Clinical trial NCT01004861
Conditions: Solid Tumor
Keywords: PVNS
Sponsor: Daiichi Sankyo
Start date: 2009-10-01; Completion date: 2018-10-25
Enrollment: 132 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
PLX3397 is a selective inhibitor of Fms, Kit, and oncogenic Flt3 activity. The primary objective of this study is to evaluate the safety and pharmacokinetics of orally administered PLX3397 in patients with advanced, incurable, solid tumors in which these target kinases are linked to disease pathophysiology. The secondary objective is to measure the pharmacodynamic activity of PLX3397 via blood, plasma and urine biomarkers of Fms activity.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: PLX3397
Intervention descriptions: intervention 1: Capsules administered once or twice daily, continuous dosing

Protocol documents:
Prot_SAP_001.pdf: 
Pexidartinib (PLX3397) 
 
Protocol PLX108-01 
 
 
Amendment 12 
 
CONFIDENTIAL 
1 
Plexxikon Inc. 
PROPRIETARY 
CLINICAL STUDY PROTOCOL 
 
Title  
A Phase 1 Study to Assess Safety, Pharmacokinetics, and 
Pharmacodynamics of PLX3397 in Patients with Advanced, Incurable, 
Solid Tumors in which the Target Kinases Are Linked to Disease 
Pathophysiology 
Protocol Number 
PLX108-01 
IND Number 
105,521 
Sponsor 
Plexxikon Inc. 
91 Bolivar Drive 
Berkeley, CA 94710, USA 
Medical Monitor 
 
Plexxikon Inc. 
91 Bolivar Drive 
Berkeley, CA 94710, USA 
Date/Version 
25 February 2020/Amendment 12 
 
 
 
 
Confidentiality Statement 
This document contains information that is confidential and proprietary to the Sponsor. This information is being 
provided to you solely for the purpose of evaluating and/or conducting a clinical study for the Sponsor. You may 
disclose the contents of this document only to study personnel under your supervision, institutional review boards 
(IRBs)/independent ethics committees (IECs), or duly authorized representatives of regulatory agencies for this 
purpose under the condition that they maintain confidentiality. The contents of this document may not be used in 
any other clinical study, disclosed to any other person or entity, and/or published without the prior written 
permission of the Sponsor. The foregoing shall not apply to disclosure required by any regulations; however, you 
will give prompt notice to the Sponsor of any such disclosure. All other nonpublic information provided by the 
Sponsor and any information that may be added to this document also is confidential and proprietary to the Sponsor 
and must be kept in confidence in the same manner as the contents of this document. 
PPD
PPD




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TABLE OF CONTENTS 
1.0 
SPONSOR SIGNATURE ..................................................................................................2 
2.0 
INVESTIGATOR SIGNATURE ......................................................................................2 
TABLE OF CONTENTS ..............................................................................................................3 
3.0 
CONTACTS .......................................................................................................................7 
3.1 
Emergency and Safety Contacts ..............................................................................7 
4.0 
LIST OF ABBREVIATIONS ...........................................................................................8 
5.0 
SYNOPSIS ........................................................................................................................11 
6.0 
INTRODUCTION............................................................................................................21 
6.1 
Background ............................................................................................................21 
6.2 
Pharmacodynamics ................................................................................................22 
6.2.1 
In Vitro Pharmacodynamics ..................................................................22 
6.2.2 
In Vivo Pharmacodynamics ..................................................................23 
6.3 
Nonclinical Metabolism and Pharmacokinetics .....................................................26 
6.4 
Summary of Nonclinical Toxicology and Safety Pharmacology ..........................27 
6.4.1 
Repeat-Dose Toxicity in Rats ...............................................................27 
6.4.2 
Repeat-Dose Toxicity in Dogs ..............................................................29 
6.4.3 
Genotoxicity ..........................................................................................31 
6.4.4 
Safety Pharmacology ............................................................................31 
7.0 
RATIONALE ...................................................................................................................32 
7.1 
Dose Escalation ......................................................................................................32 
7.2 
Route and Regimen ................................................................................................33 
7.3 
Treatment Period ....................................................................................................33 
8.0 
OBJECTIVES ..................................................................................................................33 
8.1 
Primary ...................................................................................................................33 
8.2 
Secondary ...............................................................................................................34 
9.0 
DESIGN ............................................................................................................................34 
9.1 
Description .............................................................................................................34 
9.2 
Number of Patients ................................................................................................35 
9.3 
Number of Study Centers.......................................................................................35 
9.4 
Duration of Patient Participation ...........................................................................35 
9.5 
Duration of Study ...................................................................................................35 
10.0 
SELECTION OF STUDY POPULATION ...................................................................35 
10.1 
Inclusion Criteria ...................................................................................................36 
10.2 
Exclusion Criteria ..................................................................................................37 


