of the study.  All subjects still on treatment and continuing to derive benefit from the 

 
 
 
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study drug at the Primary Completion Date will continue to follow the study schedule of 
assessments (Section 1.3) until the overall End of Study (EOS) is reached. 
Overall EOS will occur when: 
 the last subject last visit has occurred 
 all subjects have discontinued treatment or discontinued the study or have died 
 an alternative study becomes available for subjects continuing to derive benefit from 
treatment with pexidartinib, where the study drug is offered to these subjects 
 the study is discontinued by the Sponsor for other reasons (administrative, program-
level, or class-related) 
The subject’s EOS is the date of their last study visit/contact. 
4.1.3. 
Dose Regimen 
Pexidartinib will be administered at 400 mg once (2 capsules in the morning) on C1D1 to 
evaluate the PK profile for 24 hours. From C1D2 and after, pexidartinib will be administered at 
400 mg BID (2 capsules in the morning and 2 capsules in the evening).  Pexidartinib must be 
administered on an empty stomach (at least 1 hour before or 2 hours after a meal or snack), at 
approximately the same times of the day, and approximately 12 hours apart, according to the 
dosage regimen outlined in Table 6.1. 
4.1.4. 
Duration 
Study duration includes three periods: Screening Period, Treatment Period and Follow-up Period 
(which includes the LTFU). 
Duration of Treatment and Subject Participation 
Subjects who experience clinical benefit will continue to receive pexidartinib in the absence of 
disease progression, clinical progression, unacceptable toxicity, withdrawal of consent by 
subject, physician decision, protocol deviation, pregnancy, lost to follow-up, study termination 
by the sponsor, death, or other reasons (see details in Section 7.1).  Note: Only protocol 
deviations that are deemed significant by the investigator, with or without consultation with the 
sponsor, may lead to permanent study drug discontinuation.  
Overall Study Duration 
Enrollment was planned to occur over approximately 17 months for Part 1 and Part 2, with 
treatment and follow-up projected to continue for approximately 27 months after the last subject 
was enrolled in Part 2. 
Anticipated total duration of the study was planned to be approximately 44 months. 
 
In June 2024, the sponsor decided to halt the enrollment of participants after 9 subjects were 
enrolled in Part 1. For the subjects receiving the study drug in Part 1 and wish to continue 

 
 
 
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receiving it from Protocol Version 4.0 onwards, the study drug administration will be allowed to 
continue until February 2026. 
The study will continue until the overall EOS is reached.  See Section 4.1 for the definition of 
study start and Section 4.1.2 for the definition of the overall EOS. 
Study Drug Continuation After the End of Study 
Not applicable. 
4.2. 
Rationale for Study Design 
The objective of Part 1 is to evaluate the tolerability and PK of pexidartinib in Japanese TGCT 
subjects for further evaluation in Part 2.  Evaluation of tolerability by number of subjects with 
DLTs in units of 3 subjects for each dose is frequently used in oncology phase 1 dose escalation 
studies. 
The objective of Part 2 is to evaluate the safety and efficacy of pexidartinib in Japanese TGCT 
subjects.  The principal data supporting the efficacy of pexidartinib for TGCT have been 
indicated in the ENLIVEN study conducted in the US, Canada, European countries, and 
Australia.  Therefore, the design of Part 2 will be similar to the design of the ENLIVEN study. 
4.3. 
Justification for Dose 
In the phase 1 study conducted in the US (PLX108-01 study), pexidartinib 1000 mg/day given on 
an empty stomach was identified as the maximum-tolerated dose (MTD) when given to solid 
tumor subjects.  In the phase 1 study conducted in Taiwan (PL3397-A-A103 study), pexidartinib 
was also administered at 600 mg/day or 1000 mg/day for the first 2 weeks followed by 
800 mg/day given on an empty stomach in solid tumor subjects.  Pexidartinib 1000 mg/day given 
on an empty stomach was identified as the MTD in Study PL3397-A-A103. 
The dose regimen of this study, pexidartinib 800 mg/day (400 mg BID) given on an empty 
stomach, is revised from the dose regimen of 1000 mg/day for 2 weeks followed by 800 mg/day 
(400 mg BID) used in Part 1 of the ENLIVEN study and is the same as the FDA-approved dose 
regimen in the US. 
5. 
STUDY POPULATION 
5.1. 
Inclusion Criteria 
Subjects must meet all of the following criteria to be eligible for enrollment into the study: 
1. Sign and date the ICF, prior to the start of any study- specific qualification procedures. 
2. Age ≥20 years. 
3. A diagnosis of TGCT (i) that has been histologically confirmed by a pathologist1 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). 

 
 
 
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4. 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. 
5. Stable prescription of analgesic regimen during the 2 weeks prior to enrollment. 
6. Adequate hematologic, hepatic, and renal function, defined by: 
a. Absolute neutrophil count ≥1.5 × 109/L  
b. Hemoglobin >10 g/dL  
c. Platelet count ≥100 × 109/L  
d. AST and ALT ≤1.0 ×upper limit of normal (ULN) 
e. Total bilirubin and direct bilirubin ≤1.0 × ULN 
f. ALP ≤1.0 × ULN 
g. Creatinine clearance (CLCR) >15 mL/min. 
7. If the subject is a female of childbearing potential, she must have a negative serum 
pregnancy test within 14 days before enrollment and must be willing to use highly 
effective birth control with a non-hormonal method of contraception, as detailed in 
Section 10.3.4, upon enrollment, during the Treatment Period, and for 1 month following 
the last dose of study drug.  A female is considered of childbearing potential following 
menarche and until becoming postmenopausal (no menstrual period for a minimum of 12 
months and a follicle-stimulating hormone [FSH] level > 40 mIU/mL) unless permanently 
sterile (undergone a hysterectomy, bilateral salpingectomy or bilateral oophorectomy). 
8. If male, the subject must be surgically sterile or willing to use highly effective birth 
control (Section 10.3.4) upon enrollment, during the treatment period, and for 1 month 
following the last dose of study drug. 
9. Male subjects must not freeze or donate sperm starting at Screening and throughout the 
study period, and at least 1 month after the final study drug administration. 
10. Female subjects must not donate, or retrieve for their own use, ova from the time of 
screening and throughout the study treatment period, and for at least 1 month after the 
final study drug administration. 
11. Willingness and ability to undergo tumor biopsy at screening or willingness to provide 
archived tissue samples for assessment of biomarkers. 
12. Willingness and ability to complete the PROMIS Physical Function Scale and the BPI 
Worst Pain NRS Item. 
13. Willingness and ability to record a paper diary. 
5.2. 
Exclusion Criteria 
Subjects who meet any of the following criteria will be disqualified from entering the study: 
1. Inadequate washout period before enrollment, defined as: 
 Investigational drug/device use within < 28 days. 
2. Previous use of pexidartinib or any selective treatment targeting CSF-1 or the CSF1R; 
previous use of oral multi-kinase inhibitors (eg, imatinib or nilotinib) are allowed. 

 
 
 
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3. Active cancer, except for the tumor for which the subject is enrolled in the study, (either 
concurrent or within the last year of starting the 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, chronic, inactive carrier, or resolved hepatitis C or hepatitis B infection, except 
for patients only positive for HBs antibody (HBs antigen negative and HBc antibody 
negative) and with clear prior vaccination.  Or known active or chronic infection with the 
human immunodeficiency virus. 
6. Pre-existing increased serum transaminases; total bilirubin or direct bilirubin (>ULN); or 
active liver or biliary tract disease, including increased ALP. 
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 potassium-competitive acid blockers (P-CABs), or other 
products known to cause hepatotoxicity. 
10. Women who are breastfeeding or intends to breast-feed from the time of screening and 
throughout the study treatment period, and for at least 2 weeks after the final study drug 
administration. 
11. Uncontrolled or significant cardiovascular disease, including: 
a. QT interval corrected with Fridericia’s formula (QTcF) interval >450 ms (men, 
average of triplicate determinations) or >470 ms (women, average of triplicate 
determinations); 
b. Myocardial infarction within 6 months prior to screening; 
c. Uncontrolled angina pectoris within 6 months prior to screening; 
d. New York Heart Association (NYHA) Class 3 or 4 congestive heart failure; 
e. Left ventricular ejection fraction (LVEF) < 50% or institutional lower limit of normal 
f. Uncontrolled hypertension (resting systolic blood pressure >180 mmHg or diastolic 
blood pressure >110 mmHg). 
12. MRI contraindications. 
13. History of hypersensitivity to any excipients in the investigational product. 
14. Inability to swallow capsules. 

 
 
 
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5.3. 
Screening Failures, Rescreening, and Subject Replacement 
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.  
The initial screening information and the reason why the subject was not eligible for the initial 
evaluation will be recorded in the screening log.  However, it may not be necessary to repeat 
MRI, ROM and surgical assessment following consultation with the Daiichi Sankyo (DS) 
Medical Monitor.  Subjects who are withdrawn from the study prior to completing Cycle 1 of 
Part 1 for any other reason than a DLT will be replaced.  Identification numbers may not be re-
used.  Subjects who receive < 75% of the planned dose during the DLT evaluation period for any 
other reason than a DLT will not be considered evaluable and must be replaced in Part 1.  
Subjects withdrawn from the study after Cycle 2 of Part 1 and later or Part 2 will not be replaced. 

 
 
 
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6. 
STUDY TREATMENT(S) 
6.1. 
Study Drug(s) Description 
Table 6.1 describes the formulation, dose, regimen, duration, packaging, and labeling of 
pexidartinib. 
Table 6.1: 
Study Drug Dosing Information 
Study Drug Name 
PLX3397 
Dosage Formulation 
Capsules 
Dosage Level(s) 
800 mg/day 
Route of Administration 
Oral 
Dosing 
400 mg BID (2 capsules in the morning and 2 capsules in the evening).  
The study drug must be taken on an empty stomach (at least 1 hour before or 2 
hours after a meal or snack) at approximately the same time of the day with an 
approximate 12-hour interval. 
Duration 
Continuous dosing 
Packaging 
Bottles (35 capsules per bottle) 
Packaging will clearly display the name of the product, storage conditions, and 
other required information as applicable in accordance with the local regulations 
Labeling 
Bottles will be labeled as required per local regulatory requirement 
BID = twice a day 
6.2. 
Preparation, Handling, Storage, and Accountability for Study 
Drug(s) 
Preparation, Handling, and Disposal 
The preparation of study drug will be conducted in accordance with the Pharmacy Manual 
provided by the Sponsor.   
Procedures for proper handling and disposal should be followed in compliance with the standard 
operating procedures (SOP) of the site. 
Administration 
The study drug will only be given to enrolled subjects under the supervision of the principal 
investigator or identified subinvestigator(s).  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 Part 1 or Part 2 in the morning.  At this 
visit, subjects will be instructed to take 400 mg at the C1D1 visit and 400 mg BID for a total 
daily dose of 800 mg (2 capsules in the morning and 2 capsules in the evening) from C1D2 and 
thereafter.  The study drug must be taken on an empty stomach at approximately the same time 
of the day with an approximate 12-hour interval.  Each dosing cycle will be 28 days. 
For the C1D15 visit (Week 3) and any visit when an ECG and PK will be performed, subjects 
must be told NOT to take their morning dose of the study drug before coming for the study visit, 

 
 
