Clinical trial NCT04526704
Conditions: Tenosynovial Giant Cell Tumor
Keywords: Tenosynovial Giant Cell Tumor Pexidartinib TURALIO™️ PLX3397
Sponsor: Daiichi Sankyo
Start date: 2020-10-20; Completion date: 2023-07-07
Enrollment: 32 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This study is designed to evaluate the discontinuation/re-treatment of pexidartinib therapy in previously treated participants with tenosynovial giant cell tumor (TGCT).

Detailed description:
This multicenter study in previously pexidartinib-treated participants with TGCT will provide the Investigators and participants the option at Screening to either continue pexidartinib treatment (Treatment Continuation Cohort) or discontinue treatment with the possibility of re-initiating pexidartinib treatment (Treatment-Free/Re-Treatment Cohort).

Arms: arm 1: Previously-treated participants with TGCT continuing their current dose of pexidartinib treatment. arm 2: Previously-treated participants with TGCT who discontinue pexidartinib treatment (Treatment-Free Period) and had the option to resume pexidartinib treatment at dose at completion of prior study (Re-Treatment Period).
Interventions: intervention 1: Pexidartinib
Intervention descriptions: intervention 1: 200 mg capsules administered orally twice daily on an empty stomach (at least 1 hour before or at least 2 hours after a meal or snack)

Protocol documents:
Prot_SAP_000.pdf: 
CLINICAL STUDY PROTOCOL 
A PHASE 4, MULTICENTER STUDY TO EVALUATE 
DISCONTINUATION AND RE-TREATMENT IN 
SUBJECTS WITH TENOSYNOVIAL GIANT CELL 
TUMOR (TGCT) PREVIOUSLY TREATED WITH 
PEXIDARTINIB 
 
PEXIDARTINIB TGCT CONTINUATION STUDY 
 
PROTOCOL NUMBER:  PL3397-A-U4003 
IND NUMBER:  117,332 
NCT NUMBER:  NCT04526704 
[EudraCT NUMBER:  2020-000192-20] 
 
VERSION 2.0, 25 Feb 2022 
 
DAIICHI SANKYO, INC. 
211 Mt. Airy Road 
Basking Ridge, NJ 07920 United States 
 
CONFIDENTIALITY STATEMENT 
Information contained in this document is proprietary to Daiichi Sankyo, Inc.  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 Inc. 


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INVESTIGATOR AGREEMENT 
A Phase 4, multicenter study to evaluate the discontinuation and 
re-treatment in subjects with tenosynovial giant cell tumor (TGCT) 
previously treated with pexidartinib 
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) 


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DOCUMENT HISTORY 
Version Number 
Version Date 
2.0 
25 Feb 2022 
1.0 
21 Feb 2020 


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SUMMARY OF CHANGES 
Please refer to the comparison document for protocol V2.0 (dated 25 Feb 2022) versus protocol 
V1.0 (dated 21 Feb 2020) for actual changes in text.  The summary of changes below is a topline 
summary of major changes in the current PL3397-A-U4003 clinical study protocol (V2.0) by 
section. 
Amendment Rationale: 
This amendment is for clarification updates to the scheduled visits and required assessments for 
operational and clinical safety purposes.  Additionally, language has been added for the 
collection of COVID-19-related data. 
CONVENTIONS USED IN THIS SUMMARY OF CHANGES 
All locations (Section numbers and/or paragraph/bullet numbers) refer to the current protocol 
version, which incorporates the items specified in this Summary of Changes document. 
Minor edits, such as update to language that does not alter original meaning, update to version 
numbering, formatting, change in font color, corrections to typographical errors, use of 
abbreviations, moving verbiage within a section or table, change in style, or change in case, 
are not noted in the table below. 
Section # and Title 
Description of Change 
Brief Rationale 
 
Cover page 
 
1.1 Protocol Synopsis 
Added NCT number 
NCT number was received 
 
Investigator Agreement 
Removed Sponsor signature section 
Veeva Vault electronic 
signature page to replace 
sponsor wet-ink signature 
 
1.1 Protocol Synopsis 
 
5.1 Inclusion Criteria 
Updated contraception language for 
donating sperm/ova during study 
treatment 
Updated language for 
additional clarity 
 
Table 1.1 Schedule of Events:  
Treatment Continuation Cohort 
 
Table 1.2 Schedule of Events:  
Treatment-Free Period of 
Treatment-Free/Re-Treatment 
Cohort  
 
Table 1.3 Schedule of Events:  
Re-Treatment Period of 
Treatment-Free/Re-Treatment 
Cohort 
Updated all 3 Schedule of Events tables 
to: 
 
Add clarifying language for ECG 
timing (moved from vitals 
assessments) and frequency (also 
in Section 8.4.5 Other Safety) 
 
Separate out TSH from hormone 
testing (also in Section 8.4.3 
Clinical Laboratory Evaluations 
and Table 10.1 Clinical Laboratory 
Tests) 
 
Update visits when dosing diary is 
provided to patients 
 
Add a row for collection of End of 
Study form 
 
Defined a month as a 28-day 
interval for the M1/M2 visit for 
retreatment patients in the 
Treatment-Free/Re-Treatment 
Updated to more accurately 
reflect the visit schedules and 
the required assessments 


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CONVENTIONS USED IN THIS SUMMARY OF CHANGES 
Cohort and as a 30-day interval for 
all other cohorts/visits 
 
(Table 1.1 and 1.3 only) 
 
Clarified that MRI scans are 
required every 6 months for 
subjects in the Treatment 
Continuation Cohort and every 3 
months for those in the Treatment-
free period and Re-Treatment 
periods of the Treatment-Free/Re-
Treatment Cohort (also in Sections 
1 Protocol Summary and 4.1.1 
Design Overview) 
 
Clarified that subjects from 
Treatment Free/Re-Treatment 
Cohort restarting treatment should 
note MRI as due to progression 
and use the BL2 assessment as 
reference (also in Section 4.1.1 
Design Overview) 
 
Clarified that urinalysis 
assessments will be performed at 
6-month intervals (also in Section 
1 Protocol Summary) 
 
Separated EOT and EOS/AE 
Follow-up as 2 separate visits and 
reinforced that EOT must occur 
within 24 months after enrollment 
 
Removed entry for on-site study 
drug administration (also in 
Section 6.2.2 Administration) 
 
(Table 1.2 only) 
 
Updated visits to: 
o 
make M12 its own visit 
o 
combine M24 and EOT 
o 
make EOS/AE Follow-up its 
own visit 
 
Removed comments language for 
AE and ConMed rows 
 
4.1.1 Design Overview 
 
Table 10.1 Clinical Laboratory 
Tests 
Added coagulation, ECG, and hormone 
testing to list of ongoing safety 
monitoring and made albumin globulin 
(A/G) ratio optional 
Completeness of list 
 
4.1.3 Dose Regimen 
 
6.1 Study Drug(s) Description 
Reinforced message that dose 
escalations are not permitted 
Reinforcing existing language 
 
Section 4.1.4 Duration 
Clarified frequency of study 
assessments for the Re-Treatment 
period of the Treatment-Free/Re-
Treatment Cohort 
Updated language for 
additional clarity 


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CONVENTIONS USED IN THIS SUMMARY OF CHANGES 
 
6.6 Prior and Concomitant 
Medications 
 
8.4.1 Adverse Event 
 
8.4.4 Reporting of Exposure to 
COVID-19 (SARS-CoV-2 
 
9.5.2 Safety Analyses 
Updated instructions on recording 
COVID-19 vaccination data and 
reporting COVID-19-associated AEs 
Updated for clarity of 
instructions 
 
8.4.1.1 Serious Adverse Event 
Reporting 
Added overdose 
Added for completeness of list 
 
9.5.2 Safety Analyses 
Added text that descriptive statistics 
would be provided for ECG 
Updated for completeness 
 
Table 10.1 Clinical Laboratory 
Tests 
Updated Table 10.1 
 
Removed bicarbonate test 
 
Updated creatinine clearance to be 
defined by Cockcroft-Gault 
equation 
 
Required PTT only if aPTT isn’t 
collected 
 
Required FSH and TSH at 
Baseline-only 
Removed bicarbonate as being 
unnecessary for this indication 
and updated other language 
for clarity of instructions 
 
10.3.2 CYP3A4 Inhibitors and 
Inducers 
Clarified that list of CYP3A4 inhibitors 
and inducers is not complete 
Added language for accuracy 
and completeness  
 


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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 ..................................................................................................................18 
1.3. 
Schedule of Events ..........................................................................................................19 
2. 
INTRODUCTION ...........................................................................................................27 
2.1. 
Background ......................................................................................................................27 
2.1.1. 
Tenosynovial Giant Cell Tumor (TGCT) ........................................................................27 
2.1.2. 
Pexidartinib (PLX3397) ..................................................................................................27 
2.2. 
Study Rationale ...............................................................................................................28 
2.3. 
Benefit and Risk Assessment ..........................................................................................29 
3. 
OBJECTIVES, OUTCOME MEASURES, AND ENDPOINTS ....................................30 
3.1. 
Rationale for Selection of Primary and Key Secondary Endpoints ................................31 
4. 
STUDY DESIGN ............................................................................................................32 
4.1. 
Overall Design .................................................................................................................32 
4.1.1. 
Design Overview .............................................................................................................32 
4.1.2. 
End of Study ....................................................................................................................33 
4.1.3. 
Dose Regimen .................................................................................................................33 
4.1.4. 
Duration ...........................................................................................................................34 
4.2. 
Rationale for Study Design .............................................................................................34 
4.3. 
Justification for Dose .......................................................................................................34 
5. 
STUDY POPULATION ..................................................................................................35 
5.1. 
Inclusion Criteria .............................................................................................................35 
5.2. 
Exclusion Criteria ............................................................................................................35 
5.3. 
Screening Failures, Rescreening, and Subject Replacement ...........................................36 
6. 
STUDY TREATMENT(S) ..............................................................................................37 
6.1. 
Study Drug(s) Description ...............................................................................................37 
6.2. 
Preparation, Handling, Storage, and Accountability for Study Drug(s) ..........................37 
6.2.1. 
Preparation, Handling, and Disposal ...............................................................................37 


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6.2.2. 
Administration .................................................................................................................37 
6.2.3. 
Storage .............................................................................................................................38 
6.2.4. 
Drug Accountability ........................................................................................................38 
6.3. 
Measure to Minimize Bias:  Randomization and Blinding .............................................38 
6.4. 
Treatment Compliance ....................................................................................................38 
6.5. 
Guidelines for Dose Modification ...................................................................................39 
6.5.1. 
Renal Impairment ............................................................................................................41 
6.6. 
Prior and Concomitant Medications ................................................................................42 
6.6.1. 
Analgesic Use ..................................................................................................................42 
6.7. 
Prohibited Therapies/Products .........................................................................................42 
6.7.1. 
Hormonal Contraceptives ................................................................................................43 
6.7.2. 
Acid-reducing Agents ......................................................................................................43 
7. 
STUDY DRUG DISCONTINUATION AND DISCONTINUATION FROM 
THE STUDY ...................................................................................................................44 
7.1. 
Subject Withdrawal/Discontinuation from the Study ......................................................44 
7.2. 
Lost to Follow-up ............................................................................................................45 
8. 
STUDY PROCEDURES .................................................................................................46 
8.1. 
Eligibility Assessment .....................................................................................................46 
8.2. 
Enrollment .......................................................................................................................46 
8.3. 
Efficacy Assessments ......................................................................................................47 
8.3.1. 
Response Assessment ......................................................................................................47 
8.3.2. 
Patient Reported Outcomes .............................................................................................47 
8.3.3. 
Radiographic Tumor Assessments ..................................................................................47 
8.4. 
Safety Assessments .........................................................................................................48 
8.4.1. 
Adverse Event .................................................................................................................48 
8.4.1.1. Serious Adverse Events Reporting ..................................................................................49 
8.4.1.2. Adverse Events of Special Interest ..................................................................................50 
8.4.2. 
Pregnancy/Embryo-Fetal Toxicity ..................................................................................51 
8.4.3. 
Clinical Laboratory Evaluations ......................................................................................52 
8.4.4. 
Reporting of Exposure to COVID-19 (SARS-CoV-2) ....................................................52 
8.4.5. 
Other Safety .....................................................................................................................53 
8.5. 
Pharmacokinetic (PK) Assessment(s) .............................................................................53 
8.6. 
Pharmacodynamic Assessment(s) ...................................................................................53 