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10.3 
Screen Failures .......................................................................................................37 
11.0 
PRIOR TREATMENT ....................................................................................................37 
12.0 
CONCOMITANT TREATMENT .................................................................................37 
12.1 
CYP3A and UGT Inhibitors ..................................................................................38 
12.2 
Hormonal Contraceptives ......................................................................................38 
12.3 
Acid-reducing Agents ............................................................................................39 
13.0 
PROCEDURES (DOSE ESCALATION COHORTS) .................................................39 
13.1 
Screening Evaluation .............................................................................................39 
13.2 
Run-In Period (Selected Cohorts) – Cycle 1 Day(-7), Day(-6), and Day(-4) ........39 
13.3 
Pre-Treatment (Baseline):  Cycle 1 Day 1 .............................................................40 
13.4 
Post-Treatment:  Cycle 1 Day 1 and Cycle 1 and Day 2 .......................................40 
13.5 
Cycle 1 Day 8 ± 1 Day ...........................................................................................40 
13.6 
Cycle 1 Day 15 and Cycle 1 Day 16 (± 2 Days) ....................................................40 
13.7 
Cycle 2 Day 1 (± 7 Days) ......................................................................................41 
13.8 
Continued Dosing ..................................................................................................41 
13.9 
Dose Modification (Dose Escalation Cohorts) ......................................................41 
14.0 
PROCEDURES (EXTENSION COHORTS) ................................................................42 
14.1 
Screening Evaluation .............................................................................................42 
14.2 
Pre-Treatment (Baseline):  Cycle 1 Day 1 .............................................................43 
14.3 
Post-Treatment:  Cycle 1 Day 1 .............................................................................43 
14.4 
Cycle 1 Day 15 (± 2 days) .....................................................................................43 
14.5 
Cycle 2 Day 1 (± 7 days) .......................................................................................44 
14.6 
Continued Dosing ..................................................................................................44 
14.6.1 
Visits through Cycle 40 .........................................................................44 
14.6.2 
Visits after Cycle 40 ..............................................................................45 
14.7 
Dose Modification (Extension Cohorts) ................................................................45 
14.7.1 
Renal Impairment ..................................................................................47 
14.8 
End of Study/Early Withdrawal (last dose for subjects that enroll in phase 4 
continuation study or immediately transition to commercial pexidartinib; last 
+ 30 ± 7 days for all other subjects) .......................................................................48 
14.9 
Twelve-week Follow-up (last dose + 12 weeks [+4-week window]) ....................48 
15.0 
DISCONTINUATION OF TREATMENT AND WITHDRAWAL OF 
PATIENTS........................................................................................................................49 
16.0 
TEST ARTICLE ..............................................................................................................49 
16.1 
Test Article Administration ...................................................................................49 
16.2 
Packaging and Labeling .........................................................................................50 


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16.3 
Storage and Stability ..............................................................................................50 
16.4 
Dose Escalation ......................................................................................................51 
16.5 
Test Article Accountability, Reconciliation, and Return .......................................52 
16.6 
Test Article Compliance ........................................................................................52 
17.0 
MEASURES TO MINIMIZE/AVOID BIAS ................................................................52 
18.0 
SAFETY EVALUATION ................................................................................................52 
18.1 
Physical Examination.............................................................................................52 
18.2 
Vital Signs ..............................................................................................................53 
18.3 
Electrocardiograms ................................................................................................53 
18.4 
Safety Laboratory Determinations .........................................................................53 
19.0 
BIOMARKER SAMPLES ..............................................................................................53 
20.0 
PHARMACOKINETIC EVALUATION ......................................................................53 
20.1 
Blood Collection ....................................................................................................53 
20.2 
Bioanalytical Methodology ....................................................................................54 
21.0 
MEASUREMENT OF RESPONSE USING 18FDG PET SCANNING ......................54 
22.0 
TUMOR AND RELATED TISSUE COLLECTION ...................................................55 
23.0 
PATIENT REPORTED OUTCOME (PRO) QUESTIONNAIRES ...........................55 
23.1 
PRO Instruments ....................................................................................................56 
24.0 
STATISTICAL ANALYSIS ...........................................................................................56 
24.1 
Safety Analysis ......................................................................................................56 
24.2 
Efficacy Analysis ...................................................................................................58 
24.3 
Pharmacokinetic Analysis ......................................................................................59 
24.4 
Pharmacodynamic Analysis ...................................................................................59 
24.5 
Statistical Analyses ................................................................................................59 
24.6 
Sample Size and Power ..........................................................................................59 
25.0 
PRECAUTIONS ..............................................................................................................61 
26.0 
ADVERSE EVENTS .......................................................................................................61 
26.1 
Definitions..............................................................................................................61 
26.2 
Recording and Reporting .......................................................................................64 
26.3 
Serious Adverse Event Reporting ..........................................................................64 
27.0 
STUDY SUSPENSION, TERMINATION, AND COMPLETION .............................65 
28.0 
INFORMED CONSENT .................................................................................................65 
29.0 
PROTOCOL AMENDMENTS ......................................................................................66 
30.0 
QUALITY CONTROL AND ASSURANCE.................................................................66 
31.0 
DIRECT ACCESS, DATA HANDLING, AND RECORD KEEPING ......................66 