 
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which should be scheduled in the morning.  The subject must be instructed to bring their bottle of 
the study drug to the site and take their morning dose upon instruction at the study site.  The time 
of dosing must be recorded.  Subjects will then take their evening dose at home.  If the dose 
administered at the site is taken in the afternoon, the subject must be instructed to skip the 
evening dose for that day. 
For the C7D1 visit (Week 25), subjects must be told NOT to take the morning dose of the 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 the 24-week treatment, ie, a maximum dose of 800 mg/day pexidartinib. 
Between site visits, subjects must take their study drug at home and record the dosing 
information in the study dosing diary.  Missed doses (generally those outside a ± 2-hour dosing 
window) must be skipped and NOT be taken as a double dose at the next dosing time point.  
Subjects who vomit their dose must be instructed NOT to make up that dose. 
Storage 
The study drug (pexidartinib) must be stored in a secure, limited access storage area under the 
recommended storage conditions noted on the label.  The study drug must be stored at a 
temperature of up to 25°C.  Excursion is permitted up to 30°C.  Subjects must be instructed to 
store the study drugs at room temperature out of the reach of children or other cohabitants. 
If storage conditions are not maintained per specified requirements, then the Sponsor or contract 
research organization (CRO) should be contacted. 
Drug Accountability 
When a drug shipment is received, the Investigator or designee will check the amount and 
condition of the drug against the shipping documentation. 
The Receipt of Shipment Form should be faxed as instructed on the form unless receipt is 
controlled by IRT. 
In addition, the Investigator or designee shall contact the Sponsor as soon as possible if there is a 
problem with the shipment. 
The Investigator is responsible for study drug accountability, reconciliation and record 
maintenance (ie, Receipt of Shipment Form, dispensation/return record, and certificate of 
destruction/return receipt). 
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 the study drug received; the subject’s 
identification number or supply number as applicable, for whom the study drug was dispensed; 
the date and quantity of the 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 the designee as instructed by DS.  The study drug will be returned 
only after the study monitor has completed a final inventory to verify the quantity to be returned.  
Return of the study drug must be documented and the documentation must be included in the 

 
 
 
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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 the 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. 
6.3. 
Measure to Minimize Bias: Randomization and Blinding 
Method of Treatment Allocation 
This will be an open-label study.  All subjects will be receiving pexidartinib.  The second subject 
of Part 1 should start dosing at least 24 hours after the initial dosing of the first subject.  Part 2 
will begin after completing evaluation of tolerability and PK of pexidartinib in Part 1. 
Blinding 
This study has an open-label design, and no blinding will be performed. 
6.4. 
Treatment Compliance 
All subjects in this study will commence oral study drug administration under nursing 
supervision on C1D1.   
Pexidartinib will be dispensed to subjects at the study visits indicated in the Schedule of 
Assessments (Section 1.3).  The appropriate study personnel will document and maintain records 
of the 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. 
6.5. 
Guidelines for Dose Modification 
Reducing or interrupting the dose for toxicity may take place at any time during the study 
according to the guidelines in Table 6.2 and Table 6.3.  Dose modification guidelines for 
hematologic and hematologic treatment-related TEAEs are based on severity.  Dose interruption 
can be implemented at the discretion of the treating Investigator to manage intolerable or 
clinically significant toxicity.  If 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 on 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 must be taken, the 
morning and evening doses must be the same (eg, 800 mg/day = 4 capsules [2 capsules in the 

 
 
 
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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 reduction 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, dose 
re-escalation is generally not allowed unless approved after discussion with the DS Medical 
Monitor or designee. 
Table 6.2: 
Dose Modification Guidelines 
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 
The morning doses will be administered at 400 mg on C1D1 for the PK assessment. 
Dose modification guidelines for treatment-emergent toxicities as well as guidelines for their 
management are presented in Table 6.3.  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 Medical Monitor or designee.  Additional liver evaluation is presented in 
Table 6.4.  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 6.3: 
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 6.4. 
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 6.4. 

 
 
 
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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 6.4. 
Increased ALP and 
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 6.4. 
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 6.4. 
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 6.4. 
Adverse reactions or 
other laboratory 
abnormalities 
Severe or intolerable 
 
Withhold until improvement or resolution to Grade 1 
or subject’s baseline. 
 
Resume at a reduced dose upon improvement or 
resolution to Grade 1 or subject’s baseline. 
ALT = alanine aminotransferase; ALP = alkaline phosphatase; AST = aspartate aminotransferase; GGT = gamma-
glutamyl transpeptidase; ULN = upper limit of normal 
 
Table 6.4: 
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. 
Detailed medical history and physical examination 
seeking new abnormalities. 
Evaluate any abnormalities found. 

 
 
 
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Full serological evaluation for hepatitis A, B, C, D, 
E (IgG and IgM), cytomegalovirus, Epstein-Barr 
virus, and herpes simplex virus.  Check for 
autoimmune hepatitis with serological laboratory 
studies (eg, anti-nuclear antibody and anti-smooth 
muscle antibody). 
If viral hepatitis or autoimmune hepatitis 
suggested, have subject evaluated by 
hepatologist. 
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 days. 
Contact Medical Monitor. 
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 whenever the study drug is being held for 
liver function test abnormalities. 
AMA = anti-mitochondrial antibody; IgG = Immunoglobulin G; IgM = Immunoglobulin M; OTC = over-the-
counter 
6.6. 
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. 

 
 
 
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6.7. 
Prior and Concomitant Medications 
During the study, if the use of any concomitant treatment becomes necessary (eg, for treatment 
of an adverse event [AE]), the treatment must be recorded in 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 in the eCRF.  Analgesic use and the analgesic regimen will be recorded. 
Prohibited Therapies/Products 
The following medications/therapies and products will be prohibited during the Treatment 
Period: 
 Other investigational therapeutic agents 
 Other products known to cause hepatotoxicity 
 PPIs and P-CABs 
 As an alternative to a PPI or a P-CAB, 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. 
 Strong CYP3A inducers, including St John’s wort (see Section 10.3.3, a list of 
common CYP3A inhibitors and inducers) 
 Moderate or strong CYP3A inhibitors, including grapefruit juice and seville orange 
juice, or Uridine 5’-diphospho-glucuronosyltransferase (UGT) inhibitors 
 If concomitant use with a moderate or strong CYP3A inhibitor or UGT inhibitor 
cannot be avoided, reduce the pexidartinib dose according to the 
recommendations in Table 6.5.  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 6.5: 
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 
BID = twice daily 
 
 Hormonal Contraceptives 

 
 
 
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 Pexidartinib has been indicated to be a moderate CYP3A4 inducer, as concurrent 
administration of pexidartinib decreased the area under the plasma-concentration-
time curve up 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). 
 Joint aspiration* 
*: Not to be prohibited from Protocol Version 4.0 onwards. 
Permitted Therapies/Products 
Subjects are permitted to receive prophylactic or supportive treatment as standard of care during 
the Treatment Period, per the Investigator’s discretion and institutional guidelines. 
  Warfarin 
 Subjects enrolled in studies with pexidartinib who are also 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) should be 
obtained just prior to initiation of pexidartinib, within 1 to 2 weeks after initiation, 
and periodically thereafter.  Dose adjustments of warfarin should be made as 
medically indicated. 

 
 
 
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7. 
STUDY DRUG DISCONTINUATION AND DISCONTINUATION 
FROM THE STUDY 
7.1. 
Discontinuation of Study Drug 
The primary reason for the permanent discontinuation of pexidartinib treatment administration 
must be recorded.  Reasons for treatment discontinuation include: 
 AE 
 Progressive Disease (PD) 
 Withdrawal by Subject (to discontinue study drug) NOTE: in this section this is 
only withdrawal for treatment with study drug and is NOT the same thing as a 
complete withdrawal from the study.  Discuss with the subject that they will remain 
in the study (ie, continue with study visits and assessments, including LTFU). 
 Investigator Decision 
 Protocol Deviation 
 Surgery 
 Subject Noncompliance 
 Pregnancy 
 Study Termination by Sponsor 
 Death 
 Lost to Follow-up (see Section 7.3 for details on when a subject is considered Lost to 
Follow-up) 
 Other 
During the study, if a subject experiences radiological progression documented by central or 
local 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 Medical Monitor or designee to allow 
the subject to remain in the study. 
After study drug is permanently discontinued for any reason other than death or lost to follow-
up, the subject will be treated as clinically indicated by the Investigator or referring physician. 
The Investigator must discuss with the subject that their decision to permanently discontinue the 
study drug means the subject still agrees to continue into the Follow-up Period for onsite or 
modified follow-up visits.  Subjects will be followed at regularly scheduled intervals (see the 
Schedule of Assessments [Section 1.3]). 
Procedures for Discontinuation from Study Drug 
The subject should be instructed to contact the Investigator or study site staff before or at the 
time study drug is discontinued.   
If a subject is discontinued from the study drug: 

 
 
 
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 The reason(s) for discontinuation and the last dose date should be documented in the 
subject’s medical record and eCRF; 
 Due to an AE, the Investigator will follow the subject until the AE has resolved or 
stabilized; 
 The Investigator will notify DS and ensure that the procedures listed in the “post-
treatment visit” column in the Schedule of Assessments (Section 1.3) are performed 
at 28 ± 7 days after the subject’s last dose of the study drug and prior to initiating any 
new TGCT therapy, including surgery, whichever occurs first. 
 LTFU evaluations will be performed to assess disease relapse or progression status as 
described in the Schedule of Assessments (Section 1.3). 
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.   
The Investigator will complete and report the observations as thoroughly as possible up to the 
date of discontinuation, including the date of last dose.   
If a subject does not agree to continue to come to the study site, then a modified follow-up must 
be arranged to ensure the continued collection of endpoints and safety information.  Options for 
modified follow-up are noted below. 
Modified Follow-up Options for Subjects Who Discontinue the Study Drug and Do Not 
Agree to Study Visits 
The following modified follow-up options can be offered to the subject who discontinue the 
study drug and does not agree to study visits at the study site. 
 Study personnel contacting the subject by telephone (may be quarterly, bi-annually, 
annually, or only at EOS) 
 Study personnel contacting an alternative person (eg, family member, spouse, partner, 
legal representative, physician, or other healthcare provider) 
 Study personnel accessing and reviewing the subject’s medical information from 
alternative sources (eg, doctor’s notes, hospital records) 
Dates of the modified follow-up contact(s) should be recorded.  See Section 7.2 for definition of 
withdrawal by subject from the study (ie, withdrawal of consent). 
7.2. 
Subject Withdrawal/Discontinuation from the Study 
Subjects may discontinue from the study for any of the following reasons: 
 Death 

 
 
 
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 Withdrawal by Subject (from the study)  NOTE: this indicates that the subject 
withdraws consent and refuses to undergo any further study procedures or be 
followed for LTFU 
 Lost to Follow-up (see Section 7.3 for details on when a subject is considered Lost to 
Follow-up) 
 Study Termination by Sponsor 
 Other 
If the reason for study discontinuation is the death of the subject, the option for categorizing the 
primary cause of death is AE.  If reason of death is unknown every effort should be made to 
obtain the primary cause of death.  Only one AE will be recognized as the primary cause of 
death. 
Only subjects who refuse all of the following methods of follow-up will be considered to have 
withdrawn consent from study participation (ie, from the interventional portion and follow-up): 
 Attendance at study visits per protocol 
 Study personnel contacting the subject by telephone 
 Study personnel contacting an alternative person 
 Study personnel accessing and reviewing the subject’s medical information from 
alternative sources 
If the subject refuses all of the above methods of follow-up, the Investigator should personally 
speak to the subject to ensure the subject understands all of the potential methods of follow-up.  
If the subject continues to refuse all potential methods of follow up, the Investigator will 
document this as a withdrawal of consent (from the interventional portion and follow-up). 
Withdrawal Procedures 
If a subject is withdrawn from both the interventional and follow-up portions of 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, date of last contact, and 
the reason for withdrawal; 
 And disclosure of future information is also withdrawn, the Sponsor may retain and 
continue to use any data collected before such a withdrawal of consent; 
 The subject may request destruction of any samples taken and not tested, and the 
Investigator must document this in the site study records; 
 Study site personnel may use local, regional, and national public records (in 
accordance with local law) to monitor vital status. 
See the Schedule of Assessments (Section 1.3) for data to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed. 

 
 
 
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7.3. 
Lost to Follow-up 
Subjects will be considered lost to follow-up if he/she fails to return for 2 scheduled visits and is 
unable to be contacted by the study site staff.  Before a subject is deemed lost to follow-up, the 
Investigator or designee will make every effort to regain contact with the subject (where 
possible, 3 telephone calls, texts, emails, and if necessary, a certified letter to the subject’s last 
known mailing address or local equivalent methods).  These contact attempts should be 
documented. 
If direct contact with the subject is not possible the site must make every effort to collect disease 
relapse or progression status from public records (eg, obituaries, death certificates, etc.) in 
accordance with local laws. 