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9. 
STATISTICAL CONSIDERATIONS ............................................................................54 
9.1. 
General Statistical Considerations ...................................................................................54 
9.2. 
Statistical Hypothesis ......................................................................................................54 
9.3. 
Sample Size Determination .............................................................................................54 
9.4. 
Population for Analysis Sets ...........................................................................................54 
9.5. 
Statistical Analysis ..........................................................................................................54 
9.5.1. 
Efficacy Analyses ............................................................................................................55 
9.5.1.1. Primary Efficacy Analyses ..............................................................................................55 
9.5.1.2. Secondary Efficacy Analyses ..........................................................................................55 
9.5.1.3. Exploratory Analyses ......................................................................................................55 
9.5.1.4. Multiplicity Adjustment ..................................................................................................55 
9.5.2. 
Safety Analyses ...............................................................................................................55 
9.5.3. 
Other Analyses ................................................................................................................57 
9.6. 
Interim Analyses ..............................................................................................................57 
10. 
APPENDICES – SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ......................................................................................................58 
10.1. 
Appendix 1:  Regulatory and Ethical Considerations .....................................................58 
10.1.1. Regulatory Compliance ...................................................................................................58 
10.1.2. Informed Consent ............................................................................................................59 
10.1.3. Subject Confidentiality ....................................................................................................60 
10.1.4. Data Integrity and Quality Assurance .............................................................................60 
10.1.5. Committees ......................................................................................................................61 
10.1.6. Study Documentation and Storage ..................................................................................62 
10.1.7. Finances ...........................................................................................................................63 
10.1.8. Publication and Public Disclosure Policy ........................................................................63 
10.1.9. Protocol Deviations .........................................................................................................64 
10.1.10. Study and Site Closure ....................................................................................................64 
10.1.11. Product Complaints .........................................................................................................64 
10.2. 
Appendix 2:  Laboratory Assessments ............................................................................65 
10.3. 
Appendix 3:  Reference Standards ..................................................................................66 
10.3.1. Cockcroft-Gault Equation ...............................................................................................66 
10.3.2. CYP3A4 Inhibitors and Inducers ....................................................................................66 
10.4. 
Appendix 4:  Response Criteria .......................................................................................69 


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10.5. 
Appendix 5:  General Information – Adverse Events .....................................................76 
10.5.1. Definition of Adverse Event ............................................................................................76 
10.5.2. Serious Adverse Event ....................................................................................................77 
10.5.3. Grade Assessment ...........................................................................................................78 
10.5.4. Causality Assessment ......................................................................................................78 
10.5.5. Action Taken Regarding Study Drug(s) ..........................................................................79 
10.5.6. Other Action Taken for Event .........................................................................................79 
10.5.7. Adverse Event Outcome ..................................................................................................79 
10.6. 
Appendix 7:  Patient Reported Outcomes .......................................................................80 
10.6.1. PROMIS Physical Function Scale ...................................................................................80 
10.6.2. PROMIS Item Bank v. 1.2 – Physical Functioning (Upper Extremity) ..........................82 
10.6.3. EQ-5D-5L ........................................................................................................................84 
11. 
REFERENCES ................................................................................................................87 
12. 
LIST OF ABBREVIATIONS .........................................................................................88 
 


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LIST OF TABLES 
Table 1.1: Schedule of Events:  Treatment Continuation Cohort ................................................19 
Table 1.2: Schedule of Events:  Treatment-Free Period of Treatment-Free/Re-
Treatment Cohort ........................................................................................................22 
Table 1.3: Schedule of Events:  Re-Treatment Perioda of Treatment-Free/Re-Treatment 
Cohort .........................................................................................................................24 
Table 3.1: Description of Objectives, Outcome Measures, and Endpoints (Treatment-
Free/Re-Treatment Cohort) ........................................................................................30 
Table 3.2: Description of Objectives, Outcome Measures, and Endpoints (Treatment 
Continuation Cohort) ..................................................................................................31 
Table 6.1: Study Drug Dosing Information .................................................................................37 
Table 6.2: Recommended Dose Reductions for Pexidartinib for Adverse Reactions .................39 
Table 6.3: Recommended Dosage Modifications for Pexidartinib for Adverse Reactions .........39 
Table 6.4: Additional Liver Evaluation .......................................................................................40 
Table 6.5: Recommended Dosage Reductions for Pexidartinib for Concomitant Use of 
Strong CYP3A Inhibitors or UGT Inhibitors .............................................................43 
Table 10.1: Clinical Laboratory Tests ...........................................................................................65 
Table 10.2: CYP3A4 Inhibitors .....................................................................................................67 
Table 10.3: Best Overall Response When Confirmation of CR and PR Required ........................74 
 


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LIST OF FIGURES 
Figure 1.1: Study Level Flow Diagram .........................................................................................18 
 




























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f Only subjects who end their study participation early with no radiologic disease progression will have an additional MRI at 3 months ± 14 days after their last 
dose of study treatment or before any new TGCT therapy, including surgery, whichever occurs first. EOS will occur after this additional MRI. 


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2. 
INTRODUCTION 
2.1. 
Background 
2.1.1. 
Tenosynovial Giant Cell Tumor (TGCT) 
Tenosynovial giant cell tumor (TGCT) is a rare, nonmalignant neoplasm of the synovium, 
bursae, or tendon sheaths that is driven by overexpression of colony-stimulating factor-1 (CSF-1) 
often afflicting adults under 40 years of age.  Annual TGCT incidence is estimated to be 43 cases 
per one million individuals, of which approximately 10% are of the diffuse subtype.  Surgical 
resection, when feasible, is the standard treatment for TGCT; however, recurrence of the diffuse 
subtype is particularly common.  Repeated surgeries often result in increasing morbidity and 
functional limitations of the affected joints.  The diffuse disease often has more extensive 
involvement and a poorer likelihood of a successful cure with surgery, and therefore often may 
not be amenable to surgical resection due to the risk of morbidity or high risk of recurrence in 
diffuse disease.  Systemic therapies targeting CSF-1 activity are being evaluated for the 
treatment of TGCT. 
2.1.2. 
Pexidartinib (PLX3397) 
Pexidartinib is an oral small-molecule tyrosine kinase inhibitor that targets 3 kinases:  CSF-1 
receptor ([CSF-1R] or feline McDonough sarcoma [FMS] kinase); proto-oncogene receptor 
tyrosine kinase (c-Kit), and FMS-like tyrosine kinase 3. TURALIO™ (Pexidartinib) was 
approved, 02 Aug 2019, by the United States (US) Food and Drug Administration (FDA) for the 
treatment of symptomatic TGCT associated with severe morbidity or functional limitations and 
not amenable to improvement with surgery.  Pexidartinib is the first systemic therapy to show a 
robust tumor response in TGCT with improved patient symptoms and functional outcomes; 
cholestatic hepatotoxicity has been identified as a risk.  It was approved with a boxed warning 
for hepatotoxicity and is available only through a restricted program called the TURALIO Risk 
Evaluation and Mitigation Strategy (REMS) program. 
The approval was based on the durable overall response rate (ORR) observed in the Phase 3 
study PLX108-10 (ENLIVEN) which provided compelling evidence of its effectiveness for the 
treatment of subjects with TGCT.  In the ENLIVEN study, an international, multicenter, 
randomized (1:1), double-blind, placebo-controlled study, 120 subjects with TGCT not amenable 
to surgical resection and treated with pexidartinib had a robust tumor response rate versus 
placebo at Week 25 by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 
(39% vs 0%; P<0.0001) and by tumor volume score (TVS) (56% vs 0%; P<0.0001).  Further 
evidence of tumor response and clinical improvements are noted in the TGCT extension cohort 
of Study PLX108-01, as well as the longer-term data from the ENLIVEN study. 
The safety data showed serious adverse events (SAEs) occurred in 13% (8/61) of patients in the 
pexidartinib group and 2% (1/59) of patients in the placebo group.  The most frequent 
pexidartinib-associated treatment-emergent adverse events (TEAEs) were hair color changes, 
fatigue, aspartate aminotransferase (AST) increase, nausea, alanine aminotransferase (ALT) 
increase, and dysgeusia.  Pexidartinib was associated with 2 types of hepatic adverse reactions.  
The first was a dose-dependent, generally low-grade aminotransferase elevation related to the 


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CSF-1R inhibition mechanism of action.  These elevations are primarily observed during the first 
8 weeks of treatment.  The second hepatic adverse reaction, mixed or cholestatic hepatotoxicity, 
which while rarely serious can be life-threatening, also generally appeared in the first 8 weeks of 
treatment, however, is uncommon and idiosyncratic in nature. 
As noted, long-term follow-up showed further increases in tumor response with continued 
pexidartinib treatment.  For long-term pooled efficacy and safety, 130 patients in ENLIVEN and 
PLX108-01 received pexidartinib; 47% (61) patients remained on treatment at data cut-off.  
Median follow-up from first dose to data cutoff was 23 months (range, 16, 67); median treatment 
duration was 17 months (range, 1, 60+).  Four percent (5) patients discontinued pexidartinib due 
to progressive disease (PD).  Pooled RECIST v1.1-based best overall response (BOR) was 54%, 
with increased BOR from longer treatment.  The safety profile was consistent with earlier 
reports, with no new safety signals. 
Currently, besides the ENLIVEN and PLX108-01 studies, there are 2 additional Phase 1/2 
studies (Study PL3397-A-A103 and Study PL3397-A-U126) that are ongoing.  The objectives of 
these 4 pexidartinib studies in TGCT have been met and the investigational sites are to be closed.  
Eligible subjects from these studies will be included in the subject population for this study. 
Refer to the Pexidartinib Investigator’s Brochure (IB) for additional details and information. 
2.2. 
Study Rationale 
Over time, with daily treatment, many patients on long-term use of pexidartinib in these studies 
achieved significant tumor responses.  In the ENLIVEN study, with the 90-day post-treatment 
observation period, no cases of rapid tumor regrowth were observed, suggesting that quarterly 
follow-ups are of adequate frequency to identify any patients, who need to re-initiate their 
treatment.  However, beyond the 3-month post-treatment follow-up in ENLIVEN, there are no 
data to fully understand the impact of discontinuing pexidartinib treatment in patients with stable 
and/or residual disease.  And, with slow-growing disease like TGCT, 3 months is not sufficient 
to determine the time when the treatment needs to be restarted. Feasibility of intermittent on-off 
dosing remains an open medical question.   
Patients with TGCT diagnosed early in their lives face potentially several decades of daily 
treatment.  In the real-world setting, subjects and Investigators are faced with decisions 
surrounding patients’ activities of daily living and treatment with pexidartinib for TGCT.  
Further data are necessary to fully understand the safe and effective discontinuation and re-
treatment with pexidartinib therapy in this patient population. 
The purpose of this Phase 4 multicenter study in subjects with TGCT previously treated with 
pexidartinib are two-fold.  At the Screening visit/time of consent, the Investigators and subjects 
are provided the choice to either continue treatment with pexidartinib or discontinue treatment 
with the possibility of re-initiating pexidartinib treatment at a later time.  Findings from this 
study will provide important prospective discontinuation and re-treatment data with pexidartinib 
in previously treated subjects with residual disease. 
Ultimately, this study will contribute meaningful information to the body of research on 
pexidartinib treatment for patients with TGCT and the safe and effective discontinuation and re-
treatment with pexidartinib therapy. 


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2.3. 
Benefit and Risk Assessment 
As noted, in the Pexidartinib Clinical Development Program, pexidartinib has demonstrated 
statistically significant and clinically meaningful efficacy.  The efficacy data from the ENLIVEN 
study provide evidence of its effectiveness for the treatment of subjects with TGCT.  Further 
evidence of tumor response and clinical improvements are noted in the TGCT extension cohort 
of the PLX108-01, as well as the longer-term data from the ENLIVEN study.6  The benefits for 
subjects treated with pexidartinib in these studies is expected to continue to be observed in this 
study. 
Pexidartinib can cause hepatic adverse reactions, including aminotransferase abnormalities or 
mixed or cholestatic hepatotoxicity that may be fatal.  Hepatotoxicity is an important adverse 
drug reaction (ADR).  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, in 1 case, transplantation.  The 
mechanism of cholestatic hepatotoxicity is unknown, and its occurrence cannot be predicted. 
Also, guidance on protocol-defined dose reductions, discontinuation of pexidartinib, increased 
frequency of laboratory monitoring, and reporting of findings have been established.  After 
re-initiating treatment with pexidartinib the liver function tests AST, ALT, total bilirubin, direct 
bilirubin, alkaline phosphatase (ALP), and gamma-glutamyl transferase (GGT) will be monitored 
weekly for the first 8 weeks, every 2 weeks for 1 month, and every 3 months thereafter.  The 
dose of pexidartinib will be reduced, withheld or permanently discontinued based on the severity 
of hepatoxicity.  Re-challenge with pexidartinib is not to be attempted without prior discussion 
with the Sponsor’s Medical Monitor. 
Re-challenges with a reduced dose of pexidartinib may result in a recurrence of increased serum 
transaminases, bilirubin, or ALP.  The mixed or cholestatic hepatotoxicity is idiosyncratic and 
may therefore recur with re-challenge.  Therefore, liver function tests are to be monitored weekly 
for the first 2 months after re-challenge, then every 2 weeks for 1 month, and then once every 3 
months or more frequently as directed by the Investigator.  Both the Investigator and subjects 
will be educated by the Sponsor on the eligibility criteria, benefits/risks of pexidartinib, 
necessary liver monitoring testing and guidance on dose reduction, and discontinuation. 
In addition, administration with food increases pexidartinib exposure by 100% and may increase 
the risk of hepatotoxicity.  Therefore, Investigators and subjects are instructed that pexidartinib 
administration is to be on an empty stomach, at least 1 hour before or 2 hours after a meal or 
snack.  Investigators and subjects will also be instructed to avoid concomitant use of pexidartinib 
with strong cytochrome P450 (CYP)3A inhibitors or uridine 5'-diphospho-
glucuronosyltransferase (UGT) inhibitors during the study. 
Refer to the Pexidartinib IB for additional details and information. 