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31.1 
Investigator ............................................................................................................66 
31.2 
Sponsor ..................................................................................................................66 
32.0 
PRE-STUDY DOCUMENTATION ...............................................................................66 
33.0 
RECORDS RETENTION ...............................................................................................67 
34.0 
REFERENCES .................................................................................................................68 
ATTACHMENT 1:  LABORATORY TESTS ..........................................................................69 
ATTACHMENT 2:  COLLECTION, PREPARATION, AND LABELING OF 
PLASMA AND OTHER SAMPLES BEING COLLECTED ......................................71 
ATTACHMENT 3:  INSTRUCTIONS FOR SHIPPING FROZEN SAMPLES ..................72 
ATTACHMENT 4:  RECIST CRITERIA VERSION 1.1 .......................................................73 
ATTACHMENT 5:  CYP3A4 INHIBITORS AND INDUCERS ............................................85 
ATTACHMENT 6:  NUMERIC RATING SCALE (NRS) FOR PVNS SYMPTOMS ........86 
ATTACHMENT 7:  WESTERN ONTARIO AND MCMASTER UNIVERSITIES 
OSTEOARTHRITIS INDEX (WOMAC) QUESTIONNAIRE ..................................88 
 
LIST OF TABLES 
Table 1: 
IC50 Values of Pexidartinib Against Selected Kinases ..........................................22 
Table 2: 
Recommended Dosage Reductions for Pexidartinib with Concomitant Use of 
Moderate or Strong CYP3A Inhibitors or UGT Inhibitors ....................................38 
Table 3: 
Dose Modifications ................................................................................................46 
Table 4: 
Additional Liver Evaluation ..................................................................................47 
Table 5: 
Probabilities of Detecting DLTs (3 Patients) .........................................................60 
Table 6: 
Probabilities of Detecting DLTs (6 Patients) .........................................................60 
Table 7: 
Time Point Response:  Patients with Targets (+/- Non-Target) Disease ...............82 
Table 8: 
Time Point Response:  Patients with Non-Target Disease Only ...........................82 
Table 9: 
Best Overall Response When Confirmation of CR and PR Required ...................83 
 
LIST OF FIGURES 
Figure 1: 
Pexidartinib-Induced Reduction of Circulating Tumor Cells in PyMT Mouse 
Model of Breast Cancer .........................................................................................24 
Figure 2: 
Daily Oral Dosing of Pexidartinib Results in Dose-Dependent Tumor 
Suppression in MV4-11 Xenograft Model of Flt3-ITD Dependent Acute 
Myelogenous Leukemia .........................................................................................25 
 


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PROPRIETARY 
3.0 
CONTACTS 
3.1 
Emergency and Safety Contacts 
Medical Monitor: 
Name:  
 
Address:  91 Bolivar Drive 
Berkeley, CA 94710 
SAE/Safety Monitoring Contact: 
Plexxikon Safety Inbox 
PPD
PPD
PPD


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4.0 
LIST OF ABBREVIATIONS 
Abbreviation or Terma 
Definition/Explanation 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
APTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
ATC 
Anaplastic thyroid carcinoma 
AUC0-∞ 
Area under the concentration-time curve from time zero extrapolated to infinite time 
AUC0-t 
Area under the concentration-time curve from time zero to the time of the last 
quantifiable concentration 
AV 
Atrioventricular 
β-HCG 
Beta-human chorionic gonadotropin 
BAP 
Bone-specific alkaline phosphatase 
BID 
Twice daily 
BMI 
Body mass index 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
Ca++ 
Calcium 
CBC 
Complete blood count 
CEA 
Carcinoembryonic antigen 
CFR 
Code of Federal Regulations 
CHF 
Congestive heart failure 
CI 
Confidence interval 
Cl- 
Chloride 
CLcr 
Creatinine clearance 
CLT 
Total body clearance 
CL/F 
Apparent oral clearance 
Cmax 
Maximum observed concentration 
Cmin 
Trough observed concentration 
CNS 
Central nervous system 
CPE 
Clinical Planned Event 
CRF 
Case report form 
CRP 
C-reactive protein 
CTA 
Clinical Trial Agreement 
CTCs 
Circulating Tumor Cells 
CTCAE 
Common Toxicity Criteria for Adverse Events 
CTX 
C-telopeptide of type I collagen 
CTX-II 
C-telopeptide of type II collagen 
CV 
Coefficient of variation 
CYP 
Cytochrome P450 
DB 
Direct bilirubin 
D/C 
Discontinue 