 
 
 
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8. 
STUDY PROCEDURES 
See the Schedule of Assessments (Section 1.3).  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 must be performed within 28 days (Part 1) or 42 days (Part 2) before the 
first dose of the study drug, unless otherwise noted. 
If 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. 
8.1. 
Eligibility Assessment 
Review the subject's demographics, medical and target disease history, vital signs, and results of 
tests (eg, physical examination, ECHO/MUGA, ECG, laboratory assessments) and compare 
against the eligibility criteria (Sections 5.1 and 5.2).  If the subject is a screen failure, deactivate 
the subject in the IRT.  See Section 5.3 for rescreening/subject replacement. 
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 should be given the opportunity to ask 
questions and receive responses to their inquiries and should 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.  See Section 10.1.2 for additional details. 
General Medical History and Baseline Conditions 
Subject’s medical history (including TGCT treatment history and smoking history) will be 
obtained by the Investigator or a qualified designee. 
Untoward medical occurrence (including clinically relevant laboratory values that are not 
symptoms of TGCT/vital signs that are out of range) that were diagnosed or known to exist prior 
to the first dose of study medication will be recorded on the General Medical History and 
Baseline Conditions eCRF, not the Adverse Event eCRF.  Record the start date of any medical 
occurrence that started after the ICF was signed and is ongoing at the time of the first dose of 
pexidartinib on the General Medical History and Baseline Conditions eCRF. 
Demographics 
Review the subject’s demographics (including ethnicity and race) against the eligibility criteria. 

 
 
 
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8.2. 
Enrollment 
After all screening procedures have been performed, the results of screening tests are available 
(ie, between the Screening visit and C1D1), and subjects are confirmed to continue to meet all 
eligibility criteria, the eligible subjects will be enrolled in the study to receive pexidartinib.  If 
subjects do not meet the eligibility criteria on the day of enrollment, Investigators must discuss it 
with the Sponsor Clinical Leader or Scientist. 
8.3. 
Efficacy Assessments 
Radiographic Tumor Assessments 
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. 
No confirmation (ie, CR or PR at the subsequent MRI assessment) will be required for a CR or 
PR.  CR and PR will define the 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-week treatment with respect to the primary efficacy endpoint is 
shown in Table 8.1. 
To be considered a response, a tumor must meet the criteria for response and must show 
documented non-progression at Week 25.  A tumor that achieves PR at Week 13 followed by 
neither sufficient shrinkage to qualify for CR nor sufficient increase to qualify for PD (ie, non-
CR/non-PD/non-not evaluable [non-NE]) at Week 25 will be considered a responder for the 
primary efficacy endpoint. 
 

 
 
 
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Table 8.1: 
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-NEa 
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 PD 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 the 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. 
Tumor Imaging 
Noncontrast MRI of the affected joint will be performed at the study visits indicated in the 
Schedule of Assessments (Section 1.3). 
All MRI scans up to Protocol Version 3.0 will be centrally read, while MRI scans from Protocol 
Version 4.0 onwards will not be centrally read.  Local evaluation of radiological response, 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 up to Protocol Version 3.0 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 

 
 
 
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review for evaluation of disease progression.  If a central reading confirms RECIST 1.1 defined 
disease progression, the subject will be discontinued from the study unless the Investigator and 
the DS 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.  While progression status will be assessed only by 
local read from Protocol Version 4.0 onwards.  The details for MRI scan read 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. 
Tumor Volume Score 
TVS is a semi-quantitative MRI scoring system that describes tumor mass and is an extension of 
the 4-point synovitis scale of the well-established and widely used multi-feature score 
(Rheumatoid Arthritis MRI Score), originally developed for rheumatoid arthritis13 and whole-
organ MRI score (WORMS), originally developed for osteoarthritis.14  The extended scale, the 
TVS, will be based on 10% increments of the estimated volume of the maximally distended 
synovial cavity or tendon sheath involved.  Thus, a tumor that is equal in volume to that of a 
maximally distended synovial cavity or tendon sheath will be scored 10, whereas a tumor that is 
70% of that volume will be scored 7, a tumor that is twice the volume of the maximally 
distended synovial cavity or tendon sheath will be scored 20, and so on.  A score of “0” means 
no evidence of tumor. 
Individual subject outcomes by TVS will be classified according to the following criteria 
inspired by RECIST 1.1: 
 CR: 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. 
 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 (Study PLX108-0110).  The tumor response status on this 
endpoint within 24-week treatment is determined in a way similar to that for the primary efficacy 
endpoint (Table 8.1).  To minimize bias and reduce variability, MRIs for the primary 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. 

 
 
 
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Range of Motion Assessment 
ROM 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 the American Medical 
Association disability criteria.15  Measurements will be recorded in degrees.  Details of the 
measurement procedure for each joint will be provided in the manual. 
PROMIS Physical Function Scale 
Subjects will complete the PROMIS Physical Function Scale for the indicated study visits in the 
Schedule of Assessments (Section 1.3). Physical function items relevant to the assessment of 
lower and upper limb function are to be selected from the PROMIS physical function item bank.  
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. 
Brief pain inventory Worst Pain Numeric rating scale Item 
The BPI Worst Pain NRS item is a one-item self-administered questionnaire assessing the 
“worst” pain in the last 24 hours. The NRS for this item ranges from 0 (“no pain”) to 10 (“pain 
as bad as you can imagine”).  
The five-level version of EuroQol five-dimensional questionnaire 
Subjects will complete the five-level version of EuroQol five-dimensional questionnaire (EQ-
5D-5L) for the indicated study visits in the Schedule of Assessments (Section 1.3).  
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.” 
Surgical Assessment Questionnaire 
The surgical assessment questionnaire (Section 10.7.1) will be completed by a qualified 
individual (eg, orthopaedic oncologist) to assess the surgical status of the subject at the 
Screening visit and at the time points shown in the Schedule of Assessments (Section 1.3). 
Analgesic Use and Analgesic Regimen 
Subjects will have a diary in which to record any analgesics, including nonsteroidal anti-
inflammatory drugs and prescription analgesics, taken during the period before investigational 
product initiation and during the time period when the BPI Worst Pain is scheduled for 
completion.  Subjects must have a stable prescribed analgesic regimen during the 2 weeks prior 
to the first dose of the study drug.  During the study, whenever possible, the type and dose of 

 
 
 
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long-acting narcotic analgesic and non-narcotic analgesic should be kept stable while the dose of 
short-acting (or rescue) narcotic analgesic might be titrated as needed.  Analgesic use will be 
quantified by multiplying the daily dose unit by the number of units taken, averaged by the 
number of days with available data.16  For subjects who have changed narcotic type or if dosages 
have been changed in subjects concomitantly receiving different narcotic types, analgesic use 
will be calculated following equianalgesic conversion to morphine-equivalent doses.17  
Analgesic regimen, both prescription and OTC, will be collected in the eCRF in the same 
manner as other concomitant medications. 
Photographic Documentation of Tumor Size Change 
Photographic documentation will be collected to assess change in tumor size based on 
photographs if applicable. 
Long-Term Follow-up Questionnaire 
After completion of the EOS or early termination visit, the LTFU will be performed every 6 
months by telephone contact. The questionnaire is provided in Section 10.7.2. 
8.4. 
Safety Assessments 
8.4.1. 
Adverse Event 
Method to Detect Adverse Events 
The definitions of an AE or serious adverse event (SAE) can be found in Section 10.4.  AEs may 
be directly observed, reported spontaneously by the subject or by questioning the subject (or, 
when appropriate, by a caregiver, surrogate, or the subject’s legally authorized representative) 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.  The Investigator and any qualified designees are responsible 
for detecting, documenting, and recording events that meet the definition of an AE or SAE and 
remain responsible for following AEs that are serious, considered related to the study drug or 
study procedures, or that caused the subject to discontinue pexidartinib. 
All clinical laboratory results, vital signs, and ECG results or findings should be appraised by the 
Investigator to determine their clinical significance.  Isolated abnormal laboratory 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, lead to dose reduction, require 
corrective treatment, or constitute an AE in the Investigator’s clinical judgment. 
Time Period for Collecting Adverse Events, including Adverse Events of Special Interest 
and Serious Adverse Events 
All SAEs occurring after the subject signs the ICF and up to 28 ± 7 days after the last dose of 
study medication (ie, the Follow-up Period), whether observed by the Investigator or reported by 
the subject, will be recorded on the Adverse Event eCRF.  All SAEs will be followed until 
resolution, stabilization, the event is otherwise explained, or the subject is lost to follow-up. 

 
 
 
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All non-serious AEs occurring after the subject has signed the ICF until 28 ± 7 days after the last 
dose of study medication will be recorded on the Adverse Event eCRF. 
Exacerbation of a pre-existing medical condition and symptom after the subject signs the ICF 
including increase in severity of the symptom will be recorded as an AE on the Adverse Event 
eCRF, unless it is a condition of TGCT. 
Reporting Procedure for Investigators 
All AEs (including adverse events of special interests [AESIs] and SAEs) will be reported in the 
Adverse Event eCRF.  All AEs (serious and non-serious) must be reported with the 
Investigator’s assessment of seriousness, severity, and causality to the pexidartinib. 
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. 
Disease-Specific Adverse Events and Serious Adverse Events 
Disease progression/worsening of TGCT will not be recorded as an AE on the Adverse Event 
eCRF.  However, events associated with disease progression, such as joint swelling, may be 
recorded as AEs. 
Death due to disease progression should be recorded on the Death eCRF. 
8.4.1.1. 
Serious Adverse Events Reporting 
The following types of events should be reported by the Investigator in the electronic data 
capture (EDC) or on a Serious Adverse Event Report (SAVER) form within 24 hours of 
awareness: 
 SAEs (Section 10.4.2) 
 AESIs: Liver enzyme elevations and bilirubin elevation including hepatic events 
(both serious and non-serious) meeting the laboratory criteria of a potential Hy’s Law 
criteria (as defined in Section 8.4.1.2) 
 Overdose (Section 8.4.1.1.1) 
Details summarizing the course of the SAE, including its evaluation, treatment, and outcome 
should be provided.  Specific or estimated dates of AE onset, treatment, and resolution should be 
included.  Medical history, concomitant medications, and laboratory data that are relevant to the 
event should also be summarized in the SAE report.  For fatal events, the SAE report should 
state whether an autopsy was or will be performed and should include the results if available.  
Source documents (including medical reports) will be retained at the study site and should not be 
submitted to the Sponsor for SAE reporting purposes. 
If using EDC for SAE reporting: Complete the SAVER Form or the eCRF within 24 hours of 
awareness.  In the event that the eCRF is unavailable, report SAEs by faxing or emailing the 
SAVER Form to Sponsor using the provided fax transmittal form and the appropriate fax number 
provided for your country or email address.  Once EDC becomes available, please enter SAEs 

 
 
 
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reported on the SAVER Form into the eCRF as soon as possible.  Please refer to the eCRF 
Completion Guide for additional instructions. 
Call the local SAE Hotline (see Study Site Manual) or your study monitor for any questions on 
SAE reporting. 
See Section 8.4.1 for details on the time period for collecting SAEs. 
Reporting Requirement to Sites and Regulatory Authorities 
The Sponsor or CRO will inform Investigators and regulatory authorities of any suspected 
unexpected serious adverse reactions (SUSARs) occurring in study sites or other studies of 
pexidartinib, as appropriate per institutional and/or local reporting requirements. 
The Sponsor and/or CRO will comply with any additional local safety reporting requirements.  
The Investigator will assess if an AE is to be considered “unexpected” based on the “Reference 
Safety Information” section in the current IB.10 
Follow-up for Adverse Events and Serious Adverse Events 
The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated to elucidate the nature and/or causality 
of the AE or SAE as fully as possible.  This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health care 
professionals. 
Urgent safety queries must be followed up and addressed promptly.  The Investigator will submit 
any updated SAE data to the CRO or sponsor within 24 hours of receipt of the information.  
Follow-up information and response to non-urgent safety queries should be combined for 
reporting to provide the most complete data possible within each follow-up report. 
8.4.1.1.1. Overdose 
An overdose is defined as the accidental or intentional administration of any dose of a product 
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 will be reported via 
SAVER/overdose form or eCRF. 
An “excessive and medically important” overdose includes any overdose in which either an 
SAE, a non-serious AE, or no AE occurs and is considered by the Investigator as clinically 
relevant, ie, poses an actual or potential risk to the subject. 
8.4.1.2. 
Adverse Events of Special Interest 
The following are considered to be AESIs. 
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 gamma-glutamyl 
transpeptidase (GGT) greater than 2 × ULN 