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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a Phase 4, multicenter study in subjects with TGCT (pigmented villonodular synovitis 
[PVNS] or giant cell tumor of the tendon sheath [GCT-TS]) who were previously treated with 
pexidartinib in one of the following studies (hereafter referred to as prior study): (PLX108-10 
(ENLIVEN), PLX108-01, PL3397-A-A103, and PL3397-A U126).  Based on these prior studies, 
subjects will be enrolled from investigational sites in the US, European Union (EU) 
(Netherlands, Spain, Hungary, and Italy), Australia, and Taiwan.  The subject population is 
described in Section 5. 
The study start date is the date when the first subject has signed an informed consent and the 
study end date will be the completion of the last patient’s Follow-up Visit.  A subject is eligible 
to be enrolled into the study when the Investigator or designee has determined the subject is 
currently receiving pexidartinib treatment as part of one of the prior studies and meets the 
inclusion/exclusion criteria for this study (Section 5). 
4.1.1. 
Design Overview 
Subjects in the 4 ongoing TGCT studies will be screened at the “End-of-Treatment (EOT) visit” 
(i.e., the visit at which they receive their final dose of pexidartinib) of their previous study, at 
which time they can elect to enroll in the PL3397-A-U4003 study in 1 of 2 cohorts – the 
Treatment Continuation Cohort (where their existing pexidartinib treatment will continue 
uninterrupted) or Treatment-Free/ Re-Treatment Cohort (where they will discontinue 
pexidartinib treatment with the possibility to re-initiate treatment over the course of the study).  
Subjects who elect to not enroll in the PL3397-A-U4003 study will remain in their current study 
and complete their respective End-of-Study activities. 
Subjects who elect to enroll in PL3397-A-U4003 will sign an institutional review board 
(IRB)/independent ethics committee (IEC)-approved informed consent form (ICF).  By signing 
the ICF, subjects will permit acquisition and data transfer of any data collected in their precursor 
study, including, but not limited to, medical and surgical history, and prior medications.  The 
assessments performed during the preceding study’s End-of-Treatment visit will serve as the 
Baseline measurements for the PL3397-A-U4003 study. 
Eligible subject who choose to continue pexidartinib treatment in the Treatment Continuation 
Cohort will remain on their current dosage regimen of pexidartinib and undergo clinical 
assessments at 3-month intervals for the duration of the study. 
Subjects who choose to discontinue pexidartinib will be enrolled in the Treatment-Free period of 
the Treatment-Free/Re-Treatment Cohort.  These subjects will stop pexidartinib dosing at 
entry into PL3397-A-U4003 (i.e., after their final dose at the preceding study’s EOT visit).  
Subjects will undergo clinical assessments 1 month after enrollment, 3 months after enrollment, 
and then at 3-month intervals.  Subjects will remain treatment-free until retreated with 
pexidartinib, based on the Investigator and/or subject’s discretion.  Considerations are given to 
tumor response, subjective and/or functional measures, and safety parameters in the decision-
making process.  The rationale for discontinuation and re-treatment with pexidartinib will be 
recorded accordingly. 


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For subjects who restart pexidartinib treatment in the Re-Treatment period of the Treatment-
Free/Re-Treatment Cohort, pexidartinib will be administered at the dosage level at which the 
subject completed the prior study.  Doses 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 full set of study assessments will be performed (Baseline-2).  
During re-treatment, Investigators will ensure weekly liver monitoring tests for the first 8 weeks, 
then every 2 weeks for the next month, then every 3 months or more frequently as directed by 
the Investigator (see Table 6.3). 
The Investigator will evaluate the quarterly magnetic resonance imaging (MRI) scans to perform 
a qualitative tumor assessment (i.e., stable disease) for subjects in the Treatment-Free/Re-
Treatment Cohort.  Additional assessments may be conducted based on worsening of tumor 
response as deemed necessary by the Investigator.  For those subjects who restart pexidartinib 
treatment in the Re-Treatment period of the Treatment-Free/Re-Treatment Cohort, the 
response should note “Progression” and the assessments after re-treatment should use Baseline 2 
as the reference to determine Progression or Non-Progression. 
The PROs (PROMIS PF and EQ-5D-5L) will be performed every 3 months for all subjects. 
Ongoing safety will include serum chemistry, hematology, urinalysis, coagulation, ECG, 
hormone testing, and physical examination, and subjects will be monitored for adverse events 
(AEs)/TEAEs. 
Subjects on treatment who end their study participation early with no radiologic disease 
progression will undergo a final MRI 3 months ± 14 days after their last dose of study treatment 
or before any new TGCT therapy, including surgery. 
Subjects who discontinue early from the study will complete the End-of-Study (EOS)/EOT visit 
and will be withdrawn from the study. 
The subject population is described in Section 5.  A flow diagram of the study is presented in 
Figure 1.1. 
4.1.2. 
End of Study 
The primary completion date is the date when the last of those subject(s) entering the 
Treatment-Free period of the Treatment-Free/Re-Treatment Cohort either progresses to and 
completes the Re-Treatment period and/or remains treatment-free for the duration of the study.  
This date is used as the cut-off date for the analysis of the primary efficacy endpoint(s) of the 
study. 
The overall end of the study will occur when the last subject has their last visit/contact. 
The subject’s EOS is the date of their last study visit/contact. 
4.1.3. 
Dose Regimen 
Pexidartinib will be provided as an oral, daily administration at the dosage level at the end of 
their prior study.  Doses will be taken 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. 


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Note:  Dose escalation of pexidartinib treatment is not permitted during the course of this study. 
4.1.4. 
Duration 
The study start date is the date when the first subject signs the ICF and the study continues until 
the last subject has had their last visit. 
Duration of Treatment and Subject Participation 
Subjects will be evaluated for eligibility at the last visit of their prior study. 
Subject in the Treatment Continuation Cohort will undergo study assessments at 3-month 
intervals for a maximum of 24 months. 
Subjects in the Treatment-Free period of the Treatment-Free/Re-Treatment Cohort will 
undergo study assessments at 1 month after enrollment, 3 months after enrollment, and then at 
3-month intervals until either re-treatment with pexidartinib or for a maximum of 24 months. 
Subjects in the Re-Treatment period of the Treatment-Free/Re-Treatment Cohort will 
undergo study assessments at M1, M2 and then at 3-month intervals.  The maximum duration for 
any subject within the combined periods of the Treatment-Free/Re-Treatment Cohort is 
24 months.  Liver safety assessments will follow a separate schedule (See Table 1.3). 
The study will end with the last subject’s last visit.  A post-trial access plan, delineating options 
for access to pexidartinib, will be available for subjects after completing their study participation 
if the subject is benefiting from the study drug. 
Overall Study Duration 
Anticipated total duration of the study is expected to be approximately 24 months.  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 
A post-trial access plan, delineating options for access to pexidartinib, will be available for 
subjects after completing their study participation if the subject is benefiting from the study drug. 
4.2. 
Rationale for Study Design 
This Phase 4 study design assumes that in subjects with TGCT, having stable disease and who 
are being treated with pexidartinib, it is possible to suspend treatment until there are signs of 
disease progression.  It is assumed that re-initiation of treatment with pexidartinib will again lead 
to stabilization of the subject's disease and potentially to a diminution of the disease. 
4.3. 
Justification for Dose 
The dose used during the subject’s prior study was found to be safe and effective for the subject. 


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5. 
STUDY POPULATION 
5.1. 
Inclusion Criteria 
Subjects must meet all of the following criteria to be eligible for enrollment into the study: 
1. Currently enrolled and have not been discontinued from pexidartinib treatment in one of 
the following studies: Study PLX108-10 (ENLIVEN), Study PLX108-01, Study PL3397-
A-A103, or Study PL3397-A-U126. 
2. Willing and able to complete the PROMIS (Physical Function Scale) and EQ-5D-5L 
(European Quality of Life) throughout the study. 
3. Willing and able to provide written informed consent form (ICF) prior to any study-
related procedures and to comply with all study requirements. 
4. Females of reproductive potential must have a negative urine pregnancy test at 
Screening/Baseline (to be confirmed by a serum pregnancy test taken on the End-of-
Treatment visit of their prior study) and 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). 
Note:  A female is considered of reproductive potential following menarche and until 
becoming postmenopausal (no menstrual period for a minimum of 12 months) unless 
permanently sterile (undergone a hysterectomy, bilateral salpingectomy or bilateral 
oophorectomy) with a confirmed by follicle stimulating hormone (FSH) test level 
>40 mIU/mL. 
5. Male subjects must not freeze or donate sperm starting at Screening and throughout the 
study period, and for at least 5 half-lives or 1 month after the final study drug 
administration, whichever is longer. 
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 or 
5 half-lives after the final study drug administration, whichever is longer. 
5.2. 
Exclusion Criteria 
Subjects who meet any of the following criteria are NOT eligible for enrollment into the study 
1. Subject has a clinically significant abnormality identified by the Investigator at Screening 
on physical examination, laboratory tests, or electrocardiogram which, in the judgement 
of the Investigator, would preclude the subject’s safe completion of the study.  
2. Exposure to another investigational drug or current participation in other therapeutic 
investigational procedures, besides pexidartinib studies, within 1 month prior to start of 
study treatment.  Any known contraindication to treatment with, including 
hypersensitivity to, the study drug(s) or excipients in pexidartinib. 


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5.3. 
Screening Failures, Rescreening, and Subject Replacement 
If a subject does not meet eligibility criteria at Screening, they may be rescreened based on the 
Investigator’s discretion.  Details will be included in the PL3397-A-U4003 Study Manual. 


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6. 
STUDY TREATMENT(S) 
See Figure 1.1 for treatment sequence. 
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 
Pexidartinib 
Dosage Formulation 
200 mg capsules 
Dosage Level(s) 
The dose level at end of prior study will serve as the starting dose level. 
Note:  Dose escalation of pexidartinib treatment is not permitted during the 
course of this study. 
Route of Administration 
Oral 
Dosing  
Pexidartinib should be administered twice daily approximately 12 h apart on an 
empty stomach (at least 1 hour before or 2 hours after a meal or snack). 
Duration 
Daily until subject’s end of study 
Packaging 
PLX3397-HCl 200 mg capsules are manufactured, packaged, and labeled 
according to Good Manufacturing Practices and Good Clinical Practices (GCP). 
Packaging will clearly display the name of product, storage condition, and other 
required information as applicable in accordance with local regulations. 
Labeling 
Packaging will be labeled as required per local regulatory requirement. 
6.2. 
Preparation, Handling, Storage, and Accountability for Study 
Drug(s) 
6.2.1. 
Preparation, Handling, and Disposal 
All pexidartinib is supplied as 200-mg capsules that need no further preparation at the study 
sites. 
Procedures for proper handling and disposal should be followed in compliance with the Standard 
Operating Procedures (SOPs) of the Investigational site. 
6.2.2. 
Administration 
Pexidartinib is provided as 200-mg capsules for oral, daily administration.  Subjects are to be 
administered the dosage level at which they completed their prior study.  Doses 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.  Administration with 
food (particularly with high proportion of fat) may result in increased exposure to pexidartinib 
and should be avoided.  Dose reductions and interruptions are permitted according to pre-
specified guidelines. 