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Abbreviation or Terma 
Definition/Explanation 
ECOG 
Eastern Cooperative Oncology Group 
ECG 
Electrocardiogram 
Eg 
Exempli gratia (for example) 
ESR 
Erythrocyte sedimentation rate 
F 
Bioavailability 
FACS 
Fluorescence Activated Cell Sorting  
FDA 
Food and Drug Administration 
GC 
Gas chromatography 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
GGT 
Gamma glutamyl transferase 
GIST 
Gastrointestinal stromal tumor 
GLP 
Good laboratory practice  
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCO3- 
Bicarbonate 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HNSTD 
Highest non-severely toxic dose 
HPF 
High-power field 
HPLC 
High-performance liquid chromatography 
HR 
Heart rate 
hr 
Hour or hours 
IB 
Investigator’s brochure 
Ie 
Id est (that is) 
IEC 
Independent ethics committee 
IL-1β 
Interleukin-1β 
IL-6 
Interleukin-6 
INR 
International normalized ratio 
IRB 
Institutional review board 
IU 
International unit 
IV 
Intravenous, intravenously 
LDH 
Lactate dehydrogenase 
LC 
Liquid chromatography 
MedRA 
Medical Dictionary for Drug Regulatory Activities 
MIC 
Minimum inhibitory concentration 
MMP-3 
Matrix metallopeptidase-3 
MRSD 
Maximum recommended starting dose 
MRT 
Mean residence time 
MS 
Mass spectrometry 
MTD 
Maximum tolerated dose  


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Abbreviation or Terma 
Definition/Explanation 
NOAEL 
No-observed-adverse-effect level 
NOEL 
No-observed-effect-level 
NTX 
N-telopeptide of type I collagen 
NRS 
Numeric Rating Scale 
P1NP 
Procollagen type I intact N-terminal propeptide 
PCI 
Potential clinical importance 
PD 
Pharmacodynamic(s) 
PK 
Pharmacokinetic(s) 
PO 
Per os (administered by mouth) 
PRO 
Patient reported outcome 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
PVNS 
Pigmented villonodular synovitis 
QC 
Quality control 
QTcF 
QT corrected Fridericia  
RP2D 
Recommended Phase 2 dose 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SD 
Standard deviation 
STD 
Severely toxic dose 
t1/2 
Terminal elimination half-life 
T3 
Triiodothyronine 
T4 
Thyroxine 
tmax 
Time of maximum observed concentration 
TAM 
Tumor-associated macrophage 
TB 
Total bilirubin 
TEAE 
Treatment-emergent adverse event 
TRAP 5b 
Tartrate-resistant acid phosphatase 
TSH 
Thyroid-stimulating hormone 
UGT 
uridine diphosphate glucuronosyltransferase 
ULN 
Upper limit of normal 
UV 
Ultraviolet 
WBC 
White blood cell 
WOCBP 
Women of childbearing potential 
WOMAC 
Western Ontario and McMaster Universities Osteoarthritis Index 
a 
All of these abbreviations may or may not be used in protocol. 