 
 
 
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 Elevation of total bilirubin greater than ULN 
 Elevation of direct bilirubin greater than ULN 
 Combined Elevations of Aminotransferases and Bilirubin 
Hepatic events (both serious and non-serious) which meet the potential Hy’s Law 
criteria defined as an elevated (ALT and/or AST) ≥3 × ULN and an elevated total 
bilirubin >2 × ULN, regardless if it is due to disease progression per Investigator 
assessment, that may occur at different time points during the study conduct, should 
always be reported to the Sponsor.18 
These events must be reported either by a SAVER form or eCRF, with the investigator’s 
assessment of seriousness, severity, causality, and a detailed narrative.  These events should be 
reported within 24 hours of the investigator’s awareness of the event regardless of seriousness.  
A targeted questionnaire will be available as an eCRF to collect relevant additional information 
for these potential cases. 
If the subject meets the criteria described in Table 6.3 due to liver enzyme abnormalities, the 
subject will have additional clinical and laboratory evaluations as described in Table 6.4 to 
determine the nature and severity of the potential liver injury. 
8.4.2. 
Pregnancy 
Sponsor must be notified of any female subject or partner of a male subject who becomes 
pregnant while receiving or within 90 days of discontinuing pexidartinib. 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.  If a pregnancy is reported, the Investigator should inform the Sponsor 
within 24 hours of learning of the pregnancy. 
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 
partner of a male subject 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 female subject or partner of a male subject 
(upon obtaining written consent from partner) until completion of the pregnancy and complete 
the EIU Reporting Form with complete pregnancy outcome information, including normal 
delivery and induced abortion.  Any adverse pregnancy outcome, either serious or non-serious, 
should be reported in accordance with study procedures.  If the outcome of the pregnancy meets 
the criteria for immediate classification as an SAE (ie, post-partum 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. 
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 Assessments 
(Section 1.3). 

 
 
 
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For postmenopausal subjects (no childbearing potential, as indicated by a lapse 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. 
8.4.3. 
Dose-Limiting Toxicities 
Definition of Dose-Limiting Toxicity 
A DLT is defined as any TEAE not attributable to disease or disease-related processes that 
occurs during the DLT-evaluation period Day 1 to Day 28 in Cycle 1 of Part 1 and is Grade 3 or 
above, according to the National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI-CTCAE) version 5.0, with the exceptions defined in Table 8.2 below. 
Table 8.2: 
Dose-Limiting Toxicities 
Category 
Definition 
Hematological toxicities 
 
Grade 4 decreased neutrophil count lasting >7 days or a 
decreased neutrophil count that requires standard therapies, 
such as colony stimulating factor 
 
Grade ≥3 febrile neutropenia 
 
Grade 4 anemia 
 
Grade ≥3 anemia associated with transfusion 
 
Grade 4 decreased platelet count 
 
Grade ≥3 decreased platelet count lasting >7 days 
 
Grade ≥3 decreased platelet count with clinically relevant 
hemorrhage 
 
Grade ≥3 decreased platelet count associated with 
transfusion 
 
Grade 4 decreased lymphocyte count lasting ≥14 days 
Hepatic organ toxicities 
 
Grade 4 increased serum AST or serum ALT 
 
AST or ALT ≥ × 3 ULN, if accompanied by ≥2 × ULN in 
total bilirubin 
 
AST or ALT > × 5 ULN lasting >14 days 
Non-hematological, non-
hepatic major organ toxicities 
 
Symptomatic congestive heart failure 
 
LVEF decline to <40% or >20% drop from baseline 
Other 
Inability to complete at least 75% of the prescribed doses in 
Cycle 1 as a result of Grade ≥2 AE not attributed to disease 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; LVEF = left ventricular ejection fraction; 
ULN = upper limit of normal 
Toxicities will be graded according to the NCI-CTCAE version 5.0.  If multiple toxicities are 
encountered, then DLT assessment will be based on the most severe toxicity experienced.  With 
regard to other toxicities that impact the conduct of the scheduled study treatment whether they 

 
 
 
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are regarded as DLT will be determined based on consultation between the Investigator and 
Sponsor. 
The following TEAEs are NOT considered DLTs: 
 Grade 3 fatigue lasting <7 days; 
 Grade 3 nausea, vomiting, diarrhea, or anorexia that has resolved to Grade ≤2 within 
3 days; 
 Isolated laboratory findings not associated with signs or symptoms including Grade 
3/4 hyperuricemia, increased serum amylase, increased lipase, and Grade 3 
hyponatremia lasting <72 hours which has increased from Grade 1 at baseline; 
 Grade 3 decreased lymphocyte count. 
Study drug must be withheld for any subject who experiences a DLT but may resume at the same 
or lower dose level, after the toxicity has resolved or improved and following discussion between 
the Investigator(s) and the Sponsor based on Table 6.3. 
Premedication, (any treatment administered prior to study treatment administration to avoid 
TEAEs) is prohibited during the DLT evaluation period.  
Unscheduled visits should include all of the protocol scheduled procedures for that particular 
cycle/week, to ensure safety parameters are continuous throughout the subject’s study 
participation.  These visits should include but are not limited to the following assessments: 
confirming medical history conditions that were ongoing at the previous visit are still ongoing, 
physical examinations, vital signs, weight, clinical laboratories, and AEs.  Visits occurring 
during the study weeks where drug is held will be recorded as additional week(s) of the 
concurrent cycle. 
Subjects missing more than 25% of scheduled doses in the DLT period for reasons not related to 
AEs (eg, noncompliance) will not be evaluable for DLT. 
8.4.4. 
Clinical Laboratory Evaluations 
Clinical laboratory evaluations will be performed at the local laboratory at the study visits 
indicated in the Schedule of Assessments (Section 1.3).  For clinical laboratory parameters, the 
reference range of the institution that performs the measurement will be used.  Refer to 
Section 10.2 for the complete list of laboratory parameters. 
New or worsened clinically relevant abnormalities should be recorded as AEs on the Adverse 
Event eCRF. 
Others 
A serum sample must be collected for anti-mitochondrial antibody (AMA) at Screening and 
when severe hepatotoxicity is observed (Section 6.5). 

 
 
 
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8.4.5. 
Other Safety 
Physical Examinations, Weight, and Height 
The examination will be performed by a qualified individual such as the Investigator at the study 
visits indicated in the Schedule of Assessments (Section 1.3). 
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. 
Weight will be measured at the study visits mentioned in the Schedule of Assessments (Section 
1.3).  Height will be measured at the Screenings visit only. 
Vital Signs 
Vital signs, including systolic/diastolic blood pressures, pulse rate and temperature will be 
measured in accordance with the institutional standards and generally must be performed before 
any invasive procedures, eg, blood sampling.  Vital signs will be measured at the study visits 
mentioned in the Schedule of Assessments (Section 1.3).  
Blood pressure 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. 
Electrocardiograms 
A standard 12-lead ECG will be obtained at the study visits indicated in the Schedule of 
Assessments (Section 1.3). 
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 findings 
must be recorded in 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 the study drug; instead, they must be told to bring their bottle of the study drug to the site 
and take the morning dose upon instruction by the site staff. 
Whether or not measurement is performed, the date performed, results, and findings for the 
parameters will be recorded in the eCRF. 
Multi-gated Acquisition Scan or Echocardiogram 
MUGA/ECHO must be performed as per the Schedule of Assessments (Section 1.3). Subjects 
must have a LVEF ≥50% to be eligible for the study.  In this protocol, “ECHO scan” and 

 
 
 
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“MUGA scan” will be used interchangeably.  The choice of whether to perform ECHO or 
MUGA scan will be based on the preference of the investigator, but the platforms should not be 
switched during the course of a subject’s study participation.  Clinically important findings, 
including LVEF, will be recorded in the appropriate eCRF. 
8.5. 
Pharmacokinetic (PK) Assessment(s) 
Blood samples for PK analyses will be obtained at the time points shown in Table 8.3. 
Plasma concentration-time profiles of pexidartinib and ZAAD-1006a will be established based 
on the blood PK samples collected on C1D1, C1D15 intensively and on C2D1, C3D1, C5D1 
sparsely both in Part 1 and Part 2. 
Plasma concentrations of pexidartinib and ZAAD-1006a will be measured using validated assays 
at the bioanalytical laboratory. 
Table 8.3: 
Schedule of PK Sample Collection 
Visit 
Schedule 
Week 1 C1D1 - C1D2 
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) 
8 h postdose (± 20 min) 
24 hours post-dose (within 3 hours pre-dose on 
C1D2) 
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) 
Week 5 C2D1 
Predose  
Random postdose 
Week 9 C3D1 
Predose  
Random postdose 
Week 17 C5D1 
Predose  
Random postdose 
C = Cycle; D = Day; h = hour; min = minutes 
Plasma-concentration data of pexidartinib and ZAAD-1006a on C1D1 and C1D15 (Week 3) will 
be analyzed for the PK analysis set using standard non-compartmental methods.  The following 
PK parameters will be calculated. 
C1D1: Cmax, Tmax, AUC6h, AUC24h, AUClast, AUCinf*, Kel*, t1/2*, CL/F*, Vz/F* 

 
 
 
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C1D15: Cmax, Tmax, AUC6h, Ctrough AR 
*: To be calculated only if possible. 
The PK parameters of pexidartinib will be listed for each subject and summarized using 
descriptive statistics. 
The actual times of study drug administration and the exact time of blood sampling for PK 
analysis must be recorded in the eCRF. 
Detailed instructions for the collection, handling, and shipping of samples are outlined in the 
Study Laboratory Manual. 
Population Pharmacokinetic Analysis and Exposure-Response Analysis 
Plasma-concentration data from these samples will be analyzed applying a population 
pharmacokinetic (PopPK) approach using nonlinear mixed effects modeling by pooling with data 
of other studies to assess and characterize the inter- and intra-subject variability of PK and to 
identify significant covariates.  These analyses will be summarized in a separate report. 
Bayesian individual exposures of pexidartinib from the PopPK analysis will be used to explore 
the relationship between exposure metrics and biomarkers and safety and efficacy endpoints.  
The results of these analyses will be reported separately from the Clinical Study Report (CSR). 
8.6. 
Biomarker Assessments 
8.6.1. 
Biomarker Analysis for Pharmacodynamics* 
 CSF-1 and IL-34 concentrations will be measured by enzyme-linked immunosorbent 
assay (ELISA) in plasma samples collected pre-, on and at end of treatment. 
 Profile of immune cells will be evaluated with flow cytometry using blood samples 
collected pre-, on and at end of treatment. 
 Profile of immune cells will be evaluated with immunohistochemistry using tumor 
biopsies collected pre- (mandatory), on and at end of treatment (optional).  For pre-
treatment biopsies, archived tumor samples will be acceptable instead of freshly 
collected biopsies. 
*: Sample collection will not be performed from Protocol Version 4.0 onwards. 
8.6.2. 
Biomarker Analysis for Subject Characterization* 
 The status of CSF-1 rearrangements pre-treatment will be evaluated with either 
fluorescence in situ hybridization (FISH), DNA sequencing or RNA sequencing of 
tumor samples. 
 The profile of tumor-infiltrating immune cells will be evaluated with 
immunohistochemistry and/or flow cytometry of biopsied tissue and blood samples 
collected pre-treatment. 