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On the day of the scheduled visit, subjects will be instructed to take their morning and evening 
dose at the usual time of study treatment.  Subjects should be told to bring their bottle containing 
all unused study treatment to the clinic for accountability. 
Between clinic visits, subjects will administer their study treatment at home and record the 
dosing information in the study dosing Diary.  Missed doses (those generally outside of a 
± 2-hour dosing window) should be skipped and NOT administered as a double dose at the next 
dosing time point.  Subjects who vomit their dose should be instructed NOT to make up that 
dose.  Study sites will call subjects on a weekly basis as reminders to bring IP bottles to site 
visits and to complete their diaries.  During these calls, study sites may also collect other 
information, including AEs and concomitant medications. 
Further details on study treatment administration are contained in the PLX3397-A-U4003 
Pharmacy Manual. 
6.2.3. 
Storage 
Pexidartinib should be stored at the sites in a secure, controlled facility and only provided to 
subjects who signed an ICF and are participating in the study.  Pexidartinib 200 mg capsules 
should be stored at controlled room temperature (should not be stored above 25°C/77°F).  
Excursions are permitted to 15°C to 30°C (59ºF to 86ºF).  If storage conditions are not 
maintained per specified requirements, then the Sponsor or contract research organization (CRO) 
should be contacted.  Subjects will be instructed to store pexidartinib at room temperature out of 
the reach of children or other cohabitants. 
6.2.4. 
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. 
Documentation of receipt of shipment should be returned as instructed on the form.  The original 
will be retained at the study site. 
In addition, the Investigator or designee shall contact the Sponsor or designee as soon as possible 
if there is a problem with the shipment. 
The Investigator is responsible for study drug accountability, reconciliation, and record 
maintenance (i.e., documentation of receipt of shipment, dispensation/return record, and 
certificate of destruction/return receipt). 
Additional information can be found in the PL3397-A-U4003 Study Manual. 
6.3. 
Measure to Minimize Bias:  Randomization and Blinding 
Not applicable. 
6.4. 
Treatment Compliance 
Dosing compliance for pexidartinib will be assessed by means of capsule counts remaining or 
bottles returned.  All pexidartinib packaging will be returned at each subject visit; an accounting 
of capsules will be made and recorded in the electronic case report form (eCRF).  If zero 
capsules were returned, subjects are asked whether any were disposed/thrown away, rather than 


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taken orally, and this information will be recorded in the eCRF.  Subjects will record time and 
day of administration in the subject’s Diary. 
6.5. 
Guidelines for Dose Modification 
Reduction or interruption of the dose for toxicity may take place at any time according to the 
guidelines in Table 6.3.  Dose reduction/interruption guidelines for hematologic and non-
hematologic treatment-related TEAEs are based on severity.  Dose interruptions can be 
implemented at the discretion of the treating physician to manage intolerable or clinically 
significant toxicity.  If a dose interruption is required, study assessments should be performed as 
scheduled, irrespective of the study treatment delay.  Interruptions due to toxicity lasting 
>14 days require treatment discontinuation unless the Medical Monitor approves continuation. 
The recommended dose reductions for AEs are provided in Table 6.2. 
Table 6.2: 
Recommended Dose Reductions for Pexidartinib for Adverse Reactions 
Dose Reduction  
New 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 
Subjects unable to tolerate 200 mg orally twice daily will be discontinued.  Once dose reduction 
takes place for toxicity, a dose re-escalation is not allowed. 
The recommended dosage of pexidartinib for patients with mild to severe renal impairment 
(creatinine clearance [CrCL] 15 to 89 mL/min estimated by Cockcroft-Gault using actual body 
weight, Section 10.3.1) is 200 mg in the morning and 400 mg in the evening. 
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 physician.  All adjustments should be 
communicated to the Sponsor’s Medical Monitor or designee.  Re-challenge with a reduced dose 
of pexidartinib may result in a recurrence of increased serum transaminases, bilirubin, or ALP.  
Investigators will ensure weekly liver monitoring tests for the first 8 weeks after re-challenge, 
then every 2 weeks for the next month, then every 3 months or more frequently as directed by 
the Investigator. 
Additional information can be found in the PL3397-A-U4003 Study Manual and the Pexidartinib 
IB. 
Table 6.3: 
Recommended Dosage Modifications for Pexidartinib for Adverse Reactions 
Event 
Severity 
Pexidartinib Dosage Modifications 
Hepatoxicity 
Increased ALT 
and/or AST 
>3 to 5 × ULN 
 
Withhold and monitor liver tests weekly. 
 
If AST and ALT ≤3 × ULN within 4 weeks, resume at 
reduced dose. 
 
If AST or ALT not ≤3 × ULN in 4 weeks, permanently 
discontinue pexidartinib. 


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Event 
Severity 
Pexidartinib Dosage Modifications 
>5 to 10 × ULN 
 
Withhold and monitor liver tests twice weekly. 
 
If AST and ALT ≤3 × ULN within 4 weeks, resume at 
reduced dose. 
 
If AST or ALT not ≤3 × ULN in 4 weeks, permanently 
discontinue pexidartinib. 
>10 × ULN 
 
Permanently discontinue pexidartinib. 
 
Monitor liver tests twice weekly until AST or ALT ≤5 × 
ULN, then weekly until ≤3 × ULN. 
Increased 
ALPa and 
GGT 
ALP >2 × ULN with GGT 
>2 × ULN 
 
Permanently discontinue pexidartinib.  Monitor liver tests 
twice weekly until ALP ≤5 times ULN, then weekly until 
≤2 × ULN. 
Increased 
bilirubin 
TB >ULN to <2 × ULN 
or 
DB >ULN and <1.5 × ULN 
 
Withhold and monitor liver tests twice weekly. 
 
If an alternate cause for increased bilirubin is confirmed 
and bilirubin <ULN within 4 weeks, resume at reduced 
dose. 
 
If bilirubin not <ULN in 4 weeks, permanently discontinue 
pexidartinib. 
TB ≥2 × ULN 
or 
DB >1.5 × ULN 
 
Permanently discontinue pexidartinib. 
 
Monitor liver tests twice weekly until bilirubin ≤ULN. 
Adverse Reactions or Other Laboratory Abnormalities 
Any 
Severe or intolerable 
 
Withhold until improvement or resolution. 
 
Resume at a reduced dose upon improvement or resolution. 
ALT = alanine aminotransferase; ALP = alkaline phosphatase; AST = aspartate aminotransferase; DB = direct 
bilirubin; GGT = gamma-glutamyl transferase; TB = total bilirubin; ULN = upper limit of normal. 
a Confirm ALP elevations as liver isozyme fraction. 
Source:  Pexidartinib Study Manual 
Table 6.4: 
Additional Liver Evaluation 
Evaluation* 
Comments 
Increase frequency of testing liver chemistries to twice 
per week, including INR and albumin, and continue 
until liver chemistries have stabilized, and then reduce 
to weekly until liver chemistries return to normal or 
baseline 
Investigational treatment may be started after liver 
function tests recover to Grade 0 to 1 or baseline level, 
and in consultation with Medical Monitor 
Detailed history focusing on medications and 
substances used: alcohol, change in medication 
dosages, new medications added, attention to use of 
acetaminophen, OTC medication use and recreational 
drug use. Check for change in diet or use of dietary 
supplements, with particular attention to dose and 
duration of any herbal product 
Suspect medications will be discontinued or substituted 
for if possible 
Detailed medical history and physical exam seeking 
new abnormalities 
Evaluate abnormalities found 


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Evaluation* 
Comments 
Full serological evaluation for hepatitis A, B, C and E 
(IgG and IgM). Check for autoimmune hepatitis with 
serological laboratory studies 
If viral hepatitis or autoimmune hepatitis suggested, 
have subject evaluated by hepatologist 
Liver ultrasound performed to evaluate liver and 
biliary tree 
Evaluate any abnormalities found 
Check history for exposure to chemical agents  
Remove chemical exposure and have subject seen by 
hepatologist 
Obtain hepatology consult if liver function continues to 
rise beyond 14 days 
Contact Medical Monitor 
Ig = immunoglobulin; INR = international normalized ratio; OTC = over-the-counter. 
*Cases are to be discussed with the Medical Monitor whenever investigational product is being held for liver 
function test abnormality. 
All dose modifications (interruption, delay, reduction, and/or discontinuation) should be based 
on the worst preceding toxicity (National Cancer Institute-Common Terminology Criteria for 
Adverse Events [NCI-CTCAE] version 5.0) as shown in Table 6.3.  Dose increases are not 
permitted for pexidartinib.  Dose modification decisions may be based on laboratory results. 
Once the dose of pexidartinib has been reduced because of toxicity, all subsequent cycles should 
be administered at that lower dose level unless further dose reduction is required.  More than 
2 dose reductions are not allowed and if toxicity continues after 2 dose reductions, the subject 
will be withdrawn from the study treatment if further toxicity meeting the requirement for dose 
reduction occurs. 
For Grade 3 or Grade 4 events, monitoring (including local laboratory tests when appropriate) 
should be performed frequently and at an interval no greater than 7 days until the AE is 
determined to be resolving. 
6.5.1. 
Renal Impairment 
A reduced dose of 600 mg/day (200 mg in the morning and 400 mg in the evening) is 
recommended in study subjects with mild to severe renal impairment (creatinine clearance 
[CrCL] 15 to 89 mL/min estimated by Cockcroft-Gault using actual body weight). 


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6.6. 
Prior and Concomitant Medications 
During the study, if the use of any concomitant treatment becomes necessary (e.g., for treatment 
of an AE), the treatment must be recorded on the source document and 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 30 days of the Baseline visit will be recorded on the 
eCRF.  Note that vaccinations for COVID-19 are to be recorded on the source document and 
captured on the eCRF under both the concomitant medications section and on the COVID-19 
forms. 
6.6.1. 
Analgesic Use 
Analgesic use, both prescription and OTC, will be collected in the eCRF in the same manner as 
other concomitant medications. 
6.7. 
Prohibited Therapies/Products 
Subjects enrolled in studies with pexidartinib who are also receiving concomitant warfarin 
should have their anti-coagulation status carefully monitored, especially shortly after initiation of 
pexidartinib, for the potential need for adjustments in warfarin dosing.  In particular, INR should 
be obtained just prior to initiation of pexidartinib, within 1 to 2 weeks after initiation, and 
periodically thereafter.  Dose adjustments of warfarin should be made as medically indicated. 
Although pexidartinib does not appear to inhibit CYP drug-metabolizing enzymes to an 
important extent, caution is warranted when administering pexidartinib to subjects taking drugs 
that are highly dependent on CYP for metabolism and have a narrow therapeutic index.  It is not 
known whether systemic exposure to these medications will increase while subjects are receiving 
pexidartinib. 
Of the 5 major CYP isoforms, 3A4 (BFC) may be involved in Phase 1 metabolism of 
pexidartinib, with possibly CYP1A2 playing a minor role. Concomitant use of strong CYP3A4 
inhibitors (Table 10.2) and inducers should be administered with caution, in the event they alter 
the systemic exposure to pexidartinib.  In general, strong inhibitors or inducers of CYP3A4 
should be avoided unless clinically necessary.  These include anticonvulsants, certain mycin 
antimicrobials, and antiretrovirals. 
Restricted Therapies/Products 
If concomitant use with a strong CYP3A inhibitor (Table 10.2) or UGT inhibitor cannot be 
avoided, reduce the pexidartinib dose according to the recommendations in Table 6.5.  If 
concomitant use of a strong CYP3A inhibitor or UGT inhibitor is discontinued, increase the 
pexidartinib dose (after 3 plasma half-lives of the strong CYP3A inhibitor or UGT inhibitor) to 
the dose that was used before starting the inhibitor.


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Table 6.5: 
Recommended Dosage Reductions for Pexidartinib for Concomitant Use of 
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 per day; CYP = cytochrome P450; UGT = uridine 5'-diphospho-glucuronosyltransferase 
6.7.1. 
Hormonal Contraceptives 
Pexidartinib has been indicated to be a moderate CYP3A4 inducer, as concurrent administration 
of pexidartinib decreased the AUCinf of the CYP3A4 substrate midazolam by 57%.  As the 
hormonal contraceptive ethinyl estradiol is a CYP3A4 substrate, there is a potential that exposure 
of ethinyl estradiol may decrease on concurrent administration with pexidartinib.  As 
pexidartinib may cause embryo-fetal harm when administered to a pregnant woman, females of 
reproductive potential should be advised to use an effective, non-hormonal method of 
contraception during treatment with pexidartinib and for 1 month after the last dose.  Males with 
female partners of reproductive potential should be advised to use an effective method of 
contraception during treatment with pexidartinib and for 1 month after the last dose.  Female 
partners of male patients should concurrently use effective contraceptive methods (hormonal or 
non-hormonal). 
6.7.2. 
Acid-reducing Agents 
Avoid the concomitant use of proton pump inhibitors (PPIs) while taking pexidartinib.  As an 
alternative to a PPI, administer pexidartinib 2 hours before or 2 hours after taking a locally-
acting antacid, or if using a histamine 2 (H2)-receptor antagonist, administer pexidartinib at least 
2 hours before or 10 hours after taking an H2-receptor antagonist. 
Permitted Therapies/Products 
Subjects are permitted to receive prophylactic or supportive treatment as standard of care during 
treatment, per Investigator’s discretion and institutional guidelines. 
 Palliative radiation to non-measurable lesion is permitted as long as the radiation field 
does not include measurable lesion; 
 Investigators’ discretion is recommended for the following: 
 Prophylactic or supportive treatment for expected toxicities, including 
management of study drug will be as per Investigator’s discretion.  