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5.0 
SYNOPSIS 
Title 
A Phase 1 Study to Assess Safety, Pharmacokinetics, and Pharmacodynamics of PLX3397 in 
Patients with Advanced, Incurable, Solid Tumors in which the Target Kinases Are Linked to 
Disease Pathophysiology 
Study 
Objective(s) 
PLX3397 (hereafter referred to by its generic name pexidartinib) is a selective inhibitor of 
Fms, Kit, and oncogenic Flt3 kinase activity. The primary objective of this study is to evaluate 
the safety and pharmacokinetics of orally administered pexidartinib in patients with advanced, 
incurable, solid tumors in which these target kinases are linked to disease pathophysiology. 
The proliferation and metastasis of a number of tumors are driven in part by Flt3, Kit, or Fms 
activity. These tumors include, but are not limited to, gastrointestinal stromal tumor and 
melanoma (Kit); glioma, breast cancer, prostate cancer, multiple myeloma, and osteosarcoma 
(Fms/CSF-1). The secondary objective is to measure the pharmacodynamic activity of 
pexidartinib via blood, plasma and urine biomarkers of Fms activity. 
Study Design 
Open-label, sequential dose escalation design. Once the recommended phase 2 dose (RP2D) is 
reached, an additional six extension cohorts will be opened. 
Number of 
Patients 
Enrollment in the dose escalation phase is planned to include up to 50 patients (depending on 
the number of dose escalation cohorts required) to evaluate pharmacokinetics and observed 
toxicity. Approximately 70 patients are planned to be enrolled in six extension cohorts with the 
possibility of 30 additional patients in a specific cohort if necessary (Section 24.6). 
Study Procedures After providing informed consent, patients will undergo screening for eligibility to participate 
in the study. Screening will start within 21 days prior to dosing with the exception of tumor 
burden assessment (e.g., CT scan) which may have been performed within 28 days. 
A cycle of dosing is defined as 28 days. In each dose escalation cohort, patients will receive 
their assigned dose of pexidartinib on the morning of Cycle 1 Day 1 (C1D1) and will remain in 
the outpatient clinic for 8 hours for observation and pharmacokinetic (PK) sampling. For QD 
dosing, PK samples will be collected prior to dosing and 0.5, 1, 2, 4, and 8 hours following 
dosing. The initial dosing regimen of pexidartinib will be once daily by oral administration. A 
twice daily dosing regimen may be used in subsequent cohorts, depending on the PK data 
obtained from once-daily dosing in the first cohort. For BID dosing, PK samples will be 
obtained predose (AM) and 1, 2, 4, 7 hours postdose on C1D1. The second dose will then be 
administered, and a 1 hr post dose sample will be obtained (8 hours after the first dose). 
Patients will return to the clinic on the morning of C1D2 and C1D8 prior to dosing on that day 
for evaluation and blood draw to obtain the predose PK time-point (approximately 12 hours 
after the previous evening dose for a BID dosing regimen). Patients will continue to dose 
pexidartinib once or twice daily and return to the clinic for evaluation on C1D8. On C1D15 
and C1D16 (±2 days), blood samples will be obtained once again for measurement of 
pexidartinib PK, using the same sampling times as on C1D1 and C1D2. Patients will return to 
the clinic on C2D1 for evaluation. If pexidartinib has been well tolerated and there has been no 
clinical evidence of disease progression, continued dosing will be permitted. Patients with 
solid tumors will be monitored for response and disease progression with tumor burden 
assessments every two months. 
In selected cohorts, 3–6 patients will be treated with a pexidartinib dose of 100 mg QD during 
a one-week run-in period before increasing to the full dose for that cohort, in order to profile 
the pharmacodynamic (PD) dose response activity of pexidartinib at doses below 300 mg QD. 
Similarly, 3–6 patients will be treated with a pexidartinib dose of 200 mg QD during a 
one-week run-in period. After baseline predose blood is obtained on C1D(-7), the first dose of 
100 mg or 200 mg will be administered, and PK samples will be obtained. Patients will return 
to the clinic the following AM (C1D(-6)) and 2 days later (C1D(-4)) for blood draws for PK 
and the PD biomarkers. They will then return for C1D1 for initiation of dosing at the full dose 
for that cohort. 


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PROPRIETARY 
At the recommended Phase 2 dose (RP2D), a total of six Extension cohorts of approximately 
10 patients each (except for the miscellaneous cohort, which will include up to approximately 
20 patients) will be enrolled and followed for safety and tumor response as assessed by 
radiographic imaging. These six cohorts consist of 1) mucoepidermal carcinoma (MEC) of the 
salivary gland, 2) pigmented villo-nodular synovitis (PVNS), 3) GIST, 4) anaplastic thyroid 
carcinoma (ATC), 5) solid tumors with documented malignant pleural or peritoneal effusions, 
and 6) miscellaneous tumor types for which a scientific rationale exists for treatment with 
pexidartinib. For PVNS patients, imaging will also be performed approximately 30 days and 
12 weeks after last study drug. 
Patients will be monitored throughout the study for adverse reactions to the drug formulation 
and/or study procedures. 
For the dose escalation cohorts, clinical laboratory assessments (hematology, chemistry, and 
urinalysis) will be performed at screening, C1D8, C1D15, and at the beginning of each 
subsequent 28 day cycle for those patients who continue on therapy, and at study completion 
or upon early withdrawal. Urinary, blood and serum biomarkers of response will be evaluated 
on C1D1, C1D8, and C2D1. 
Blood pressure, respiratory rate, pulse, and temperature will be measured at screening and 
predose at each study visit except for C1D2 and C1D16. Blood pressure and pulse will also be 
monitored at 1 and 4 hours postdose on C1D1. 
Triplicate ECGs (within 2 minutes apart) will be obtained at screening, prior to dosing on 
C1D1, and at 2, 4, and 6 hours postdose on C1D1 and C1D15. 
A physical examination will be performed for each patient at screening, C1D8, C1D15, C2D1, 
and then monthly while continuing study drug administration, and at study completion or upon 
early withdrawal. 
For the Extension cohorts, a simplified study plan will be used, as detailed in the study flow 
chart. Patients enrolled after the implementation of Amendment 8 will complete two patient 
reported outcome (PRO) instruments:  the Western Ontario and McMaster Universities 
Osteoarthritis Index (WOMAC®) and the Numeric Rating Scale (NRS) for PVNS Symptoms 
questionnaire. These will be completed predose at the clinic on C1D1, C1D15, C2D1, and 
monthly thereafter while continuing study drug administration, and at the End of Study visit. 
In addition, these patients will complete the NRS for PVNS Symptoms questionnaire on an 
outpatient basis for 6 consecutive days (Day -6 to Day -1) prior to each monthly clinic visit on 
C1D1, C2D1, C3D1, etc. while continuing study drug administration. 
The visit schedule for extension patients will be changed to every 12 weeks/3 cycles (with an 
option to complete on-site visits every 24 weeks/6 cycles if local safety laboratory testing and 
telephone check-ins are completed 12 weeks after each on-site visit) after a subject has 
completed at least C40 and if there are no ongoing safety or treatment issues. Imaging will be 
performed every 24 weeks/6 cycles, and PK, Urinalysis, and ECOG will be discontinued. 
Key Patient 
Selection Criteria 
Inclusion 
1. Male or female patients ≥18 years old 
2. For the dose escalation cohorts, patients with advanced, incurable, solid malignancies 
in which the target kinases are thought to be linked to disease pathophysiology and 
whose cancers are confirmed histologically. The tumors must fulfill BOTH of the 
following criteria:  a) refractory to standard therapy, OR standard or curative therapy 
does not exist or is not considered appropriate by the investigator, AND b) tumor 
proliferation or metastasis could be driven or promoted in part by Flt3, Kit, or 
Fms/CSF-1 activity. 
3. For the Extension cohorts, patients must have measurable disease by RECIST criteria 
and meet the following disease-specific criteria: 


