Clinical trial NCT03291288
Conditions: Drug Interaction Potential
Keywords: Tenosynovial Giant Cell Tumors (TGCT) Kit-mutant melanoma Kit-mutant gastrointestinal stromal tumor (GIST) Cocktail drug-drug interaction (DDI)
Sponsor: Daiichi Sankyo
Start date: 2018-02-26; Completion date: 2021-04-16
Enrollment: 32 participants; Allocation: NA; Intervention model: SEQUENTIAL

Brief summary:
This study has two parts.

Part 1 will evaluate how pexidartinib affects the way the body processes CYP3A4 and CYP2C9 substrates using midazolam and tolbutamide, respectively, as probe agents.

Part 2 will test the efficacy and safety of pexidartinib treatment in various tumor types.

In Part 2, the same participants will continue to receive pexidartinib twice daily.

Participants will be allowed to continue using pexidartinib as long as the participant derives benefit.

Detailed description:

Arms: arm 1: Part 1 (Drug-drug Interaction Phase):

On Day 1, all participants will receive a single oral dose each of midazolam (2 mg) and tolbutamide (500 mg). On Day 3, pexidartinib (800 mg/d) in twice daily (400 mg BID) dosing will be initiated and continue throughout the remainder of Part 1 and into Part 2. On the first day of pexidartinib treatment (Day 3), a single dose of midazolam (2 mg) and tolbutamide (500 mg) will be co-administered with the morning pexidartinib dose (400 mg). On Day 13, a single dose of midazolam (2 mg) and tolbutamide (500 mg) will be co-administered with the morning dose of pexidartinib (400 mg).

Part 2 (Efficacy and Safety Phase):

All participants will continue to receive pexidartinib 400 mg BID.
Interventions: intervention 1: Tolbutamide intervention 2: Midazolam intervention 3: Pexidartinib
Intervention descriptions: intervention 1: Commercially available tolbutamide intervention 2: Commercially available midazolam intervention 3: Pexidartinib is formulated as opaque, white, 200-mg capsules

Protocol documents:
Prot_SAP_000.pdf: 
Proprietary and Confidential 
Page 1 
CLINICAL STUDY PROTOCOL 
 
AN OPEN-LABEL, SINGLE SEQUENCE, 
CROSSOVER STUDY ASSESSING THE EFFECT OF 
PEXIDARTINIB ON THE PHARMACOKINETICS 
OF MIDAZOLAM AND S-WARFARIN IN PATIENTS 
 
PL3397-A-U126 
 
IND 105521 
 
VERSION 1.0, 28 APRIL 2017 
 
DAIICHI SANKYO INC. 
211 MT AIRY ROAD 
BASKING RIDGE, NJ 07920-2311 
 
 
 
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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Print Name 
Signature 
Title 
Date (DD MMM YYYY) 


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PROTOCOL SYNOPSIS 
IND Number: 
105521 
EudraCT: 
2017-001687-38 
Protocol Number: 
PL3397-A-U126 
Investigational Product: 
PLX3397 
Active Ingredient/INN: 
Pexidartinib 
Study Title: 
An open-label, single sequence, crossover study assessing the 
effect of pexidartinib on the pharmacokinetics of midazolam and 
S-warfarin in patients  
Study Phase: 
Phase 1, drug-drug interaction (DDI) study  
Indication Under Investigation: Pexidartinib DDI with midazolam and S-warfarin 
Safety and efficacy will also be evaluated in various tumors. 
Study Objectives: 
Primary Objective: 
 
To assess the effects of pexidartinib on the 
pharmacokinetic (PK) parameters of single-dose 
midazolam and S-warfarin in patients 
Secondary Objectives: 
 
To determine the overall response rate (ORR) in 
patients with tenosynovial giant cell tumor (TGCT), 
kit-mutant melanoma, kit-mutant gastrointestinal 
stromal tumor (GIST), or other tumors 
 
To assess the safety and tolerability of pexidartinib 
alone and in combination with single-dose 
midazolam and S-warfarin 
 
To determine the safety of pexidartinib given as 
monotherapy over longer periods 
 
To evaluate the PK of pexidartinib and 
ZAAD-1006a 




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(400 mg), and PK samples will be collected over 10 
h (pexidartinib), 48 h (midazolam), or 96 h 
(S-warfarin).  
 
On Day 15, a single dose of midazolam (2 mg) and 
S-warfarin (10 mg with vitamin K [5 mg]) will be 
co-administered with the morning dose of 
pexidartinib (400 mg), and PK samples will be 
collected over 10 h (pexidartinib), 48 h (midazolam), 
or 96 h (S-warfarin). 
In Part 2, patients will continue to receive pexidartinib BID at a 
dose of 800 mg/d or 1000 mg/d depending upon the tumor type 
as defined in the protocol. Patients will be assessed for safety 
and efficacy. An optional tumor biopsy or archival tumor 
specimen under specific informed consent and/or blood samples 
for circulating tumor DNA may be collected at Screening and 
during pexidartinib treatment for exploratory analysis of tumor 
biomarkers at the discretion of the Investigator/patient.  
Study Duration: 
Patients will be screened no longer than 21 d prior to dosing on 
Day 1. 
The duration of Part 1 of the study will be approximately 18 d 
for each patient. Part 2 of the study will continue until there is no 
longer clinical benefit or until other reasons for discontinuation 
are met. 
First patient enrolled: approximately Q2 2017 
Last patient last visit for primary DDI objective phase: 
approximately Q4 2017 
Last patient last visit overall: approximately Q3 2018 
Study Sites and Location: 
Approximately 12 sites in Australia, South Korea, New Zealand, 
Taiwan, US, EU, and other countries. 
Patient Eligibility Criteria: 
Inclusion Criteria: 
Patients must meet the following inclusion criteria to be enrolled 
in the study: 
1. Age ≥ 18 y or  the legal age for being considered as an 
adult in the country where the patient is screened at the 
time of signing informed consent. 
2. A diagnosis of TGCT, kit-mutant melanoma, kit-mutant 
GIST, leukemia, or other tumor for which there is no 
other standard systemic therapy. Patients with TGCT or 
other non-malignant tumor must be approved by the 
Sponsor prior to Screening and enrollment. Prior 
pexidartinib is permitted for TGCT patients unless 


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ineffective or not tolerated and there has been a washout 
period of at least 4 wk. 
3. Women of childbearing potential must have a negative 
serum pregnancy test within 14 d prior to enrollment. 
(Where demanded by local regulations, this test may be 
required within 72 h prior to enrollment). 
4. Men and women of childbearing potential are permitted 
in the study as long as they consent to avoid getting their 
partner pregnant or becoming pregnant, respectively, by 
using a highly effective contraception method, as 
described below, throughout the study and up to 90 d 
after completion. Highly effective methods of 
contraception include intra-uterine device (nonhormonal 
or hormonal); bilateral tubal occlusion; vasectomy; 
sexual abstinence (only if this is in line with the patient’s 
current lifestyle); or barrier methods (eg, condom, 
diaphragm) used in combination with hormonal methods 
associated with inhibition of ovulation. Women of 
nonchildbearing potential may be included if they are 
either surgically sterile or have been postmenopausal for 
≥ 1 y. Women who have documentation of at least 
12 mo of spontaneous amenorrhea and have a 
follicle-stimulating hormone level > 40 mIU/mL will be 
considered postmenopausal. 
5. Adequate hematologic, hepatic, and renal function, 
defined by: 
 
Absolute neutrophil count ≥ 1.5 × 109/L.  
 
Hemoglobin > 10 g/dL.  
 
Platelet count ≥ 100 × 109/L.  
 
Aspartate aminotransferase (AST) and alanine 
aminotransferase (ALT) ≤ 1.5 × upper limit of 
normal (ULN).  
 
Total bilirubin (TBil) ≤ ULN with an exception of 
patients with confirmed Gilbert’s syndrome. For 
patients with confirmed Gilbert’s syndrome, the total 
bilirubin should be ≤ 1.5 × ULN. 
 
Serum creatinine ≤ 1.5 × ULN. 
6. Willingness and ability to use a pill diary. 


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7. Willingness and ability to provide written informed 
consent prior to any study-related procedures and to 
comply with all study requirements. 
Exclusion Criteria: 
Patients must not meet the following exclusion criteria to be 
enrolled in the study: 
1. Known active or chronic human immunodeficiency virus 
(HIV) or hepatitis C virus (HCV) infection, or positive 
hepatitis B (HepB) surface antigen. 
2. Known active tuberculosis. 
3. Hepatobiliary diseases including biliary tract diseases, 
autoimmune hepatitis, inflammation, fibrosis, cirrhosis 
of liver caused by viral, alcohol, or genetic reasons. 
Gilbert’s disease is allowed if TBil is ≤ 1.5 × ULN. 
4. Women who are breastfeeding. 
5. Patients with poor metabolizer status of Cytochrome 
P450 (CYP) 2C9.  
6. Patients on potent CYP2C9, CYP3A4, and Uridine 
5'-diphospho-glucuronosyltransferase family 1 member 
A4 (UGT1A4) inducer and inhibitors and potent 
P-glycoprotein (P-gp) inhibitors and inducers, unless 
these medications are discontinued at least 14 d before 
study drug administration. Foods or beverages 
containing CYP3A4/5 inhibitors (eg, grapefruit, 
pomegranate, pomelo, and star fruit) should be avoided 
throughout the study. 
7. A screening Fridericia-corrected QT (QTcF) interval 
≥ 450 ms (men) or ≥ 470 ms (women). 
8. History of hypersensitivity to any investigational 
products, including their excipients. 
9. Inability to swallow capsules. 
10. Inability to complete study procedures. 
Dosage Form, Dose and Route 
of Administration: 
 
Pexidartinib will be administered orally at a total 
daily dose of 1000 mg administered as a split dose 
of 400 mg (am) and 600 mg (pm) given 
continuously in 28-d cycles. The dose of 
pexidartinib for patients with TGCT or other 
non-malignant tumor will be reduced to 800 mg/d 
(400 mg BID) after 14 d of treatment (after 
completion of Part 1). The dose of pexidartinib will 


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be modified depending upon tolerance as defined in 
the protocol. 
 
Midazolam will be administered as a single oral 
dose of 2 mg. 
 
S-warfarin will be administered as a single oral dose 
of 10 mg with vitamin K (5 mg).  
Study Treatment Administration 
Time and Duration:  
 
S-warfarin reference treatment: single oral dose of 
S-warfarin (10 mg) on Day 1 with vitamin K (5 mg). 
 
Midazolam reference treatment: single oral dose of 
midazolam (2 mg) on Day 1. 
 
S-warfarin test treatment: single oral dose of 
warfarin (10 mg) with vitamin K (5 mg) on Day 5 
concomitantly with pexidartinib and on Day 15 
following approximately 10 d of pexidartinib BID 
dosing.  
 
Midazolam test treatment: single oral dose of 
midazolam (2 mg) on Day 5 concomitantly with 
pexidartinib and on Day 15 following approximately 
10 d of pexidartinib BID dosing.  
 
Pexidartinib treatment: Pexidartinib will be 
administered orally as a total daily dose of 1000 mg 
administered as split dose of 400 mg (am) and 
600 mg (pm) continuously in 28-d cycles starting 
from Day 5. The dose of pexidartinib for patients 
with TGCT or other non-malignant tumor will be 
reduced to 800 mg/d (400 mg BID) after 14 d of 
treatment (after completion of Part 1). The dose of 
pexidartinib will be modified depending upon 
tolerance as defined in the protocol.  
PK sampling Time Points: 
 
Plasma samples for midazolam will be collected at 
predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 24, and 48 h 
(10 min up to 1 h, 10% thereafter) on Days 1 to 3 
and also when co-administered with pexidartinib on 
Days 5 to 7 and Days 15 to 17. 
 
Plasma samples for S-warfarin will be collected at 
predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 (±1), 24 (±2), 
48 (±2), 72 (±2), and 96 (±2) h on Days 1 to 5 and 
also when co-administered with pexidartinib on 
Days 5 to 9 and Days 15 to 19.  


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 
Plasma samples for pexidartinib and its metabolites 
will be collected at predose, 0.5, 1, 2, 3, 4, 6, 8, and 
10 (±1) h after the first dose on Day 5 and at steady 
state when co-administered with midazolam and 
S-warfarin on Day 15. 
Efficacy Assessments: 
Efficacy will be assessed by magnetic resonance imaging, 
computerized tomography scan, or other method appropriate to 
the type of tumor and read locally. Assessments will be 
performed during Screening and ±7 d after the end of every two 
28-d treatment cycles, or other frequency appropriate to the 
tumor type, starting with the first dose of pexidartinib in Part 1. 
Safety Assessments:  
 
A physical examination will be performed at 
Screening, at subsequent times as defined in the 
schedule of events, and at the end of treatment. 
 
Serum chemistry, hematology, and urinalysis will be 
obtained at Screening, at subsequent times as 
defined in the schedule of events, and at the end of 
treatment. 
 
Liver function tests as part of serum chemistry will 
be conducted on an at least weekly basis for the first 
8 wk of pexidartinib treatment starting from the first 
dose in Part 1 (Day 5). After Week 8, the frequency 
of liver function tests will be reduced to once every 
2 wk through Cycle 3, followed by monthly. If any 
abnormality is detected in the liver function tests, 
then follow-up laboratory tests will be performed on 
a weekly basis. The frequency of follow-up liver 
function tests will be increased to twice weekly for 
all Grade 3 aminotransferase increases and for any 
grade aminotransferase increase associated with 
bilirubin increase. (No bilirubin increase is defined 
as any 1 or more of the following: TBil ≤ ULN, TBil 
< 20% above baseline, or direct bilirubin < ULN). 
 
Vital signs and 12-lead electrocardiograms (ECGs) 
will be performed at Screening, at subsequent times 
as defined in the schedule of events, and at the end 
of treatment. 


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 
A blood sample (10 mL) for pharmacogenomic 
analysis will be collected from each patient at 
Screening.  
 
Adverse events and concomitant medications will be 
evaluated throughout the study starting from the 
time of informed consent. 
Other Assessments: 
Optional tumor biopsy samples or archival tumor specimen 
under specific informed consent or blood samples for circulating 
tumor DNA may be collected at Screening and during 
pexidartinib treatment at the discretion of the 
Investigator/patient. 
Planned Sample Size: 
Approximately 30 patients will be enrolled to achieve 24 patients 
evaluable for DDI. 
PK Parameters:  
 
Plasma concentration-time data will be analyzed 
using noncompartmental methods. The following 
PK parameters of midazolam and S-warfarin will be 
calculated: Cmax, tmax, and AUClast. If data 
permits, other PK parameters including t1/2 and 
AUCinf will be reported for midazolam and 
S-warfarin. 
 
Plasma PK parameters (Cmax, tmax, and AUClast) 
will be calculated for pexidartinib and its primary 
metabolite, ZAAD-1006a after the first dose and 
multiple doses. 
Key Efficacy Parameters: 
 
Best objective response per Response Evaluation 
Criteria in Solid Tumors, version 1.1 (RECIST 1.1) 
 
Duration of response 
 
Time to progression (for TGCT and other 
non-malignant tumors) 
 
Progression-free survival (for malignant tumors) 
Safety Parameters: 
 
Treatment emergent adverse events 
 
Vital signs 
 
12-lead ECGs 
 
Clinical laboratory tests including AST/ALT/TBil 
PK Analysis:  
Individual plasma concentration-time data and descriptive 
summary statistics will be listed, tabulated, and presented 
graphically by treatment and visit. Pharmacokinetic parameters 


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for midazolam, 5-hydroxy midazolam, S-warfarin, and 
pexidartinib and ZAAD-1006a will be summarized using 
descriptive statistics and graphically (Cmax and AUC).  
An analysis of variance (ANOVA) model with treatment as fixed 
effects, and patient as random effect will be used to compare 
natural-log transformed PK parameters (Cmax and AUClast) of 
the substrates with and without the co-administration of 
pexidartinib. The combination treatments (pexidartinib + 
substrate) will be the test and substrate alone will be the 
reference for the comparison in regards to each substrate. 
Geometric mean ratios and their corresponding 90% confidence 
intervals (CI) between the treatments will be calculated by 
anti-log transformation. Time to reach maximum plasma 
concentration will be analyzed using a nonparametric method. 
The point estimate of the treatment difference and the 
corresponding 95% confidence intervals will be calculated and 
anti-logged to obtain the point estimate and 95% CI on the linear 
scale for the ratio of geometric means of the test as compared 
with the reference. 
No DDI will be concluded if the 90% CI of the ratio of the test to 
the reference completely remains within 80-125%. 
Statistical Analyses: 
Safety and efficacy will be summarized using descriptive 
statistics. 
Sponsor: 
Daiichi Sankyo Inc. 
211 Mt Airy Road 
Basking Ridge, NJ 07920-2311, USA 
(Sponsor in a specific country will be the regional Daiichi 
Sankyo clinical research office.) 


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TABLE OF CONTENTS 
INVESTIGATOR AGREEMENT ........................................................................ 2 
PROTOCOL SYNOPSIS ...................................................................................... 4 
TABLE OF CONTENTS ..................................................................................... 13 
LIST OF TABLES ............................................................................................... 20 
LIST OF FIGURES ............................................................................................. 21 
LIST OF ABBREVIATIONS .............................................................................. 22 
1. 
INTRODUCTION ............................................................................ 25 
1.1. 
Scientific Background – Pexidartinib (PLX3397) ............................ 25 
1.2. 
Clinical Experience ........................................................................... 25 
1.2.1. 
Clinical Safety .................................................................................. 25 
1.2.2. 
Tenosynovial Giant Cell Tumor ....................................................... 26 
1.2.3. 
Other Tumors .................................................................................... 27 
1.3. 
Study Rationale ................................................................................. 28 
1.3.1. 
Rationale ........................................................................................... 28 
1.3.1.1. 
S-Warfarin ........................................................................................ 28 
1.3.1.2. 
Midazolam ........................................................................................ 30 
1.3.2. 
Study Purpose ................................................................................... 31 
1.4. 
Risks and Benefits for Study Subjects .............................................. 31 
2. 
STUDY OBJECTIVES AND HYPOTHESIS ................................. 32 
2.1. 
Study Objectives ............................................................................... 32 
2.1.1. 
Primary Objectives ........................................................................... 32 
2.1.2. 
Secondary Objectives ....................................................................... 32 
2.1.3. 
Exploratory Objectives ..................................................................... 32 
2.2. 
Study Hypothesis .............................................................................. 32 
2.3. 
Study Endpoints ................................................................................ 32 
2.3.1. 
Primary Endpoints ............................................................................ 32 
2.3.2. 
Secondary Endpoints ........................................................................ 33 
2.3.2.1. 
PK ..................................................................................................... 33 
2.3.2.2. 
Efficacy ............................................................................................. 33 
2.3.2.3. 
Safety ................................................................................................ 33 
2.3.3. 
Exploratory Endpoints ...................................................................... 33 


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3. 
STUDY DESIGN ............................................................................. 34 
3.1. 
Overall Design .................................................................................. 34 
3.1.1. 
Overview........................................................................................... 34 
3.1.2. 
Study Stopping Criteria .................................................................... 35 
3.1.3. 
Duration of Patient Participation ...................................................... 35 
3.2. 
Discussion of Study Design .............................................................. 36 
3.3. 
Selection of Doses ............................................................................ 36 
4. 
STUDY POPULATION ................................................................... 37 
4.1. 
Inclusion Criteria .............................................................................. 37 
4.2. 
Exclusion Criteria ............................................................................. 38 
5. 
STUDY TREATMENT .................................................................... 39 
5.1. 
Assigning Patients to Treatment Group/Sequence and Blinding ..... 39 
5.1.1. 
Treatment Group ............................................................................... 39 
5.1.2. 
Method of Treatment Group/Sequences Allocation ......................... 39 
5.1.3. 
Blinding ............................................................................................ 39 
5.1.4. 
Emergency Unblinding Procedure .................................................... 39 
5.2. 
Study Drug ........................................................................................ 39 
5.2.1. 
Description ........................................................................................ 39 
5.2.2. 
Labeling and Packaging .................................................................... 40 
5.2.3. 
Preparation ........................................................................................ 40 
5.2.4. 
Administration .................................................................................. 40 
5.2.5. 
Storage .............................................................................................. 41 
5.2.6. 
Drug Accountability ......................................................................... 41 
5.2.7. 
Retention Samples ............................................................................ 42 
5.3. 
Control Treatment ............................................................................. 42 
5.4. 
Dose Interruptions and Reductions ................................................... 42 
5.5. 
Method of Assessing Treatment Compliance ................................... 46 
5.6. 
Prior and Concomitant Medications ................................................. 47 
5.6.1. 
Dietary and Lifestyle Restrictions .................................................... 48 
5.7. 
Patient Withdrawal/Discontinuation ................................................. 48 
5.7.1. 
Reasons for Withdrawal ................................................................... 48 
5.7.2. 
Withdrawal Procedures ..................................................................... 49 
5.7.3. 
Patient Replacement ......................................................................... 49 