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7. 
STUDY DRUG DISCONTINUATION AND DISCONTINUATION 
FROM THE STUDY 
This section describes subjects who discontinue pexidartinib treatment as part of this study for 
reasons listed below and NOT subjects who are participating in the Treatment-Free period of the 
Treatment-Free/Re-Treatment Cohort. 
7.1. 
Subject Withdrawal/Discontinuation from the Study 
Subjects may discontinue from the study for any of the following reasons: 
 Completed 
 Complete Response 
 Death 
 Adverse Event 
 Progressive Disease 
 Clinical Progression 
 Lack of Efficacy 
 Withdrawal by Subject (to discontinue study drug) 
 Physician Decision 
 Lost to Follow-up (see Section 7.2 for details on when a subject is considered Lost to 
Follow-up) 
 Pregnancy 
 Protocol Deviation 
 Study Termination by Sponsor 
 Other 
If the reason for study discontinuation is the death of the subject, the options for categorizing the 
primary cause of death are progressive disease or adverse event.  If reason of death is unknown, 
every effort should be made to obtain the primary cause of death.  Only 1 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 (i.e., 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 
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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 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; 
 If 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 Schedule of Events (Section 1.3) for data to be collected at the time of study discontinuation 
and for any further evaluations that need to be completed. 
7.2. 
Lost to Follow-up 
A subject will be considered lost to follow-up if he/she fails to return for 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, multiple 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, site personnel must make every effort to collect 
survival status from public records (e.g., obituaries, death certificates, etc.) in accordance with 
local laws. 


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8. 
STUDY PROCEDURES 
See Schedule of Events (Section 1.3) for Screening, Baseline, Treatment, and EOS/EOT Follow-
up study procedures. 
8.1. 
Eligibility Assessment 
Review the subject's demographics, medical and target disease history (if permitted via the 
subjects signed ICF, these may be transferred from their prior study records), vital signs, and 
results of tests (e.g., physical examination, ECG, laboratory assessments) and compare against 
the eligibility criteria (Section 5.1 and Section 5.2). 
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. 
Tenosynovial Giant Cell Tumor History 
Subject’s TGCT history will be obtained by the Investigator or a qualified designee.  This may 
be obtained from the subject’s file from the prior study. 
General Medical History and Baseline Conditions 
Subject’s medical history will be obtained by the Investigator or a qualified designee. 
This may be obtained from the subject’s file from the prior study (e.g., the concomitant 
medications taken during the course of the preceding study will be recorded under prior 
medications in PL3397-A-U4003).  Untoward medical occurrences (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 consent date 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 before 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; which, if permitted via the subjects signed ICF, may be 
transferred from the subject’s file from their prior study, against the eligibility criteria. 
8.2. 
Enrollment 
Once a subject has been deemed eligible as per Section 5.1 and Section 5.2, the subject should be 
enrolled into this study.  For subjects choosing to continue treatment with pexidartinib, they will 
remain on their dosage level at the end of the prior study.  For subjects choosing to enroll into the 


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Treatment-Free period of the Treatment-Free/Re-Treatment Cohort, pexidartinib treatment 
should be immediately stopped. 
8.3. 
Efficacy Assessments 
8.3.1. 
Response Assessment 
Assess the subject based upon the local laboratory results using the Response Criteria 
(Section 10.4).  Additional details will be available in the Study Laboratory Manual. 
8.3.2. 
Patient Reported Outcomes 
The PROMIS PF (Section 10.6.1) and EQ-ED-5L (Section 10.6.3) questionnaires will be used 
for PROs. 
8.3.3. 
Radiographic Tumor Assessments 
The Investigator will evaluate the MRI scans in order to perform a qualitative tumor assessment 
(i.e., stable disease).  These data will be used to inform the Investigator and patient regarding the 
next steps in the course of treatment. 
The Sponsor may retain the MRI scans to retrospectively evaluate the tumor response, by central 
radiographic readers, for study and non-study related purposes. 
Individual subject outcomes by TVS will be classified according to the following criteria 
inspired by RECIST: 
 Complete response:  Lesion completely gone. 
 Partial response:  ≥50% decrease in volume score relative to baseline. 
 Progressive disease:  ≥30% increase in volume relative to lowest score during the 
study whether at baseline or some other visit. 
 Stable disease:  Does not meet any of the prior criteria based on score during study. 
The cutoffs of 50% for partial response (PR) and ≥30% for progressive disease (PD) were 
developed in consultation with clinical experts. 
The 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 Magnetic Resonance Imaging (RAMRIS), originally developed for 
rheumatoid arthritis,8 and Whole-Organ Magnetic Resonance Imaging Score (WORMS), 
originally developed for osteoarthritis.9  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. 


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Re-Treatment Assessment 
At each visit, subjects who are in the Treatment-Free period will be assessed by the Investigator 
for pexidartinib re-treatment based on Investigator and subject’s discretion. 
8.4. 
Safety Assessments 
8.4.1. 
Adverse Event 
Methods to Detect Adverse Events 
The definitions of an AE, TEAE, and SAE can be found in Section 9.5.2 and Section 10.5.  
Adverse events 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.  Between scheduled clinic visits, 
subjects should be instructed to enter all AEs in their Diary.  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 (i.e., 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. 
COVID-19 assessments are detailed in Section 8.4.4. 
Time Period for Collecting Adverse Events, Serious Adverse Events 
All serious adverse events (SAEs) occurring after the subject signs the ICF and up to 30 days 
after the last dose of study medication if applicable or EOS/FU visit, whether observed by the 
Investigator or reported by the subject, will be recorded on the AE eCRF.  All SAEs will be 
followed until resolution, stabilization, the event is otherwise explained, or the subject is lost to 
follow-up. 
All non-serious AEs occurring after the subject has taken the first dose of study medication/signs 
the ICF until 30 days after the last dose of study medication will be recorded on the AE 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 AE eCRF, unless 
it is a condition of TGCT. 
Reporting Procedure for Investigators 
All AEs (including adverse events of special interest [AESIs] and SAEs) will be reported in the 
AE eCRF.  All AEs (serious and non-serious) must be reported with the Investigator’s 
assessment of seriousness, severity, and causality to pexidartinib. 


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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 AEs and SAEs 
Disease progression/worsening of TGCT will not be recorded as an AE on the Adverse Event 
eCRF.  However, events associated with disease progression, 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 SAVER (Serious Adverse Event Report) form within 24 hours of 
awareness: 
 SAEs (Section 10.5.2) 
 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 (as defined in 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 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 or 
CRO using the provided fax transmittal form and the appropriate fax number provided for the 
country or email address.  Once EDC becomes available, please enter SAEs 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 PL3397-A-U4003 Study Site Manual) or 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/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 inform Investigators and regulatory authorities of all SAEs, 
regardless of relatedness, reported from this study, and any Suspected Unexpected Serious 


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Adverse Event Reactions (SUSARs) occurring in other studies of pexidartinib, as appropriate per 
institutional/local reporting requirements. 
Sponsor 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 pexidartinib IB.6 
Follow-up for AEs and SAEs 
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 Sponsor or CRO 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 Sponsor and/or CRO within 24 hours of awareness.  Overdose will be reported via 
the 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. 
Occupational exposures must be reported via the SAVER form. 
8.4.1.2. 
Adverse Events of Special Interest 
Pexidartinib can cause serious and potentially fatal liver injury.  Hepatotoxicity with ductopenia 
and cholestasis occurred in patients treated with pexidartinib.  Across 768 patients who received 
pexidartinib in clinical trials, there were 2 irreversible cases of cholestatic liver injury.  One 
patient died with advanced cancer and ongoing liver toxicity and 1 patient required a liver 
transplant.  The mechanism of cholestatic hepatotoxicity is unknown and its occurrence cannot 
be predicted. 
It is unknown whether liver injury occurs in the absence of increased transaminases.  Avoid 
pexidartinib in patients with pre-existing increased serum transaminases; total bilirubin or direct 
bilirubin (>ULN); or active liver or biliary tract disease, including increased ALP.  Taking 
pexidartinib with food increases drug exposure by 100% and may increase the risk of 
hepatotoxicity.  Administer pexidartinib on an empty stomach, at least 1 hour before or 2 hours 
after a meal or snack.  Monitor liver tests, including AST, ALT, total bilirubin, direct bilirubin, 
ALP and GGT, prior to initiation of pexidartinib, and as defined within the appropriate SoE for 
the cohorts (Section 1.3).  Withhold and dose reduce, or permanently discontinue pexidartinib 
based on the severity of the hepatotoxicity (Table 6.3). 


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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 TBIL >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.  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 
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 discontinues study drug due to liver enzyme abnormalities, the subject will have 
additional clinical and laboratory evaluations as described in Section 10.2 in order to determine 
the nature and severity of the potential liver injury. 
Additional information can be found in the PL3397-A-U4003 Study Manual and the Pexidartinib 
IB. 
8.4.2. 
Pregnancy/Embryo-Fetal Toxicity 
Based on animal studies and its mechanism of action, pexidartinib may cause fetal harm when 
administered to a pregnant woman.  Oral administration of pexidartinib to pregnant rats and 
rabbits during the period of organogenesis resulted in malformations, increased post-
implantation loss, and abortion at exposures approximately equal to the human exposure at the 
recommended dose of 800 mg based on area under the curve (AUC). 
Advise pregnant women of the potential risk to a fetus.  As pexidartinib is a moderate CYP3A4 
inhibitor, concurrent administration of pexidartinib with ethinyl estradiol may lead to reduced 
exposure of ethinyl estradiol.  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). 
Sponsor must be notified of any female subject or partner of a male subject who becomes 
pregnant while receiving or within 30 days of discontinuing pexidartinib. 
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 


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the criteria for immediate classification as an SAE (i.e., 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 females of reproductive potential (as defined in Section 5.1), document the results of a 
negative serum pregnancy test.  A positive pregnancy test at Screening will exclude female 
subject enrollment.  Any females enrolled in the study and receiving pexidartinib who become 
pregnant must discontinue pexidartinib and communicate this information to the Investigator, 
and have their pregnancy followed to outcome. 
8.4.3. 
Clinical Laboratory Evaluations 
The clinical laboratory tests including hematology, coagulation, serum chemistry, TSH and 
urinalysis will be performed. De-identified laboratory reports with all local laboratory results 
from samples collected for hematology, coagulation, serum chemistry, TSH, and urinalysis will 
be collected on the local laboratory form in EDC to be data entered into the clinical database.  
Refer to Table 10.1 for the complete list of laboratory parameters.  Laboratories parameters from 
the previous pexidartinib studies may be used at Baseline. 
Abnormal laboratory values (NCI-CTCAE Grade 3 or 4) occurring during the clinical study will 
be followed until repeat test results return to normal (or Baseline), stabilize, or are no longer 
clinically relevant, as determined by the Investigator.  New or worsened clinically relevant 
abnormalities should be recorded as AEs on the Adverse Event eCRF. 
8.4.4. 
Reporting of Exposure to COVID-19 (SARS-CoV-2) 
All confirmed or suspected COVID-19 events must be recorded in the eCRF. 
 Subjects who test positive for COVID-19 should be reported as “Confirmed COVID-19” 
either as an AE or serious adverse event (SAE). 
The usual protocol mandated SAE reporting requirements should be followed for confirmed or 
suspected COVID-19 (or SARS-CoV-2) as done for any other AE, ie, the Investigator should 
assess whether any seriousness criteria are met per protocol, and appropriate protocol reporting 
requirements should be followed. 
In the event that the Investigator assesses that a COVID-19 case does not meet any seriousness 
criteria as outlined in the protocol, it should be reported as a non-serious AE in the eCRF. 
All study drug interruption or dose reduction or discontinuation due to the COVID-19 event must 
be recorded on the AE and drug administration eCRFs. 
For both serious and non-serious COVID-related AEs, the following information should be 
provided as applicable: 
 Date and laboratory results confirming the COVID-19 diagnosis (including viral antigen 
test and/or antiviral antibody serological test) in the eCRF.  


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 Clinical course of the case, including presenting signs, symptoms, exposure, actions 
taken with the investigational products, medications used for treatment or prophylaxis of 
COVID-19, and outcome in relevant eCRF (eg, concomitant medication, AE). 
 Findings from diagnostic imaging (including computed tomography scan or other chest 
imaging). 
8.4.5. 
Other Safety 
Physical Examinations 
A complete physical examination should include a weight measurement and an evaluation of the 
head, eyes, ears, nose, and throat and the cardiovascular, dermatological, musculoskeletal, 
respiratory, gastrointestinal, genitourinary, and neurological systems.  Any abnormality 
identified at Baseline should be recorded on the General Medical History and Baseline 
Conditions eCRF.  At subsequent visits (or as clinically indicated), limited, symptom-directed 
physical examinations should be performed.  Changes from Baseline abnormalities should be 
collected in the subject’s study record.  New or worsened clinically relevant abnormalities should 
be recorded as AEs on the Adverse Event eCRF. 
Vital Signs 
Vital signs will include the measurements of respiratory rate, heart rate, systolic and diastolic 
blood pressures, temperature, height (may be obtained from subject’s prior study file), and body 
weight [for Screening/Baseline this may be obtained from the subject’s prior study].  Vital signs 
should be taken prior to ECG measurement.  Blood pressure and pulse rate will be measured 
after the subject has rested in a recumbent position for at least 5 minutes and prior to laboratory 
draws. 
Electrocardiograms 
12 lead-electrocardiograms (ECGs) will be performed and recorded for every subject at 
Screening.  The ECG will be measured after the subject has rested in a recumbent position for at 
least 5 minutes and the ECG results will be read locally.  At any visit during which a subject 
exhibits a heart rate ≤50 bpm or other clinical indications for ECG, the ECG will be repeated.  
Any abnormal finding should be confirmed with a repeated ECG.  Abnormal, clinically relevant 
findings occurring post-baseline will be reported as AEs.  Whether or not the measurement is 
performed, the date the ECG is to be performed, heart rate, PR interval, RR interval, QRS 
amplitude, QT interval, QTcF interval, and results will be recorded in the eCRF. 
8.5. 
Pharmacokinetic (PK) Assessment(s) 
Not applicable. 
8.6. 
Pharmacodynamic Assessment(s) 
Not applicable. 