 
 
 
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 The profile of drug-metabolizing enzyme and transporter gene mutations will be 
evaluated with Thermo Fisher Pharmacoscan™ assay in blood samples collected pre-
treatment. 
 The status of CSF1R gene mutation will be evaluated with next generation 
sequencing (NGS) in blood samples collected pre-treatment. 
*: Sample collection will not be performed from Protocol Version 4.0 onwards. 
The results of these biomarker analyses will be reported separately from the CSR. 
8.6.3. 
Biomarker Analysis Potential for In Vitro Diagnostics / Companion Diagnostics 
Not applicable. 
8.6.4. 
Additional Biomarker Assessments 
The remaining samples of each subject who consented will be stored for a maximum of 15 years 
after the finalization of the CSR for this protocol. 
Biopsied tissue sample banking for future biomarker analyses, which may include 
comprehensive gene mutation and gene expression profiling with NGS and /or RNA-sequencing. 
8.6.5. 
Pharmacogenomic (Inherited Genetic) Analysis 
A single blood sample for pharmacogenetic analysis will be collected pre-treatment from each 
randomized subject.  Detailed instructions for the collection, handling, and shipping of samples 
are outlined in the Study Laboratory Manual.  The pharmacogenetic analysis is as follows; 1) 
Profile of drug-metabolizing enzyme and transporter gene mutations will be evaluated with 
Thermo Fisher Pharmacoscan™ assay in blood samples collected pre-treatment. 2) Status of 
CSF1R gene mutation will be evaluated with NGS in blood samples collected pre-treatment, as 
described in Section 8.6.2. 
Genetic analyses will not be performed on whole blood samples collected for PK or safety 
assessments unless consent for this was obtained.  Subject confidentiality will be maintained.  If 
the subjects agree, the remaining DNA will be stored, as outlined in Section 8.6.5.1 to perform 
pharmacogenetic analysis in the future, otherwise all remaining DNA samples will be destroyed. 
8.6.5.1. 
Banking of Specimens for Inherited Genetic Analysis 
Procedures for the long-term preservation (banking) of blood and/or DNA specimens extracted 
from subjects’ blood samples for each subject who consented are described in the Study 
Laboratory Manual. 
The banked samples may be analyzed for genes involved in absorption, distribution, metabolism, 
elimination, safety, and efficacy of pexidartinib.  Additionally, samples may be analyzed for 
genes involved in pexidartinib-related signaling pathways, or to examine diseases or physiologic 
processes related to pexidartnib.  This information may be useful in increasing the knowledge of 
differences among individuals in the way they respond to the study drug, as well as helping in 
the development of new drugs or improvement of existing drugs. 

 
 
 
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Storage and Disposal of Specimens 
Banked DNA samples will be stored for a maximum of 15 years after the finalization of the CSR 
for this protocol.  These specimens will be kept for pharmacogenetic analysis in case new 
genomic or genetic information is obtained in the future regarding the response (PK or 
pharmacodynamic [Pdy]) to pexidartinib or in case serious adverse drug reactions are noted in a 
clinical study and pharmacogenetic analysis is to be conducted for investigation into the cause. 
During the storage period, the samples will be coded with labels having no personal information 
and will not be immortalized or sold to anyone.  Subjects will have the right to withdraw consent 
and have their sample destroyed at any time.  However, the data will not be discarded if analysis 
has been completed before the subject withdraws consent. 
Disclosure of the Results of Future Pharmacogenetic Analysis 
Because the nature and value of future pharmacogenetic analysis cannot be known at this time, 
any results obtained from research involving pharmacogenetic samples will not be disclosed to 
the subject or Investigators now or in the future. 

 
 
 
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9. 
STATISTICAL CONSIDERATIONS  
9.1. 
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. The final analysis of the study will occur after 
all subjects have discontinued the study. Data collected beyond the primary analysis cut-off time 
point will be presented as appropriate in a CSR addendum. 
The data cutoff for safety and PK analysis in Part 1 will occur after all subjects have received 
pexidartinib and have either completed the minimum safety evaluation requirements over the 
DLT evaluation period (28 days) or have experienced a DLT during the DLT evaluation period. 
Data analysis will also be conducted separately by Part 1 and Part 2. The pooled analysis may be 
planned in the Statistical Analysis Plan (SAP). 
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 
non-missing value of a variable taken before the first dose of the 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 and secondary efficacy endpoints, with the exception of duration of response, the 
point estimate and accompanying 95% CI will be computed.  For duration of response, Kaplan-
Meier product limit methodology will be utilized to provide estimates, including those for the 
median and 25th and 75th percentiles. 
No formal interim analysis is planned in Part 1 or Part 2.  
 
For all analysis, the Part 1 data at the end of Part 1 will be used. 
The all analysis including the efficacy analysis of the subjects in Part 1 was originally planned to 
be performed at the end of Part 2.  However, the sponsor decided not to proceed with Part 2. 
Depending on this decision, the Part 1 data will be analyzed at the end of Part 1, and the efficacy 
analysis will be performed as the exploratory analysis. 
9.2. 
Statistical Hypothesis 
In Part 1: 
The following is the hypothesis in Part 1, but there is no specific statistical criteria to evaluate 
this hypothesis:  
Treatment with pexidartinib (800 mg/day [400 mg BID]) will be well tolerated in Japanese 
TGCT patients. 
In Part 2: 

 
 
 
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The following is the hypothesis in Part 2, but there is no specific statistical criteria to evaluate 
this hypothesis: 
Treatment with pexidartinib (800 mg/day [400 mg BID]) will present an acceptable and 
manageable safety profile in Japanese TGCT patients. 
There is no formal statistical hypothesis. 
In June 2024, the sponsor decided not to proceed with Part 2.  Therefore, the statistical 
hypothesis for Part 2 will not be confirmed. 
9.3. 
Sample Size Determination 
In Part 1: 
Sample size was determined based on practical considerations and no formal statistical 
assessment has been performed.  The total sample size is 3 to 6 DLT evaluated subjects. 
In Part 2: 
15 subjects.  
The assumed ORR of the primary endpoint is 37.7% based on the ORR for pexidartinib in the 
ENLIVEN study.  Based on the use of a one-side, exact binomial test of a proportion against the 
null hypothesis of 5% at the one-sided alpha = 0.05 level of significance, a sample size of 13 
subjects provides more than 90% power to detect this magnitude of difference.  
The sample size calculation was performed in SAS version 9.4. 
9.4. 
Population for Analysis Sets 
Analysis Sets 
 The Full Analysis Set (FAS) will include all subjects who received at least 1 dose of 
pexidartinib. 
 The Safety Analysis Set will include all subjects who received at least 1 dose of 
pexidartinib. The safety analysis set and FAS are identical in this study. 
 The DLT Evaluable Set will include all subjects who received at least 1 dose of 
pexidartinib and experienced a DLT prior to Day 28 of Cycle 1 or completed the DLT 
evaluation period (Day 1 of Cycle 1 to Day 28 of Cycle 1). 
 The PK Analysis Set will include all subjects who received at least 1 dose of 
pexidartinib and had measurable plasma concentrations of pexidartinib. 
 The Biomarker Analysis Set will include all subjects who received at least 1 dose of 
pexidartinib and had Pdy biomarker evaluation. 
The DLT evaluable set will be used for analysis in Part 1.  Other analysis sets will be used both 
in Part 1 and Part 2.  

 
 
 
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9.5. 
Statistical Analysis 
The SAP will be developed and finalized before database lock and will describe the subject 
populations to be included in the analyses, and procedures for accounting for missing, unused, 
and spurious data.  This section is a summary of the planned statistical analyses of the primary, 
secondary and exploratory endpoints. 
9.5.1. 
Efficacy Analyses 
Table 3.1 lists the primary and secondary efficacy endpoints and their corresponding definitions 
of all endpoints.  Additional details for the analysis is noted in the following sections. 
 
In June 2024, the sponsor decided not to proceed with Part 2.  Therefore, the primary efficacy 
analysis and the secondary efficacy analysis will be performed as the exploratory efficacy 
analysis using Part 1 data. 
9.5.1.1. 
Primary Efficacy Analyses 
The primary efficacy analysis will be based on the data from FAS in Part 2.  
The primary efficacy endpoint is shown in Table 8.1.  It will be the proportion of subjects who 
achieved a CR or PR (ORR) based on RECIST 1.1 by centrally reviewed MRI scan. No 
confirmation (ie, CR or PR at the subsequent MRI assessment) will be required for a CR or PR.  
The estimate of the proportion and two-sided 95% CI based on the Clopper-Pearson method will 
be provided. 
Additional subgroup analyses to assess the homogeneity of the treatment effect based on 
demographic and baseline disease characteristics may be performed; details about the subgroups 
to be included will be provided in the study SAP. 
9.5.1.2. 
Secondary Efficacy Analyses 
The secondary efficacy endpoints will be provided in Part 2: 
 Proportion of TVS responders who achieve a CR or PR at Week 25 based on TVS by 
centrally reviewed MRI scan 
 Mean change from baseline in ROM of the affected joint, relative to a reference 
standard for the same joint at Week 25 
 Mean change from baseline in the PROMIS Physical Function Scale at Week 25 
 Proportion of BPI responders based on the BPI Worst Pain NRS item and analgesic 
use by BPI-30 definition (subject who (i) experienced a decrease of at least 30% in 
the mean BPI Worst Pain NRS item and (ii) did not experience a 30% or greater 
increase in narcotic analgesic use when compared to baseline) 
 Best overall response (BOR) based on RECIST 1.1 by centrally reviewed MRI scan 
 BOR based on TVS by centrally reviewed MRI scan 
 Duration of response (DoR) based on RECIST 1.1 by centrally reviewed MRI scan 

 
 
 
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 DoR based on TVS by centrally reviewed MRI scan 
A brief description of each analysis is provided below: 
 An estimate of the proportion of TVS responders and BPI responders and the two-
sided 95% CI based on the Clopper-Pearson method will be calculated.  Subjects who 
do not provide data for each endpoint will be considered to be non-responders. 
 Change from baseline in ROM and PROMIS will also be summarized with point 
estimates and 95% CIs. 
 The percentage and 95% CI will be provided for the BOR 
 DoR will also be analyzed as a secondary endpoint and will be summarized only for 
responders based on RECIST 1.1 and TVS.  For subjects who do not have 
radiological progression, the duration of response will be censored.  Subjects not 
known to have experienced an event at the time of data cut-off will be censored at the 
date of the last tumor assessment before the cut-off date.  The SAP includes 
additional censoring rules.  The Kaplan-Meier product limit method will be used to 
compute the estimate and 95% CI of the median and 25th and 75th percentiles. 
9.5.1.3. 
Exploratory Analyses 
The exploratory efficacy endpoints will be provided in Part 2: 
 Proportion of subjects who achieve a CR or PR (ORR) at Week 25 based on RECIST 
1.1 by locally reviewed MRI scan. 
 Proportion of subjects who achieve a CR or PR (ORR) at Week 25 based on modified 
RECIST 1.1- sum of the short-axis dimension (SSD) by centrally reviewed MRI scan.  
 Mean change from baseline score in the EQ-5D-5L at Week 25 
 BOR based on RECIST 1.1 by locally reviewed MRI scan 
 DoR based on RECIST 1.1 by locally reviewed MRI scan 
 DoR based on modified RECIST 1.1-SSD by centrally reviewed MRI scan 
A brief description of each analysis is provided below: 
 An estimate of the proportion responders based on (i) RECIST 1.1 by local and (ii) 
modified RECIST 1.1-SSD by central evaluation and the two-sided 95% CI based on 
the Clopper-Pearson method will be calculated.  Subjects who do not provide data for 
the endpoint will be considered to be non-responders. 
 Change from baseline in EQ-5D-5L will also be summarized with point estimates and 
95% CIs. 
 The percentage and 95% CI will be provided for BOR in the order of CR, PR, SD, 
PD, and NE. 
 DoR will also be analyzed as a secondary endpoint and will be summarized for 
responders based on (i) RECIST 1.1 by local and (ii) modified RECIST 1.1-SSD by 
central evaluation.  For subjects who do not have radiological progression, the 

 
 