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5.7.4. 
Patient Re-Screening Procedures ...................................................... 49 
6. 
STUDY PROCEDURES .................................................................. 50 
6.1. 
Informed Consent ............................................................................. 50 
6.2. 
Screening .......................................................................................... 50 
6.2.1. 
Screening (Day -21 to Day -1).......................................................... 50 
6.3. 
Part 1 – Treatment Period ................................................................. 51 
6.3.1. 
Part 1 – Day 1 ................................................................................... 51 
6.3.2. 
Part 1 – Day 2 ................................................................................... 51 
6.3.3. 
Part 1 – Day 3 ................................................................................... 51 
6.3.4. 
Part 1 – Day 4 ................................................................................... 52 
6.3.5. 
Part 1 – Day 5 (C1D1) ...................................................................... 52 
6.3.6. 
Part 1 – Day 6 (C1D2) ...................................................................... 53 
6.3.7. 
Part 1 – Day 7 (C1D3) ...................................................................... 53 
6.3.8. 
Part 1 – Day 8 (C1D4) ...................................................................... 53 
6.3.9. 
Part 1 – Day 9 (C1D5) ...................................................................... 54 
6.3.10. 
Part 1 – Day 15 (C1D11) .................................................................. 54 
6.3.11. 
Part 1 – Day 16 (C1D12) .................................................................. 55 
6.3.12. 
Part 1 – Day 17 (C1D13) .................................................................. 55 
6.3.13. 
Part 1 – Day 18 (C1D14) .................................................................. 56 
6.4. 
Part 2 – Treatment Period ................................................................. 56 
6.4.1. 
Part 2 – Day 19 (C1D15) .................................................................. 56 
6.4.2. 
Part 2 – Day 26 (C1D22) .................................................................. 57 
6.4.3. 
Part 2 – Day 33 (C2D1) .................................................................... 57 
6.4.4. 
Part 2 – Day 40 (C2D8) .................................................................... 57 
6.4.5. 
Part 2 – Day 47 (C2D15) .................................................................. 58 
6.4.6. 
Part 2 – Day 54 (C2D22) .................................................................. 58 
6.4.7. 
Part 2 – Day 61 (C3D1) .................................................................... 58 
6.4.8. 
Part 2 – Day 75 (C3D15) .................................................................. 59 
6.4.9. 
Part 2 – Day 89 (C4D1) .................................................................... 59 
6.4.10. 
Part 2 – Day # (C5+D1) .................................................................... 60 
6.5. 
Posttreatment .................................................................................... 60 
7. 
PHARMACOKINETIC/PHARMACODYNAMIC 
ASSESSMENTS .............................................................................. 61 


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7.1. 
Pharmacokinetic Assessment(s) ....................................................... 61 
7.2. 
Pharmacodynamic Assessment ......................................................... 61 
7.3. 
Immunogenicity ................................................................................ 62 
7.4. 
Pharmacogenomic Analysis ............................................................. 62 
7.4.1. 
Genomic or Genetic Banking and Analysis...................................... 62 
7.4.2. 
Metabolizers for CYP2C19 .............................................................. 62 
7.4.2.1. 
Collection of Specimens for Genomic or Genetic Banking and 
Analysis ............................................................................................ 62 
7.4.2.2. 
Genomic or Genetic Analysis Endpoint(s) ....................................... 63 
7.4.2.3. 
Disclosure of the Results of Genomic or Genetic Analysis ............. 63 
7.4.2.4. 
Storage and Disposal of Specimens for Genomic or Genetic Banking 
and Analysis...................................................................................... 63 
8. 
EFFICACY ASSESSMENTS .......................................................... 64 
8.1. 
Primary Efficacy Endpoint ............................................................... 64 
8.2. 
Secondary Efficacy Endpoint ........................................................... 64 
8.3. 
Appropriateness of Selected Efficacy Endpoints ............................. 64 
9. 
SAFETY EVALUATION AND REPORTING ............................... 65 
9.1. 
Adverse Event Collection and Reporting ......................................... 65 
9.2. 
Safety Endpoint Events..................................................................... 66 
9.3. 
Adverse Events of Special Interest ................................................... 66 
9.3.1. 
Combined Elevation of Aminotransferases and Bilirubin ................ 66 
9.4. 
Adverse Event ................................................................................... 66 
9.4.1. 
Definition of Adverse Event ............................................................. 66 
9.4.2. 
Serious Adverse Event ...................................................................... 66 
9.4.3. 
Grade Assessment ............................................................................. 67 
9.4.4. 
Causality Assessment ....................................................................... 68 
9.4.5. 
Action Taken Regarding Study Drug(s) ........................................... 68 
9.4.6. 
Other Action Taken for Event .......................................................... 69 
9.4.7. 
Adverse Event Outcome ................................................................... 69 
9.5. 
Serious Adverse Events Reporting – Procedure for Investigators.... 69 
9.6. 
Notifying Regulatory Authorities, Investigators, and Institutional 
Review Board/Ethics Committee ..................................................... 70 
9.7. 
Exposure in Utero During Clinical Studies ...................................... 70 


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9.8. 
Clinical Laboratory Evaluations ....................................................... 71 
9.9. 
Vital Signs ........................................................................................ 72 
9.10. 
Electrocardiograms ........................................................................... 72 
9.11. 
Physical Examinations ...................................................................... 73 
9.12. 
Other Examinations .......................................................................... 73 
9.12.1. 
Pregnancy Test.................................................................................. 73 
10. 
OTHER ASSESSMENTS ................................................................ 74 
10.1. 
Tumor Assessment............................................................................ 74 
11. 
STATISTICAL METHODS ............................................................. 75 
11.1. 
General Statistical Considerations .................................................... 75 
11.2. 
Analysis Sets ..................................................................................... 75 
11.2.1. 
Enrolled Analysis Set ....................................................................... 75 
11.2.2. 
Full Analysis Set/Safety Analysis Set .............................................. 75 
11.2.3. 
Per-Protocol Analysis Set ................................................................. 75 
11.2.4. 
Pharmacokinetic Analysis Set .......................................................... 75 
11.3. 
Procedures for Handling Missing, Unused, and Spurious Data ....... 76 
11.4. 
Study Population Data ...................................................................... 76 
11.5. 
Statistical Analysis............................................................................ 76 
11.5.1. 
Pharmacokinetics and Exposure-Response Analyses ....................... 76 
11.5.1.1. 
Noncompartmental Pharmacokinetic Analysis................................. 76 
11.5.2. 
Efficacy Analyses ............................................................................. 77 
11.5.2.1. 
Primary Efficacy Analysis ................................................................ 77 
11.5.2.2. 
Secondary Efficacy Analyses ........................................................... 77 
11.5.3. 
Pharmacodynamic Analyses ............................................................. 77 
11.5.4. 
Safety Analyses ................................................................................ 77 
11.5.4.1. 
Adverse Event Analyses ................................................................... 78 
11.5.4.2. 
Clinical Laboratory Evaluation Analyses ......................................... 78 
11.5.4.3. 
Vital Sign Analyses .......................................................................... 78 
11.5.4.4. 
Electrocardiogram Analyses ............................................................. 78 
11.5.4.5. 
Physical Examination Analyses ........................................................ 78 
11.5.4.6. 
Concomitant Medication Analyses ................................................... 79 
11.5.4.7. 
Other Analysis .................................................................................. 79 
11.6. 
Interim Analysis................................................................................ 79 


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11.7. 
Sample Size Determination .............................................................. 79 
11.8. 
Statistical Analysis Process .............................................................. 80 
12. 
DATA INTEGRITY AND QUALITY ASSURANCE .................... 81 
12.1. 
Monitoring and Inspections .............................................................. 81 
12.2. 
Data Collection ................................................................................. 81 
12.3. 
Data Management ............................................................................. 82 
12.4. 
Study Documentation and Storage ................................................... 82 
12.5. 
Record Keeping ................................................................................ 83 
13. 
FINANCING AND INSURANCE ................................................... 84 
13.1. 
Finances ............................................................................................ 84 
13.2. 
Reimbursement, Indemnity, and Insurance ...................................... 84 
14. 
PUBLICATION POLICY ................................................................ 85 
15. 
ETHICS AND STUDY ADMINISTRATIVE INFORMATION .... 86 
15.1. 
Compliance Statement, Ethics and Regulatory Compliance ............ 86 
15.2. 
Patient Confidentiality ...................................................................... 86 
15.3. 
Informed Consent ............................................................................. 86 
15.4. 
Regulatory Compliance .................................................................... 87 
15.5. 
Protocol Deviations .......................................................................... 88 
15.6. 
Supply of New Information Affecting the Conduct of the Study ..... 88 
15.7. 
Protocol Amendments ...................................................................... 89 
15.8. 
Study Termination ............................................................................ 89 
15.9. 
Data and Safety Monitoring Board ................................................... 89 
15.10. 
Address List ...................................................................................... 90 
15.10.1. 
Sponsor’s Clinical Study Leader ...................................................... 90 
15.10.2. 
Sponsor’s Clinical Study Manager ................................................... 90 
15.10.3. 
Sponsor’s Medical Monitor .............................................................. 90 
15.10.4. 
Sponsor’s Pharmacologist ................................................................ 90 
15.10.5. 
Sponsor’s Safety Contacts ................................................................ 91 
15.10.6. 
Contract Research Organizations ..................................................... 91 
15.10.7. 
Electronic Data Capture Vendor ....................................................... 91 
15.10.8. 
Interactive Web Response System Vendor....................................... 91 
15.10.9. 
Bioanalytical Vendor ........................................................................ 91 
15.10.10. 
Pharmacogenomics Vendor .............................................................. 91 


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15.10.10.1. Pharmacogenomics Vendor (CYP2C9 Analysis) ............................. 91 
15.10.10.2. Pharmacogenomics Vendor (Long-Term Storage) ........................... 92 
15.10.11. 
Central Laboratory ............................................................................ 92 
15.10.12. 
Sponsor’s Biostatistician .................................................................. 92 
15.10.13. 
Sponsor’s East Regional Project Leader........................................... 92 
15.10.14. 
Sponsor’s Regional Contacts ............................................................ 92 
16. 
REFERENCES ................................................................................. 93 
17. 
APPENDICES .................................................................................. 94 
17.1. 
List of Common CYP3A4 Inhibitors and Inducers .......................... 94 
17.2. 
Schedule of Events ........................................................................... 95 
17.2.1. 
Schedule of Assessments – Part 1 .................................................... 95 
17.2.2. 
Schedule of Assessments – Part 2 .................................................... 97 
 


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LIST OF TABLES 
Table 5.1: Dose Modification Guidelines for Treatment-Related Toxicities, 
Excluding Liver Function ................................................................. 43 
Table 5.2: Dose Modification Guidelines for Liver Function Abnormalities ... 45 
Table 5.3: Additional Liver Evaluation ............................................................. 46 
Table 11.1: 95% Confidence Intervals by Ratio and Intra-Patient Coefficient of 
Variation of Area Under the Plasma Concentration-Time Curve 
(N=24) .............................................................................................. 80 


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LIST OF FIGURES 
Figure 3.1: Study Schema ................................................................................... 35 
 
 


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LIST OF ABBREVIATIONS 
ABBREVIATION 
DEFINITION 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area under the plasma concentration-time curve 
AUCinf 
Area under the plasma concentration-time curve up to infinity 
AUClast 
Area under the plasma concentration-time curve up to the last 
measurable time 
BID 
Twice daily 
C#D# 
Cycle # Day # 
CI 
Confidence interval 
Cmax 
Maximum Plasma Concentration 
CR 
Complete response 
CRO 
Contract Research Organization 
CSF1 
Colony-stimulating factor 1 
CSF1R 
Colony-stimulating factor 1 receptor 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P450 
DCR 
Disease control rate 
DDI 
Drug-drug interaction  
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EIU 
Exposure In Utero 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FLT3 
Fms-like tyrosine kinase 3 
GCP 
Good Clinical Practice  
GGT 
Gamma glutamyl transferase 
GIST 
Gastrointestinal stromal tumor 
HCl 
Hydrochloride 
HCV 
Hepatitis C virus 


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ABBREVIATION 
DEFINITION 
HepB 
Hepatitis B 
HIV 
Human immunodeficiency virus 
IB 
Investigator’s Brochure 
IC50 
Half maximal inhibitory concentration 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
ITD 
Internal tandem duplications 
ITT 
Intent-to-treat 
KIT 
Receptor for stem cell factor 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
NCI 
National Cancer Institute 
ORR 
Overall response rate 
OTC 
Over-the-counter 
PD 
Progressive disease 
PDy 
Pharmacodynamics 
P-gp 
P-glycoprotein 
PGx 
Pharmacogenomics 
PK 
Pharmacokinetics 
PR 
Partial response 
PRO 
Patient-reported outcome 
PT 
Preferred term 
QTcF 
Fridericia corrected QT interval 
RECIST 1.1 
Response Evaluation Criteria in Solid Tumors, versions 1.1 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SAVER 
Serious Adverse Event Report 
SCF 
Stem cell factor 
SD 
Stable disease 


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ABBREVIATION 
DEFINITION 
SOC 
System organ class 
SUSAR 
Suspected unexpected serious adverse reaction 
t1/2 
Terminal elimination half-life 
TBil 
Total bilirubin 
TEAE 
Treatment-emergent adverse event 
TGCT 
Tenosynovial giant cell tumor 
Tmax 
Time to Reach Maximum Plasma Concentration 
ULN 
Upper limit of normal 


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1. 
INTRODUCTION 
1.1. 
Scientific Background – Pexidartinib (PLX3397) 
Pexidartinib is a novel orally active small-molecule tyrosine kinase inhibitor that targets 
Colony-stimulating factor 1 (CSF1) receptor (CSF1R), KIT (the receptor for stem cell 
factor), and oncogenic fms-like tyrosine kinase 3 (FLT3), the receptor for FLT3 ligand. 
When screened in vitro against a broad panel of 226 kinases, pexidartinib showed potent 
and selective inhibition against its intended targets: CSF1R, KIT, and activated FLT3. 
Pexidartinib also blocked osteoclast differentiation and cell growth of CSF1-dependent 
cell lines. Pexidartinib blocks CSF1R activity in a variety of in vivo models. Pexidartinib 
shows dose-dependent inhibition of splenomegaly in an engineered CSF1R-dependent 
mouse model. In the collagen-induced arthritis model, pexidartinib shows substantial 
efficacy by blocking the activity of macrophages and osteoclasts that infiltrate the 
diseased joints, reduces synovial inflammation and cartilage destruction, and reduces 
clinical scores for joint and digit swelling and redness even with treatment of advanced 
disease. 
The effects of pexidartinib on multiple aspects of tumorigenesis have been characterized 
in cellular and in vivo assays. The proliferation of cell lines that depend on CSF1, stem 
cell factor (SCF), or endogenous FLT3- internal tandem duplications (ITD) is inhibited at 
half maximal inhibitory concentration (IC50) values below 1 μmol/L. Furthermore, 
CSF1-induced autophosphorylation of CSF1R and SCF-induced autophosphorylation of 
KIT are potently inhibited by pexidartinib. Finally, the receptor activator of NF-kappa B 
ligand (RANK-L)- and CSF-1-dependent differentiation of osteoclast precursors is also 
potently inhibited by pexidartinib. These in vitro results translate to pexidartinib effects 
in a variety of in vivo models for CSF1R-dependent proliferation, CSF1R-dependent 
osteoclast differentiation, FLT3-ITD-dependent tumor growth, and KIT-dependent mast 
cell proliferation. 
Additional detailed information regarding the nonclinical pharmacology and toxicology 
of pexidartinib can be found in the Investigator’s Brochure (IB).1 
1.2. 
Clinical Experience 
1.2.1. 
Clinical Safety 
Across the clinical program, the most frequent treatment-emergent adverse events 
(TEAEs) (20%) among all treated patients included fatigue, nausea, decreased appetite, 
diarrhea, vomiting, anemia, constipation, hair color changes (depigmentation), headache, 
and increased aspartate transaminase (AST). Severe skin reactions including erythema 
multiforme and drug reaction with eosinophilia and systemic symptoms have been 
observed in the clinical studies, though a relationship to pexidartinib has not been 
established. In addition acute febrile neutrophilic dermatosis has been observed in acute 
myeloid leukemia subjects.  
In uncontrolled clinical studies of single agent pexidartinib and in combination with other 
anti-cancer agents, bone marrow suppression with leukopenia (neutropenia and/or 
lymphopenia), anemia and thrombocytopenia, either alone or with pancytopenia, has 


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been observed. If clinically significant reduction of neutrophils, serum hemoglobin, or 
platelets counts is observed, the patient should be monitored closely and protocol-defined 
dose modification should be followed. Standard of care supportive measures should be 
initiated, including broad spectrum antibiotics, or hematopoietic growth factors, as 
appropriate. 
Elevations of liver transaminases and bilirubin have been observed in studies with 
pexidartinib, together with cases of drug-induced cholestasis. Cases of cholestasis have 
been observed in the first 8 wk, have generally resolved with treatment discontinuation, 
but in some cases have been severe, requiring liver dialysis and had a protracted course 
(> 5 mo).  
Further details on the clinical and preclinical safety with pexidartinib is provided in the 
IB.1  
1.2.2. 
Tenosynovial Giant Cell Tumor 
Tenosynovial giant cell tumor (TGCT) is a group of neoplasms including pigmented 
villonodular synovitis and giant cell tumor of the tendon sheath (GCT-TS). It is a rare, 
usually non metastatic tumor that affects the synovium, joints, and tendon sheaths, 
resulting in swelling, pain, stiffness, and reduced mobility in the affected joint or limb. It 
is estimated that TGCT has an annual incidence of 11 cases per million.3 Primary 
treatment of TGCT includes surgery to remove the tumor; however, in patients with a 
diffuse form where it can wrap around bone, tendons, ligaments, and other parts of the 
joint, the tumor is more difficult to remove and may require multiple surgeries or joint 
replacements, eventually advancing to the point where surgery is no longer an option and 
amputation may be considered. It is estimated that the rate of recurrence in the diffuse 
type of the disease can be 40% or higher. New, effective, nonsurgical treatment options 
are greatly needed for the treatment of TGCT. 
Study PLX108-01 is an ongoing open-label 2-part dose-escalation study with an 
expansion cohort. In the initial dose escalation part of the study, patients with advanced 
solid tumors received pexidartinib daily at oral doses ranging from 200 mg to 1200 mg. 
At the conclusion of this part of the study, the identified Recommended Phase 2 Dose 
was 1000 mg/d administered as a split dose. The objective of the ongoing extension 
cohort part of PLX108-01 is to evaluate the potential antitumor activity of pexidartinib in 
patients with selected tumor types, including TGCT. 
A total of 39 patients with TGCT were enrolled and treated with pexidartinib in this 
ongoing study. The first patient was enrolled on 18 Jul 2012, and the last patient was 
enrolled on 04 Jun 2015. Based upon the last data cut (21 Jan 2016), median treatment 
duration for this cohort was 379 d, and the longest duration was 1134 d (approximately 
38 mo). Thirty-three subjects were treated for 6 mo or longer, 23 subjects were treated for 
1 y or longer, and 7 subjects were on treatment for more than 2 y. 
Of the 39 intent-to-treat (ITT) subjects, 36 were evaluable (ie, had a baseline and at least 
one post-baseline radiographic scan) for response by Response Evaluation Criteria in 
Solid Tumors, version 1.1 (RECIST 1.1) per local reading, and 20 had a confirmed 
partial response (PR), for an objective response rate of 51% (95% confidence interval 