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9. 
STATISTICAL CONSIDERATIONS  
9.1. 
General Statistical Considerations 
This is a phase 4, multicenter study to evaluate the discontinuation and re-treatment of 
pexidartinib in subjects with TGCT (PVNS or GCT TS) who were previously treated with 
pexidartinib in one of the following studies: (PLX108-10 (ENLIVEN), PLX108-01, PL3397-A-
A103, and PL3397-A U126).  There is no statistical hypothesis for this study.  The statistical 
analysis will be descriptive in nature.  No p-values will be reported. 
9.2. 
Statistical Hypothesis 
Not applicable. 
9.3. 
Sample Size Determination 
The study sample size is not based on statistical consideration.  Subjects currently enrolled in 
Studies PLX108-10 (ENLIVEN), PLX108-01, PL3397-A-A103, and PL3397-A-U126 who are 
eligible can participate in this study. 
9.4. 
Population for Analysis Sets 
Analysis Sets 
 The Safety Analysis Set will include all subjects who entered this study.  Subjects 
will be analyzed according to their cohort (Treatment-Free/Re-Treatment Cohort; 
Treatment Continuation Cohort). 
 The Full Analysis Set (FAS) for the Treatment-Free/Re-Treatment Cohort will 
include all subjects who entered the Treatment-Free/Re-Treatment Cohort.  This data 
set will be the primary population for the primary endpoint. 
 The Full Analysis Set (FAS) for the Treatment Continuation Cohort will include 
all subjects who entered the Treatment Continuation Cohort. 
 The Evaluable Analysis Set (EAS) will include all subjects who entered the study 
with Baseline measure and at least 1 post-baseline measures available.  The data set 
will be used for PRO measures. 
 The Re-Treatment Analysis Set (RAS) will include all subjects who received at least 
1 dose of pexidartinib in the Treatment-Free/Re-Treatment Cohort after stopping 
pexidartinib.  The data will be used for both efficacy and safety analyses for 
re-treated subjects in the Treatment-Free/Re-Treatment Cohort. 
9.5. 
Statistical Analysis 
The Statistical Analysis Plan (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 and secondary endpoints. 


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9.5.1. 
Efficacy Analyses 
Table 3.1 and Table 3.2 list the primary and secondary endpoints and their corresponding 
definitions of all endpoints.  Additional details for the analysis and censoring rules are noted in 
the following sections.  Detailed censoring rules for the primary and applicable secondary 
efficacy endpoints will be specified in the SAP. 
9.5.1.1. 
Primary Efficacy Analyses 
The primary endpoint in this study is the proportion of subjects who remain treatment-free at 
Month 12 and Month 24 after entering the Treatment-Free period in the Treatment-Free/Re-
Treatment Cohort.  The primary efficacy analysis will be based on the data from the FAS. 
Kaplan-Meier methods will be used to estimate the proportion of subjects who remain 
treatment-free at Month 12 and Month 24.  Estimate of the proportion will be provided with its 
95% confidence interval (CI) using Greenwood’s formula. 
The subjects who resume pexidartinib treatment or died will be considered as an event.  The 
subjects who take subsequent systemic therapy or undergo surgery for the treatment of TGCT 
will also be counted as an event.  The subjects who withdraw consent or lost to follow up with be 
censored at the last contact date. 
9.5.1.2. 
Secondary Efficacy Analyses 
The PRO measures will be summarized descriptively over time along with its 95% CI by each 
cohort.  The mean change from Baseline for these measures will also be reported over time along 
with its 95% CI by each cohort.  The analysis will be conducted in the Evaluable Analysis Set 
(EAS). 
Similar analyses will be conducted in the Re-treatment Analysis Set subjects (RAS).  In this 
analysis, the Baseline measure of the retreated subjects is defined as the latest measure prior to or 
on the date of re-treatment of pexidartinib. 
Qualitative assessments of the tumor will be summarized descriptively for pexidartinib re-treated 
subjects in the Treatment-Free/Re-Treatment Cohort and for all subjects in the Treatment 
Continuation Cohort. 
9.5.1.3. 
Exploratory Analyses 
Exploratory analysis will be descriptive only.  Details of the exploratory analysis will be 
specified in the SAP. 
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 by 
cohort separately. 


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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 30 days after last dose of study drug.  AEs collected after 30 
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.  Incidence of TEAEs occurring over time, (e.g., 0 to 6 months, 6 to 
12 months, etc.) will be summarized.  The number and percentage of subjects reporting TEAEs 
will be calculated overall, by system organ class, by preferred term, and by cohort. 
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, and TEAEs leading to 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.  AEs due to COVID-19 will be also summarized and listed. 
Clinical Laboratory Evaluation 
Descriptive statistics will be provided for the clinical laboratory results by scheduled time of 
evaluation and by cohort, 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 Baseline will be presented for the maximum and minimum post-treatment values 
and the values at the EOT visit. 
Abnormal clinical laboratory results will be graded according to NCI-CTCAE version 5.0, if 
applicable, and the grade will be presented in a by-subject data listing.  A shift table, presenting 
by cohort 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. 
ECG 
Descriptive statistics will be provided for the ECG measurements by scheduled time of 
evaluation and by cohort, 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 
ECG data will be generated. 
Vital Signs 
Descriptive statistics will be provided for the vital sign measurements by scheduled time of 
evaluation and by cohort, 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 data will be generated. 


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Other 
Listings of all other safety endpoints (e.g., physical examination findings) will be generated. 
9.5.3. 
Other Analyses 
No other analyses are planned in this study. 
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 (e.g., 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 IRB or IEC 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, IEC, and/or applicable regulatory 
authorities. 
The Investigator should notify the IRB or IEC 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. 
The Sponsor will appoint a Coordinating Investigator.  Among other possible duties, the 
Coordinating Investigator will be responsible for reviewing the Final Clinical Study Report and 
testifying to the accuracy of the description of the study conduct.  Because the Coordinating 
Investigator should have personal knowledge of the conduct of the study, he or she will normally 
be chosen from among those Investigators who have enrolled and treated at least 1 subject.  
However, where an Investigator has special knowledge of the field or of the study, the 
Coordinating Investigator can be chosen prior to enrollment of the first subject.  In all cases, the 
Coordinating Investigator must be chosen prior to locking the database. 
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 Harmonization (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 Food and Drug Administration (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; 


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 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(s), and of any suspected/actual serious GCP non-compliance brought to the attention of 
the Investigator. 
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, 
ECs/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 EC/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 EC/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. 


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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 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. 
For study sites in the US, an additional consent is required for the Health Insurance Portability 
and Accountability Act (HIPAA). 
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 Sponsor will observe the rules laid down in the European Data Protection Directive 
95/46/EC and General Data Protection Regulation 2016/679 on the protection of individuals with 
regard to the processing of personal data and the free movement of such data. 
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 
(e.g., 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 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 (e.g., 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 PL3397-A-U4003 Study 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. 


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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 (e.g., 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. 
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 Sponsor or 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 such as local laboratories will be entered into the clinical 
database. 
All AEs will be coded using MedDRA.  Serious adverse events in the clinical database will be 
reconciled with the safety database. 
All concomitant medications and prior cancer therapies will be coded using the World Health 
Organization Drug Reference (WHODRUG) Dictionary. 
10.1.5. 
Committees 
Not applicable. 


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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 (i.e., there is no other written or electronic record of data).  In this study, eCRFs may 
be used as source documents. 
Records of subjects, source documents, monitoring visit logs, data correction forms, eCRFs, 
inventory of study drug, regulatory documents (e.g., 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 site personnel 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). 
 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. 


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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 2 years* after the 
last approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 2 years* have lapsed since the 
formal discontinuation of clinical development of the investigational 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 the Sponsor.  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 and Public Disclosure Policy 
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 participating country 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). 
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 disclosure) based on data generated in this 
study must be reviewed and approved in writing by the Sponsor prior to submission. 


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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 
(e.g., inclusion/exclusion criteria, dosing, missed study visits) within 24 hours of knowledge and 
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 
1 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 
Study termination may also be requested by (a) competent authority/ies. 
10.1.11. 
Product Complaints 
A product complaint is any dissatisfaction with a product that may be attributed to the identity, 
quality, durability, reliability, or safety of the product.  Individuals who identify a potential 
product complaint situation should immediately report the event.  Whenever possible, the 
associated product should be maintained in accordance with the label instructions pending 
further guidance from a quality representative form the Sponsor. 
For product complaints, refer to the PLX3397-A-U4003 Pharmacy Manual for instructions and 
details. 


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10.2. 
Appendix 2:  Laboratory Assessments 
The clinical laboratory tests listed in Table 10.1 are to be performed in this study. 
Table 10.1: 
Clinical Laboratory Tests 
Test 
Analytes 
 
Blood Chemistry 
albumin 
albumin globulin (A/G) ratio (optional) 
alanine aminotransferase (ALT) 
alkaline phosphatase (ALP) 
aspartate aminotransferase (AST) 
bilirubin (total) 
bilirubin (direct) 
blood urea nitrogen (BUN)/urea 
calcium (Ca) 
chloride (Cl) 
creatinine 
cholesterol (total) 
creatinine clearance (Cockcroft-Gault 
Equation) 
creatine phosphokinase (CPK) 
gamma-glutamyl transaminase (GGT) 
glucose (fasting) 
lactate dehydrogenase 
lipase 
lipoprotein, high density/HDL-
cholesterol 
lipoprotein, low density/LDL-
cholesterol 
magnesium (Mg) 
phosphorus 
potassium (K) 
protein (total) 
sodium (Na) 
triglycerides 
uric acid 
Hematology 
hemoglobin 
hematocrit 
platelet count 
red blood cell (RBC) count 
white blood cell (WBC) count 
differential WBC count: 
basophils  
eosinophils 
lymphocytes 
monocytes 
neutrophils 
Coagulation 
prothrombin time (PT)- international normalized ratio (INR) 
activated partial thromboplastin time (aPTT) 
optional:  partial thromboplastin time (PTT) if aPTT is not collected 
Urinalysis 
(abbreviated) 
bilirubin 
glucose 
ketone bodies 
occult blood 
pH 
protein 
urobilinogen 
sediments: 
casts 
RBC 
WBC 
Hormone testing 
Follicular Stimulating Hormone (FSH) 
(females only) 
Thyroid Stimulating Hormone (TSH) 
Baseline and BL-2 only 
 


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10.3. 
Appendix 3:  Reference Standards 
10.3.1. 
Cockcroft-Gault Equation  
The estimated creatinine clearance (CrCL; mL/min) will be calculated using the Cockcroft-Gault 
equation based on [actual/ideal] weight in kilograms (1 kilogram = 2.2 pounds):10 
Conventional – serum creatinine in mg/dL: 
Male: 
CrCL (mL/min) =  
Female: 
CrCL (mL/min) = 
  × 0.85 
 
International System of Units (SI) – serum creatinine in μmol/L: 
Male: 
CrCL (mL/min) =  
Female: 
CrCL (mL/min) = 
         × 0.85 
10.3.2. 
CYP3A4 Inhibitors and Inducers 
Table 10.2 lists the generic names of strong, moderate, and weak CYP3A4 inhibitors.11  This is 
not a complete list and information for all non-listed medications should be confirmed against 
their prescribing information. 
[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 
      [140 - age (in years)] × weight (in kg) 
       serum creatinine (in µmol/L) × 72 × 0.0113 


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Table 10.2: 
CYP3A4 Inhibitors 
Inhibitor Type 
Generic Drug Name 
Allowance 
Strong 
boceprevir 
clarithromycin 
conivaptan 
grapefruit 
grapefruit juice 
indinavir 
itraconazole 
ketoconazole 
lopinavir 
mibefradil 
nefazodone 
nelfinavir 
posaconazole 
ritonavir 
saquinavir 
telaprevir 
telithromycin 
voriconazole 
Use should be avoided if 
possible. 
Requires pexidartinib dose 
reduction. 
Moderate 
amprenavir 
aprepitant 
atazanavir 
ciprofloxacin 
crizotinib 
darunavir 
diltiazem 
erythromycin 
fluconazole 
fosamprenavir 
imatinib 
verapamil 
Use allowed.  
No requirement for pexidartinib 
dose reduction. 