 
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duration of response will be censored.  Subjects not known to have experienced an 
event at the time of the data cut-off will be censored at the date of the last tumor 
assessment before the cut-off date.  The SAP includes additional censoring rules.  The 
Kaplan-Meier product limit method will be used to compute the estimate and 95% CI 
of the median and the 25th and 75th percentiles.   
Exploratory efficacy analyses will also be performed in Part 1.  
9.5.1.4. 
Multiplicity Adjustment 
Not applicable 
9.5.2. 
Safety Analyses 
Safety analyses will be performed using the Safety Analysis Set and subjects will be analyzed 
according to their actual treatment received in each Part except for DLT analyses. 
Safety analyses in general will be descriptive and will be presented in tabular format with the 
appropriate summary statistics.  
Dose-limiting Toxicities 
The number of DLTs identified among the DLT-evaluable subjects in the DLT Evaluable Set will be 
listed and summarized. 
Adverse Events 
TEAEs are defined as new AEs or pre-existing conditions that worsen in CTCAE grade after the 
first dose of study drug and up to 28 day after the last dose of study drug.  AEs collected after 28 
days after the last dose of study drug will not be considered TEAEs unless they are treatment-
related.  AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
dictionary.  An AE will be assigned to the study period in which it started, even if it resolved in a 
subsequent period.  The number and percentage of subjects reporting TEAEs will be calculated 
overall, by system organ class, and by preferred term. 
TEAEs will be further summarized by CTCAE grade and relationship to study drug.  Similarly, 
the number and percentage of subjects reporting treatment-emergent SAEs and related treatment-
emergent SAEs will be tabulated, treatment-emergent AESIs, and TEAEs associated with 
discontinuation of study drug. 
A by-subject AE (including treatment-emergent) data listing including but not limited to 
verbatim term, preferred term, system organ class, CTCAE grade, and relationship to study drug 
will be provided.  Deaths, other SAEs, AESIs, and AEs associated with study drug 
discontinuation, will be listed. 
Clinical Laboratory Evaluation 
Descriptive statistics will be provided for the clinical laboratory results by scheduled time of 
evaluation as well as for the change from baseline.  The baseline value is defined as the last non-
missing value before the initial administration of study drug.  In addition, mean change from 

 
 
 
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baseline will be presented for the maximum and minimum post-treatment values and the values 
at the end of treatment visit. 
Additionally, for ALT, AST, total bilirubin, direct bilirubin, and ALP, the number and 
percentage of subjects who meet the criteria specified in the FDA Drug-Induced Liver Injury 
guideline18 will be tabulated and evaluation of the drug-induced serious hepatotoxicity plot will 
also be provided.   
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 two-way frequency tabulation for baseline and the worst post-treatment value according to 
the CTCAE grade, will be provided for clinical laboratory tests.  A listing of abnormal clinical 
laboratory test results deemed of clinical significance or of Grade 3 or 4 will be generated. 
Electrocardiogram 
Descriptive statistics will be provided for the ECG measurements by scheduled time of 
evaluation, as well as for the change from baseline.  The baseline value is defined as the last non-
missing value before the initial administration of study drug.  In addition, the number and 
percentage of subjects with ECG interval values meeting the criteria will be tabulated (eg, 
corrected QT interval [QTc] ≤450 ms, >450 to ≤480 ms, >480 ms to ≤500 ms, and >500 ms). 
A listing of ECG data will be generated. 
Vital Signs and Weight 
Descriptive statistics will be provided for the vital signs measurements and weight by scheduled 
time of evaluation, as well as for the change from baseline.  The baseline value is defined as the 
last non-missing value before the initial administration of study treatment.  A listing of vital sign 
and weight data will be generated. 
Other 
Listings of all other safety endpoints (eg, ECHO/MUGA) will be generated. 
9.5.3. 
HEOR Analysis  
Not applicable 
9.5.4. 
Other Analyses 
The following other analyses are planned in this study. 
Pharmacokinetics 
Pharmacokinetics analyses will be performed using the PK Analysis Set.  Plasma concentrations 
for pexidartinib and ZAAD-1006a will be listed, plotted, and summarized using descriptive 
statistics for each study day, dose, and time points.  Pharmacokinetic parameters will be listed 
and summarized using descriptive statistics.  These may include PopPK and PK/PD modeling 
and/or exposure-response analyses in a separate report, to characterize the relationship between 
exposure and PD endpoints and clinical outcomes. 

 
 
 
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Pharmacodynamics / Biomarkers 
Pdy and biomarker analyses will be performed on the Biomarker analysis set. 
Concerning pexidartinib-related biomarkers, for categorical data, frequency tables at each time 
point, and shift tables showing changes from before the start of treatment with pexidartinib will 
be prepared; for quantitative data, summary statistics of measured values and changes from pre-
treatment will be calculated at each time point, and the time courses will be depicted in figures. 
9.6. 
Interim Analyses 
Not applicable. 
 

 
 
 
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10. 
APPENDICES - SUPPORTING DOCUMENTATION AND 
OPERATIONAL CONSIDERATIONS  
10.1. 
Appendix 1 Regulatory and Ethical Considerations 
10.1.1. 
Regulatory Compliance 
The study protocol, the Investigator Brochure, available safety information, recruitment 
procedures (eg, advertisements), subject information and consent form, any subject written 
instructions to be given to the subject, information about payments and compensation available 
to the subjects, and documentation evidencing the Investigator’s qualifications should be 
submitted to the independent institutional review board (IRB) or ethical committee (EC) for 
ethical review and approval according to local regulations, prior to the study start.  The written 
approval should 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.  Written approval of all protocol amendments and changes to any of 
the above listed documents must be obtained from the IRB or EC. 
The Investigator should notify the IRB or EC of deviations from the protocol or SAEs occurring 
at the study site and other AE reports received from the Sponsor/CRO, in accordance with local 
procedures. 
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, the International Council for Harmonisation (ICH) 
consolidated Guideline E6 for Good Clinical Practice (GCP) (CPMP/ICH/135/95), and 
applicable regulatory requirement(s) including the following: 
 European Commission Directive (2001/20/EC Apr 2001) and/or; 
 European Commission Directive (2005/28/EC Apr 2005) and/or; 
 US FDA GCP Regulations: Code of Federal Regulations (CFR) Title 21, parts 11, 50, 
54, 56 and 312 as appropriate and/or; 
 Japanese Ministry of Health, Labor and Welfare Ordinance No. 28 (27 Mar 1997) 
and/or; 
 The Act on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical 
Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products, and 
Cosmetics No. 1 (25 Nov 2014); 
 Other applicable local regulations. 
In addition, the Investigator will inform the Sponsor in writing within 24 hours 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. 

 
 
 
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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, the Sponsor will inform all Investigators involved in the clinical study, 
independent ethics committees (IECs)/IRBs, and regulatory authorities of such information, and 
when needed, will amend the protocol and/or subject information. 
The Investigator should 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 should be documented on medical 
records, for example, and it should 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 
should 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 explanations and the subject should sign and date 
the revised ICF. 
10.1.2. 
Informed Consent 
In obtaining and documenting informed consent, the Investigator should comply with the 
applicable regulatory requirements, and should adhere to GCP and to the ethical principles that 
have their origin in the Declaration of Helsinki.  The ICF and any revision(s) should be approved 
by the IEC/IRB prior to being provided to potential subjects. 
The subject’s written informed consent should be documented in the subject’s medical records.  
The ICF should 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 
should be retained in accordance with institutional policy, and a copy of the signed ICF should 
be provided to the subject.  The date and time (if applicable) that informed consent was given 
must be recorded in the eCRF. 
If the subject cannot read, then according to ICH GCP Guideline, Section 4.8.9, an impartial 
witness should be present during the entire informed consent discussion.  This witness should 
sign the ICF after the subject has consented to their participation.  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. 
A separate special consent for inherited genetic analysis will be obtained from subjects in 
accordance with health authorities in their particular region/country. 
Suggested model text for the ICF for the study and any applicable subparts (PK, Pdy, etc.) is 
provided in the Sponsor’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 the 
Sponsor. 

 
 
 
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10.1.3. 
Subject Confidentiality 
The Investigators and the Sponsor 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 the Sponsor or the CRO, subjects should be identified by a unique SID 
as designated by the Sponsor.  Documents that are not for submission to the Sponsor 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 
independent IRB/EC 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. 
10.1.4. 
Data Integrity and Quality Assurance 
Monitoring and Inspections 
The 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, eCRFs, 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 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 deviations from the protocol, SOPs, 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 the sponsor and 
documented. 
In accordance with ICH GCP and the Sponsor’s audit plans, this study may be selected for audit 
by representatives from the Sponsor.  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, the Sponsor shall be notified immediately. 

 
 
 
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Data Collection 
An eCRF must be completed for each subject who signs an ICF and undergoes any screening 
procedure.  If a subject is not treated, the reason must be recorded on the eCRF.  All data 
collected during the study will be recorded in this individual, subject-specific eCRF.  Instructions 
will be provided for the completion of the eCRF and any corrections made will be automatically 
documented via an “audit trail.” 
The eCRF should be kept current to enable the study monitor to review the subject’s status 
throughout the course of the study.  Upon completion of the subject’s eCRF, it will be reviewed 
and signed off by the Investigator via the EDC system’s electronic signature.  This signature will 
indicate that the Investigator inspected or reviewed the data in the subject-specific eCRF, the 
data queries, and the site notifications and agrees with the eCRF content. 
Data Management 
Each subject will be identified in the database by a unique SID. 
To ensure the quality of clinical data across all subjects and study sites, a DS/CRO Clinical and 
Data Management review will be performed on subject data according to specifications 
developed by the Sponsor.  Data will be vetted both electronically by programmed data rules 
within the application and manually.  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 will be reconciled to the clinical database. 
All AEs will be coded using MedDRA.  SAEs in the clinical database will be reconciled with the 
safety database. 
All concomitant medications and prior therapies will be coded using the World Health 
Organization Drug Reference (WHODRUG) Dictionary. 
10.1.5. 
Committees 
Safety Monitoring Committee 
The SMC will be established for the purpose of assessing safety and tolerability of the subjects.  
The SMC meetings will be held after a certain number of the enrolled subjects in Part 1 have 
completed the DLT evaluation period.  Ad hoc meetings will be held to discuss subject safety 
and DLT determination as needed. 
The SMC will evaluate progress of the study, assess safety and other relevant information, and 
then make recommendations on study continuation or discontinuation.  The SMC members may 
include the Sponsor or external medical experts, the Sponsor’s clinical leader, and Investigators 
of study sites.  Detailed procedures of the SMC will be specified in the SMC Charter. 
Hepatic Adjudication Committee 
An external hepatic adjudication committee (HEAC) will be used for evaluating important 
hepatic AEs.  Details on the membership, responsibilities, and working procedures of the 
external HEAC will be described in a separate charter.  This additional data collection will cover 

 
 
 
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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. 
10.1.6. 
Study Documentation and Storage 
The Investigator will maintain a Signature List of appropriately qualified persons to whom 
he/she has delegated study duties.  All persons authorized to obtain informed consent and make 
entries and/or corrections on eCRFs will be included on the Signature List. 
Investigators will maintain a confidential screening log of all potential study candidates that 
includes limited information of the subjects, date and outcome of the screening process. 
Investigators will be expected to maintain an Enrollment Log of all subjects enrolled in the study 
indicating their assigned study number. 
Investigators will maintain a confidential subject identification code list.  This confidential list of 
names of all subjects allocated to study numbers on enrolling in the study allows the Investigator 
to reveal the identity of any subject when necessary. 
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. 
Electronic CRF 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, IEC/IRB 
correspondence and approvals, approved and signed ICFs, Investigator’s Agreement, clinical 
supplies receipts, distribution and return records), and other Sponsor correspondence pertaining 
to the study must be kept in appropriate study files at the study site (site specific 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 local 
laws or regulations or study site policy.  Prior to transfer or destruction of these records, the 
Sponsor must be notified in writing and be given the opportunity to provide further instruction. 
Record Keeping 
The Investigator and study staff are responsible for maintaining a comprehensive and centralized 
filing system (site specific Trial Master File) of all study-related (essential) documentation, 
suitable for inspection at any time by representatives from the Sponsor and/or applicable 
regulatory authorities.  Essential documents include: 
 Subject files containing completed eCRFs, ICFs, and supporting source 
documentation (if kept). 