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[CI]: 35% to 68%) and 56% (95% CI: 38% to 72%) for the ITT and evaluable 
populations, respectively. An additional 16 subjects had stable disease (SD), including 
one unconfirmed PR at the time of the analysis, for a disease control rate (DCR) 
(DCR = PR + SD) of 92% and 100% for the ITT and evaluable subjects, respectively. 
Nine subjects experienced at least 50% reduction in longest tumor diameter. 
Four subjects who had progressed on or after prior use of imatinib or nilotinib 
experienced either PR (3 subjects) or SD (1 subject). Most of the subjects who achieved a 
PR with pexidartinib treatment did so within the first 6 mo of treatment, and many of 
these subjects are continuing on treatment for more than 1 y. These results demonstrate 
that pexidartinib provides prolonged control of this disease. 
The Phase 1 study was amended to collect patient-reported outcome (PRO) data for Brief 
Pain Inventory Worst Pain and Worst Stiffness. Based upon a cut-off of 31 Jul 2015, a 
summary of the PRO data and their correlation to tumor size changes shows that clinical 
benefit is observed on these PRO endpoints and the improvement is associated with 
reduction in tumor size change. 
The most frequently reported TEAEs among subjects with TGCT were fatigue (82.1%), 
hair color changes (69.2%), nausea (64.1%), arthralgia (46.2%), periorbital edema 
(38.5%), dysgeusia (35.9%), diarrhea (33.3%), pruritus (33.3%), rash (33.3%), and 
headache (30.8%). The most common severe or life-threatening (Grade 3 or Grade 4) 
adverse events (AEs) were diarrhea (7.7%), alanine transaminase (ALT) increased 
(7.7%), and AST increased (7.7%). These AEs were reversible and well-managed with 
dose interruption or reduction. The following treatment-related severe adverse events 
(SAEs) were reported for the TGCT subjects in PLX108-01: hyponatremia, rash, and 
pruritus, with 1 subject for each. Adverse events leading to study treatment 
discontinuation occurred in 11 subjects. These events included cognitive change or 
concentration impairment (4 subjects), fatigue (2 subjects), left hand pain (1 subject), 
recurrent inflammatory arthritis (1 subject), diarrhea and deep vein thrombosis 
(1 subject), AST/ALT increase (1 subject), exacerbation of sciatica (1 subject), and 
exacerbation of psoriasis (1 subject). 
Pexidartinib is now being evaluated in a Phase 3 clinical study for the treatment of 
symptomatic TGCT, where surgical resection is potentially associated with worsening 
functional limitation or severe morbidity. Three cases of suspected cholestatic liver injury 
were reported. As a result, an increased frequency of liver function monitoring and other 
hepatic safety risk mitigation procedures have been implemented into this study. 
1.2.3. 
Other Tumors 
Pexidartinib has been or is being evaluated in multiple clinical studies in a variety of 
other tumor types, including relapsed or refractory Hodgkin’s lymphoma, recurrent and 
in newly diagnosed glioblastoma multiforme, advanced metastatic prostate cancer, and 
relapsed or refractory acute myeloid leukemia. Pexidartinib is also being evaluated in 
combination with paclitaxel and separately with pembrolizumab in advanced incurable 
solid tumors. These studies and the safety and efficacy results are described in detail in 
the IB.1 Preclinical studies of pexidartinib in a variety of tumor models are also 
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1.3. 
Study Rationale 
1.3.1. 
Rationale  
This study will assess how pexidartinib affects the pharmacokinetics (PK) of midazolam 
(a known probe substrate of Cytochrome P450 [CYP]3A4) and S-warfarin (a known 
probe substrate of CYP2C9) after single and multiple doses of pexidartinib. 
Based on in vitro data, pexidartinib has the potential to inhibit CYP3A4 and CYP2C9 
with Ki values of 15.9 μM and 12.1 μM, respectively. Additionally, based on a 
physiologically based PK model, CYP3A4 and CYP2C9 are predicted to have an AUCR 
values of 11.9 and 2.2, respectively, which exceed FDA’s cut off (1.25) for determining 
whether in vivo studies are needed or additional clinical evaluation is needed (FDA 
Guidance 2012). In vitro data indicates that pexidartinib has potential for both 
time-dependent inhibition and an induction potential for CYP3A4 isozyme. Therefore, in 
Part 1 of this study, the effect of pexidartinib on the CYP3A4 substrate midazolam will 
be investigated following both single and multiple doses of pexidartinib. The PK of 
midazolam will be evaluated upon the initial administration of pexidartinib to evaluate 
the direct inhibitory effects of pexidartinib on CYP3A4. Finally, the PK of midazolam 
will be evaluated again after multiple doses of pexidartinib administration to assess the 
net effect of possible induction and time-dependent inhibition of pexidartinib on 
CYP3A4. S-warfarin, which is the sensitive probe for CYP2C9, has a half-life of 
approximately 40 h. To maintain pexidartinib exposure during the elimination phase of 
warfarin PK, pexidartinib dosing has to be continued following a single dose of warfarin. 
Additionally, following multiple dosing with 1000 mg/d administered as split dose of 
400 mg and 600 mg, pexidartinib exposure is approximately 2 to 3 fold the exposure after 
the first dose. Therefore, this multiple dose study will allow evaluation of the perpetrator 
potential of pexidartinib at the clinically relevant exposure.  
After Part 1, the study will be continued in patients with a diagnosis of TGCT, kit-mutant 
melanoma, kit-mutant gastrointestinal stromal tumor (GIST), leukemia, or other tumor 
for which there is no other standard systemic therapy. These patients will continue to 
receive pexidartinib treatment to generate more information on the safety and efficacy of 
pexidartinib in a variety of tumors. 
1.3.1.1. 
S-Warfarin 
Warfarin is utilized in this study because it is a known probe substrate of CYP2C9. 
Warfarin is an anticoagulant which acts by inhibiting vitamin K-dependent coagulation 
factors, which include Factors II, VII, IX, and X, and the anticoagulant proteins C and S. 
Warfarin is thought to interfere with clotting factor synthesis by inhibition of the 
regeneration of vitamin K1 epoxide. The degree of depression is dependent upon the 
dosage administered. 
Warfarin is essentially completely absorbed after oral administration with peak 
concentration generally attained within the first 4 hours. Warfarin distributes into a 
relatively small apparent volume of distribution (V/F) of about 0.14 L/kg. Approximately 
99% of the drug is bound to plasma proteins. The elimination of S-warfarin is almost 
entirely by metabolism. Warfarin is stereo-selectively metabolized by hepatic CYP 


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enzymes to inactive hydroxylated metabolites. The CYP450 isozymes involved in the 
metabolism of S-warfarin include CYP2C9, CYP2C19, CYP2C8, CYP2C18, CYP1A2, 
and CYP3A4. CYP2C9 is likely to be the principal form of human liver cytochrome 
P450 which metabolizes S-warfarin. 
The t1/2 of S-warfarin after a single dose is approximately 1 wk; however, the effective 
t1/2 ranges from 20 to 60 hours, with a mean of about 40 hours. The Absorption, 
Distribution, Metabolism, and Excretion study showed that up to 92% of the orally 
administered dose is recovered in urine. Very little S-warfarin is excreted unchanged in 
urine. Urinary excretion is in the form of metabolites. 
Potential adverse reactions to warfarin may include: 
 Fatal or nonfatal hemorrhage from any tissue or organ 
 Bleeding 
 Necrosis of skin and other tissue and 
 Hypersensitivity/allergic reactions, systemic cholesterol microembolization, 
purple toes syndrome, hepatitis, cholestatic hepatic injury, and jaundice 
Since warfarin is a known and FDA-recommended probe substrate of CYP2C9 (see 
FDA, C. C. [2006] Guidance for Industry: drug interaction studies-study design, data 
analysis, and implications for dosing and labeling) and it has been validated in previous 
Cooperstown 5 + 1 cocktail studies,2 it has been selected in the current study as a probe 
drug to test the effect of single and multiple doses of pexidartinib on the PK of drugs 
metabolized by CYP2C9. 
In the current study design, vitamin K will be dosed with warfarin at the same time to 
prevent the pharmacodynamic effects of warfarin without altering the stereoisomer PK.2 
Vitamin K is a group of structurally similar, fat-soluble vitamins that are needed for the 
post-translational modification of certain proteins, mostly required for blood coagulation 
but also involved in metabolic pathways in bone and other tissue. 
Vitamin K is capable of blocking the blood thinning action of anticoagulants like 
warfarin, which work by interfering with the action of vitamin K. They also reverse the 
tendency of these drugs to cause arterial calcification in the long term. In addition, it has 
been also validated in previous Cooperstown 5 + 1 cocktail studies.2 Therefore, in the 
current study, vitamin K will be dosed with warfarin at the same time to prevent the 
pharmacodynamics (PDy) effects of warfarin without altering the stereoisomer PK. 


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1.3.1.2. 
Midazolam 
Midazolam is utilized in this study because it is a known probe substrate of CYP3A4. 
Midazolam is a short-acting drug in the benzodiazepine class that is used for treatment of 
acute seizures, moderate to severe insomnia, and for inducing sedation and amnesia 
before medical procedures. Intravenous midazolam is indicated for procedural sedation 
(often in combination with an opioid, such as fentanyl), for pre-operative sedation, for the 
induction of general anesthesia, and for sedation of ventilated patients in critical care 
units. Oral midazolam is indicated for the short-term treatment of moderately severe 
insomnia in patients who have not reacted adequately to other hypnotics, and who have 
persistent trouble in falling asleep. 
In adults, midazolam has a t1/2 of 1 to 4 hours; however, in the elderly, as well as young 
children and adolescents, the t1/2 is longer. 
Midazolam is poorly absorbed orally with only 50% of the drug reaching the 
bloodstream, and midazolam is metabolized by CYP enzymes and by glucuronide 
conjugation. Midazolam is metabolized into an active metabolite 
alpha-hydroxymidazolam by CYP3A4. Age-related deficits and renal and liver status 
affect the PK factors of midazolam as well as its active metabolite. 
The therapeutic as well as adverse effects of midazolam are due to its effects on the 
gamma-aminobutyric acid (GABA) type A receptors; midazolam does not activate 
GABA type A receptors directly but, as with other benzodiazepines, it enhances the 
effect of the neurotransmitter GABA on the GABA type A receptors resulting in neural 
inhibition. Almost all of the properties can be explained by the actions of 
benzodiazepines on GABA type A receptors. 
Potential adverse reactions to midazolam may include: 
 Ataxia  
 Dysarthria 
 Nystagmus  
 Slurred speech 
 Somnolence (difficulty staying awake) 
 Mental confusion 
 Hypotension  
 Respiratory arrest and  
 Vasomotor collapse 
Since midazolam is a known and FDA-recommended probe substrate of CYP3A4 (per 
the FDA, C. C. [2006] Guidance for Industry: drug interaction studies-study design, data 
analysis, and implications for dosing and labeling) and it has been also validated in 
previous Cooperstown 5 + 1 cocktail studies,2 it has been selected in the current study as 
a probe drug to test the effect of single and multiple doses of pexidartinib on the PK 
profiles of drugs metabolized by CYP3A4. 


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1.3.2. 
Study Purpose 
The purpose of this study is to evaluate the effect of pexidartinib on the PK of midazolam 
and S-warfarin as an assessment of pexidartinib’s potential for DDI with substrates of 
CY3A4 and CYP2C9, respectively. This study will also evaluate the efficacy and safety 
of pexidartinib treatment in various tumors. 
1.4. 
Risks and Benefits for Study Subjects 
Pexidartinib demonstrated pharmacologic and anti-tumor activity in a variety of in vitro 
and tumor models. It is currently being investigated in a variety of Phase 1-3 studies for 
the treatment of tumors and TGCT. Evidence of clinical activity has been observed in 
TGCT.  
Safety data for pexidartinib are from nonclinical and clinical studies. Liver toxicity and 
myelosuppression are important identified risks and embryofetal toxicity is considered as 
an important potential risk with pexidartinib. Liver toxicity observed in clinical studies 
includes cases of liver cholestasis with single agent treatment in the Phase 3 PLX108-10 
study. Risk minimization measures, such as frequent monitoring during the first 8 wk of 
pexidartinib treatment, are included in this protocol. Protocol-defined dose reductions 
and discontinuations of pexidartinib, increased frequency of laboratory monitoring, and 
reporting of findings should be followed. In addition, rechallenge with pexidartinib 
should not be attempted without prior discussion with the Sponsor’s Medical Monitor. 
Risk benefit of pexidartinib should be assessed for each potential patient. 


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2. 
STUDY OBJECTIVES AND HYPOTHESIS 
2.1. 
Study Objectives 
2.1.1. 
Primary Objectives 
To assess the effects of pexidartinib on the PK parameters of single-dose midazolam and 
S-warfarin in patients. 
2.1.2. 
Secondary Objectives 
To evaluate:   
 To determine the overall response rate (ORR) in patients with TGCT, 
kit-mutant melanoma, kit-mutant GIST, or other tumors 
 To assess the safety and tolerability of pexidartinib alone and in combination 
with single-dose midazolam and S-warfarin  
 To determine the safety of pexidartinib given as monotherapy over longer 
periods 
 To evaluate the PK of pexidartinib and ZAAD-1006a 
2.1.3. 
Exploratory Objectives 
To evaluate:   
 Other measures of efficacy including: 
 Duration of response 
 Time to progression (for TGCT and other non-malignant tumors) 
 Progression-free survival (for malignant tumors) 
 Pharmacogenomic (PGx) analysis 
 Optional (at the discretion of the Investigator/patient): Pharmacodynamics 
(PDy) of pexidartinib in treated patients 
 Optional (at the discretion of the Investigator/patient): Tumor biomarker 
analysis 
2.2. 
Study Hypothesis 
This study is not hypothesis testing, but is intended to characterize the effects of 
pexidartinib on the PK parameters of single-dose midazolam and S-warfarin. 
2.3. 
Study Endpoints 
2.3.1. 
Primary Endpoints 
PK parameters of midazolam and S-warfarin: Cmax, tmax, and AUClast. If data permits, 
other PK parameters including t1/2 and AUCinf will be calculated. 


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2.3.2. 
Secondary Endpoints 
2.3.2.1. 
PK 
 Plasma PK parameters (Cmax, Tmax, AUClast) will be calculated for 
pexidartinib and its metabolite, ZAAD-1006a 
 Plasma PK parameters (Cmax, Tmax, AUClast) will be calculated for 
midazolam metabolite, 5-hydroxy midazolam and also metabolite to parent 
ratio (MPR) for 5-hydroxy midazolam and midazolam will be calculated 
2.3.2.2. 
Efficacy 
 Best objective response per RECIST 1.1 
 Duration of response 
 Time to progression (for TGCT and other non-malignant tumors) 
 Progression-free survival (for malignant tumors) 
2.3.2.3. 
Safety 
 TEAEs 
 Vital signs 
 Electrocardiograms (ECGs) 
 Clinical laboratory tests including AST/ALT/Total bilirubin (TBil) 
2.3.3. 
Exploratory Endpoints 
 PGx biomarkers 
 Optional: PDy biomarkers 
 Optional: Tumor biomarker analysis 


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3. 
STUDY DESIGN 
3.1. 
Overall Design 
3.1.1. 
Overview 
This open-label, single sequence crossover study will comprise 2 parts: 
Part 1: An initial single sequence crossover part to evaluate the effect of pexidartinib on 
the PK of midazolam and S-warfarin, the DDI Phase. 
Part 2: An evaluation of efficacy and safety of pexidartinib treatment in various tumors. 
Screening will take place between Day -21 and Day -1. The total duration of participation 
(excluding Screening) for each patient in Part 1 will be approximately 18 d. Pexidartinib 
treatment (1000 mg/d) will commence on Day 5. Thereafter, pexidartinib treatment will 
continue BID into Part 2 of the study at the doses defined below to evaluate efficacy and 
safety until there is no longer clinical benefit or until other reasons for discontinuation are 
met. 
Part 1: 
 On Day 1 patients will receive the single oral dose of midazolam (2 mg) and 
S-warfarin (10 mg with vitamin K [5 mg]), and PK samples will be collected 
approximately 48 h and 96 h, respectively.  
 On Day 5 (C1D1) pexidartinib (1000 mg/d) in twice daily (BID) dosing will 
be initiated and continue throughout the remainder of Part 1 and into Part 2. 
On the first day of pexidartinib treatment (Day 5), a single dose of midazolam 
(2 mg) and S-warfarin (10 mg with vitamin K [5 mg]) will be co-administered 
with the morning pexidartinib dose (400 mg), and PK samples will be 
collected over 10 h (pexidartinib), 48 h (midazolam), or 96 h (S-warfarin).  
 On Day 15, a single dose of midazolam (2 mg) and S-warfarin (10 mg with 
vitamin K [5 mg]) will be co-administered with the morning dose of 
pexidartinib (400 mg), and PK samples will be collected over 10 h 
(pexidartinib), 48 h (midazolam), or 96 h (S-warfarin). 
In Part 2, and specifically starting on Day 19 (C1D15) of pexidartinib treatment, the dose 
of pexidartinib will be reduced to 800 mg/d (400 mg BID) for patients with TGCT or 
other non-malignant tumors. For patients with malignant tumors, the pexidartinib dose 
will remain at 1000 mg/d. Patients will be assessed for safety and efficacy. An optional 
tumor biopsy or archival tumor specimen under specific informed consent and/or blood 
samples for circulating tumor DNA may be collected at Screening and during 
pexidartinib treatment for exploratory analysis of tumor biomarkers at the discretion of 
the Investigator/patient. 
Pexidartinib drug will be administered BID, every day, unless criteria for interruption are 
met (Section 5.4). For the first 2 wk, patients will take 2 capsules in the morning and 
3 capsules in the evening, for a total daily dose of 1000 mg/d pexidartinib. Thereafter, for 
patients with TGCT or other non-malignant tumor, the pexidartinib dose will be reduced 




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After all patients have completed the C7D1 assessments or discontinued pexidartinib 
treatment, the primary efficacy and safety analyses will be performed. Patients remaining 
on pexidartinib treatment with ongoing clinical benefit may continue in the study 
thereafter and the extent of assessments and data collection may be reduced upon 
Investigator and Sponsor discretion. 
3.2. 
Discussion of Study Design 
This open-label, single sequence, crossover study design is appropriate to assess the 
effect of pexidartinib on the PK of midazolam and S-warfarin. The PK of midazolam and 
S-warfarin will be determined first prior to the administration of pexidartinib to establish 
reference PK parameters for these compounds in patients. Then, the PK of the midazolam 
and S-warfarin will be evaluated again upon the initial administration of pexidartinib to 
evaluate the direct and immediate inhibitory effects of pexidartinib on CYP3A4 and 
CYP2C9. Finally, the PK of midazolam and S-warfarin will be evaluated again after 
multiple doses of pexidartinib administration to assess the net effect of possible induction 
and time-dependent inhibition potential of pexidartinib on CYP3A4 and to assess the 
effect of pexidartinib direct inhibition of CYP2C9 at steady state exposure of 
pexidartinib. 
After the DDI study in Part 1, pexidartinib administration will continue in this population 
of patients with untreatable tumors to assess anti-tumor activity and safety of pexidartinib 
in Part 2. 
3.3. 
Selection of Doses 
The study drug doses are as follows:  
 S-warfarin: 10 mg with vitamin K (5 mg) 
 Midazolam: 2 mg 
 Pexidartinib: 1000 mg/d administered as a split dose of 400 mg (am) and 
600 mg (pm). The dose will be reduced to 800 mg/d (400 mg BID) for 
patients with TGCT or other non-malignant tumor after 14 d of treatment. See 
Section 5.4. 
These are commonly used doses for S-warfarin and midazolam. Vitamin K will be 
administered to prevent the PDy effects of S-warfarin without altering the stereoisomer 
PK. 
 


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4. 
STUDY POPULATION 
Patients must sign and date the Informed Consent Form (ICF) provided by the study site 
before any study-specific qualification procedures are conducted. 
4.1. 
Inclusion Criteria 
Patients must meet the following inclusion criteria to be enrolled in the study:  
1. Age  18 y or  the legal age for being considered as an adult in the country 
where the patient is screened at the time of signing informed consent. 
2. A diagnosis of TGCT, kit-mutant melanoma, kit-mutant GIST, leukemia, or other 
tumor for which there is no other standard systemic therapy. Patients with TGCT 
or other non-malignant tumor must be approved by the Sponsor prior to Screening 
and enrollment. Prior pexidartinib is permitted for TGCT patients unless 
ineffective or not related and there has been a washout period of at least 4 wk.  
3. Women of childbearing potential must have a negative serum pregnancy test 
within 14 d prior to enrollment. (Where demanded by local regulations, this test 
may be required within 72 h prior to enrollment). 
4. Men and women of childbearing potential are permitted in the study as long as 
they consent to avoid getting their partner pregnant or becoming pregnant, 
respectively, by using a highly effective contraception method, as described 
below, throughout the study and up to 90 d after completion. Highly effective 
methods of contraception include intra-uterine device (nonhormonal or 
hormonal); bilateral tubal occlusion; vasectomy; sexual abstinence (only if this is 
in line with the patient’s current lifestyle); or barrier methods (eg, condom, 
diaphragm) used in combination with hormonal methods associated with 
inhibition of ovulation. Women of nonchildbearing potential may be included if 
they are either surgically sterile or have been postmenopausal for ≥ 1 y. Women 
who have documentation of at least 12 mo of spontaneous amenorrhea and have a 
follicle-stimulating hormone level > 40 mIU/mL will be considered 
postmenopausal. 
5. Adequate hematologic, hepatic, and renal function, defined by: 
 Absolute neutrophil count ≥ 1.5 × 109/L 
 Hemoglobin > 10 g/dL  
 Platelet count ≥ 100 × 109/L 
 AST and ALT ≤ 1.5 × upper limit of normal (ULN) 
 TBil ≤ ULN with an exception of patients with confirmed Gilbert’s syndrome. 
For patients with confirmed Gilbert’s syndrome, the TBil should be 
≤ 1.5 × ULN 
 Serum creatinine ≤ 1.5 × ULN 


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6. Willingness and ability to use a pill diary. 
7. Willingness and ability to provide written informed consent prior to any 
study-related procedures and to comply with all study requirements. 
4.2. 
Exclusion Criteria 
Patients must not meet the following exclusion criteria to be enrolled in the study: 
1. Known active or chronic human immunodeficiency virus (HIV) or hepatitis C 
virus (HCV) infection, or positive hepatitis B (Hep B) surface antigen. 
2. Known active tuberculosis. 
3. Hepatobiliary diseases including biliary tract diseases, autoimmune hepatitis, 
inflammation, fibrosis, cirrhosis of liver caused by viral, alcohol, or genetic 
reasons. Gilbert’s disease is allowed if TBil is ≤ 1.5 × ULN. 
4.  Women who are breastfeeding. 
5. Patients with a poor metabolizer status of CYP2C9. 
6. Patients on potent CYP2C9, CYP3A4, and Uridine 5'-diphospho-
glucuronosyltransferase family 1 member A4 (UGT1A4) inducer and inhibitors 
and potent P-glycoprotein (P-gp) inhibitors and inducers, unless these 
medications are discontinued at least 14 d before study drug administration. Food 
or beverages containing CYP3A4/5 inhibitors (eg, grapefruit, pomegranate, 
pomelo, and star fruit) should be avoided throughout the study.  
7. A screening Fridericia corrected QT interval (QTcF) ≥ 450 ms (men) or ≥ 470 ms 
(women). 
8. History of hypersensitivity to any investigational products, including their 
excipients. 
9. Inability to swallow capsules. 
10. Inability to complete study procedures. 