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Inhibitor Type 
Generic Drug Name 
Allowance 
Weak 
alprazolam 
amiodarone 
amlodipine 
atorvastatin 
bicalutamide 
cilostazol 
cimetidine 
cyclosporine 
fluoxetine 
fluvoxamine 
ginkgo 
goldenseal 
isoniazid 
lapatinib 
oral contraceptives 
nilotinib 
pazopanib 
ranitidine 
ranolazine 
ticagrelor 
tipranavir 
zileuton 
Use allowed. 
No requirement for pexidartinib 
dose reduction 
Adapted from:  http://medicine.iupui.edu/clinpharm/ddis/main-table 


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10.4. 
Appendix 4:  Response Criteria 
The Investigator will evaluate the MRI scans to perform a qualitative tumor assessment (i.e., 
stable disease).  These data will be used to inform the Investigator and patient regarding the next 
steps in course of treatment. 
The Sponsor may retain the MRI scans for possible future (not study-related) use to 
retrospectively evaluate the tumor response (i.e., RECIST) and TVS by central radiographic 
readers, as outlined in the criteria below. 
Response Evaluation Criteria in Solid Tumors (Version 1.1) 
Assessment of tumor responses will be performed according to revised RECIST Guidelines, 
Version 1.1.13  Some of these definitions and criteria are highlighted below. 
Measurability of Tumor at Baseline Definitions 
At Baseline, tumor lesions/lymph nodes will be categorized as measurable or non-measurable as 
follows: 
Measurable 
Tumor lesions: Must be accurately measured in at least 1 dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of: 
 10 mm by computed tomography (CT) scan (CT scan slice thickness no greater than 5 
mm) 
 10 mm caliper measurement by clinical examination (lesions which cannot be 
accurately measured with calipers should be recorded as non-measurable) 
 20 mm by chest X-ray 
Measurable malignant lymph nodes: To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm in the short axis when assessed by CT scan (CT scan slice 
thickness is recommended to be no greater than 5 mm).  At Baseline and quarterly scans, only 
the short axis will be measured and followed.  See also notes below on “Baseline documentation 
of target and non-target lesions” for information on lymph node measurement. 
Non-measurable 
All other lesions, including small lesions (longest diameter <10 mm or pathological lymph nodes 
with ≥10 to <15 mm short axis) as well as truly non-measurable lesions.  Lesions considered 
truly non-measurable include leptomeningeal disease, ascites, pleural or pericardial effusion, 
inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by physical examination that is not measurable by 
reproducible imaging techniques. 
Special Considerations Regarding Lesion Measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment: 
Bone lesions: 


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 Bone scan, positron emission tomography (PET) scan or plain films are not 
considered adequate imaging techniques to measure bone lesions.  However, these 
techniques can be used to confirm the presence or disappearance of bone lesions. 
 Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as CT 
or MRI can be considered as measurable lesions if the soft tissue component meets 
the definition of measurability described above. 
 Blastic bone lesions are non-measurable. 
Cystic lesions: 
 Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 
 ‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above.  
However, if noncystic lesions are present in the same subject, these are preferred for 
selection as target lesions. 
Lesions with prior local treatment: 
 Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are not considered measurable unless there has been 
demonstrated progression in the lesion since the therapy. 
Specifications by Methods of Measurements  
Measurement of Lesions 
All measurements should be recorded in metric notation, using calipers if clinically assessed. 
Method of Assessment 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during quarterly scans.  Imaging-based evaluation 
should always be done rather than clinical examination unless the lesion(s) being followed 
cannot be imaged but are assessable by clinical examination. 
CT, MRI: CT is the best currently available and reproducible method to measure lesions selected 
for response assessment.  This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less.  When CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness.  
MRI is also acceptable in certain situations (e.g., for body scans). 
Tumor Response Evaluation 
Assessment of Overall Tumor Burden and Measurable Disease 
To assess objective response or future progression, it is necessary to estimate the overall tumor 
burden at Baseline and use this as a comparator for subsequent measurements. 


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Baseline Documentation of ‘Target’ and ‘Non-Target’ Lesions 
When more than 1 measurable lesion is present at baseline all lesions up to a total of 2 lesions 
per organ and a maximum of 5 lesions total representative of all involved organs should be 
identified as target lesions and will be recorded and measured at baseline (this means in instances 
where subjects have only 1 or 2 organ sites involved a maximum of 2 and 4 lesions respectively 
will be recorded). 
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements.  It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest lesion which 
can be measured reproducibly should be selected. 
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor.  As noted above, pathological nodes which are 
defined as measurable and may be identified as target lesions must meet the criterion of a short 
axis of ≥15 mm by CT scan.  Only the short axis of these nodes will contribute to the baseline 
sum.  The short axis of the node is the diameter normally used by radiologists to judge if a node 
is involved by solid tumor.  Nodal size is normally reported as two dimensions in the plane in 
which the image is obtained (for CT scan this is almost always the axial plane; for MRI the plane 
of acquisition may be axial, sagittal, or coronal).  The smaller of these measures is the short axis.  
For example, an abdominal node which is reported as being 20 mm × 30 mm has a short axis of 
20 mm and qualifies as a malignant, measurable node.  In this example, 20 mm should be 
recorded as the node measurement.  All other pathological nodes (those with short axis ≥10 mm 
but <15 mm) should be considered non-target lesions.  Nodes that have a short axis <10 mm are 
considered non-pathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum.  The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease. 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline.  Measurements are not required, and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal 
progression’. 
Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm. 
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking 
as reference the baseline sum diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study).  In addition to the relative increase of 20%, the sum must also demonstrate an 


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absolute increase of at least 5 mm. (Note: the appearance of 1 or more new lesions is also 
considered progression.) 
Stable Disease: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD, taking as reference the smallest sum diameters while on study. 
Special Notes on the Assessment of Target Lesions 
Lymph nodes: Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline examination), 
even if the nodes regress to below 10 mm on study.  This means that when lymph nodes are 
included as target lesions, the ‘sum’ of lesions may not be zero even if CR criteria are met, since 
a normal lymph node is defined as having a short axis of < 10 mm.  For PR, stable disease, and 
PD, the actual short axis measurement of the nodes is to be included in the sum of target lesions. 
Target lesions that become ‘too small to measure’: All lesions (nodal and non-nodal) recorded 
at baseline should have their actual measurements recorded at each subsequent evaluation, even 
when very small (e.g., 2 mm).  However, sometimes lesions or lymph nodes which are recorded 
as target lesions at baseline become so faint on CT scan that the radiologist may not feel 
comfortable assigning an exact measure and may report them as being ‘too small to measure’.  
When this occurs, it is important that a value be recorded on the eCRF.  If it is the opinion of the 
radiologist that the lesion has likely disappeared, the measurement should be recorded as 0 mm.  
If the lesion is believed to be present and is faintly seen but too small to measure, a default value 
of 5 mm should be assigned.  (Note: It is unlikely that this rule will be used for lymph nodes 
since they usually have a definable size when normal and are frequently surrounded by fat such 
as in the retro-peritoneum.)  This default value is derived from the 5 mm CT slice thickness (but 
should not be changed with varying CT slice thickness.)  The measurement of these lesions is 
potentially non-reproducible; therefore, providing this default value will prevent false responses 
or progressions based upon measurement error. 
If the Radiologist is able to provide an actual measurement, that should be recorded, even if it is 
below 5 mm. 
Lesions that split or coalesce on treatment: When non-nodal lesions ‘fragment’, the longest 
diameters of the fragmented portions should be added together to calculate the target lesion sum.  
Similarly, as lesions coalesce, a plane between them may be maintained that would aid in 
obtaining maximal diameter measurements of each individual lesion.  If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest diameter in this 
instance should be the maximal longest diameter for the ‘coalesced lesion’. 
Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level.  All lymph nodes must be non-pathological in size (<10 mm short axis). 
Non-CR/Non-PD: Persistence of 1 or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
Progressive Disease (PD): Unequivocal progression (see comments below) of existing non-
target lesions.  (Note: the appearance of 1 or more new lesions is also considered progression. 


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Special Notes on Assessment of Progression of Non-target Disease 
The concept of progression of non-target disease requires additional explanation as follows, 
when the subject also has measurable disease.  In this setting, to achieve ‘unequivocal 
progression’ on the basis of the non-target disease, there must be an overall level of substantial 
worsening in non-target disease such that, even in presence of stable disease (SD) or PR in target 
disease, the overall tumor burden has increased sufficiently to merit discontinuation of therapy.  
A modest ‘increase’ in the size of 1 or more non-target lesions is usually not sufficient to qualify 
for unequivocal progression status.  The designation of overall progression solely on the basis of 
change in non-target disease in the face of SD or PR of target disease will therefore be extremely 
rare. 
New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important.  There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal, i.e., not attributable to differences in scanning technique, change in imaging 
modality, or findings thought to represent something other than tumor (for example, some ‘new’ 
bone lesions may be simply healing or flare of pre-existing lesions).  This is particularly 
important when the subject’s baseline lesions show partial or complete response.  For example, 
necrosis of a liver lesion may be reported on a CT scan report as a ‘new’ cystic lesion, which it is 
not. 
A lesion in an anatomical location that was not scanned at baseline is considered a new lesion 
and will indicate disease progression.  An example of this is the subject who has visceral disease 
at baseline and while on study has a CT or MRI of the brain which reveals metastases.  The 
subject’s brain metastases are considered to be evidence of PD even if he/she did not have brain 
imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued therapy and follow-
up evaluation will clarify if it represents truly new disease.  If repeat scans confirm there is 
definitely a new lesion, then progression should be declared using the date of the initial scan that 
indicated its presence. 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the study treatment until 
the EOT.  Confirmatory measurement for CR or PR is [not] required in this study.  The subject’s 
best overall response assignment will depend on the findings of both target and non-target 
disease and will also take into consideration the appearance of new lesions. 
Missing Assessments and In-evaluable Designation 
When no imaging/measurement is done at all at a particular time point, the subject is not 
evaluable (NE) at that time point.  If only a subset of lesion measurements is made at an 
assessment, usually the case is also considered NE at that time point, unless a convincing 
argument can be made that the contribution of the individual missing lesion(s) would not change 
the assigned time point response.  This would be most likely to happen in the case of PD.  For 
example, if a subject had a baseline sum of 50 mm with 3 measured lesions and at follow-up 


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only 2 lesions were assessed, but those gave a sum of 80 mm, the subject will have achieved PD 
status, regardless of the contribution of the missing lesion. 
Best Overall Response: All Time Points 
The best overall response is determined once all the data for the subject are known. 
Best response determination in studies where confirmation of complete or partial response IS 
NOT required: Best response in these studies is defined as the best response across all time 
points (for example, a subject who has stable disease at first assessment, PR at second 
assessment, and PD on last assessment has a best overall response of PR).  When stable disease 
is believed to be best response, it must also meet the protocol specified minimum time from 
baseline (within 4 weeks prior to the first dose of study drug), 7 weeks, in the case of scan 
intervals of 8 weeks (or “5 weeks”, in the case of scan intervals of 6 weeks.)  If the minimum 
time is not met when stable disease is otherwise the best time point response, the subject’s best 
response depends on the subsequent assessments.  For example, a subject who has stable disease 
at first assessment, PD at second and does not meet minimum duration for stable disease, will 
have a best response of PD.  The same subject lost to follow-up after the first stable disease 
assessment would be considered NE. 
Table 10.3: 
Best Overall Response When Confirmation of CR and PR Required 
Overall response 
 
Overall response 
First time point 
Subsequent time point 
Best 
CR 
CR 
CR 
CR 
PR 
SD, PD or PRa 
CR 
SD 
SD provided minimum criteria for SD duration 
met, otherwise, PD 
CR 
PD 
SD provided minimum criteria for SD duration 
met, otherwise, PD 
CR 
NE 
SD provided minimum criteria for SD duration 
met, otherwise, PD 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD duration 
met, otherwise, PD 
PR 
NE 
SD provided minimum criteria for SD duration 
met, otherwise, PD 
NE 
NE 
NE 
CR = complete response; PR = partial response; SD = stable disease; NE = not evaluable; PD = progressive disease 
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR).  
Best response would depend on whether minimum duration for SD was met.  However, sometimes ‘CR’ may be 
claimed when subsequent scans suggest small lesions were likely still present and in fact the patient had PR, not 


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CR at the first time point.  Under these circumstances, the original CR should be changed to PR and the best 
response is PR. 
Source: Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: Revised 
RECIST guideline (version 1.1). Table 3. Euro J of Can. 2009:45;228-47 
Special Notes on Response Assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to ‘normal’ 
size (< 10 mm), they may still have a measurement reported on scans.  This measurement should 
be recorded even though the nodes are normal in order not to overstate progression should it be 
based on increase in size of the nodes.  As noted earlier, this means that subjects with CR might 
not have a total sum of ‘0’ on the eCRF. 
Subjects with a global deterioration of health status requiring discontinuation of pexidartinib 
without objective evidence of disease progression at that time should be reported as ‘clinical 
progression.’  Every effort should be made to document objective progression even after 
discontinuation of treatment.  Symptomatic deterioration is not a descriptor of an objective 
response: it is a reason for stopping study drug.  The objective response status of such subjects is 
to be determined by evaluation of target and non-target disease.  If a radiographic tumor 
assessment has not been performed within 4 weeks of the time of clinical progression, then 
another radiographic assessment should be performed without waiting for the next regularly 
scheduled scan. 
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic changes 
or necrosis in existing lesions), treatment may continue until the next scheduled assessment.  If at 
the next scheduled assessment, progression is confirmed, the date of progression should be the 
earlier date when progression was suspected. 
Frequency of Tumor Re-evaluation 
In this study, tumor measurement will be conducted at Screening, and then at the intervals 
specified or sooner if clinically indicated.  The interval between scans is based on the last scan 
visit.  Tumor measurement will be performed during the EOT visit if it was not done within the 
previous 8 weeks or the previous assessment demonstrated disease progression. 
Baseline tumor assessments must be performed within 4 weeks prior to the first dose of study 
drug. 
All efforts should be made to ensure consistency between the Baseline measurements and all 
subsequent measurements in reference to utilization of scanning method, equipment, technique 
(including slice thickness and field of view), and radiographic interpreter. 
The radiographic evaluation may include CT or MRI scanning of the chest, abdomen, and pelvis.  
Any additional suspected sites of disease should also be imaged.  All evaluations should meet the 
standard of care for imaging of lesions in the respective organ(s) and should conform to the 
image acquisition guidelines according to institutional standards. 
All target and non-target sites are evaluated at each time point of tumor assessment. 