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a. 
For advanced or recurrent MEC of the salivary gland, patients must not be 
candidates for curative surgery or radiotherapy. 
b. For PVNS (including tenosynovial giant cell tumor), patients must have a 
histologically confirmed diagnosis of inoperable progressive or relapsing PVNS, 
or resectable tumor requiring mutilating surgery, as well as demonstrated 
progressive disease in the last 12 months. 
c. 
For GIST, patients must have failed previous therapy with imatinib and sunitinib. 
Patients with known PDGFR mutations are excluded, but mutation testing is not 
required for study entry. 
d. For ATC, patients must have histologically or cytologically diagnosed advanced 
ATC. 
e. 
For metastatic solid tumors with documented malignant pleural, pericardial, 
and/or peritoneal effusions, patients must not be receiving specific therapy for the 
effusion (other than periodic drainage by needle) or have an indwelling drain. 
f. 
Other solid tumor types can be included in a miscellaneous cohort, provided there 
is a clear scientific rationale for treatment with pexidartinib and upon approval by 
the Medical Monitor. 
4. Women of child-bearing potential must have a negative pregnancy test within 7 days 
of initiation of dosing and must agree to use an acceptable non-hormonal method of 
birth control from the time of the negative pregnancy test for one month after the last 
dose of study drug. Highly effective non-hormonal methods of contraception include: 
intra-uterine device (non-hormonal), bilateral tubal occlusion, vasectomy, sexual 
abstinence, or barrier methods (e.g., condom, diaphragm). Women of non-
childbearing potential may be included if they are either surgically sterile or have 
been postmenopausal for ≥1 year. Fertile men must also agree to use an acceptable 
method of birth control while on study drug and for one month after the last dose of 
study drug. 
5. All associated toxicity from previous or concurrent cancer therapy must be resolved 
(to ≤Grade 1 or Baseline) prior to administration of pexidartinib. 
6. Willing and able to provide written informed consent prior to any study related 
procedures and to comply with all study requirements. 
7. ECOG performance status 0 or 1. 
8. Life expectancy ≥3 months. 
9. Adequate hematologic, hepatic, and renal function (absolute neutrophil count 
≥1.5 x 109/L, Hgb >9 g/dL, platelet count ≥100 x 109/L, AST/ALT ≤2.5 x ULN or 
<5 x ULN in the presence of liver metastases, albumin ≥3 g/dL, creatinine 
≤1.5 x ULN or calculated CrCl >60 mL/min using Cockcroft-Gault formula). 
Exclusion 
1. Specific anti-cancer therapy within 3 weeks prior to study drug administration. 
2. Investigational drug use within 28 days of the first dose of pexidartinib. 
3. Uncontrolled intercurrent illness. 
4. Refractory nausea and vomiting, malabsorption, external biliary shunt, or significant 
small bowel resection that would preclude adequate absorption. 
5. QTcF ≥450 msec (for males) or ≥470 msec (for females) at screening. 
6. The presence of a medical or psychiatric condition that, in the opinion of the Principal 
Investigator, makes the patient inappropriate for inclusion in this study. 