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5. 
STUDY TREATMENT 
5.1. 
Assigning Patients to Treatment Group/Sequence and Blinding 
5.1.1. 
Treatment Group 
This is a single arm study. Patients will receive midazolam (2 mg) and S-warfarin 
(10 mg) as a single oral dose on Days 1. On Days 5 and 15, patients will receive a single 
oral dose of midazolam (2 mg), S-warfarin (10 mg), and pexidartinib (400 mg) at the site. 
Patients will receive also pexidartinib of 1000 mg/d (400 mg in the morning 
[co-administered with midazolam and S-warfarin on Days 5 and 15] and 600 mg in the 
evening) starting on Day 5. Thereafter, for Part 2, the dose will be as follows: 
 Patients with TGCT or other non-malignant tumors – the dose would be 
reduced to 800 mg/d (400 mg in the morning and 400 mg in the evening). 
After patients have been on pexidartinib treatment for at least 6 mo, including 
possible pexidartinib treatment prior to this study, the dose of pexidartinib 
may be reduced or otherwise modified, eg, treatment holiday, at Investigator 
discretion provided that the pexidartinib dose does not exceed 1000 mg/d. 
 Patients with malignant tumors – the 1000 mg/d dose will continue into 
Part 2, unless criteria for dose modification have been met. 
5.1.2. 
Method of Treatment Group/Sequences Allocation 
Treatment allocation will not be applied to this single arm design. The study design is 
described in Section 3.  
5.1.3. 
Blinding 
This study is open-label and no blinding will occur.  
5.1.4. 
Emergency Unblinding Procedure 
Not applicable.  
5.2. 
Study Drug 
5.2.1. 
Description  
Pexidartinib is a hydrochloride (HCl) salt with a white to off white crystalline solid 
appearance. Pexidartinib HCl supplied as a 200 mg capsule formulation J 3397 AF 
(200 mg free base equivalent) for oral administration contains the following excipients: 
poloxamer 407, mannitol, crospovidone, and magnesium stearate. The Investigator must 
ensure that the study drug will be used only in accordance with the protocol. 
Pexidartinib is formulated as opaque, white, 200-mg capsules, which will be supplied by 
the Sponsor. 
Commercially available S-warfarin and midazolam will be supplied by DS. 


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5.2.2. 
Labeling and Packaging 
Adequate amounts of study drug will be provided, with contents identified on the label. 
Investigational product labels will include all of the information required by federal and 
local regulations. Applicable supporting product information will be provided by the 
Sponsor.  
5.2.3. 
Preparation 
All pexidartinib will be supplied by the Sponsor, and require no further preparation at the 
study site.  
5.2.4. 
Administration 
Midazolam and S-warfarin will always be administered to enrolled patients after an 
overnight fast of approximately 10 h to avoid food effects. Administration will be done at 
the clinical site under the supervision of the principal Investigator or identified 
sub-Investigator(s). On the intensive PK sampling days, pexidartinib will be administered 
at the clinical site. The study drug for home administration during the study will be 
dispensed to the patient for the first time on the evening of pexidartinib treatment 
initiation. During Part 1, the number of pexidartinib capsules, which is just adequate until 
next scheduled visit, will be dispensed to ensure no home administration on the PK 
sampling days. Capsules should be swallowed and not crushed, chewed, or dissolved in 
liquid. In this study, patients will receive pexidartinib capsules for administration at 
home; and pexidartinib, midazolam, and S-warfarin will be co-administered in the clinic. 
Pexidartinib administration will begin at the Day 5 visit in the morning in Part 1. At this 
visit, patients will be instructed to take 5 capsules a day for the first 2 wk, 1000 mg/d 
pexidartinib; this amount will be divided into a morning dose of 2 capsules and an 
evening dose of 3 capsules. After 2 wk (at the C1D15 visit, after completion of Part 1), 
the dose will be reduced to 2 capsules in the morning and 2 capsules in the evening 
(800 mg/d pexidartinib) for patients with TGCT or other non-malignant tumor. Patients 
who had a dose reduction during the first 2 wk will continue treatment at their reduced 
dose. Doses should be taken in the fasting state (ie, no food for 1 h before and 2 h after 
dose administration). During the fasting period, patients will be permitted to eat a low-fat 
snack (eg, crackers, toast, tea) if needed. Doses will be taken at approximately the same 
time of the day and approximately 12 h apart. Each dosing cycle will be 28 d. 
During Part 1, the patient should be instructed to bring their bottle of study drug to the 
site and only take their morning dose upon instruction by the study site. The time of 
dosing should be recorded. Patients will then take their evening dose at home. If dose 
administered at the site is taken in the afternoon, then the patient should be instructed to 
skip their evening dose for that day. 


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Between site visits, patients are to administer their study drug at home and record the 
dosing information in the study dosing diary. Missed doses (those generally outside of a 
± 2 h dosing window) should be skipped and NOT administered as a double dose at the 
next dosing time point. Patients who vomit their dose should be instructed to NOT make 
up that dose. 
5.2.5. 
Storage 
Drug supplies must be stored in a secure, limited access storage area within the 
recommended storage conditions. Contact Daiichi Sankyo Inc. if storage conditions go 
outside the specified range. All drug supplies should be quarantined pending decision 
from Daiichi Sankyo Inc. 
5.2.6. 
Drug Accountability 
When a drug shipment is received, the Investigator or designee is to check the amount, 
condition and temperature recording of the drug, the appropriate local language is used 
on the label, and the drug expiration date, and to sign the Receipt of Shipment Form 
provided. 
In addition, the Investigator or designee shall contact Daiichi Sankyo Inc. or designee as 
soon as possible if there is a problem with the shipment. 
A drug accountability record will be provided for the investigational medicinal products 
or the site can use their own Daiichi Sankyo Inc. approved drug accountability log. The 
record must be kept current and should contain the dates and quantities of the drug 
received, the patient’s identification number and/or initials or supply number, as 
applicable, to whom the investigational medicinal product was dispensed, the date and 
quantity of the investigational medicinal product dispensed and remaining (if from 
individual patient drug units), as well as the initials of the dispenser. The dispenser’s 
information must be noted on the delegation of duties log. 
At the end of the study, or as directed, all investigational medicinal products, including 
unused, partially used, or empty containers, will be destroyed after full accountability per 
drug unit. If the investigational medicinal product products are destroyed at the study 
center, approval in writing from the Sponsor must be received, and the Sponsor must 
receive copies of the study center’s drug handling and disposition standard operating 
procedures. Dosage form (ie, capsule) site-level accountability documentation is required 
as part of the disposition records of the investigational medicinal product. The dosage 
form site-level accountability documentation should be appended to the Certificate of 
Destruction and provided to Daiichi Sankyo Inc.  
The investigational medicinal products will only be returned to a designee, as instructed 
by the Sponsor, if the study center is unable to perform the destruction of the products. 
The investigational medicinal products will be returned only after the study monitor has 
completed a final inventory to verify the quantity to be returned. The return/destruction 
of investigational medicinal products must be documented, and the documentation must 
be included in the shipment. At the end of the study, a final investigational medicinal 
product reconciliation statement must be completed by the investigator, or designee, and 
provided to the Sponsor.  


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Dosage form (ie, capsule) site-level accountability documentation must be included with 
each drug supply return shipment or other returning facility, such as another depot.  
The aforementioned documentation is required as part of the receiving records for return 
shipments.  
All investigational medicinal product inventory forms must be made available for 
inspection by a Sponsor-authorized representative or designee and regulatory agency 
inspectors. The investigator is responsible for the accountability of all used and unused 
study drug at the site. 
5.2.7. 
Retention Samples 
Not applicable.  
5.3. 
Control Treatment 
Not applicable.  
5.4. 
Dose Interruptions and Reductions 
Reductions or interruptions of the dose for toxicity may take place at any time during the 
study according to the guidelines in Table 5.1. Dose reduction/interruption guidelines for 
hematologic and nonhematologic treatment-related TEAEs are based on severity. Dose 
interruptions can be implemented at the discretion of the treating Investigator to manage 
intolerable or clinically significant toxicity. If a dose interruption is required, study 
assessments should be performed as scheduled, irrespective of the study drug delay, with 
the exception of PK assessments, which should be deferred until treatment is resumed. 
When an odd number of capsules are taken in a day, the larger number of capsules should 
be taken as the evening dose. For example, 600 mg/d = 3 capsules (1 capsule in the 
morning and 2 capsules in the evening). When an even number of capsules per day is to 
be taken, the morning and evening doses should be the same (eg, 800 mg/d = 4 capsules 
[2 capsules in the morning and 2 capsules in the evening] or 400 mg/d = 2 capsules 
[1 capsule in the morning and 1 capsule in the evening]). 
Dose reductions should be applied in increments of 200 mg/d (1 capsule). Patients unable 
to tolerate 400 mg/d (2 capsules) will be discontinued. Once dose reduction takes place 
for toxicity, a dose re-escalation is generally not allowed unless approved after discussion 
with the Daiichi Sankyo Inc. Medical Monitor or designee. 
Dose modification guidelines for treatment-related toxicities as well as guidelines for 
their management are presented in Table 5.1, Table 5.2, and Table 5.3. These parameters 
are only a guide and are not intended to supersede the clinical judgment of the treating 
Investigator. All adjustments should be communicated to Daiichi Sankyo Inc.’s Medical 
Monitor or designee. 
Once a patient reduces the dose of study drug, no further probe drugs will be 
administered to that patient, and he/she will be excluded from the PK Evaluable Set. 
 
 


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Table 5.1: 
Dose Modification Guidelines for Treatment-Related Toxicities, 
Excluding Liver Function 
Toxicity Grade 
(CTCAE v4.0), 
Frequency 
When to Hold or Stop 
When and How to Restart Dosing 
■ Hematologic – Grade 3 or 4 neutropenia 
1st appearance 
Interrupt until ANC recovers 
to ≥ 1 × 109/L; growth factor 
support 
If recovered to ANC ≥ 1 × 109/L in ≤ 7 d, 
resume at same dose. 
If not recovered to ANC ≥ 1 × 109/L in 
≤ 7 d, reduce dose by 1 capsule. 
2nd appearance 
Interrupt until ANC recovers 
to ≥ 1 × 109/L; growth factor 
support 
If recovered to ANC ≥ 1 × 109/L in ≤ 7 d, 
reduce dose by 1 capsule. 
If not recovered to ANC ≥ 1 × 109/L in 
≤ 7 d, reduce dose by an additional 
capsule. 
3rd appearance 
Interrupt until ANC recovers 
to ≥ 1 × 109/L 
If recovered to ANC ≥ 1 × 109/L in ≤ 7 d, 
reduce dose by 1 capsule. 
If not recovered to ANC ≥ 1 × 109/L in 
≤7 d, discontinue permanently. 
4th appearance 
Discontinue permanently 
n/a 
■ Hematologic Grade 3 or 4 febrile neutropenia  
1st appearance 
Interrupt until ANC and fever 
recover; provide growth 
factor support 
Once resolved to ANC ≥ 1 × 109/L and 
T ≤ 38°C, reduce dose by 1 capsule. 
2nd appearance 
Interrupt until ANC and fever 
recover; provide growth 
factor support 
Once resolved to ANC ≥ 1 × 109/L and 
T ≤ 38°C, reduce dose by an additional 
capsule. 
3rd appearance 
Discontinue permanently 
n/a 
AE = adverse event; ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate 
aminotransferase; CTCAE = Common Terminology Criteria for Adverse Events; n/a = not applicable; PLT 
= platelets; T = temperature.  
a Dose interruptions for Grade 2 AEs may be instituted at the discretion of the treating physician after 
discussion with the Daiichi Sankyo Inc. Medical Monitor or designee. 


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Table 5.1: 
Dose Modification Guidelines for Treatment-Related Toxicities, 
Excluding Liver Function (Continued) 
■ Hematologic – Grade 3 or 4 thrombocytopenia  
1st appearance 
Interrupt until PLT 
≥ 75 × 109/L 
Reintroduce at the same dose. 
2nd appearance 
Interrupt until PLT 
≥ 75 × 109/L 
If PLT does not recover to ≥ 75 × 109/L in 
≤ 7 d, reduce dose by 1 capsule. 
3rd appearance 
Interrupt until PLT 
≥ 75 × 109/L 
Reduce dose by an additional capsule. 
4th appearance 
Discontinue permanently 
n/a 
■ Nonhematologic Grade 3a (excluding transaminase increases [AST/ALT]): start symptomatic 
treatment when possible  
1st appearance 
Interrupt until resolved 
(Grade 0-1) 
If recovered in < 5 d, resume at same 
dose. Reduce by 1 capsule if symptoms 
persist for ≥ 5 d despite supportive 
management. 
2nd appearance 
Interrupt until resolved 
(Grade 0-1) 
Reduce by an additional capsule. 
3rd appearance 
Discontinue permanently 
n/a 
■ Nonhematologic Grade 4 (excluding transaminase increases [AST/ALT]): start symptomatic 
treatment when possible  
1st appearance 
Interrupt until resolved 
(Grade 0-1) 
Reduce by 1 capsule. 
2nd appearance 
Discontinue permanently 
n/a 
AE = adverse event; ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = 
aspartate aminotransferase; CTCAE = Common Terminology Criteria for Adverse Events; n/a = not 
applicable; PLT = platelets; T = temperature.  
a Dose interruptions for Grade 2 AEs may be instituted at the discretion of the treating physician after 
discussion with the Daiichi Sankyo Inc. Medical Monitor or designee. 
 


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Table 5.2: 
Dose Modification Guidelines for Liver Function Abnormalities  
Toxicity Grade 
CTCAE v0.4 
Initial Action 
Outcome 
Action 
ALT or AST Grade 2 
(> 3-5  ULN); No 
increase in bilirubina 
Re-check ALT and AST immediately  
Hold study drug 
Monitor weeklyb 
Check for changes to medications and for symptoms 
Resolution to Grade 0-1 or 
baseline (no bilirubin 
increase) 
Restart on resolution Grade 0-1 or baseline at 
1 dose lower (reduce by one 200 mg capsule) 
Grade 3 ALT or AST 
increase (> 5-20  ULN); 
No increase in bilirubina 
Re-check ALT and AST immediately 
Hold study drug 
Monitor 2x/wkb 
Check for changes to medications and for symptoms 
Resolution to Grade 0-1 or 
baseline (no bilirubin 
increase) within 14 d 
Restart on resolution to Grade 0-1 or baseline at 
1 dose lower (reduce by one 200 mg capsule) 
ALT and AST not 
decreasing within 14 d of 
holding study drug 
Proceed to liver evaluation as outlined below. 
Restart only on resolution to Grade 0-1/baseline 
at 1 dose lower (reduce by one 200 mg capsule); 
For max AST or ALT > 8  ULN, consult with 
medical monitor prior to re-start 
Grade 4 ALT or AST 
(> 20  ULN) 
Discontinue treatment 
Monitor 2x/wk until resolution to Grade 2 
Follow-up until resolution Grade 0-1 or baseline 
Check for changes to medications and for symptoms 
All outcomes 
Discontinue treatment; Proceed to liver 
evaluation as outlined below; If clear confirmed 
alternate cause, restart on resolution to Grade 0-1 
or baseline at 1 dose lower (reduce by one 
200 mg capsule) 
Any grade ALT or AST 
increasea with any 
bilirubin increase or signs 
of hypersensitivity 
Discontinue treatment 
Monitor 2x/wk until resolution to Grade 2 
Follow-up until resolution Grade 0-1 or baseline 
Check for changes to medications and for symptoms 
All outcomes 
Discontinue treatment; Proceed to liver 
evaluation as outlined below; If clear confirmed 
alternate cause, restart on resolution to Grade 0-1 
or baseline at 1 dose lower (reduce by one 
200 mg capsule) 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; CTCAE = Common Terminology Criteria for Adverse Events; ULN = upper limit of normal. 
a. 
An increase in bilirubin is defined as all of the following: total bilirubin > ULN, total bilirubin > 20% above baseline, and direct bilirubin is > ULN. If all of these 
conditions are met, then bilirubin is considered increased and should be immediately re-checked. Pexidartinib treatment should be immediately discontinued for 
increased bilirubin unless and until there is a clear, confirmed alternate cause.  
b. If ALT, AST, or bilirubin worsens during the monitoring period, follow the applicable guidance for the worst toxicity grade.  


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Table 5.3: 
Additional Liver Evaluation  
Evaluation 
Comments 
Increase frequency of testing liver 
chemistries to twice per wk, including INR, 
and continue until liver chemistries have 
stabilized, and then reduce to weekly until 
liver chemistries return to normal or baseline. 
Investigational treatment may be started after 
liver function tests recover to Grade 0 to 1 or 
baseline level, and in consultation with 
Medical Monitor. 
Detailed history focusing on medications and 
substances used: alcohol, change in 
medication dosages, new medications added, 
attention to use of acetaminophen, OTC 
medication use, and recreational drug use. 
Check for change in diet or use of dietary 
supplements, with particular attention to dose 
and duration of any herbal product. 
Suspect medications will be discontinued or 
substituted for if possible. 
Detailed medical history and physical 
examination seeking new abnormalities. 
Evaluate abnormalities found. 
Full serological evaluation for hepatitis A, B, 
C, and E (IgG and IgM). Check for 
autoimmune hepatitis with serological 
laboratory studies. 
If viral hepatitis or autoimmune hepatitis 
suggested, have patient 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 patient 
seen by hepatologist. 
Obtain hepatology consult if liver function 
continues to rise beyond 14 d. 
Contact Medical Monitor. 
We request that cases be discussed with the Medical Monitor as defined in the protocol 
whenever investigational product is being held for liver function test abnormality. 
Ig = Immunoglobulin; INR = international normalized ratio; OTC = over-the-counter. 
For suspected cases of cholestatic liver injury, eg, aminotransferase increase concurrent 
with hyperbilirubinemia, or liver biopsy suggesting cholestasis or ductopenia, patients 
will be followed to assess long-term outcome. Additional diagnostic and follow-up 
procedures might be implemented as appropriate to fully assess the event.  
5.5. 
Method of Assessing Treatment Compliance 
Pexidartinib will be dispensed to patients at the study visits indicated in the Schedule of 
Events. The appropriate study personnel will document and maintain records of study 
drug dispensed to each patient and any returns at each study visit. 
Patients will complete a dosing diary to record the number of capsules/date/time the dose 
was taken during each dosing cycle. 


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At each site visit, patients will be assessed for compliance with study drug administration, 
ie, actual capsules taken/expected capsules taken. If there is a dose reduction, the number 
of expected capsules taken should be adjusted accordingly. The patient must also return 
all bottles (used/unused) at each dispensing visit. Returned capsules must be recorded in 
the Drug Accountability log.  
Further details can be found in the Study Reference Manual. 
5.6. 
Prior and Concomitant Medications 
No potent inhibitors or inducers of CYP3A4, CYP2C9, UGT1A4, and P-gp are allowed 
from 14 d before C1D1 through the completion of Part 1. No systemic pH modifiers are 
permitted during Part 1. Also, no additional administration of midazolam and S-warfarin 
beyond the protocol-defined administrations is permitted during this time. Pexidartinib 
exposure is reduced when administered with pH modifiers like esomeprazole. Therefore, 
pH modifiers should be avoided 14 d before dosing. Nonsystemic pH modifiers such as 
antacids can be taken 4 h after pexidartinib administration. 
Otherwise, during the study, if the use of any concomitant treatment becomes necessary 
(eg, for treatment of an AE), the treatment must be recorded on the source document and 
electronic Case Report Form (eCRF), including the reason for treatment, name of the 
drug, dosage, route, and date of administration. All medications including prescription, 
over-the-counter (OTC), herbal and other nutritional vitamins and/or supplements taken 
within 28 d of C1D1 will be recorded on the eCRF. Analgesic use and analgesic regimen 
will be recorded. 
Anti-cancer therapy, including antibody, retinoid, or hormonal treatment (except 
megestrol acetate as supportive care), and radiation will not be permitted within 2 wk 
before dosing.   
Patients enrolled in studies with pexidartinib and receiving concomitant warfarin, except 
for the protocol-required administrations, should have their anticoagulation status 
carefully monitored, especially shortly after initiation of pexidartinib, for the potential 
need to make adjustments in warfarin dosing. In particular, international normalized ratio 
(INR) should be obtained just prior to initiation of pexidartinib, within 1 to 2 wk after 
initiation, and periodically thereafter. Dose adjustments of warfarin should be made as 
medically indicated. 
Of the 5 major CYP isoforms, 3A4 may be involved in Phase 1 metabolism of 
pexidartinib, with possibly CYP1A2 playing a minor role. Until information regarding 
exposure-toxicity and exposure-response relationships is available with pexidartinib, 
concomitant CYP3A4 inhibitors and inducers should be administered with caution, in the 
event they alter the systemic exposure to pexidartinib (see Section 17.1 for a list of 
common CYP3A4 inhibitors and inducers). In general, strong inhibitors or inducers of 
CYP3A4 should be avoided unless clinically necessary. These include anticonvulsants, 
certain mycin antimicrobials, and antiretrovirals. Some common examples include 
inhibitors such as erythromycin, clarithromycin, and inducers such as rifampicin, 
carbamazepine, phenytoin, efavirenz, and nevirapine.4  


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The following medications and products will be prohibited: 
 Other investigational agents/devices. 
 Pexidartinib is a substrate for CYP3A4/5 and some fruits are CYP3A4/5 
inhibitors. Foods or beverages containing CYP3A4/5 inhibitors (eg, 
grapefruit, pomegranate, pomelo, and star fruit) should be therefore avoided 
throughout the study. 
5.6.1. 
Dietary and Lifestyle Restrictions 
Study drugs will be administered at the clinical site orally with 240 mL of water 
following at least a 10 h overnight fast. For pexidartinib home dosing, patients will fast 
1 h before pexidartinib dosing and continue to fast for 2 h after dosing. 
Potent CYP2C9, CYP3A4, and UGTA4 inducer and inhibitors (see Section 17.1) and 
potent P-gp inhibitors and inducers must be discontinued at least 14 d before study drug 
administration. No systemic pH modifiers are permitted during Part 1. Nonsystemic pH 
modifiers such as antacids can be taken 4 h after pexidartinib administration.  
Except when ECGs are performed, patients will remain seated in an upright position with 
minimal ambulation (ie, only to and from the washroom or for study procedures) for the 
first 4 h following dosing.  
Men and women of childbearing potential are permitted in the study as long as they 
consent to avoid getting their partner pregnant or becoming pregnant, respectively, by 
using a highly effective contraception method, as described below, throughout the study 
and up to 90 d after completion. Highly effective methods of contraception include 
intra-uterine device (nonhormonal or hormonal); bilateral tubal occlusion; vasectomy; 
sexual abstinence (only if this is in line with the patient’s current lifestyle); or barrier 
methods (eg, condom, diaphragm) used in combination with hormonal methods 
associated with inhibition of ovulation. Women of nonchildbearing potential may be 
included if they are either surgically sterile or have been postmenopausal for 1 y. 
Women who have documentation of at least 12 mo of spontaneous amenorrhea and have 
a follicle stimulating hormone level > 40 mIU/mL will be considered postmenopausal. 
5.7. 
Patient Withdrawal/Discontinuation 
5.7.1. 
Reasons for Withdrawal 
The reason for discontinuation should be recorded for any patient discontinuing from the 
study. 
The reasons a patient may discontinue or be withdrawn from the study permanently 
include but are not limited to: 
 AE 
 Disease progression 
 Patient request 
 Investigator decision 


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 Protocol violation 
 Surgery 
 Patient noncompliance 
 Pregnancy 
 Study termination by Daiichi Sankyo Inc. or institutional review board 
(IRB)/independent ethics committee (IEC) 
5.7.2. 
Withdrawal Procedures 
If a patient is withdrawn from the study, the Investigator will complete and report the 
observations as thoroughly as possible up to the date of withdrawal including the date of 
last dose and the reason for withdrawal. 
If the patient is withdrawn due to an AE, the Investigator will follow the patient until the 
AE has resolved or stabilized. 
All patients who are withdrawn from the study should complete protocol-specified 
withdrawal procedures. 
When a patient discontinues or is permanently withdrawn from the study, the Investigator 
will notify Daiichi Sankyo Inc. and ensure that the procedures listed in the “posttreatment 
visit” column in the Schedule of Events are performed 28 d ± 7 d after the patient’s last 
dose of study drug. 
The consequence of a patient’s withdrawal of all consent will be that no new information 
will be collected from that patient and added to the existing data or any database. 
However, every effort should be made to follow all patients for safety. 
The reason for study withdrawal will be recorded.  
5.7.3. 
Patient Replacement 
Patients withdrawn from the study will not be replaced except if needed to achieve the 
target number of evaluable patients for the DDI PK analysis. 
5.7.4. 
Patient Re-Screening Procedures 
Re-screening is permitted for any candidate who failed to meet the eligibility criteria 
upon initial screening. The subject identification number must remain the same at the 
time of re-screening. The initial screening information and the reason why the patient was 
ineligible for the initial evaluation will be recorded on the Screening log. No data from 
the initial evaluation will be entered into the clinical database for a patient who is 
re-screened. 