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10.5. 
Appendix 5:  General Information – Adverse Events 
10.5.1. 
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.14 
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 (e.g., ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically relevant in the 
medical and scientific judgment of the Investigator (i.e., 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. 
 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 (e.g., 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 


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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. 
10.5.2. 
Serious Adverse Event 
A serious adverse event 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, 
influenza, and accidental trauma (e.g., 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. 


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 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. 
Events Exempted from SAE Reporting 
Serious events that are also efficacy endpoints and/or safety endpoints will be exempted from 
SAE processing and expedited reporting.14  Endpoints are captured on designated eCRF.  These 
events are clinically anticipated events in the target treatment population. 
10.5.3. 
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 (i.e., cannot be life-threatening or fatal), whereas sepsis can only be Grade 4 
or 5 (i.e., 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. 
10.5.4. 
Causality Assessment 
The Investigator should assess causal relationship between an adverse event 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. 
 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 
(e.g., disease under study, concurrent diseases, and concomitant medications). 


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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 (e.g., 
disease under study, concurrent diseases, and concomitant medications). 
10.5.5. 
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. 
 Not Applicable  
 Unknown: Subject is lost to follow-up 
10.5.6. 
Other Action Taken for Event 
 None. 
 No treatment was required. 
 Medication required. 
 Prescription and/or over the counter medication was required to treat the adverse 
event. 
 Hospitalization or prolongation of hospitalization required. 
 Hospitalization was required or prolonged due to the AE, whether or not 
medication was required. 
 Other. 
10.5.7. 
Adverse Event Outcome 
 Recovered/Resolved 
 The subject fully recovered from the AE with no sequelae observed. 
 Recovered/Resolved with Sequelae 
 The subject fully recovered from the AE but with sequelae. 
 Recovering/Resolving 
 The AE is improving but not recovered 






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10.6.2. 
PROMIS Item Bank v. 1.2 – Physical Functioning (Upper Extremity) 
Please respond to each item by marking 1 box per row. 
 
 
Without 
any 
difficulty 
With a 
little 
difficulty 
With 
some 
difficulty 
With 
much 
difficulty 
Unable 
to do 
PFB34 
Are you able to change a light bulb overhead?
 .......................................................................................  
□ 
5 
□ 
4 
□ 
3 
□ 
2 
□ 
1 
 
 
 
 
 
 
 
PFA16r1 
Are you able to dress yourself, including tying 
shoelaces and buttoning up your clothes? 
 .......................................................................................  
□ 
5 
□ 
4 
□ 
3 
□ 
2 
□ 
1 
 
 
Not at all 
Very 
little 
Somewhat 
Quite a 
lot 
Cannot 
do 
PFB54 
Does your health now limit you in going OUTSIDE the 
home, for example to shop or visit a doctor’s office? 
 .......................................................................................  
□ 
5 
□ 
4 
□ 
3 
□ 
2 
□ 
1 
 
 
 
 
 
 
 
PFA4 
Does your health now limit you in doing heavy work 
around the house like scrubbing floors, or lifting or 
moving heavy furniture? 
 .......................................................................................  
□ 
5 
□ 
4 
□ 
3 
□ 
2 
□ 
1 
 
 
Without 
any 
difficulty 
With a 
little 
difficulty 
With 
some 
difficulty 
With 
much 
difficulty 
Unable 
to do 
PFA12 
Are you able to push open a heavy door? 
 .......................................................................................  
□ 
5 
□ 
4 
□ 
3 
□ 
2 
□ 
1 
 
 
 
 
 
 
 
PFB28r1 
Are you able to lift 10 pounds (5 kg) above your 
shoulder?
 .......................................................................................  
□ 
5 
□ 
4 
□ 
3 
□ 
2 
□ 
1 
 
 
 
 
 
 
 
PFA14r1 
Are you able to carry a heavy object (over 10 pounds/5 
kg)? 
 .......................................................................................  
□ 
5 
□ 
4 
□ 
3 
□ 
2 
□ 
1 
 
 
Not at all 
Very 
little 
Somewhat 
Quite a 
lot 
Cannot 
do 
PFB1 
Does your health now limit you in doing moderate work 
around the house like vacuuming, sweeping floors or 
carrying in groceries? 
 .......................................................................................  
□ 
5 
□ 
4 
□ 
3 
□ 
2 
□ 
1 
 
 
 
 
 
 
 
PFA5 
Does your health now limit you in lifting or carrying 
groceries? 
 .......................................................................................  
□ 
5 
□ 
4 
□ 
3 
□ 
2 
□ 
1 


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Without 
any 
difficulty 
With a 
little 
difficulty 
With 
some 
difficulty 
With 
much 
difficulty 
Unable 
to do 
PFA42 
Are you able to carry a laundry basket up a flight of 
stairs? 
 .......................................................................................  
□ 
5 
□ 
4 
□ 
3 
□ 
2 
□ 
1 
 
 
 
 
 
 
 
PFA13 
Are you able to exercise for an hour? 
 .......................................................................................  
□ 
5 
□ 
4 
□ 
3 
□ 
2 
□ 
1 
 
 
 
 
 
 
 
 
 


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10.6.3. 
EQ-5D-5L 
 
 
 
Health Questionnaire 
 
 
English version for the USA 
 
 
 
 
 
 
 
1 
USA (English) © 2009 EuroQol Group. EQ-5D™ is a trade mark of the EuroQol Group


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




Protocol PL3397-A-U4003 
Version 2.0, 25 Feb 2022 
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11. 
REFERENCES 
1. Tap WD, Gelderblom H, Palmerini E, et al. Pexidartinib versus placebo for advanced 
tenosynovial giant cell tumour (ENLIVEN): a randomised phase 3 trial. Lancet. 2019 
Aug 10; 394(10197):478-487. 
2. Coffelt SB, Hughes R, Lewis CE. Tumor-associated macrophages: effectors of 
angiogenesis and tumor progression. Biochem Biophys Acta. 2009;1796(1):11–8. 
3. Tam WF, Gilliland DG. Can FLT3 inhibitors overcome resistance in AML? Best Pract 
Res Clin Haematol. 2008;21:13–20. 
4. Fletcher JA, Rubin BP. KIT mutations in GIST. Curr Opin Genet Dev. 2007;17:3–7. 
5. O’Sullivan B, Cummings B, Catton C, et al. Outcome following radiation treatment for 
high-risk pigmented villonodular synovitis. Int J Radiat Oncol Biol Phys. 1995;32:777–
86. 
6. Pexidartinib Investigator’s Brochure, Edition 13.0. Daiichi Sankyo, Basking Ridge, NJ. 
03 Nov 2021. 
7. Gerhardt JJ, Cocchiarella L, Lea RD. The Practical Guide to Range of Motion 
Assessment. Chicago, IL. Amer Med Assoc Press; 2002. 
8. 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. 
9. Peterfy C, Guermazi A, Zaim S, et al. Whole-Organ Magnetic Resonance Imaging Score 
(WORMS) of the knee in osteoarthritis. Osteoarthritis Cartilage. 2004;12(3):177–90. 
10. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. 
Nephron 1976;16:31-41. 
11. Flockhart DA (2007). Drug Interactions: Cytochrome P450 Drug Interaction Table. 
http://medicine.iupui.edu/clinpharm/ddis/main-table. Indiana University School of 
Medicine 
12. 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 
13. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: Revised RECIST guideline (version 1.1). Euro J Can. 2009:45;228–47. 
14. ICH E2A Guideline. Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting, Oct 1994. 
https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Effica 
cy/E2A/Step4/E2A_Guideline.pdf 


Protocol PL3397-A-U4003 
Version 2.0, 25 Feb 2022 
Proprietary and Confidential 
Page 88 
12. 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ADR 
adverse drug reaction  
AE 
adverse event 
AESI 
adverse event of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukemia 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BID 
twice a day 
CI 
confidence interval 
CFR 
code of federal regulations 
CR 
complete response  
CrCl 
creatinine clearance 
CRF 
case report form 
CRO 
contract research organization 
CSF1R 
Colony stimulating factor 1 receptor 
CSF1 
Colony stimulating factor 1  
CT 
computed tomography 
CTC 
common toxicity criteria 
CTCAE 
common terminology criteria for adverse events 
CYP 
cytochrome P450 
DMC 
data monitoring committee 
DSI 
Daiichi-Sankyo, Inc. 
EAS 
evaluable analysis set 
EC 
ethics committee 
ECI 
event of clinical interest 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EIU 
exposure in utero 
EOS 
End of Study 


Protocol PL3397-A-U4003 
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Proprietary and Confidential 
Page 89 
Abbreviation 
Definition 
EOT 
End of Treatment 
EQ-5D-5L 
European Quality of Life Five Dimension Five Level Scale 
EU 
European Union 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FMS 
feline McDonough sarcoma 
FSH 
follicle stimulating hormone  
GCP 
good clinical practice 
GCT-TS 
giant cell tumor of the tendon sheath [ 
GGT 
gamma-glutamyl transferase  
GI 
gastrointestinal 
GISTs 
Gastrointestinal stromal tumors  
H2 
histamine 2  
HIPAA 
health insurance portability and accountability act 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
ICMJE 
International Council of Medical Journal Editors 
IEC 
independent ethics committee 
INN 
international non-proprietary name 
INR 
international normalized ratio 
IRB 
institutional review board 
LFT 
liver function test  
M-CSF 
macrophage-colony stimulating factor  
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
NCI 
National Cancer Institute 
NCI-CTCAE 
National Cancer Institute – Common Terminology Criteria for Adverse Events 
NE 
not evaluable 
ORR 
overall response rate 
OS 
overall survival 
OTC 
over-the-counter 
PET 
positron emission tomography  
PD 
progressive disease 


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Abbreviation 
Definition 
PFS 
progression-free survival 
PR 
partial response  
pRBC 
packed red blood cell 
PPI 
proton pump inhibitors  
PROs 
patient reported outcomes 
PROMIS PF 
Patient-Reported Outcomes Measurement Information System – Physical 
Function 
PVNS 
pigmented villonodular synovitis  
QTc 
corrected QT interval 
QTcF 
QT interval corrected with Fridericia’s formula 
RAMRIS 
Rheumatoid Arthritis Magnetic Resonance Imaging  
RAS 
re-treatment analysis set 
RECIST 
response evaluation criteria in solid tumors version 1.1 
RES 
response evaluable set 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAVER 
Serious Adverse Event Report 
SCF 
stem cell growth factor  
SCR 
Screening 
SD 
stable disease 
SID 
subject identifier 
SOC 
system organ class 
SoE 
Schedule of Events 
SOP 
Standard Operating Procedure 
SUSAR 
suspected unexpected serious adverse reaction 
TAMs 
Tumor-associated macrophages  
TBIL 
total bilirubin  
TEAE 
treatment-emergent adverse event 
TGCT 
Tenosynovial giant cell tumor  
TVS 
tumor volume score 
UGT 
Uridine 5'-diphospho-glucuronosyltransferase 
ULN 
upper limit of normal 
US 
United States 
WHO 
World Health Organization 


Protocol PL3397-A-U4003 
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Abbreviation 
Definition 
WHODD 
World Health Organization Drug Dictionary 
WORMS 
Whole-Organ Magnetic Resonance Imaging Score  
 


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