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Duration of Study The duration of the study is contingent on the number of dose levels in the dose escalation 
phase. Each dose escalation cohort will take approximately 6 weeks (7 weeks for cohorts with 
a one-week run-in period), including 2 weeks of recruitment. 
The PK analysis and MTD determination will be limited to the first 28 days of drug 
administration. Safety and response assessments will continue for the duration of drug 
administration for patients who continue study drug administration beyond 28 days. 
For the Extension cohorts, patients will be treated with study drug until progression or toxicity, 
until the phase 4 PVNS continuation study has been opened. Upon study termination, patients 
that don’t transition to the phase 4 continuation study will be provided information regarding 
potential transition to commercial drug. 
Dosage and 
Regimen 
The proposed starting dose is 200 mg QD. A BID dosing regimen may be used in subsequent 
cohorts, pending review of the PK from the initial cohort. 
Cohorts of patients with solid tumors will be enrolled using 100% dose increments in the 
absence of drug-attributable Grade 2 toxicity. In each cohort (and following the one-week run-
in period for applicable patients), the first patient will be observed for at least one week before 
additional patients in that cohort are treated with pexidartinib. Following the one-week run-in 
period for applicable patients, upon the occurrence of Grade 2 or greater drug-attributable 
toxicity, in the absence of dose limiting toxicity (DLT), dose escalation will proceed 
sequentially by 50% increments. From that point forward, the standard “3+3” design will be 
used. Following the one-week run-in period for applicable patients, if DLT is observed in one 
patient at a given cohort, at least 6 patients will be treated at that dose. Following the one-week 
run-in period for applicable patients, if DLT is observed in 2 or more of 6 patients at a dose 
level, then the next lower dose level will be expanded or an intermediate dose level will be 
introduced. The MTD is defined as the dose at which ≤1 of 6 patients experience a DLT during 
Cycle 1, with the next higher dose having at least 2 of the up to 6 patients experiencing a DLT 
during Cycle 1. If no DLT is observed, the recommended dose for further evaluation will be 
established based on toxicity, PK, and convenience of dosing in approximately 3–6 patients 
treated at that dose. Dose escalation will only be permitted if adequate safety and tolerability 
have been demonstrated at the previous lower dose for 28 days. 
The dosage for the Extension cohorts will be the RP2D level of 1000 mg/day, using a BID 
regimen.  
Stopping Rules 
For the dose escalation cohorts, two patients in any cohort of 6 patients with any of the 
following Dose Limiting Toxicities during the first 28 days of pexidartinib administration: 
 
Any CTCAE (version 4) Grade 4 toxicity (Grade 4 neutropenia for ≥3 days) 
 
Any CTCAE Grade 3 toxicity other than Grade 3 lymphopenia 
 
CTCAE Grade 2 vomiting within two hours of drug administration on 3 consecutive 
days despite optimal anti-emetic therapy 
 
If, for any reason, either the Principal Investigator or Sponsor deems further dose 
escalation inappropriate 
For the Extension cohorts, detailed guidance is provided in the protocol body for dose 
reduction criteria and discontinuation of therapy due to safety concerns. 
Safety and 
Tolerability 
Assessments 
Physical examinations, vital signs, 12-lead electrocardiograms, adverse events, hematology, 
serum chemistry, and urinalysis will be used to assess safety and tolerability.  


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PK Parameters 
The PK profile of plasma pexidartinib will be analyzed by measurement of area under the 
plasma concentration-time curve [AUC0-t, AUC0-∞], peak concentration (Cmax), time to peak 
concentration (Tmax), half-life (T1/2), and terminal elimination rate constant (Kel). 
Dose proportionality following study medication will be explored by analyzing natural log-
transformed pharmacokinetic variables, AUC0-t, AUC0-∞, and Cmax, with a linear model 
including the natural log-transformed dose as a covariate. Dose linearity for AUC0-t, AUC0-∞, 
and Cmax will also be explored by a linear model. 
PK assessments will be measured for each dose cohort of patients with correlations of Cmax and 
AUC to any SAEs. Dose-response trends in Cmax and AUC will be analyzed within each 
patient group for any suggestion of drug accumulation or alterations in PK based on 
concomitant medications. 
PD Parameters 
 
Morning urine:  N-Telopeptide of Type I Collagen (NTX) and C-Telopeptide of Type II 
Collagen (CTX-II) 
 
Serum markers:  Serum C-Telopeptide of Type I Collagen (CTX), Procollagen Type I 
Intact N-Terminal Propeptide (P1NP), Bone-specific Alkaline Phosphatase (BAP), 
Tartrate-Resistant Acid Phosphatase (TRAP 5b), Interleukin-6 (IL-6), Interleukin-1β 
(IL-1β), Matrix Metallopeptidase 3 (MMP-3), Erythrocyte Sedimentation Rate (ESR), 
C-Reactive Protein (CRP), Colony-Stimulating Factor-1 (CSF-1) 
 
Blood markers:  Circulating Tumor Cells (CTC), CD14+/CD16+ monocytes 
 


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TRIAL FLOW CHART (no Run-in Period) 
STUDY DAY► 
EVENT▼ 
Day –21 
to -1 
C1 
D11 
C1 
D2 
C1 
D8 
C1 
D15 
C1 
D16 
C2 
D1 
D1 of  
C3+ 2 
End 
of  
Rx3 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
Height/Weight 
X 
 
 
 
 
 
 
 
 
Physical Exam 
X 
 
 
X 
X 
 
X 
X 
X 
Chem, Hem, Coag, UA 
X 
 
 
X 
X 
 
X 13 
X 13 
X 
TSH 
X 
 
 
 