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6. 
STUDY PROCEDURES 
Patients should arrive to the clinical site fasted (approximately 10 h) on Study Days 1, 5, 
and 15. 
6.1. 
Informed Consent 
Signed informed consent must be collected before any study-related procedures are 
performed. 
6.2. 
Screening  
6.2.1. 
Screening (Day -21 to Day -1)  
The following procedures must be performed within the 21 d period before enrollment 
unless otherwise noted, and the results must be obtained and evaluated for eligibility prior 
to the enrollment: 
 Collect signed informed consent 
 Collect prior and concomitant medications 
 Collect demographic information 
 Collect medical/surgical history 
 Measure height and weight 
 Perform physical examination 
 Record vital signs, measured after patient has rested in the recumbent position 
for 5 min or more 
 Perform 12-lead ECG, collected after patient has rested in the supine position 
for 5 min or more 
 Perform pregnancy testing on women of childbearing potential only 
 Collect blood sample for: 
 Serum chemistry, hematology, and coagulation 
 Follicle-stimulating hormone (FSH) level, for postmenopausal women 
only 
 Collect urine sample for urinalysis 
 Perform drug and alcohol screening 
 Perform tumor assessment 
 Collect PGx sample and submit for analysis of metabolizer status of CYP2C9 
to determine eligibility 
 Perform optional tumor biopsy under specific informed consent and/or blood 
sample for circulating tumor DNA at the discretion of the Investigator/patient  


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6.3. 
Part 1 – Treatment Period 
6.3.1. 
Part 1 – Day 1 
The following assessments will be performed on Day 1 of Part 1: 
 Perform physical examination 
 Measure weight 
 Collect blood sample for: 
 Predose serum chemistry and hematology 
 PK sampling for midazolam (predose, 0.5, 1, 2, 3, 4, 6, 8, and 10 [±10 min 
up to 1 h, 10% thereafter] h postdose) 
 PK sampling for S-warfarin (predose, 0.5, 1, 2, 3, 4, 6, 8, and 10 [±1] h 
postdose) 
 Predose PGx sampling 
 Record vital signs (predose and 2 and 4 h postdose), measured after patient 
has rested in the recumbent position for 5 min or more 
 Perform 12-lead ECG (predose), measured after the patient has rested in the 
supine position for 5 min or more 
 Co-administer midazolam and S-warfarin (with Vitamin K) at the clinical site 
 Record concomitant medications 
 Assess AEs 
6.3.2. 
Part 1 – Day 2 
The following assessments will be performed on Day 2 of Part 1:  
 Record concomitant medications 
 Assess AEs 
 Collect blood sample for: 
 PK sampling for midazolam (24 [±10%] h postdose) 
 PK sampling for S-warfarin (24 [±2] h postdose) 
6.3.3. 
Part 1 – Day 3 
The following assessments will be performed on Day 3 of Part 1:  
 Record concomitant medications 
 Assess AEs 


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 Collect blood sample for:  
 PK sampling for midazolam (48 [±10%] h postdose) 
 PK sampling for S-warfarin (48 [±2] h postdose) 
6.3.4. 
Part 1 – Day 4 
The following assessments will be performed on Day 4 of Part 1:  
 Record concomitant medications 
 Assess AEs 
 Collect blood sample for PK sampling for S-warfarin (72 [±2] h postdose) 
6.3.5. 
Part 1 – Day 5 (C1D1) 
The following assessments will be performed on Day 5 of Part 1 (C1D1): 
Note: Patients may delay the Day 5 visit up to 2 days, in which case the 96 h sample from 
Day 1 should be collected on Day 5 or up to 1 d later. Day 5 is the start of the first 28-d 
pexidartinib cycle.  
 Perform physical examination 
 Record concomitant medications 
 Assess AEs 
 Measure weight 
 Collect blood sample for:  
 Predose serum chemistry and hematology 
 PK sampling for midazolam (predose, 0.5, 1, 2, 3, 4, 6, 8, and 10 [±10 min 
up to 1 h, 10% thereafter] h) 
 PK sampling for S-warfarin (predose, 0.5, 1, 2, 3, 4, 6, 8, and 10 [±1] h) 
 PK sampling for pexidartinib and ZAAD-1006a (predose, 0.5, 1, 2, 3, 4, 6, 
8, and 10 [±1] h) 
 Record vital signs (predose and 2 and 4 h postdose), measured after patient 
has rested in the recumbent position for 5 min or more 
 Perform 12-lead ECG (predose), measured after the patient has rested in the 
supine position for 5 min or more 
 Co-administer midazolam, S-warfarin (with Vitamin K), and pexidartinib at 
the clinical site 
 Dispense pexidartinib capsules for evening dose or administer at the clinic 


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6.3.6. 
Part 1 – Day 6 (C1D2) 
The following assessments will be performed on Day 6 of Part 1:  
 Record concomitant medications 
 Assess AEs 
 Collect blood sample for: 
 PK sampling for midazolam (24 [±10%] h postdose) 
 PK sampling for S-warfarin (24 [±2] h postdose) 
 Administer pexidartinib morning dose, preferably at the clinic 
 Assess pexidartinib treatment compliance (if applicable) 
 Dispense pexidartinib capsules 
6.3.7. 
Part 1 – Day 7 (C1D3) 
The following assessments will be performed on Day 7 of Part 1 (C1D3): 
 Record concomitant medications 
 Assess AEs 
 Collect blood sample for: 
 PK sampling for midazolam (48 [±10%] h postdose) 
 PK sampling for S-warfarin (48 [±2] h postdose) 
 Administer pexidartinib morning dose, preferably at the clinic 
 Assess pexidartinib treatment compliance 
 Dispense pexidartinib capsules 
6.3.8. 
Part 1 – Day 8 (C1D4) 
The following assessments will be performed on Day 8 of Part 1 (C1D4):  
 Record concomitant medications 
 Assess AEs 
 Collect blood sample for PK sampling for S-warfarin (72 [±2] h postdose) 
 Administer pexidartinib morning dose, preferably at the clinic 
 Assess pexidartinib treatment compliance 
 Dispense pexidartinib capsules 


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6.3.9. 
Part 1 – Day 9 (C1D5) 
The following assessments will be performed on Day 9 of Part 1 (C1D5).  
Note: Patients may delay the Day 9 visit up to 1 d: 
 Record concomitant medications 
 Assess AEs 
 Predose serum chemistry and hematology (Alkaline phosphatase, ALT, AST, 
total and direct bilirubin, and gamma-glutamyl transferase [GGT] must be 
evaluated for the possible need to modify pexidartinib treatment before the 
patient leaves the clinic) 
 Collect blood sample for S-warfarin (96 [±2] h postdose); can be delayed by 
1 d 
 Administer pexidartinib morning dose, preferably at the clinic 
 Assess pexidartinib treatment compliance 
 Dispense pexidartinib capsules 
6.3.10. 
Part 1 – Day 15 (C1D11) 
The following assessments will be performed on Day 15 of Part 1 (C1D11): 
Note: May be delayed up to 1 d for patients with TGCT or other non-malignant tumor or 
up to 4 d for patients with malignant disease, if needed. This visit cannot be delayed by 
more than 1 d for patients with TGCT or other non-malignant tumor because they require 
a pexidartinib dose reduction to 800 mg/d after 14 d of treatment that cannot be 
completed before the last PK sample is taken. If the Part 1 Day 15 visit is delayed, 
pexidartinib BID administration and weekly safety assessments must continue (±1 d) 
despite the delay. The cycle day count begins from the first dose of pexidartinib (C1D1) 
and continues regardless of any delay.  
 Perform physical examination 
 Record concomitant medications 
 Assess AEs 
 Measure weight 
 Collect blood samples for:  
 Predose chemistry and hematology (Alkaline phosphatase, ALT, AST, 
total and direct bilirubin, and GGT must be evaluated for the possible need 
to modify pexidartinib treatment before the patient leaves the clinic) 
 PK sampling for midazolam (predose, 0.5, 1, 2, 3, 4, 6, 8, and 10 [±10 min 
up to 1 h, 10% thereafter] h postdose) 


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 PK sampling for S-warfarin (predose, 0.5, 1, 2, 3, 4, 6, 8, and 10 [±1] h 
postdose) 
 PK sampling for pexidartinib and ZAAD-1006a (predose, 0.5, 1, 2, 3, 4, 6, 
8, and 10 [±1] h postdose) 
 Record vital signs (predose and 2 and 4 h postdose), measured after patient 
has rested in the recumbent position for 5 min or more 
 Perform 12-lead ECG (predose), measured after the patient has rested in the 
supine position for 5 min or more 
 Co-administer midazolam, S-warfarin (with Vitamin K), and pexidartinib at 
the clinical site 
 Assess pexidartinib treatment compliance  
 Dispense pexidartinib capsules for evening dose or administer at the clinic 
6.3.11. 
Part 1 – Day 16 (C1D12) 
The following assessments will be performed on Day 16 of Part 1 (C1D12):  
 Record concomitant medications 
 Assess AEs 
 Collect blood samples for: 
 PK sampling for midazolam (24 [±10%] h postdose) 
 PK sampling for S-warfarin (24 [±2] h postdose) 
 Administer pexidartinib morning dose, preferably at the clinic 
 Assess pexidartinib treatment compliance 
 Dispense pexidartinib capsules 
6.3.12. 
Part 1 – Day 17 (C1D13) 
The following assessments will be performed on Day 17 of Part 1 (C1D13):  
 Record concomitant medications 
 Assess AEs 
 Collect blood samples for:  
 PK sampling for midazolam (48 [±10%] h postdose) 
 PK sampling for S-warfarin (48 [±2] h postdose) 
 Administer pexidartinib morning dose, preferably at the clinic 
 Assess pexidartinib compliance 
 Dispense pexidartinib capsules 


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6.3.13. 
Part 1 – Day 18 (C1D14) 
The following assessments will be performed on Day 18 of Part 1 (C1D14).  
 Record concomitant medications  
 Assess AEs  
 Perform physical examination (or upon early withdrawal); may be done after 
last PK draw on the final day of the Part 1 DDI Phase 
 Collect blood sample for S-warfarin (72 [±2] h postdose) 
 Administer pexidartinib morning dose, preferably at the clinic 
 Assess pexidartinib treatment compliance 
 Dispense pexidartinib capsules 
6.4. 
Part 2 – Treatment Period 
6.4.1. 
Part 2 – Day 19 (C1D15) 
The following assessments will completed on Day 19 of Part 2 (C1D15):  
Note: Patients may delay the Day 19 visit by 1 d.  
 Record concomitant medications. 
 Assess AEs. 
 Record vital signs (predose), measured after patient has rested in the 
recumbent position for 5 min or more. 
 Perform 12-lead ECG (predose), measured after the patient has rested in the 
supine position for 5 min or more. 
 Collect blood samples for: 
 Predose serum chemistry and hematology. (Alkaline phosphatase, ALT, 
AST, total and direct bilirubin, and GGT must be evaluated for the 
possible need to modify pexidartinib treatment before the patient leaves 
the clinic). 
 PK sample for S-warfarin (96 [±2] h postdose); can be delayed by 1 d.  
 Collect urine sample for urinalysis.  
 Assess pexidartinib treatment compliance.  
 Dispense pexidartinib capsules; for patients with TGCT or other benign 
tumors, the pexidartinib dose should be reduced to 800 mg/d (400 mg BID) 
after 14 d of treatment.  


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6.4.2. 
Part 2 – Day 26 (C1D22) 
The following assessments will be performed on Day 28 (±2 d) of Part 2 (C1D22):  
 Record concomitant medications.  
 Assess AEs.  
 Collect blood sample for predose serum chemistry and hematology. (Alkaline 
phosphatase, ALT, AST, total and direct bilirubin, and GGT must be 
evaluated for the possible need to modify pexidartinib treatment before the 
patient leaves the clinic). 
 Dispense pexidartinib capsules.  
 Assess pexidartinib treatment compliance. 
6.4.3. 
Part 2 – Day 33 (C2D1) 
The following assessments will be performed on Day 33 (±2 d) of Part 2:  
 Record concomitant medications.  
 Assess AEs.  
 Perform physical examination. 
 Collect blood sample for predose serum chemistry and hematology. (Alkaline 
phosphatase, ALT, AST, total and direct bilirubin, and GGT must be 
evaluated for the possible need to modify pexidartinib treatment before the 
patient leaves the clinic).  
 Record vital signs (predose), measured after patient has rested in the 
recumbent position for 5 min or more. 
 Perform pregnancy test for women of childbearing potential only.  
 Dispense pexidartinib capsules.  
 Assess pexidartinib treatment compliance.  
 Perform optional tumor biopsy under specific informed consent or blood 
sample for circulating tumor DNA at the discretion of the Investigator/patient.  
6.4.4. 
Part 2 – Day 40 (C2D8) 
The following assessments will be performed on Day 40 (±2 d) of Part 2 (C2D8):  
 Record concomitant medications.  
 Assess AEs. 
 Collect blood sample for predose serum chemistry and hematology. (Alkaline 
phosphatase, ALT, AST, total and direct bilirubin, and GGT must be 
evaluated for the possible need to modify pexidartinib treatment before the 
patient leaves the clinic).  


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 Dispense pexidartinib capsules.  
 Assess pexidartinib treatment compliance.  
6.4.5. 
Part 2 – Day 47 (C2D15) 
The following assessments will be performed on Day 47 (±2 d) of Part 2 (C2D15):  
 Record concomitant medications.  
 Assess AEs. 
 Collect blood sample for predose serum chemistry and hematology. (Alkaline 
phosphatase, ALT, AST, total and direct bilirubin, and GGT must be 
evaluated for the possible need to modify pexidartinib treatment before the 
patient leaves the clinic).  
 Dispense pexidartinib capsules.  
 Assess pexidartinib treatment compliance.  
6.4.6. 
Part 2 – Day 54 (C2D22) 
The following assessments will be performed on Day 54 (±2 d) of Part 2 (C2D22):  
 Record concomitant medications.  
 Assess AEs. 
 Collect blood sample for predose serum chemistry and hematology. (Alkaline 
phosphatase, ALT, AST, total and direct bilirubin, and GGT must be 
evaluated for the possible need to modify pexidartinib treatment before the 
patient leaves the clinic).  
 Dispense pexidartinib capsules.  
 Assess pexidartinib treatment compliance.  
6.4.7. 
Part 2 – Day 61 (C3D1) 
The following assessments will be performed on Day 61 (±2 d) of Part 2 (C3D1):  
 Record concomitant medications.  
 Assess AEs. 
 Perform tumor assessment.  
 Collect blood sample for predose serum chemistry and hematology. (Alkaline 
phosphatase, ALT, AST, total and direct bilirubin, and GGT must be 
evaluated for the possible need to modify pexidartinib treatment before the 
patient leaves the clinic).  
 Record vital signs (predose), measured after patient has rested in the 
recumbent position for 5 min or more. 
 Perform pregnancy test for women of childbearing potential only.  


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 Dispense pexidartinib capsules.  
 Assess pexidartinib treatment compliance.  
6.4.8. 
Part 2 – Day 75 (C3D15) 
The following assessments will be performed on Day 75 (±7 d) of Part 2 (C3D15):  
 Record concomitant medications.  
 Assess AEs.  
 Collect blood sample for predose serum chemistry and hematology. (Alkaline 
phosphatase, ALT, AST, total and direct bilirubin, and GGT must be 
evaluated for the possible need to modify pexidartinib treatment before the 
patient leaves the clinic). 
 Assess pexidartinib treatment compliance.  
 Dispense pexidartinib capsules.  
6.4.9. 
Part 2 – Day 89 (C4D1)  
The following assessments will be performed on Day 89 (±7 d) of Part 2 (C4D1):  
 Record concomitant medications.  
 Assess AEs.  
 Perform physical examination.  
 Collect blood sample for predose serum chemistry and hematology. (Alkaline 
phosphatase, ALT, AST, total and direct bilirubin, and GGT must be 
evaluated for the possible need to modify pexidartinib treatment before the 
patient leaves the clinic). 
 Record vital signs (predose), measured after patient has rested in the 
recumbent position for 5 min or more. 
 Perform pregnancy test for women of childbearing potential only. 
 Assess pexidartinib treatment compliance.  
 Dispense pexidartinib capsules.  
 Perform optional tumor biopsy under specific informed consent or blood 
sample for circulating tumor DNA at the discretion of the Investigator/patient.  


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6.4.10. 
Part 2 – Day # (C5+D1) 
Note: The 28-d treatment cycles will continue until there is no longer any clinical benefit 
or until other reasons for discontinuation are met.  
The following assessments will be performed during the remainder of the study cycles on 
Day 1 (±7 d) of that cycle unless otherwise specified:  
 Record concomitant medications.  
 Assess AEs.  
 Perform physical examination every 2 cycles. 
 Perform tumor assessment every 2 cycles. May be reduced after Cycle 4 if 
clinically appropriate and approved by the Sponsor’s Medical Monitor.  
 Collect blood sample for predose serum chemistry and hematology. (Alkaline 
phosphatase, ALT, AST, total and direct bilirubin, and GGT must be 
evaluated for the possible need to modify pexidartinib treatment before the 
patient leaves the clinic). 
 Record vital signs (predose), measured after patient has rested in the 
recumbent position for 5 min or more. 
 Perform pregnancy test for women of childbearing potential only. 
 Assess pexidartinib treatment compliance.  
 Dispense pexidartinib capsules.  
6.5. 
Posttreatment 
The following assessments will be performed 28 d (±7 d) after the last dose:  
 Record concomitant medications.  
 Assess AEs.  
 Perform physical examination. 
 Perform 12-lead ECG, measured after the patient has rested in the supine 
position for 5 min or more. 
 Collect urine for urinalysis.  
 Collect blood sample for serum chemistry and hematology.  
 Record vital signs, measured after patient has rested in the recumbent position 
for 5 min or more. 
 Perform pregnancy test for women of childbearing potential only.  
 