 
 
 
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 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 independent IRB/EC and the Sponsor. 
 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 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 laws or 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. 
Subjects’ 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 the Sponsor 
and the Investigator.  Should the Investigator wish to assign the study records to another party or 
move them to another location, he/she must notify the Sponsor in writing of the new responsible 
person and/or the new location. 
10.1.7. 
Finances 
Prior to starting the study, the Principal Investigator and/or Institution will sign a clinical study 
agreement with DS.  This agreement will include the financial information agreed upon by the 
parties. 
Reimbursement, Indemnity, and Insurance 
The Sponsor 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. 
10.1.8. 
Publication, Public Disclosure Policy, and Data Sharing 
The Sponsor is committed to meeting the highest standards of publication and public disclosure 
of information arising from clinical studies sponsored by the company.  The Sponsor will 
comply with US, EU, and Japanese policies for public disclosure of the clinical study protocol 
and clinical study results, and for sharing of clinical study data.  The Sponsor will 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). 

 
 
 
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In order to ensure 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 disclosures) based on data generated in this 
study must be reviewed and approved in writing by the Sponsor prior to submission. 
The data from this study may be shared with or used by third parties, including commercial 
partners. 
10.1.9. 
Protocol Deviations 
The Investigator should conduct the study in compliance with the protocol agreed to by the 
Sponsor and, if required, by the regulatory authority(ies), and which was given 
approval/favorable opinion by the IECs/IRBs. 
A deviation to any protocol procedure or waiver to any stated criteria will not be allowed in this 
study except where necessary to eliminate immediate hazard(s) to the subject. 
The Sponsor must be notified in writing of all intended or unintended deviations to the protocol 
(eg, inclusion/exclusion criteria, dosing, missed study visits) within 24 hours or in accordance 
with the clinical study agreement between the parties. 
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 study drug, data should be collected for safety purposes. 
If applicable, the Investigator should notify the IEC/IRB of deviations from the protocol in 
accordance with local procedures. 
10.1.10. 
Study and Site Closure 
The Sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the Sponsor.  Study sites will be closed upon study completion.  A 
study site is considered closed when all required documents and study supplies have been 
collected and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
 Failure of the Investigator to comply with the protocol, the requirements of the 
IEC/IRB or local health authorities, the Sponsor’s procedures, or GCP guidelines 
 Inadequate recruitment of subjects by the Investigator 
 Discontinuation of further study intervention development 
10.2. 
Appendix 2: Local Laboratory 
The clinical laboratory tests listed in Table 10.1 are to be performed in this study. 

 
 
 
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Table 10.1: 
Clinical Laboratory Tests 
Test 
Analytes 
 
Blood Chemistry 
albumin 
blood urea nitrogen (BUN)/urea 
calcium (Ca) 
chloride (Cl) 
creatinine clearance (CLCR)/creatinine 
cholesterol (total)* 
glucose* 
HCO3-** 
lactate dehydrogenase 
lipoprotein, high density (HDL)* 
lipoprotein, low density (LDL)* 
phosphorus 
potassium (K) 
protein (total) 
sodium (Na) 
triglycerides* 
uric acid 
<Liver Function Tests> 
alanine aminotransferase (ALT) 
alkaline phosphatase (ALP) 
aspartate aminotransferase (AST) 
 
bilirubin (total) 
bilirubin (direct) 
gamma-glutamyl transaminase (GGT) 
Hematology 
hemoglobin 
hematocrit 
platelet count 
red blood cell (RBC) count 
white blood cell (WBC) count with 
differential 
Coagulation 
prothrombin time (PT) 
prothrombin time (PT)- international normalized ratio (INR) 
activated partial thromboplastin time (aPTT) 
Urinalysis 
(dipstick and 
microscopic 
analysis) 
glucose/sugar 
hemoglobin/blood 
ketones/acetone 
nitrites 
pH 
protein/albumin 
sediments: 
bacteria, casts, crystals, epithelial 
cells, RBCs, WBCs 
Hormone 
<Females> 
estradiol 
follicle stimulating hormone (FSH) 
luteinizing hormone (LH) 
progesterone 
<Males> 
FSH 
LH 
testosterone 
Hepatitis Panel 
hepatitis B virus surface antigen test 
hepatitis B virus core antibody test 
hepatitis B virus surface antibody test 
hepatitis B virus DNA (only subjects who are on the treatment with other 
chemotherapy or immunosuppressive therapy) 
hepatitis C virus antibody test 
Others 
anti-mitochondrial antibody 
* Fasting is recommended but not required. 
** HCO3- concentration calculated from pH and pCO2 measured with blood gas analyzers, using the Henderson-
Hasselbalch equation, is acceptable as an alternative. 

 
 
 
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10.3. 
Appendix 3: Reference Standards 
10.3.1. 
Cockcroft-Gault Equation 
The estimated CLCR (mL/min) will be calculated using the Cockcroft-Gault equation based on 
[actual/ideal] weight in kilograms (1 kilogram = 2.2 pounds):19 
Conventional – serum creatinine in mg/dL: 
Male: 
CLCR (mL/min) =  
Female: 
CLCR (mL/min) = 
× 0.85 
 
International System of Units (SI) – serum creatinine in μmol/L: 
Male: 
CLCR (mL/min) =  
Female: 
CLCR (mL/min) = 
× 0.85 
10.3.2. 
New York Heart Association (NYHA) 
The NYHA classifications are summarized below.20 
Table 10.2: 
New York Heart Association classifications 
Class 
Functional Capacity 
Objective Assessment 
I 
Subjects with cardiac disease but without resulting 
limitation of physical activity.  Ordinary physical 
activity does not cause undue fatigue, palpitation, 
dyspnea, or anginal pain. 
A. No objective evidence of 
cardiovascular disease. 
II 
Subjects with cardiac disease resulting in slight 
limitation of physical activity.  They are comfortable 
at rest.  Ordinary physical activity results in fatigue, 
palpitation, dyspnea, or anginal pain. 
B. Objective evidence of minimal 
cardiovascular disease. 
III 
Subjects with cardiac disease resulting in marked 
limitation of physical activity.  They are comfortable 
at rest.  Less than ordinary activity causes fatigue, 
palpitation, dyspnea, or anginal pain. 
C. Objective evidence of moderately 
severe cardiovascular disease. 
IV 
Subjects with cardiac disease resulting in inability to 
carry on any physical activity without discomfort.  
Symptoms of heart failure or anginal syndrome may 
be present even at rest.  If any physical activity is 
undertaken, discomfort is increased. 
D. Objective evidence of severe 
cardiovascular disease. 
Source: American Heart Association. Classification of Functional Capacity and Objective Assessment, Ninth edition 
March 14, 1994. 
[140 - age (in years)] × weight (in kg) 
serum creatinine (in µmol/L) × 72 × 0.0113 
[140 - age (in years)] × weight (in kg) 
serum creatinine (in mg/dL) × 72 
[140 - age (in years)] × weight (in kg) 
serum creatinine (in mg/dL) × 72 
[140 - age (in years)] × weight (in kg) 
serum creatinine (in µmol/L) × 72 × 0.0113 

 
 
 
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http://my.americanheart.org/professional/StatementsGuidelines/ByPublicationDate/PreviousYears/Classification-of- 
Functional-Capacity-and-Objective-Assessment_UCM_423811_Article.jsp 
10.3.3. 
CYP3A4 Inhibitors and Inducers 
Table 10.3: 
Common CYP3A Inhibitors and Inducers CYP3A4 Inhibitors 
Strong Inhibitors 
Moderate inhibitors 
Strong Inducers 
• Boceprevir 
• Aprepitant 
• Apalutamide 
• Clarithromycin 
• Ciprofloxacin 
• Carbamazepine 
• Cobicistat 
• Conivaptan 
• Enzalutamide 
• Danoprevir and ritonavir  
• Crizotinib 
• Mitotane 
• Elvitegravir and ritonavir 
• Cyclosporine 
• Phenytoin 
• Grapefruit juice, seville 
orange juice 
• Diltiazem 
• Rifampin 
• Idelalisib 
• Dronedarone 
• St. John’s wort 
• 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 Jun 2020). Available from: https://www.fda.gov/drugs/drug-interactions-
labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers 

 
 
 
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10.3.4. 
Highly Effective Contraception 
As multiple doses of pexidartinib may decrease the efficacy of hormonal contraceptives, female 
subjects of reproductive potential should use an effective, non-hormonal method of 
contraception. Methods considered to be highly effective contraception include:21 
 Intrauterine device 
 Bilateral tubal occlusion 
 Vasectomy 
 Complete sexual abstinence 
10.4. 
Appendix 4: General Information - Adverse Events 
10.4.1. 
Definition of Adverse Event 
An AE is any untoward medical occurrence in a subject administered a 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.22 
It is the responsibility of Investigators, based on their knowledge and experience, to determine 
those circumstances or abnormal laboratory findings which should be considered AEs. 
Events Meeting the AE Definition 
 Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically relevant in the 
medical and scientific judgment of the Investigator (ie, not related to progression of 
underlying disease). 
 Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
 New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study. 
 Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.  Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent.  Such overdoses should be reported regardless of sequelae. 
Events NOT Meeting the AE Definition 
 Any clinically relevant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the subject’s condition. 

 
 
 
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 The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the subject’s 
condition. 
 Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
 Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
  “Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE.  Such instances will be captured in the efficacy 
assessments.  However, the signs, symptoms, and/or clinical sequelae resulting from 
lack of efficacy will be reported as AE or SAE if they fulfill the definition of an AE 
or SAE. 
 Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen. 
10.4.2. 
Serious Adverse Event 
A SAE is any untoward medical occurrence that at any dose: 
 Results in death 
 Is life-threatening 
 The term 'life-threatening' in the definition of 'serious' refers to an event in which 
the subject was at risk of death at the time of the event.  It does not refer to an 
event, which hypothetically might have caused death, if it were more severe 
 Requires inpatient hospitalization or prolongation of existing hospitalization 
 In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting.  Complications that occur during 
hospitalization are AEs.  If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious.  When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered serious. 
 Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline or for administration of anticancer therapy after 
discontinuation of study drug is not considered an AE. 
 Results in persistent or significant disability/incapacity 
 The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
 This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 

 
 
 
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influenza, and accidental trauma (eg, sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
 Is a congenital anomaly/birth defect 
 Is an important medical event 
 Medical or scientific judgment should be exercised in deciding whether SAE 
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 medical or surgical intervention to prevent one 
of the other outcomes listed in the above definition.  These events should usually be 
considered serious. 
 Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse. 
10.4.3. 
Grade Assessment 
The severity of AEs will be graded using the latest NCI-CTCAE (version 5.0).  For each episode, 
the highest severity grade attained should be reported. 
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. 
 Grade 1: Mild AE 
 Grade 2: Moderate AE 
 Grade 3: Severe AE 
 Grade 4: Life-threatening consequences; urgent intervention indicated 
 Grade 5: Death related to AE 
Difference between Severity and Seriousness 
The term "severe" is often used to describe the intensity (severity) of a specific event (as in mild, 
moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor 
medical significance (such as severe headache).  This is not the same as "serious," which is based 
on subject/event outcome or action criteria usually associated with events that pose a threat to a 
subject's life or functioning.  Seriousness (not severity) serves as a guide for defining regulatory 
reporting obligations. 
10.4.4. 
Causality Assessment 
The Investigator should assess causal relationship between an AE and the study drug based on 
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. 

 
 
 
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 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). 
10.4.5. 
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 drug completed/permanently discontinued prior 
to reaction/event, or reaction/event occurred prior to start of treatment 
 Unknown: Subject is lost to follow-up 
10.4.6. 
Other Action Taken for Event 
 None. 
 No treatment was required. 
 Medication required. 
 Prescription and/or OTV medication was required to treat the AE. 
 Hospitalization or prolongation of hospitalization required. 
 Hospitalization was required or prolonged due to the AE, whether or not 
medication was required. 
 Other. 
10.4.7. 
Adverse Event Outcome 
 Recovered/Resolved 
 The subject fully recovered from the AE with no sequelae observed. 