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7. 
PHARMACOKINETIC/PHARMACODYNAMIC 
ASSESSMENTS 
Patients will be assessed for the PK and optional PDy endpoints at the discretion of the 
Investigator/patient. 
7.1. 
Pharmacokinetic Assessment(s) 
PK parameters of midazolam and S-warfarin: Cmax, Tmax, and AUClast. Other PK 
parameters including t1/2 and AUCinf will also be calculated. For 5-hydroxy midazolam, 
Cmax, Tmax, AUClast, and AUCinf will be calculated. Additionally, MPR for 5-hydroxy 
midazolam and midazolam will also be calculated. 
PK parameters (Cmax, tmax, and AUClast) will be calculated for pexidartinib and its 
primary metabolite, ZAAD-1006a after the first dose and multiple doses.  
PK sampling will be performed at the study visits indicated in the Schedule of Events:  
 Plasma samples for midazolam will be collected at predose, 0.5, 1, 1.5, 2, 3, 4, 6, 
8, 10, 24, and 48 h (10 min up to 1 h, 10% thereafter) on Day 1 to 3 and also 
when co-administered with pexidartinib on Days 5 to 7 and Days 15 to 17. 
These samples will also be analyzed for 5-hydroxy midazolam. 
 Plasma samples for S-warfarin will be collected predose, 0.5, 1, 1.5, 2, 3, 4, 6, 
8, 10 (±1), 24 (±2), 48 (±2), 72 (±2), and 96 (±2) h on Days 1 to 5 and also 
when co-administered with pexidartinib on Days 5 to 9 and Days 15 to 19.  
 Plasma samples for pexidartinib and its metabolites will be collected at 
predose, 0.5, 1, 2, 3, 4, 6, 8, and 10 (±1) h after the first dose on Day 5 and at 
steady state when co-administered with midazolam and S-warfarin on Day 15. 
Patients should be told to NOT take the morning dose of study drug on the days of PK 
sampling. Additionally, only an adequate number of capsules to cover dosing till the next 
clinic visit will be dispensed. 
The exact time of dose administration should be recorded along with the corresponding 
PK blood samplings. The exact time of the 3 preceding doses should also be recorded. 
Blood samples of approximately 3 mL for PK analyses will be collected at the time points 
specified in the Schedule of Events.  
Detailed instructions on collection, processing, handling, storage, and sample shipment 
are provided in the Laboratory Manual. 
7.2. 
Pharmacodynamic Assessment 
Plasma for circulating PDy biomarkers may be collected optionally at the discretion of 
the Investigator/patient as defined in the Schedule of Events and analyzed for PDy 
biomarkers of pexidartinib. 
Detailed instructions on collection, processing, handling, storage, and sample shipment is 
provided in the Laboratory Manual. 


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7.3. 
Immunogenicity 
Not applicable.  
7.4. 
Pharmacogenomic Analysis 
7.4.1. 
Genomic or Genetic Banking and Analysis 
A blood sample (10 mL) for PGx analysis will be collected from each patient at 
Screening and at predose on Day 1 (Period 1) of the study. 
The following procedures will be used for the long-term preservation (banking) of 
deoxyribonucleic acid specimens extracted from patients' blood samples. 
Pharmacogenomic samples may be analyzed for genes involved in absorption, 
distribution, metabolism, elimination, safety, and efficacy of pexidartinib. Additionally, 
samples may be analyzed for genes involved in pexidartinib-related signaling pathways, 
or to examine diseases or physiologic processes related to pexidartinib. Deoxyribonucleic 
acid samples will not be immortalized or sold to anyone. This information may be useful 
in increasing the knowledge of differences among individuals in the way they respond to 
the study drug, as well as helping in the development of new drugs or improvement of 
existing drugs. 
Specimen shipping and handling details are provided below and will be included in the 
procedures manual. 
7.4.2. 
Metabolizers for CYP2C19 
A genotyping blood sample will be taken at Screening to identify and exclude CYP2C9 
poor metabolizers. Patients with poor metabolizer genotype status for CYP2C9 will be 
excluded from the study to ensure that the study population is sensitive to a potential 
interaction and to reduce variability.  
Poor metabolizers are defined as follows:  
 CYP2C9 poor metabolizer status will be determined by genotyping CYP2C9 
*2 (rs1799853) and CYP2C9 *3 (rs1057910). Patients with the CYP2C9 
*2/*2, *2/*3 or *3/*3 genotypes will be considered CYP2C9 poor 
metabolizers. 
7.4.2.1. 
Collection of Specimens for Genomic or Genetic Banking and Analysis 
On the morning of Screening and Day 1 (Period 1) pre-dose, a 10-mL blood sample for 
PGx analysis will be collected from patients. The sample will be collected into a 10 mL 
K2EDTA polypropylene blood collection tube. It is very important to collect a full tube. 
Each sample must be labeled with a unique identifier. GLP requires a chain of custody 
that is traceable to the sample donor. In order to ensure patient confidentiality, sample 
tubes will be identified only by patient identification number. 
Labels must be legible and waterproof. It is recommended that labels be created using 
waterproof ink and covered with clear label tape. 


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The tubes should be placed in an ice bath immediately following collection and then 
stored upright in a freezer set at -20°C (± 10°C) until packed for shipping.  
The following shipping procedures are to be followed: 
1. Prepare samples for shipment only on the day of transit. The samples must be 
shipped on the first available day following collection. 
2. Place samples in plastic specimen bag. 
3. Place 2 inches depth of packing material in a Styrofoam box. 
4. Place the sealed plastic specimen bag on top of packing material. 
5. Place 5 pounds of dry ice on top of specimen bag. 
6. Fill Styrofoam container completely with packing material. 
7. Seal box and select an overnight courier for shipment. 
8. Place a “dry ice” and 2 IATA Biological Materials label (opposing sides) on the 
side of the box. 
9. Attach an appropriate shipping label. 
10. Indicate the amount of dry ice in kg on the label (5 lb dry ice = 2.5 kg). 
11. Schedule courier for pick-up. DO NOT ship samples on Friday without prior 
consent from the PGx vendor. Samples should be shipped via an overnight carrier 
to arrive the next morning. Prior to shipment, fax the Shipment Notification Form 
to the PGx vendor Study Manager as indicated in the Statement of Work. 
7.4.2.2. 
Genomic or Genetic Analysis Endpoint(s) 
Not applicable.  
7.4.2.3. 
Disclosure of the Results of Genomic or Genetic Analysis 
Because the nature and value of future PGx research cannot be known at this time, any 
results obtained from research involving PGx samples will not be disclosed to the patient 
or Investigators now or in the future. 
7.4.2.4. 
Storage and Disposal of Specimens for Genomic or Genetic Banking and 
Analysis 
Samples will be retained until exhausted or until the Sponsor requests destruction. 
If the patient withdraws consent, the banked blood specimens will be promptly managed 
regarding proper disposition. However, the data will not be discarded if genetic analysis 
has been completed before the patient withdraws consent. For screen failures, PGx 
samples will be destroyed post CYP2C9 analysis.  
 


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8. 
EFFICACY ASSESSMENTS 
Patients will be assessed for the efficacy endpoints listed in Section 2.3. 
8.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint will be ORR, defined as the proportion of patients who 
achieve a confirmed complete response (CR) or PR based on locally read tumor 
assessments according to RECIST 1.1 or other applicable assessment of treatment 
response based upon the applicable tumor. TGCT tumors should be assessed by MRI. 
The RECIST 1.1 response categories are defined by the following criteria: 
 Complete Response — Disappearance of all tumors. 
 Partial Response — At least a 30% decrease in the sum of diameters of target 
tumors, taking as reference the baseline sum diameters. 
 Progressive Disease — At least a 20% increase in the sum of diameters of 
target tumors, using the smallest sum on study as the reference. In addition to 
the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. The appearance of one or more new tumors is also 
considered progression. 
 Stable Disease — Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for progressive disease (PD). 
Complete and PR will define response for the primary endpoint and additional efficacy 
analyses. Determination of an overall response for each time point is based on the 
combination of responses for target lesions, and the presence or absence of one or more 
new lesions, in alignment with RECIST 1.1. 
8.2. 
Secondary Efficacy Endpoint 
The following evaluations comprise the secondary endpoints based upon the locally read 
tumor assessments: 
 Duration of response (CR or PR) based on RECIST 1.1 
 Time to progression (for TGCT and other non-malignant tumors) 
 Progression-free survival (for malignant tumors) 
8.3. 
Appropriateness of Selected Efficacy Endpoints 
The selected efficacy endpoints are commonly used and widely accepted endpoints 
appropriate for the efficacy evaluation of investigational treatments in patients with these 
tumors.  


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9. 
SAFETY EVALUATION AND REPORTING 
9.1. 
Adverse Event Collection and Reporting 
All AEs (see Section 9.4.1 for definitions) occurring after the patient signs the ICF and 
through the posttreatment visit (28 d ± 7 d after the last dose of study drug), whether 
observed by the Investigator or reported by the patient, will be recorded on the AE eCRF 
page. Medical conditions (including laboratory values/vital signs that are out of range) 
that were diagnosed or known to exist prior to informed consent will be recorded as part 
of medical history. 
All AEs and SAEs are to be reported according to the procedures in Section 9.5. 
All laboratory results, vital signs, and ECG results or findings should be appraised by the 
Investigator to determine their clinical significance. Isolated abnormal laboratory results, 
vital sign findings, or ECG findings (ie, not part of a reported diagnosis) should be 
reported as AEs if they are symptomatic, lead to study drug discontinuation, dose 
reduction, require corrective treatment, or constitute an AE in the Investigator’s clinical 
judgment. 
At each visit, the Investigator will determine whether any AEs have occurred by 
evaluating the patient. Adverse events may be directly observed, reported spontaneously 
by the patient, or by questioning the patient at each study visit. Patients should be 
questioned in a general way, without asking about the occurrence of any specific 
symptoms. The Investigator must assess all AEs to determine seriousness, severity, and 
causality, in accordance with the definitions in Section 9.4. The Investigator’s assessment 
must be clearly documented in the site’s source documentation with the Investigator’s 
signature. 
Always report the diagnosis as the AE or SAE term. When a diagnosis is unavailable, 
report the primary sign or symptom as the AE or SAE term with additional details 
included in the narrative until the diagnosis becomes available. If the signs and symptoms 
are distinct and do not suggest a common diagnosis, report them as individual entries of 
AE or SAE. 
For events that are serious due to hospitalization, the reason for hospitalization must be 
reported as the SAE (diagnosis or symptom requiring hospitalization). A procedure is not 
an AE or SAE, but the reason for the procedure may be an AE or SAE. Preplanned (prior 
to signing the ICF) procedures or treatments requiring hospitalization for preexisting 
conditions that do not worsen in severity should not be reported as SAEs (see 
Section 9.4.2 for definitions). For deaths, the underlying or immediate cause of death 
should always be reported as an SAE. 
Disease progression is a study endpoint and, consequently, should not be reported as an 
AE/SAE. However, when a patient dies from disease progression with no other 
immediate causes, “disease progression” should be reported as an SAE. In addition, any 
serious untoward event that may occur subsequent to the reporting period that the 
Investigator assesses as related to study drug should also be reported and managed as an 
SAE. 


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The Investigator should follow patients with AEs until the event has resolved or the 
condition has stabilized. In case of unresolved AEs, including significant abnormal 
laboratory values at the end of study assessment, the events will be followed up until 
resolution or until they become clinically not relevant. 
9.2. 
Safety Endpoint Events 
Safety endpoints include physical examination, vital signs, 12-lead ECG, AE reports, 
serum chemistry, hematology, coagulation tests, urinalysis, and concomitant medications. 
All AEs will be graded according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI-CTCAE) version 4.0. 
9.3. 
Adverse Events of Special Interest 
9.3.1. 
Combined Elevation of Aminotransferases and Bilirubin 
Combined elevations of aminotransferases and bilirubin, either serious or nonserious and 
whether or not causally related, meeting the laboratory criteria of a potential Hy’s Law 
(ALT or AST ≥ 3 × ULN with simultaneous TBil ≥ 2 × ULN) should always be reported 
to Daiichi Sankyo Inc. using a Serious Adverse Event Report (SAVER) Form or a special 
collection in the eCRF along with the Investigator’s assessment of seriousness, causality, 
and a detailed narrative. These events should be reported within 24 h of the Investigator’s 
awareness of the events. 
If the patient discontinues the study drug due to liver enzyme abnormalities, the patient 
will have additional clinical and laboratory evaluations as described in Section 5.4 in 
order to determine the cause and severity of the potential liver injury. 
9.4. 
Adverse Event 
9.4.1. 
Definition of Adverse Event 
An AE is any untoward medical occurrence in a patient administered 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 clinical 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 (ICH E2A Guideline. Clinical Safety Data Management: Definitions 
and Standards for Expedited Reporting, Oct 1994). 
It is the responsibility of Investigators, based on their knowledge and experience, to 
determine those circumstances or abnormal clinical laboratory findings which should be 
considered AEs. 
9.4.2. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
 Results in death 
 Is life-threatening 


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 Requires inpatient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability/incapacity 
 Is a congenital anomaly/birth defect or 
 Is an important medical event 
Note: The term “life-threatening” in the definition of “serious” refers to an event in which 
the patient was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe (ICH E2A Guideline. 
Clinical Safety Data Management: Definitions and Standards for Expedited Reporting, 
Oct 1994). 
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize 
the patient or may require intervention to prevent one of the other outcomes listed in the 
definition above. Examples include allergic bronchospasm, convulsions, and blood 
dyscrasias or development of drug dependency or drug abuse. 
Note:  
 Procedures are not AEs or SAEs, but the reason for the procedure may be an 
AE or SAE.  
 Pre-planned (prior to signing the ICF) procedures or treatments requiring 
hospitalizations for pre-existing conditions that do not worsen in severity are 
not SAEs. 
9.4.3. 
Grade Assessment 
All AEs will be graded (1 to 5; see below) according to the latest NCI-CTCAE, for each 
episode. 
 Grade 1: Mild – awareness of sign or symptom, but easily tolerated, ie, does 
not interfere with patient’s usual function 
 Grade 2: Moderate – discomfort enough to cause interference with usual 
activity 
 Grade 3: Severe – incapacitating with inability to work or do usual activity, ie, 
interferes significantly with patient’s usual function 
 Grade 4: Life-threatening or disabling AE – urgent intervention indicated 
 Grade 5: Death related to AE 
The NCI-CTCAE guidelines do not allow certain grades for certain AEs. For example, 
pain can be Grade 1 to 3 only (ie, cannot be life-threatening or fatal), whereas sepsis can 
only be Grade 4 or 5 (ie, can only be life-threatening or fatal). In addition, alopecia can 
only be Grade 1 or 2. The NCI-CTCAE guidelines should be followed closely. 
Severity vs. Seriousness: Severity is used to describe the intensity of a specific event 
while the event itself, however, may be of relatively minor medical significance (such as 


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severe headache). This is not the same as "seriousness", which is based on patient/event 
outcome at the time of the event. For example, the NCI-CTCAE Grade 4 (life-threatening 
consequences; urgent intervention indicated) is assessed based on unique clinical 
descriptions of severity for each AE, and these criteria may be different from those used 
for the assessment of AE seriousness. An AE assessed as Grade 4 based on the 
NCI-CTCAE grade may or may not be assessed as serious based on the seriousness 
criteria. 
9.4.4. 
Causality Assessment 
The Investigator should assess causal relationship between an AE and the study drug on 
the basis of his/her clinical judgment and the following definitions. The causality 
assessment must be made based on the available information and can be updated as new 
information becomes available. 
 Related: 
 The AE follows a reasonable temporal sequence from study drug 
administration, and cannot be reasonably explained by the patient’s 
clinical state or other factors (eg, disease under study, concurrent diseases, 
and concomitant medications). 
or 
 The AE follows a reasonable temporal sequence from study drug 
administration, and is a known reaction to the drug under study or its 
chemical group, or is predicted by known pharmacology. 
 Not related: 
 The AE does not follow a reasonable sequence from study drug 
administration, or can be reasonably explained by the patient’s clinical 
state or other factors (eg, disease under study, concurrent diseases, and 
concomitant medications).  
9.4.5. 
Action Taken Regarding Study Drug(s) 
 Dose Not Changed: No change in study drug dosage was made. 
 Drug Withdrawn: The study drug was permanently stopped. 
 Dose Reduced: The dosage of study drug was reduced. 
 Drug Interrupted: The study drug was temporarily stopped. 
 Dose Increased: The dosage of study drug was re-escalated. 
 Not Applicable: Patient died, study treatment had been completed prior to 
reaction/event, or reaction/event occurred prior to start of drug. 


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9.4.6. 
Other Action Taken for Event 
 None 
 No treatment was required. 
 Medication required 
 Prescription and/or OTC medication was required to treat the AE. 
 Hospitalization or prolongation of hospitalization required 
 Hospitalization was required or prolonged because of the AE, whether or 
not medication was required. 
 Other 
9.4.7. 
Adverse Event Outcome 
 Recovered/Resolved 
 The patient fully recovered from the AE with no residual effect observed. 
 Recovered/Resolved with Sequelae 
 The residual effects of the AE are still present and observable. 
 Document sequelae/residual effects. 
 Not Recovered/Not Resolved 
 The AE itself is still present and observable. 
 Fatal 
 Fatal should be used when death is a direct outcome of the AE. 
 Unknown 
9.5. 
Serious Adverse Events Reporting – Procedure for 
Investigators 
All AEs, SAEs, and events of special interest will be reported in the eCRF. 
The following types of events should be reported by the Investigator on the SAE 
(SAVER) form within 24 h of awareness: 
 SAEs (see Section 9.4.2) 
 Hepatic events meeting combination abnormalities (ALT or AST ≥ 3 × ULN 
with simultaneous TBil ≥ 2 × ULN); potential Hy’s Law case), both serious 
and nonserious 
All events (serious and nonserious) must be reported along with the Investigator’s 
assessment of the event’s seriousness, severity, and causality to the study drug. A detailed 
narrative summarizing the course of the event, including its evaluation, treatment, and 
outcome should be provided. Specific or estimated dates of event onset, treatment, and 


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resolution should be included when available. Medical history, concomitant medications, 
and laboratory data that are relevant to the event should also be summarized in the 
narrative. For fatal events, the narrative should state whether an autopsy was or will be 
performed, and include the results if available. Source documents (including medical 
reports) will be retained at the study site and should not be submitted to Daiichi Sankyo 
Inc. for SAE reporting purpose. 
Urgent safety queries must be followed up and addressed promptly. Follow-up 
information and response to nonurgent safety queries should be combined for reporting to 
provide the most complete data possible within each follow-up. 
See Section 15.10.5 for contact information for SAE reporting. Please call the local SAE 
Hotline (see Study Reference Manual) or your study monitor for any questions on SAE 
reporting. 
9.6. 
Notifying Regulatory Authorities, Investigators, and 
Institutional Review Board/Ethics Committee 
Daiichi Sankyo Inc. and/or designee will inform Investigators, IRBs/IECs, and regulatory 
authorities of any suspected unexpected serious adverse reactions (SUSARs) occurring in 
other study sites or other Daiichi Sankyo Inc. studies of the investigational product, as 
appropriate per local reporting requirements. Daiichi Sankyo Inc. and/or designee will 
comply with any additional local safety reporting requirements. 
In China, upon receipt of Daiichi Sankyo Inc.’s notification of SUSARs that occurred 
with the investigational product, unless delegated to Daiichi Sankyo Inc., it is the 
Investigator’s responsibility to inform the IRB according to reporting guideline of the 
IRBs. 
9.7. 
Exposure in Utero During Clinical Studies 
Daiichi Sankyo Inc. must be notified of any female patient or any male patient whose 
female partner becomes pregnant while receiving or within 90 d of discontinuing the 
study drug. Reporting after follow-up visit or early termination is done voluntarily by the 
Investigator. 
Although pregnancy is not technically an AE, all pregnancies must be followed to 
conclusion to determine their outcome. This information is important for both drug safety 
and public health concerns. It is the responsibility of the Investigator or designee to report 
any pregnancy in a female patient or a male patient’s female partner using the Exposure 
In Utero (EIU) Reporting Form. Please contact your study monitor to receive the EIU 
Reporting Form upon learning of a pregnancy. The Investigator should make every effort 
to follow the patient 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 nonserious, should 
be reported in accordance with study procedures. If the outcome of pregnancy meets the 
criteria for immediate classification as an SAE (ie, postpartum complications, 
spontaneous or induced abortion, stillbirth, neonatal death, or congenital anomaly, 
including that in an aborted fetus), the Investigator should follow the procedures for 


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reporting SAEs outlined in Section 9.5. For reports of pregnancy in the female partner of 
a male patient, the EIU Reporting Form (or SAE form if associated with an adverse 
outcome) should be completed with the patient’s enrollment number, initials, and date of 
birth, and details regarding the female partner should be entered in the narrative section. 
9.8. 
Clinical Laboratory Evaluations 
Clinical laboratory evaluations will be performed by local laboratories at the study visits 
indicated in the Schedule of Events. For laboratory parameters, the reference range of the 
institution that performs the measurement will be used. 
Clinical laboratory evaluations will be performed as outlined below.  
Blood samples for analysis of the following clinical chemistry, hematologic, and 
coagulation parameters will be obtained: 
Clinical Chemistry 
Sodium 
Total protein  
Potassium 
Albumin  
Chloride 
Triglycerides* 
CO2 
Total cholesterol* 
Calcium 
HDL-cholesterol* 
Phosphorus 
LDL-cholesterol* 
Glucose* 
Uric acid  
Blood urea nitrogen 
Lactate dehydrogenase 
Creatinine 
 
CO2 = carbon dioxide; HDL = high-density lipoprotein; LDL = low-density lipoprotein. 
* Fasting is recommended but not required. 
Liver function tests as part of serum chemistry will be conducted on an at least weekly 
basis for the first 8 wk of pexidartinib treatment starting from the first dose in Part 1. 
After Week 8, the frequency of liver function tests will be reduced to once every 2 wk 
through Cycle 3, followed by monthly. If any abnormality is detected in the liver function 
tests, then follow-up laboratory tests will be performed on a weekly basis. The frequency 
of follow-up liver function tests will be increased to twice weekly for all Grade 3 
aminotransferase increases and for any grade aminotransferase increase associated with 
bilirubin increase. (No bilirubin increase is defined as any 1 or more of the following: 
TBil ≤ ULN, TBil <20% above baseline, or direct bilirubin < ULN). 
Liver Function Tests 
Alkaline phosphatase 
Total bilirubin 
AST 
Direct bilirubin 
ALT 
GGT 
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Hematology 
Red blood cell count 
Hemoglobin 
White blood cell count with differential 
Hematocrit 
Platelet count 
 
Hepatitis Panel 
Hepatitis B virus surface antigen test and HCV antibody test. 
Coagulation 
Prothrombin time, activated partial thromboplastin time, and INR. 
Hormone Tests 
Follicle-stimulating hormone will be measured for women of non-childbearing potential 
only. 
Urine samples will be obtained for analysis of the following parameters: 
Urinalysis (dipstick and microscopic analysis*) 
pH 
Ketones/acetone  
Protein/albumin 
Hemoglobin/blood  
Glucose/sugar 
Red blood cells, white blood cells, epithelial cells, 
bacteria, casts, crystals  
Nitrites 
*Microscopic analysis required only in the event the dipstick is abnormal.  
9.9. 
Vital Signs 
Vital signs, including systolic/diastolic blood pressure, pulse rate, and temperature will be 
measured in accordance with institutional standards and generally should be performed 
before any invasive procedures, eg, blood withdraws. Vital signs and weight will be 
measured at the study visits mentioned in the Schedule of Events. Height will be 
measured at the Screening visit only. 
Blood pressure and pulse rate will be measured after the patient has rested in a recumbent 
position for 5 min or more. 
Information will be entered in the eCRF on whether or not measured, date of 
measurement, and measurement results. 
9.10. 
Electrocardiograms 
A standard 12-lead ECG will be obtained at the study visits indicated in the Schedule of 
Events.  
Patients should rest in the supine position for at least 5 min before the ECG recording is 
started. The ECG recordings must be performed using a standard high-quality and 
high-fidelity electrocardiography machine equipped with computer-based interval 
measurements. For safety monitoring purposes, the ECGs should be reviewed, signed, 


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and dated promptly by a qualified Investigator (or Investigator’s assistant or nurse 
practitioner) and any clinically important finding must be recorded on the appropriate 
eCRF. The Investigator is responsible for interpreting all ECGs. The results will include 
heart rate, RR interval, PR interval, QRS interval, QT interval, and QTcF interval. 
At the visits when ECGs are to be performed, patients should be told to NOT take the 
morning dose of study drug; instead, they should be told to bring their bottle of study 
drug to the site and take the morning dose upon instruction by the site staff. 
Whether or not measurement is performed, date performed, results, and findings for the 
parameters will be recorded in the eCRF. 
9.11. 
Physical Examinations 
The examination will be performed by a qualified individual such as the Investigator at 
the study visits indicated in the Schedule of Events.  
Physical examination findings will be used to evaluate the following systems or areas: 
general appearance, oral cavity and neck, cardiothoracic, dermatologic, abdominal, 
musculoskeletal, and neurological. 
9.12. 
Other Examinations 
9.12.1. 
Pregnancy Test 
For women of childbearing potential only, a serum pregnancy test (β-human chorionic 
gonadotropin) will be performed at the study visits indicated in the Schedule of Events. 
For postmenopausal patients (no childbearing potential, as indicated by an elapse of at 
least 12 mo after the last menstruation) or female patients who have no possibility of 
pregnancy due to sterilization surgery, etc. the pregnancy test will not be required. 
Female patients who have been amenorrheic for 12 mo or longer due to medical reasons 
other than sterilization surgery (eg, effect of medication) will be regarded as women of 
childbearing potential and are required to undergo the pregnancy test. 


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10. 
OTHER ASSESSMENTS 
Patients will be assessed for the efficacy endpoints and endpoints listed in Section 2.3.  
10.1. 
Tumor Assessment 
 Patients with TGCT – Noncontrast MRI of the affected joint will be 
performed at the study visits indicated in the Schedule of Events. Local 
evaluation of radiological response, SD or PD according to RECIST 1.1 will 
be recorded in the eCRF. The frequency of tumor assessments after Cycle 4 
can be reduced if clinically appropriate and agreed with the Sponsor Medical 
Monitor. 
 Patients with other tumors – The response of the tumor to study treatment 
should be assessed using a standard procedure applicable to the patients’ 
tumor, eg, MRI, CT, or other. The same procedure should be used throughout 
the study. The frequency of tumor assessments after Cycle 4 can be reduced if 
clinically appropriate and agreed with the Sponsor Medical Monitor. 


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11. 
STATISTICAL METHODS  
11.1. 
General Statistical Considerations 
The data cutoff for the primary PK analysis will occur after all patients have either 
discontinued or completed the last Part 1 assessments. The data cutoff for the primary 
efficacy and safety analyses will occur after all patients have either discontinued the 
study or completed the end of C7D1 assessments. 
Continuous variables will be summarized by the number of observations, mean, standard 
deviation, median, 25th and 75th percentile, and minimum and maximum values. 
Categorical variables will be summarized using frequency counts and percentages. 
Assessments of change from baseline to posttreatment or the ratio of posttreatment to 
baseline will include only those patients with both baseline and posttreatment 
measurements. The last nonmissing value of a variable taken before the first dose of 
study drug will be used as the baseline value, unless otherwise specified. In general, 
missing or dropout data will not be imputed for the purpose of data analysis, unless 
otherwise specified. 
When the number of patients with a particular tumor is at least 4, the baseline efficacy 
and safety parameters will be summarized and calculated for that tumor in addition to the 
overall result. 
11.2. 
Analysis Sets 
11.2.1. 
Enrolled Analysis Set 
The Enrolled Analysis Set will include all patients who sign the ICF and are enrolled in 
the study. 
11.2.2. 
Full Analysis Set/Safety Analysis Set 
The Full Analysis Set (FAS)/Safety Analysis Set will include all patients who received at 
least 1 dose of pexidartinib. 
11.2.3. 
Per-Protocol Analysis Set 
Not applicable.  
11.2.4. 
Pharmacokinetic Analysis Set 
The PK Analysis Set will include all patients in the Enrolled Analysis Set who received at 
least 1 dose of study drug (pexidartinib, midazolam, or S-warfarin) and had measurable 
plasma concentrations of pexidartinib or midazolam and S-warfarin.  


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11.3. 
Procedures for Handling Missing, Unused, and Spurious Data 
For the primary efficacy analysis as well as for all analyses of responder proportion 
endpoints performed on the FAS, patients who do not provide data for the responder 
endpoint will be considered nonresponders, ie, assigned to the less favorable outcome for 
the endpoint. 
11.4. 
Study Population Data 
Patient disposition will be summarized for patients in the Enrolled Analysis Set. The total 
number of patients for each defined analysis population will also be tabulated. The 
demographic and baseline characteristics will be summarized descriptively for the 
FAS/Safety Analysis Sets. Study drug exposure and study duration will be summarized 
using descriptive statistics for the Safety Analysis Set. 
Continuous demographic variables (age [calculated from the date of birth to the date 
when the ICF was signed], weight, height, and body mass index) for all patients will be 
summarized with descriptive statistics. Categorical demographic variables (sex, race, and 
ethnicity) will be summarized with frequency counts and corresponding percentages. 
Medical/Surgical history data, physical examination data, and prior/concomitant 
medications will be listed. 
11.5. 
Statistical Analysis 
11.5.1. 
Pharmacokinetics and Exposure-Response Analyses 
11.5.1.1. Noncompartmental Pharmacokinetic Analysis 
The PK analyses will be performed on the PK Analysis Set. Plasma-concentration time 
data for S-warfarin, midazolam, 5-hydroxy midazolam, pexidartinib, and ZAAD-1006a 
will be summarized by visit and time using descriptive statistics and graphically. 
An analysis of variance (ANOVA) model with treatment as fixed effects, and patient as 
random effect will be used to compare natural-log transformed PK parameters (Cmax and 
AUClast) of the substrates with and without the co-administration of pexidartinib. The 
combination treatments (pexidartinib + substrate) will be the test and substrate alone will 
be the reference for the comparison in regards to each substrate. Geometric mean ratios 
and their corresponding 90% confidence intervals (CI) between the treatments will be 
calculated by anti-log transformation. Time to reach maximum plasma concentration will 
be analyzed using a nonparametric method. The point estimate of the treatment difference 
and the corresponding 95% confidence intervals will be calculated and anti-logged to 
obtain the point estimate and 95% CI on the linear scale for the ratio of geometric means 
of the test as compared with the reference. 
No DDI will be concluded if the 90% CI of the ratio of the test to the reference 
completely remains within 80-125%. 


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11.5.2. 
Efficacy Analyses 
11.5.2.1. Primary Efficacy Analysis 
The primary efficacy endpoint is the proportion of patients who achieve a CR or PR 
based on local tumor assessments (see Section 8). The primary analysis will be completed 
using the FAS. The estimate of the proportion and two sided 95% CI based on Clopper 
Pearson method will be provided. The ORRs will also be calculated. 
11.5.2.2. Secondary Efficacy Analyses 
The efficacy endpoints to be calculated and summarized include: 
 Duration of response 
 Time to progression (for TGCT and other non-malignant tumors) 
 Progression-free survival (for malignant tumors) 
Duration of response will be analyzed as a secondary endpoint and will be summarized 
for responders based on RECIST 1.1. Duration of response is defined from the date of the 
first recorded response to the first date of documented disease progression. For patients 
who do not have radiological progression, the duration will be censored at the date of the 
last tumor assessment. The Kaplan-Meier product limit method will be used to compute 
the estimate and 95% CI of the median and 25th and 75th percentiles. The number of 
responders, the number with subsequent disease progression, and the number with 
censored values will be displayed as well. Within the framework of Kaplan-Meier 
methodology, the estimates for proportions of responders with response durations longer 
than 3, 6, 12, 18, and 24 mo will also be provided. 
11.5.3. 
Pharmacodynamic Analyses 
Optional blood samples collected at the discretion of the Investigator/patient at specified 
time points may be analyzed for PDy biomarkers. No formal statistical analysis of PDy 
endpoints will be performed. Pharmacodynamic data from each assay will be listed. 
Biomarker data will be summarized by visit using descriptive statistics. 
11.5.4. 
Safety Analyses 
The analyses of safety will be performed on the Safety Analysis Set. The summary and 
display of TEAEs will be performed. 
Terminology of the Medical Dictionary for Regulatory Activities (MedDRA) will be used 
to assign system organ class (SOC) and preferred term (PT) classification to AEs and 
diseases, based on the original terms entered in the eCRF. 
The incidence of TEAEs will be summarized by SOC, PT, relationship to the study drug, 
and severity for each treatment group. A by-patient listing will be provided for those 
patients who experience an SAE, including death, or experience an AE associated with 
early withdrawal from the study or study drug. 


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11.5.4.1. Adverse Event Analyses 
Treatment-emergent adverse events are AEs that occur, having been absent before the 
first dose of study drug, or worsen in severity after initiating the study drug. 
Treatment-emergent adverse events will be coded using MedDRA and assigned grades 
based on version 4.0 of the NCI-CTCAE. The number and percentage of patients 
reporting TEAEs will be tabulated by the worst CTCAE grade, SOC, and PT. Similarly, 
the number and percentage of patients reporting treatment-emergent SAEs will be 
tabulated, as well as TEAEs leading to discontinuation of study drug. 
A by-patient AE (including treatment-emergent) data listing including but not limited to 
verbatim term, SOC, PT, CTCAE grade, and relationship to study drug will be provided. 
Deaths, other SAEs, and other significant AEs, including those leading to discontinuation 
of study drug, will be listed. 
11.5.4.2. Clinical Laboratory Evaluation Analyses 
Descriptive statistics will be provided for the clinical laboratory results by scheduled time 
of evaluation for the Safety Analysis Set, as well as for the change from baseline. In 
addition, mean change from baseline will be summarized for the maximum and minimum 
posttreatment values and the values at the end of treatment visit. 
Abnormal clinical laboratory results will be graded according to NCI-CTCAE 
version 4.0, if applicable, and the grade will be presented in a by-patient data listing. A 
shift table, presenting the 2-way frequency tabulation for baseline and the worst 
posttreatment value according to the NCI-CTCAE grade, will be provided for clinical 
laboratory tests. 
Abnormal clinical laboratory test results deemed of clinical significance or of Grade 3 or 
4 will be listed.  
11.5.4.3. Vital Sign Analyses 
Descriptive statistics will be provided for the vital signs measurements by scheduled time 
of evaluation for the Safety Analysis Set, as well as for the change from baseline. In 
addition, mean change from baseline will be presented by treatment group for the 
maximum and minimum posttreatment values and the values at the end of treatment visit. 
11.5.4.4. Electrocardiogram Analyses 
Descriptive statistics will be provided for the ECG measurements by scheduled time of 
evaluation for the Safety Analysis Set, as well as for the change from baseline. In 
addition, the number and percentage of patients with ECG interval values meeting the 
criteria will be tabulated (eg, QTcF ≤ 450 ms, > 450 to ≤ 480 ms, > 480 ms to ≤ 500 ms, 
and > 500 ms) and QTcF maximum changes from baseline (> 30 and > 60 ms) over all 
posttreatment evaluations will be summarized. Electrocardiogram data will also be 
presented in the data listings. 
11.5.4.5. Physical Examination Analyses 
Physical examination data will be listed. 


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11.5.4.6. Concomitant Medication Analyses 
Concomitant medications will be coded using the World Health Organization drug 
dictionary (most recent version). Number and percentage of patients taking concomitant 
medications will be summarized for the Safety Analysis Set. 
11.5.4.7. Other Analysis 
Results for pharmacogenomics, pharmacodynamics, and biomarker analyses will be 
listed.  
11.6. 
Interim Analysis  
Preliminary PK analysis will be done with approximately 12 patients and if deemed 
adequate will proceed with a data snapshot and formal analysis.  
11.7. 
Sample Size Determination 
Approximately 30 patients are planned to be enrolled to achieve 24 patients evaluable for 
DDI. The sample size is not based on statistical hypothesis testing, but a sample size of 
24 patients will provide a certain magnitude of precision for DDI evaluation.  
 Assuming an intrapatient coefficient of variation for AUC of 22% for 
S-warfarin (estimated from ARQ 197-A-U158), and assuming pexidartinib 
had no or only minor effect (ratio <1.05) on S-warfarin PK, a sample size of 
24 patients was required to provide at least 80% power to conclude the 
absence of effect of pexidartinib on AUClast of S-warfarin, using the criteria 
of 90% CI within 80% to 125% no effect boundaries. 
 Assuming an intrapatient coefficient of variation for AUC of 42% for 
midazolam (estimated from ARQ 197-A-U158), Table 11.1 shows expected 
95% confidence intervals of AUC ratio will be available for DDI evaluation 
with a sample size of 24 patients under an intrapatient coefficient of variation 
of 40% and 50%. 
 
 


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Table 11.1: 
95% Confidence Intervals by Ratio and Intra-Patient Coefficient of 
Variation of Area Under the Plasma Concentration-Time Curve 
(N=24) 
Ratio of AUC 
Intra-patient coefficient of variation 
40% 
50% 
Lower bound 
Upper bound 
Lower bound 
Upper bound 
1.0 
0.79 
1.27 
0.74 
1.35 
1.2 
0.95 
1.52 
0.89 
1.62 
1.4 
1.10 
1.78 
1.04 
1.89 
1.6 
1.26 
2.03 
1.19 
2.16 
1.8 
1.42 
2.29 
1.34 
2.43 
2.0 
1.58 
2.54 
1.48 
2.70 
AUC = area under the plasma concentration-time curve. 
11.8. 
Statistical Analysis Process 
The clinical study will be analyzed by Daiichi Sankyo Inc. or its agent/CRO following 
this protocol and Statistical Analysis Plan (SAP), which will demonstrate all 
methodologies and displays/shells for statistical analyses. 
The SAP will provide the statistical methods and definitions for the analysis of the 
efficacy and safety data, as well as describe the approaches to be taken for summarizing 
other clinical study information such as patient disposition, demographic and baseline 
characteristics, study drug exposure, and prior and concomitant medications. The SAP 
will also include a description of how missing, unused, and spurious data will be 
addressed. 
To preserve the integrity of the statistical analysis and clinical study conclusions, the SAP 
will be finalized prior to database lock. 
All statistical analyses will be performed using SAS® Version 9.2 or higher (SAS 
Institute, Cary, NC 27513). 


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12. 
DATA INTEGRITY AND QUALITY ASSURANCE 
The Investigator/investigational study site will permit study-related monitoring, audits, 
IRB review, and regulatory inspections by providing direct access to the source 
data/documents. Direct access includes permission to examine, analyze, verify, and 
reproduce any records and reports that are important to the evaluation of a clinical study. 
12.1. 
Monitoring and Inspections 
Daiichi Sankyo Inc./CRO monitor and regulatory authority inspectors are responsible for 
contacting and visiting the Investigator for the purpose of inspecting the facilities and, 
upon request, inspecting the various records of the study (eg, eCRFs, source data, and 
other pertinent documents). 
The verification of adherence to the protocol; completeness, accuracy, and consistency of 
the data; and adherence to ICH GCP and local regulations on the conduct of clinical 
research will be accomplished through a combination of onsite visits by the monitor and 
review of study data remotely. The frequency of monitoring visits 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 patient’s medical records and other study-related records needed to verify the entries 
on the eCRFs. Detailed information is provided in the monitoring plan. 
The monitor will communicate to the Investigator any deviations from the protocol, 
Standard Operating Procedures, GCP, and applicable regulations and will ensure that 
appropriate action(s) designed to prevent recurrence of the detected deviations is taken 
and documented. The site will keep a running log of all protocol deviations. 
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 
Daiichi Sankyo Inc. and documented. 
In accordance with ICH GCP and the Daiichi Sankyo Inc. audit plans, this study may be 
selected for audit by representatives from Daiichi Sankyo Inc. Audit of study site 
facilities (eg, pharmacy, drug storage areas, laboratories) and review of study-related 
records will occur in order to evaluate the study conduct and compliance with the 
protocol, ICH GCP, and applicable regulatory requirements. The Investigator should 
respond to audit findings. In the event that a regulatory authority informs the Investigator 
that it intends to conduct an inspection, Daiichi Sankyo Inc. shall be notified 
immediately. 
12.2. 
Data Collection 
Daiichi Sankyo Inc. or its designee will provide the study sites with secure access to and 
training on the Electronic Data Capture (EDC) application, sufficient to permit site 
personnel to enter or correct information in the eCRFs for the patients for which they are 
responsible. 


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eCRFs will be completed for each study patient. It is the Investigator’s responsibility to 
ensure the accuracy, completeness, clarity, and timeliness of the data reported in the 
patient’s eCRF. 
The Investigator, or designated representative, should complete the eCRF as specified in 
the eCRF Completion Guidelines. 
The audit trail entry will show the user’s identification information, and the date and time 
of the correction. The Investigator must provide through the EDC application formal 
approval of all the information in the eCRFs and changes to the eCRFs to endorse the 
final submitted data for the patient for which he or she is responsible. 
Daiichi Sankyo Inc. or a designee will retain the eCRF data and corresponding audit 
trails. A copy of the final archival eCRF in the form of a compact disk or other electronic 
media will be placed in the Trial Master file. 
12.3. 
Data Management 
Each patient will be identified in the database by a unique patient identifier as defined by 
Daiichi Sankyo Inc. 
To ensure the quality of clinical data across all patients and sites, a clinical data 
management review will be performed on patient data according to specifications given 
by Daiichi Sankyo Inc. or designee. Data will be vetted both electronically and manually 
for eCRFs, and the data will be electronically vetted by programmed data rules within the 
application. Queries generated by rules and raised by reviewers will be generated within 
the EDC application. During this review, patient data will be checked for consistency, 
omissions, and any apparent discrepancies. 
Data received from external sources such as central laboratories will be reconciled to the 
clinical database. 
Serious adverse events in the clinical database will be reconciled with the safety database. 
All AEs will be coded using MedDRA. 
12.4. 
Study Documentation and Storage 
Source documents are original documents, data, and records from which the patient’s 
eCRF data are obtained. These include, but are not limited to, hospital records, clinical 
and office charts, laboratory and pharmacy records, diaries, microfiches, X rays, and 
correspondence. eCRF entries may be considered source data if the eCRF is the site of 
the original recording (ie, there is no other written or electronic record of data). 
Records of patients’ source documents, monitoring visit logs, data correction forms, 
eCRFs, inventory of study drug, regulatory documents (eg, protocol and amendments, 
IRB correspondence and approvals, approved and signed ICFs, Investigator’s Agreement, 
clinical supplies receipts, distribution and return records), and other Daiichi Sankyo Inc. 
correspondence pertaining to the study must be kept in appropriate study files at the study 
site (Trial Master File). Source documents include all recordings and observations or 
notations of clinical activities and all reports and records necessary for the evaluation and 
reconstruction of the clinical study. These records will be retained in a secure file for the 


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period required by the institution or study site policy. Prior to transfer or destruction of 
these records, Daiichi Sankyo Inc. must be notified in writing and be given the 
opportunity to further store such records. 
12.5. 
Record Keeping 
The Investigator and study site staff are responsible for maintaining a comprehensive and 
centralized filing system (Trial Master File) of all study-related (essential) 
documentation, suitable for inspection at any time by representatives from the Sponsor 
and/or applicable regulatory authorities. The Trial Master File includes: 
 Patient files containing completed eCRFs, ICFs, and supporting copies of 
source documentation (if kept) 
 Study files containing the protocol with all amendments, IB, copies of relevant 
essential documents required prior to commencing a clinical study, and all 
correspondence to and from the IRB/IEC and the Sponsor 
 Records related to the study drug(s), including acknowledgment of receipt at 
site, accountability records, final reconciliation, and applicable 
correspondence 
In addition, all original source documents supporting entries in the eCRFs must be 
maintained and be readily available. 
Patient's medical files should be retained in accordance with applicable legislation and in 
accordance with the maximum period of time permitted by the hospital, institution, or 
private practice. 
No study document should be destroyed without prior written agreement between Daiichi 
Sankyo Inc. 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 Daiichi Sankyo Inc. 
in writing of the new responsible person and/or the new location. 
 