 
 
 
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 Recovered/Resolved with Sequelae 
 The subject fully recovered from the AE but with sequelae. 
 Recovering/Resolving 
 The AE is improving but not recovered 
 Not Recovered/Not Resolved 
 The AE continues without improving. 
 Fatal 
 Fatal should be used when death is a direct outcome of the AE 
 Unknown 
10.5. 
Appendix 5: Instructions Related to Severe Acute Respiratory 
Syndrome Coronavirus 2 
Due to the potential impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), 
ie COVID-19, on subject safety, the Sponsor recommends the following dose modification and 
management plan for subjects with confirmed or suspected SARS-CoV-2 while being treated 
with pexidartinib.  Use CTCAE version 5.0 general grading criteria to evaluate SARS-CoV-
2.  All dose modifications (discontinuation, interruptions or reductions) must be recorded on the 
AE and drug administration eCRFs. 
Dose Modification for Suspected or Confirmed SARS-CoV-2 
If SARS-CoV-2 infection is suspected, interrupt pexidartinib and rule out SARS-CoV-2 per local 
guidance. 
 If SARS-CoV-2 is ruled out, follow dose modification and management guidance as 
outlined in Table 6.3. 
 If SARS-CoV-2 is confirmed or is still suspected after evaluation, dosing of the 
investigational product should be withheld until consultation with the DS Medical 
Monitor is completed. In the event that a participant tests positive for SARS-CoV-2, 
or if testing is not available, Investigators should withhold dosing until such time as 
the symptoms resolve. If a positive SARS-CoV-2 test result is reported, consult with 
the DS Medical Monitor on whether resolution of symptoms alone without retesting 
is adequate to resume dosing of the investigational product. Investigators may 
consider dose modification of the study drug according to the subject’s condition and 
after discussion with the study Medical Monitor or designee and manage SARS-CoV-
2 per local guidance until recovery of SARS-CoV-2.  SARS-CoV-2 recovery is 
defined as no signs/symptoms of SARS-CoV-2, at least 1 negative real-time reverse 
transcription polymerase chain reaction (RT-PCR) test result, and nearly or 
completely resolved chest CT findings. 

 
 
 
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PK Assessment(s) if Chloroquine or Hydroxychloroquine is Administered 
Additional PK serum samples should be collected if chloroquine (CQ) or hydroxychloroquine 
(HCQ) is administered for SARS-CoV-2 infection at the time points specified in the Schedule of 
Assessments (Section 1.3). 
The chloroquine or HCQ administration time and the exact time of blood sample collection for 
PK analysis must be recorded on the eCRF. 
SARS-CoV-2 Assessment(s) 
All confirmed or suspected SARS-CoV-2 infection events must be recorded in the eCRF.  If a 
subject presents to the clinic with symptoms suggestive of SARS-CoV-2, but the real-time 
RT-PCR test is not available at the site, a nasopharyngeal swab/saliva sample kit will be 
provided for sample collection to be tested at a central laboratory.  The results will be provided 
to the site from the central laboratory. 
Serum samples will be used for SARS-CoV-2 testing from each subject who provides 
consent.  Samples will be collected prior to the study drug dosing, shipped to a central 
laboratory, and stored there until the tests become available. 
If subjects consent, the remaining serum samples will also be stored for future analysis. 
Serum, nasopharyngeal swab/saliva, and PK sample collection, preparation, handling, storage, 
and shipping instructions are provided in the Study Laboratory Manual. 
Statistical Analysis - Assessment of the Impact of SARS-CoV-2 
If deemed appropriate, analyses will be performed to explore the impact of SARS-CoV-2 on the 
safety and efficacy results reported for the study. 
As a result of the impact of SARS-CoV-2 on study conduct, adjustments to the statistical 
analysis and interpretation will be made, if required.  These will be described in the SAP. 
10.6. 
Appendix 6 Key Data Analysis Requirements 
Table 10.4: 
Key Data Requirements 
Endpoint/Analysis 
Key Data Requirements 
Primary endpoint in 
Part 1 - DLT 
All eCRF collected data and key external source data (eg. AEs and 
other safety data) 
Primary endpoint in 
Part 2 - ORR 
All tumor assessment data as assessed by centrally reviewed MRI 
scan based on RECIST 1.1 are required. 
AE = adverse event; DLT = dose-limiting toxicity; eCRF = electronic case report form; MRI = magnetic resonance 
imaging; ORR = objective response rate; RECIST 1.1 = Response Evaluation Criteria in Solid Tumors Version 1.1. 
 

 
 
 
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10.7. 
Appendix 7 Patient Reported Outcomes, Surgical Assessment 
Questionnaire, and Long-Term Follow-up Questionnaire 
10.7.1. 
Surgical Assessment Questionnaire 
Table 10.5: 
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 
 
 

 
 
 
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10.7.2. 
Long-Term Follow-up Questionnaire 
Table 10.6: 
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; MRI = magnetic resonance imaging; NE = not evaluable; PD = progressive disease; PR = 
partial response; SD = stable disease; TGCT = tenosynovial giant cell tumor 
 

 
 
 
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10.8. 
Appendix 8 Supplement List 
Supplements are printed separately from the protocol, and their versions are independent from 
the study protocol. 
Supplements are listed as follow:  
 Supplement 1: Serious Adverse Event Report Form  
 Supplement 2: Exposure In Utero Reporting Form 
 Supplement 3: Compensation and Insurance 
 Supplement 4: Study Administrative Structure 
 

 
 
 
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11. 
REFERENCES 
1. de St. Aubain Somerhausen N, van de Rijn M. Tenosynovial giant cell tumour. In: 
Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F, editors. WHO classification of 
tumours of soft tissue and bone. 4th ed., vol 5. Geneva: WHO Press; 2013;100-3. 
2. 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. 
2017:7402570. 
3. 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 Rheumatol. 2017; 44(10):1476-83. 
4. 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. 
5. 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.  
6. 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 Orthop. 2017; 88(6):688-94. 
7. 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(3):547-50. 
8. 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(2):210-17. 
9. Brahmi M, Vinceneux A, Cassier PA. 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. 
10. PEXIDARTINIB Investigator’s Brochure. Version 12.0, 23 Mar 2020. 
11. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: Revised RECIST guideline (version 1.1). Euro J Cancer. 2009:45(2);228-47. 
12. FDA. Guidance for Industry. Clinical Trial Endpoints for the Approval of Cancer Drugs 
and Biologics. December 2018.  
https://www.fda.gov/media/71195/download 
13. Ostergaard M, Peterfy C, Conaghan P, et al. OMERACT Rheumatoid Arthritis Magnetic 
Resonance Imaging Studies. Core set of MRI acquisitions, joint pathology definitions, 
and the OMERACT RA-MRI scoring system. J Rheumatol. 2003;30(6):1385-6. 

 
 
 
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14. 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. 
15. Gerhardt JJ, Cocchiarella L, Lea RD. The Practical Guide to Range of Motion 
Assessment. Chicago, IL. Amer Med Assoc Press; 2002 
16. Basch E, Autio KA, Smith MR, et al, Effects of Cabozantinib on Pain and Narcotic Use 
in Patients with Castration-resistant Prostate Cancer: Results from a Phase 2 
Nonrandomized Expansion Cohort. Eur Urol. 2015;67(2):310-8. 
17. The Management of Postoperative Pain Working Group. VHA/DoD clinical practice 
guidelines for the management of postoperative pain. Version 1.2. Washington, DC: 
Veterans Health Administration, Department of Defense; 2002. P. 44-5. 
18. FDA. Guidance for industry. Drug-induced Liver Injury. Premarketing Clinical 
Evaluation. July 2009.  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM072278.pdf 
19. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. 
Nephron 1976;16(1):31-41. 
20. American Heart Association. Classification of Functional Capacity and Objective 
Assessment, Ninth edition March 14, 1994.  
https://professional.heart.org/en/guidelines-and-statements/classification 
21. Heads of Medicines Agencies. Clinical Trial Facilitation Group (CTFG). 
Recommendations related to contraception and pregnancy testing in clinical trials. 
September 2014.  
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf 
22. Cheson BD, Bennett JM, Kopecky KJ, et al. Revised Recommendations of the 
International Working Group for diagnosis, Standardization of response Criteria, 
Treatment Outcomes, and reporting Standards for Therapeutic Trials in Acute Myeloid 
Leukemia. J Clin Oncol. 2003;21(24):4642-9. 
 

 
 
 
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12. 
LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
AE 
Adverse event 
AESI 
Adverse events of special interest 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AMA 
Anti-mitochondrial antibody 
AR 
Observed accumulation ratio 
AST 
Aspartate aminotransferase 
AUCt (e.g. AUC6h) 
Area under the plasma concentration-time curve up to time t 
AUCinf 
Area under the plasma concentration-time curve up to infinity 
AUClast 
Area under the plasma concentration-time curve up to the last quantifiable time 
BID 
Twice a day 
BOR 
Best overall response 
BPI 
Brief pain inventory 
C1D1 
Cycle 1 Day 1 
CFR 
Code of federal regulations 
CI 
Confidence interval 
CLCR 
Creatinine clearance 
CL/F 
Apparent total body clearance 
Cmax 
Maximum plasma concentration  
CQ 
Chloroquine 
CR 
Complete response 
CRO 
Contract research organization 
CSF-1 
Colony stimulating factor 1 
CSF1R 
Colony-stimulating factor 1 receptor 
CSR 
Clinical Study Report 
CTCAE 
Common terminology criteria for adverse events 
Ctrough 
Trough plasma concentration 
CYP 
Cytochrome P450 
DLT 
Dose-limiting toxicity 
DoR 
Duration of response 
DS 
Daiichi Sankyo 

 
 
 
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Abbreviation 
Definition 
EC 
Ethical committee 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture 
EIU 
Exposure in utero 
ELISA 
Enzyme-linked immunosorbent assay 
EOS 
End of Study 
EQ-5D-5L 
The five-level version of EuroQol five-dimensional questionnaire 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FISH 
Fluorescence in situ hybridization 
FLT3 
FMS-like tyrosine kinase 3 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GCT-TS 
Giant cell tumor of the tendon sheath 
GGT 
Gamma-glutamyl transpeptidase 
H2 
histamine 2 
HCQ 
Hydroxychloroquine 
HEAC 
Hepatic adjudication committee 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
ICMJE 
International Council of Medical Journal Editors 
IEC 
Independent ethics committee 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
INR 
International normalized ratio 
IRB 
Institutional review board 
IRT 
Interactive response technology 
ITD 
Internal tandem duplication 
Kel 
Elimination rate constant associated with the terminal phase 
KIT 
KIT proto-oncogene receptor tyrosine kinase 

 
 
 
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Abbreviation 
Definition 
LH 
Luteinizing hormone 
LTFU 
Long-term follow-up 
LVEF 
Left ventricular ejection fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
MUGA 
Multigated acquisition 
NCI 
National Cancer Institute 
NE 
Not evaluable 
NGS 
Next generation sequencing 
NRS 
Numeric Rating Scale 
NYHA 
New York Heart Association 
ORR 
Objective response rate 
OTC 
Over-the-counter 
P-CAB 
Potassium-competitive acid blocker 
PD 
Progressive disease 
Pdy 
Pharmacodynamic(s) 
PGx 
Pharmacogenomic(s) 
PK 
Pharmacokinetic(s) 
PopPK 
Population pharmacokinetic(s) 
PPI 
Proton pump inhibitor 
PR 
Partial response 
PRO 
Patient-reported outcomes 
PROMIS 
Patient-Reported Outcomes Measurement Information System 
Pt 
Patient 
PVNS 
Pigmented villonodular synovitis 
QTc 
Corrected QT interval 
QTcF 
QT interval corrected with Fridericia’s formula 
RECIST 
Response Evaluation Criteria in Solid Tumors 
ROM 
Range of motion 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2, ie COVID-19 
SAVER 
Serious Adverse Event Report 
SCR 
Screening 

 
 
 
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Abbreviation 
Definition 
SD 
Stable disease 
SID 
Subject identifier 
SMC 
Safety monitoring committee 
SOP 
Standard operating procedures 
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 to reach maximum plasma concentration 
TVS 
Tumor Volume Score 
Tx 
Treatment 
t1/2 
Terminal half-life 
UGT 
Uridine 5’-diphospho-glucuronosyltransferase 
ULN 
Upper limit of normal 
US 
United States 
Vz/F 
Apparent volume of distribution based on the terminal phase 
WORMS 
Whole-organ MRI score 
 

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