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13. 
FINANCING AND INSURANCE 
13.1. 
Finances 
Prior to starting the study, the principal Investigator and/or institution will sign a clinical 
study agreement with Daiichi Sankyo Inc./CRO. This agreement will include the 
financial information agreed upon by the parties. 
13.2. 
Reimbursement, Indemnity, and Insurance 
Daiichi Sankyo Inc. provides insurance for study patients 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. 
 


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14. 
PUBLICATION POLICY 
A study site may not publish results of a study until after a coordinated multicenter 
publication has been submitted for publication or until 1 y after the study has ended, 
whichever occurs first. Therefore, the study site will have the opportunity to publish the 
results of the study, provided that Daiichi Sankyo Inc. has had the opportunity to review 
and comment on the study site’s proposed publication prior to it being submitted for 
publication with the prior advice of Legal Affairs (intellectual property council) and with 
proper regard to the protection of patients’ identities. 


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15. 
ETHICS AND STUDY ADMINISTRATIVE INFORMATION 
15.1. 
Compliance Statement, Ethics and Regulatory Compliance 
This study will be conducted in accordance with ethical principles founded in the 
Declaration of Helsinki and in compliance with the protocol, GCP, and applicable 
regulatory requirements (including ICH guidelines and applicable local regulatory 
requirements). The IRB/IEC will review all appropriate study documentation in order to 
safeguard the rights, safety, and well-being of the patients. The study will only be 
conducted at sites where IRB/IEC approval has been obtained. The protocol, IB, ICF, 
advertisements (if applicable), written information given to the patients (including diary 
cards and PRO instruments), safety updates, annual progress reports, and any revisions to 
these documents will be provided to the IRB/IEC by the Investigator or Daiichi Sankyo 
Inc., as allowable by local regulations. 
15.2. 
Patient Confidentiality 
The Investigators and Daiichi Sankyo Inc. will preserve the confidentiality of all patients 
taking part in the study, in accordance with GCP and local regulations. 
The Investigator must ensure that the patient’s anonymity is maintained on the eCRFs or 
other documents submitted to Daiichi Sankyo Inc. or the CRO; patients should be 
identified by a unique patient identifier as designated by Daiichi Sankyo Inc. Documents 
that are not for submission to Daiichi Sankyo Inc. or the CRO (eg, signed ICF) should be 
kept in strict confidence by the Investigator. 
In compliance with ICH GCP Guidelines, it is required that the Investigator and 
institution permit authorized representatives of the company, the regulatory agency(s), 
and the IRB/IEC direct access to review the patient’s original medical records for 
verification of study-related procedures and data. The Investigator is obligated to inform 
the patient that his/her study-related records will be reviewed by the above named 
representatives without violating the confidentiality of the patient. 
15.3. 
Informed Consent 
Before a patient’s participation in the study, it is the Investigator’s responsibility to obtain 
freely given consent, in writing, from the patient 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. Patients should be 
given the opportunity to ask questions and receive satisfactory answers 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 patient 
population. 
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 IRB/IEC prior to being provided to potential 
patients. 


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The patient’s written informed consent should be documented in the patient’s medical 
records. The ICF should be signed and personally dated by the patient 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 consent form should be provided to the patient. The date and time (if 
applicable) that informed consent was given should be recorded on the eCRF. 
If the patient 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 patient has consented to the patient’s participation 
and, if possible, signed the ICF. By signing the ICF, the witness attests that the 
information in the ICF and any other written information was adequately explained to and 
apparently understood by the patient and that informed consent was freely given by the 
patient. 
Suggested model text for the ICF for the study and any applicable subparts (genomic, PK, 
etc.) are provided in the Daiichi Sankyo Inc.’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. 
15.4. 
Regulatory Compliance 
The study protocol, patient ICF, IB, any written instructions to be given to the patient, 
available safety information, patient recruitment procedures (eg, advertisements), 
information about payments and compensation available to the patients, and 
documentation evidencing the Investigator’s qualifications should be submitted to the 
IRB 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. 
The Investigator and/or Daiichi Sankyo Inc. must submit and, where necessary, obtain 
approval from the IRB for all subsequent protocol amendments and changes to the ICF. 
The Investigator should notify the IRB of deviations from the protocol or SAEs occurring 
at the study site and other AE reports received from Daiichi Sankyo Inc. or CRO, in 
accordance with local procedures. 
As required by local regulations, the Daiichi Sankyo Inc. local regulatory affairs group or 
representative to whom this responsibility has been delegated will ensure all legal aspects 
are covered, and approval from the appropriate regulatory bodies obtained, prior to study 
initiation, and that implementation of changes to the initial protocol and other relevant 
study documents happens only after the approval by the relevant regulatory bodies. 
In the event of any prohibition or restriction imposed (eg, clinical hold) by applicable 
regulatory authorities in any area of the world, or if the Investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the study drug, 
Daiichi Sankyo Inc. should be informed immediately. 


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In addition, the Investigator will inform Daiichi Sankyo Inc. immediately of any urgent 
safety measures taken by the Investigator to protect the study patients against any 
immediate hazard, and of any suspected/actual serious GCP noncompliance that the 
Investigator becomes aware of. 
15.5. 
Protocol Deviations 
The Investigator should conduct the study in compliance with the protocol agreed to by 
Daiichi Sankyo Inc. and, if required, by the regulatory authority(ies), and that was given 
approval/favorable opinion by the IRB/IEC. 
A deviation to any protocol procedure, or a waiver to any stated criteria will not be 
allowed in this study except where necessary to eliminate immediate hazard(s) to the 
patient. Daiichi Sankyo Inc. must be notified of all intended or unintended deviations to 
the protocol (eg, inclusion/exclusion criteria, dosing, missed study visits) on an expedited 
basis. 
The Investigator, or person designated by the Investigator, should document and explain 
any deviation from the approved protocol. 
If a patient was ineligible or received the incorrect dose or investigational treatment and 
had at least one administration of the study drug, data should be collected for safety 
purposes, and the Daiichi Sankyo Inc.’s Medical Monitor or designee should be informed 
immediately. 
The Investigator should notify the IRB/IEC of deviations from the protocol in accordance 
with local procedures. 
15.6. 
Supply of New Information Affecting the Conduct of the Study 
When new information becomes available that may adversely affect the safety of patients 
or the conduct of the study, the Sponsor will inform all Investigators involved in the 
clinical study, IRBs/ECs, and regulatory authorities of such information, and when 
needed, will amend the protocol and/or patient information. 
The Investigator should immediately inform the patient whenever new information 
becomes available that may be relevant to the patient’s consent or may influence the 
patient’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 
patient is willing to remain in the study.  
If the patient information is revised, it must be re-approved by the IRB/IEC. The 
Investigator should obtain written informed consent to continue participation with the 
revised written information even if patients were already informed of the relevant 
information. The Investigator or other responsible personnel who provided the 
explanations and the patient should sign and date the revised ICF. 


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15.7. 
Protocol Amendments 
Any amendments to the study protocol that seem to be appropriate as the study 
progresses will be communicated to the Investigator by Daiichi Sankyo Inc. or the CRO. 
Also, Daiichi Sankyo Inc. will ensure the timely submission of amendments to regulatory 
authorities. 
A global protocol amendment will affect study conduct at all study sites in all regions of 
the world. Such amendments will be incorporated into a revised protocol document. 
Changes made by such amendments will be documented in a summary of changes 
document. These protocol amendments will undergo the same review and approval 
process as the original protocol. 
A local protocol amendment will affect study conduct at a particular study site(s) and/or 
in a particular region/country. Daiichi Sankyo Inc. approval of local amendments will be 
clearly documented. 
A protocol amendment may be implemented after it has been approved by the IRB/IEC 
and by regulatory authorities where appropriate, unless immediate implementation of the 
change is necessary for patient safety. 
15.8. 
Study Termination 
The study may be terminated at any time by the IRB, Daiichi Sankyo Inc., or regulatory 
agencies as part of their duty is to ensure that the research patients are protected. 
Daiichi Sankyo Inc. reserves the right to temporarily suspend or prematurely discontinue 
this study either at a single study site or at all study sites at any time for reasons 
including, but not limited to, safety or ethical issues or severe noncompliance. If Daiichi 
Sankyo Inc. determines such action is needed, then Daiichi Sankyo Inc. will discuss this 
with the Investigator (including the reasons for taking such action) at that time. When 
feasible, Daiichi Sankyo Inc. will provide prior notification to the Investigator of the 
impending action prior to its taking effect. 
Daiichi Sankyo Inc. will promptly inform all other Investigators and/or study sites 
conducting the study if the study is suspended or terminated for safety reasons, and will 
also inform the regulatory authorities of the suspension or termination of the study and 
the reasons for the action. If required by applicable regulations, the Investigator must 
inform the IRB promptly and provide the reasons for the suspension or termination. 
If the study is prematurely discontinued, all study data must be returned to Daiichi 
Sankyo Inc. In addition, arrangements will be made for return of all unused study drugs 
in accordance with Daiichi Sankyo Inc.’s applicable procedures for the study. 
Financial compensation to the Investigators and/or institutions will be in accordance with 
the agreement established between the Investigator and Daiichi Sankyo Inc. 
15.9. 
Data and Safety Monitoring Board 
Not applicable.  








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16. 
REFERENCES 
1. PLX3397 Investigator’s Brochure, v.7.1. Berkeley, CA: Plexxikon Inc. Mar 2016. 
2. Dumond JB, Vourvahis M, Rezk NL, Patterson KB, Tien HC, White N, et al. A 
phenotype-genotype approach to predicting CYP450 and P-glycoprotein drug 
interactions with the mixed inhibitor/inducer tipranavir/ritonavir. Clin Pharmacol 
Ther 2010;87(6):735-42. 
3. Myers BW, Masi AT. Pigmented villonodular synovitis and tenosynovitis: a 
clinical epidemiologic study of 166 cases and literature review. Medicine. 
1980;(59):223-38. 
4. Flockhart, DA. Drug interactions: Cytochrome P450 drug interaction table. 
Indiana University School of Medicine [2009]. Available from: 
http://medicine.iupui.edu/clinpharm/ddis/main-table/. Accessed October 22, 2014. 
 
 


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17. 
APPENDICES 
17.1. 
List of Common CYP3A4 Inhibitors and Inducers 
Strong Inhibitors 
Strong Inducers 
Protease inhibitors 
Anticonvulsants, mood stabilizers 
 
• Ritonavir 
 
• Phenytoin 
 
• Indinavir 
 
• Carbamazepine 
 
• Nelfinavir 
 
• Oxcarbazepine 
Macrolide antibiotics 
Non-nucleoside reverse transcriptase 
inhibitors 
 
• Erythromycin  
 
• Efavirenz 
 
• Telithromycin 
 
• Nevirapine 
 
• Clarithromycin 
 
• Etravirine  
Azole antifungals 
Phenobarbital (barbiturate) 
 
• Fluconazole  
Rifampicin (bactericidal) 
 
• Ketoconazole 
Modafinil (stimulant) 
 
• Itraconazole 
Hyperforin (constituent of St. John’s Wort) 
Chloramphenicol (antibiotic)  
Cyproterone (antiandrogen, progestin) 
Nefazodone (antidepressant) 
 
Bergamottin (constituent of grapefruit 
juice)  
 
Aprepitant (antiemetic)  
 
Verapamil (calcium channel blocker)  
 
Source: Flockhart, DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School 
of Medicine [2009]. Available from: http://medicine.iupui.edu/clinpharm/ddis/main-table/. Accessed October 22, 
2014. 
 
 


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17.2. 
Schedule of Events 
17.2.1. 
Schedule of Assessments – Part 1 
Events 
Screening 
 
 
Part 1 DDI Phase 
Study Daya  
≤ 21b  
1 
2 
3 
4 
5 
6 
7 
8 
9 
15 
16 
17 
18 
Pexidartinib Cycle/Day 
 
n/a 
n/a 
n/a 
n/a 
C1D1c  
C1D2 
C1D3 
C1D4 
C1D5 
C1D11 
C1D12 
C1D13 
C1D14 
Visit Window 
 
 
 
 
 
+2d 
 
 
 
+1d 
d  
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant Medication 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic Information 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Surgical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH Levele  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV/Hepatitis B, HCV 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
X 
 
 
 
X 
 
 
 
 
X 
 
 
Xf  
Drug/Alcohol Screening 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
Tumor Assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation Test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Chemistry, Hematology, and 
Coagulation 
X 
Xg  
 
 
 
Xg  
 
 
 
Xh  
Xh 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsi   
X 
Xk  
 
 
 
Xk 
 
 
 
 
Xk 
 
 
 
12-lead ECGj  
X 
Xm  
 
 
 
Xm 
 
 
 
 
Xm  
 
 
 
Pregnancy Testl 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Midazolam and S-warfarin Administration 
 
X 
 
 
 
Xo  
 
 
 
 
Xo  
 
 
 
PK Sampling for Midazolam 
 
Xn  
Xq  
Xr  
 
Xn  
Xq  
Xr 
 
 
Xn  
Xq  
Xr  
 
PK Sampling for S-warfarin 
 
Xn 
Xq 
Xr 
Xs  
Xn 
Xq 
Xr 
Xs  
Xt  
Xn 
Xq  
Xr  
Xs  
Pexidartinib Administration at Clincu  
 
 
 
 
 
Xo  
X 
X 
X 
X 
Xo  
X 
X 
X 
Pexidartinib Dosingv  
 
 
 
 
 
BID continuously 
PK Sampling for Pexidartinib 
 
 
 
 
 
Xp   
 
 
 
 
Xp  
 
 
 
Pexidartinib Dipsensationw  
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pexidartinib Treatment Compliance 
 
 
 
 
 
 
Xx  
X 
Optional Tumor Biopsy or Blood Sample 
for Pdy or Circulating Tumor DNA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacogenomic Sampling 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Record of Concomitant Medication 
X 
AE Reporting 
X 
AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BID = twice daily; C#D# = cycle number, day number; DDI = drug-drug interaction; ECG = electrocardiogram; 
GGT = gamma-glutamyl transferase; HCV = Hepatitis C virus; HIV = human immunodeficiency virus; n/a = not applicable; PK = pharmacokinetic; TGCT = tenosynovial giant cell tumor.  
a. 
Patients must arrive to the clinical site fasted (approximately 10 h) on Days 1, 5, and 15. 
b. 
Screening will take place between Day -21 and Day -1. Patients may be rescreened.  
c. 
Cycle and day of pexidartinib, where C1D1 is the first day of pexidartinib treatment in Part 1 and C1D9 is the 9th day of pexidartinib treatment. Pexidartinib treatment continues seamlessly from 
Part 1 into Part 2, where the first approximately 2 wk of treatment are given in Part 1. For the Day 5 visit, patients may delay visit up to 2 days, in which case the 96h samples should be collected 
on Day 5 or up to 1 d later.  


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d. 
May be delayed up to 1 d for patients with TGCT or up to 4 d for patients with malignant disease, if needed. This visit cannot be delayed by more than 1 d for patients with TGCT or other 
non-malignant tumor because they require a pexidartinib dose reduction to 800 mg/d after 14 d of treatment that cannot be completed before the last PK sample is taken. If the Part 1 Day 15 visit is 
delayed, pexidartinib BID administration and weekly safety assessments must continue (±1 d) despite the delay. The cycle day count begins from the first dose of pexidartinib (C1D1) and 
continues regardless of any delay.  
e. 
For postmenopausal women only.  
f. 
Or upon early withdrawal. The assessments can be done after the last PK draw on the final day of Part 1 DDI Phase.  
g. 
Predose.  
h. 
Predose. Alkaline phosphatase, ALT, AST, total and direct bilirubin, and GGT must be evaluated for the possible need to modify pexidartinib treatment before the patient leaves the clinic 
i. 
Measured after patient has rested in the recumbent position at least 5 min.  
j. 
Measured after patient has rested in the supine position at least 5 min.  
k. 
Predose and 2 and 4 h postdose.  
l. 
Women of childbearing potential only. Women who have been amenorrheic for ≥ 12 mo due to medical reasons other than sterilization will be regarded as women of childbearing potential. 
m. 
Predose. 
n. 
Predose and 0.5, 1, 2, 3, 4, 6, 8, and 10 h postdose (10 min up to 1 h, 10% thereafter). 
o. 
Coadminister midazolam, S-warfarin (with Vitamin K), and pexidartinib. 
p. 
Collect sample for pexidartinib and ZAAD-1006a predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 10 (1) h postdose. 
q. 
24 (10%) h postdose. 
r. 
48 (10%) h postdose. 
s. 
72 (2) h postdose.  
t. 
96 (2) h postdose.  
u. 
Patients must be administered the morning dose of pexidartinib at the clinic on Days 5 and 15, and the evening dose may be administered optionally at the clinic on these days. On other days with a 
clinic visit, the morning dose is preferably administered in the clinic, in which case patients will be instructed not to take pexidartinib in the morning at home on these days. Otherwise, pexidartinib 
is taken outside the clinic. 
v. 
Pexidartinib will be taken BID from Day 5 onwards. Patients will be instructed to take 2 capsules (400 mg/d) in the morning and 3 capsules (600 mg/d) in the evening (total 1000 mg/d). Patients 
are to be fasted 1 h before dosing and continue fasting 2 h after dosing. The dose of pexidartinib will decrease to 800 mg/d (400 mg BID) after 14 d of treatment for patients with TGCT or other 
non-malignant tumor. Patients will be instructed to not take study drug at home on days when pexidartinib will be administered at the clinical site. Pexidartinib may need to be interrupted or the 
dose reduced or discontinued depending upon tolerance. 
w. 
Patients will be dispensed only enough pexidartinib to reach the next study visit. 
x. 
If applicable. 
 
 


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17.2.2. 
Schedule of Assessments – Part 2  
Events 
 
Part 2 Pexidartinib Extension Phase 
Post Tx 
Study Day 
19 
26 
33 
40 
47 
54 
61 
75 
89 
n/a 
n/a 
Pexidartinib Cycle/Day 
C1D15 
C1D22 
C2D1 
C2D8 
C2D15 
C2D22 
C3D1 
C3D15 
C4D1 
C5+D1a  
28 days 
Visit Window 
+1d 
±2d  
±2d 
±2d 
±2d 
±2d 
±2d 
±7d 
±7d 
±7d 
±7d 
Physical Examination 
 
 
X 
 
 
 
 
 
X 
Q2 cycles 
X 
Tumor Assessment 
 
 
 
 
 
 
X 
 
 
Q2 cyclesb  
 
Serum Chemistry/Hematologyc  
X 
X 
X 
X  
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
X 
Vital Signsd  
X 
 
X 
 
 
 
X 
 
X 
X 
X 
12-Lead Ecge  
X 
 
 
 
 
 
 
 
 
 
X 
Pregnancy Testf  
 
 
X 
 
 
 
X 
 
X 
X 
X 
PK Sampling for S-Warfarin 
Xg  
 
 
 
 
 
 
 
 
 
 
Pexidartinib Dosingh  
BID continuously 
 
Pexidartinib Dipsensationi  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pexidartinib Treatment Compliance 
X 
 
Optional Tumor Biopsy or Blood 
Sample for Pdy or Circulating 
Tumor DNA 
 
 
X 
 
 
 
 
 
X 
 
 
Record of Concomitant Medication 
X 
AE Reporting 
X 
AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BID = twice daily; C#D# = cycle number, day number; ECG = electrocardiogram; GGT = gamma-glutamyl 
transferase; n/a = not applicable; PDy = pharmacodynamics; PK = pharmacokinetic; Q = every; TGCT = tenosynovial giant cell tumor; Tx = treatment.  
a. 
The 28-d treatment cycles will continue until there is no longer any clinical benefit or until other reasons for discontinuation are met.  
b. 
May be reduced after Cycle 4 if clinically appropriate and agreed upon by the Sponsor’s Medical Monitor.  
c. 
Predose. Alkaline phosphatase, ALT, AST, total and direct bilirubin, and GGT must be evaluated for the possible need to modify pexidartinib treatment before the patient leaves the study center 
(except Post Tx visit). More frequent assessments may be required in the case of abnormalities as defined in the protocol.  
d. 
Measured after patient has rested in the recumbent position at least 5 min.  
e. 
Measured after the patient has rested in the supine position at least 5 min. 
f. 
Women of childbearing potential only. Women who have been amenorrheic for ≥ 12 mo due to medical reasons other than sterilization will be regarded as women of childbearing potential. 
g. 
96 (±2) h postdose.  
h. 
The dose of pexidartinib will decrease to 800 mg/d (400 mg BID) after 14 d of treatment for patients with TGCT or other non-malignant tumors. 
i. 
Pexidartinib will be taken BID. Patients will be instructed to take 2 capsules (4000 mg/d) in the morning and 3 capsules (6000 mg/d) in the evening (total 1000 mg/d). The dose of pexidartinib will 
be 800 mg/d (400 mg BID) for patients with TGCT or other non-malignant tumor. Pexidartinib may need to be interrupted or the dose reduced or discontinued depending upon tolerance.