 
 
X 
X 
X 
ECG 4 
X 
X 
 
 
X 
 
 
 
 
Vital Signs 5 
X 
X 
 
X 
X 
 
X 
X 
X 
Plasma for PK 6 
 
X 
X 
X 
X 
X 
X 
X 
 
Pregnancy Test 7 
X 
 
 
 
 
 
 
 
 
ECOG Performance Status Assessment 
X 
 
 
 
 
 
X 
X 
X 
Serum and Urine for Biomarker 
Assessment 8 
 
X 
 
X 
 
 
X 
 
 
Circulating Tumor Cell (CTC) 
Assessment 9 
 
X 
 
 
 
 
X 
 
 
CD14+/CD16+ monocyte Assessment 
10 
 
X 
 
X 
 
 
 
 
X 
Radiographic Assessment of Tumor 
Burden 11 
X 
 
 
 
 
 
 
X 
 
Test article compliance 
 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 12 
 
X 
X 
X 
X 
X 
X 
X 
X 
C = cycle; D = day; CxDx = Cycle x, Day x; UA = urinalysis 
For footnotes, see Explanation of Subscripts below. 
 


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TRIAL FLOW CHART (with one-week Run-in Period) 
STUDY DAY► 
EVENT▼ 
Day 
-28 
to -7 
C1 
D -7 
C1 
D -6 
C1 
D -4 
C1 
D11 
C1 
D2 
C1 
D8 
C1 
D15 
C1 
D16 
C2 
D1 
D1 of  
C3+2 
End 
of  
Tx 3 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
Height/Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
 
 
 
 
 
X 
X 
 
X 
X 
X 
Chem, Hem, Coag, UA 
X 
 
 
 
 
 
X 
X 
 
X 13 
X 13 
X 
TSH 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
ECG 4 
X 
 
 
 
X 
 
 
X 
 
 
 
 
Vital Signs 5 
X 
X 
 
 
X 
 
X 
X 
 
X 
X 
X 
Plasma for PK 6 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pregnancy Test 7 
X 
 
 
 
 
 
 
 
 
 
 
 
ECOG Performance Status 
Assessment 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
Serum and Urine for 
Biomarker Assessment 8 
 
 
 
 
X 
 
X 
 
 
X 
 
 
Circulating Tumor Cell (CTC) 
Assessment 9 
 
X 
 
 
 
 
 
 
 
X 
 
 
CD14+/CD16+ monocyte 
Assessment 10 
 
X 
X 
X 
X 
 
X 
 
 
 
 
X 
Radiographic Assessment of 
Tumor Burden 11 
X 
 
 
 
 
 
 
 
 
 
X 
 
Test article compliance 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 12 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
C = cycle; D = day; CxDx = Cycle x, Day x; Tx = treatment; UA = urinalysis 
Explanation of Superscripts: 
1 
Day 1–16 apply to first cycle only. 
2 
If well tolerated and no tumor progression; clinic visits, laboratories at one month intervals with radiographic 
assessment performed every two months. 
3 
End or treatment or early withdrawal procedures should be completed within 30 days of the last dose of study 
drug and prior to initiation of any new therapy. 
4 
Triplicate ECG’s (within 2 minutes apart) at screening and prior to dosing on C1D1, and at 2, 4, and 6 hours 
postdose on C1D1 and C1D15. 
5 
Blood pressure, respiratory rate, pulse, and oral temperature will be recorded predose and at each clinic visit 
noted; blood pressure and pulse will also be recorded 1 and 4 hours postdose on C1D1. 
6 
For QD dosing, obtained predose (AM) and 0.5, 1, 2, 4, and 8 hours postdose on C1D(-7), C1D1 and C1D15, 
and predose on C1D(-6), C1D(-4), C1D2 , C1D8, and C1D16. For BID dosing on C1D1 and C1D15, obtained 
predose (AM) and 1, 2, 4, and 7 hours postdose. The second dose will then be administered, and PK obtained 
1 hour post the second dose (8 hours post the first dose). For BID dosing, no run-in is planned, with predose 
samples obtained on C1D2, C1D8, and C1D16. During continued dosing, obtained once every 4 weeks 
(predose). In the event of a DLT or SAE, a single blood sample should also be obtained within 48 hours. 
7 
For women of child-bearing potential; at screening should be within 7 days of first dose of study drug. 


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8 
Morning urine NTX and CTX-II and the following serum markers:  CTX, P1NP, BAP, TRAP 5b, IL-6, IL-1β, 
MMP-3, ESR, CRP, CSF-1. 
9 
Obtain blood sample for circulating tumor cells (CTC) predose (AM) on C1D1 and C2D1. 
10 
Obtain blood sample for CD14+/CD16+ monocytes predose (AM) on C1D1 and C1D8; if feasible, also obtain a 
sample 1 week after discontinuing study drug. 
11 
Screening window for radiographic assessment of tumor burden is 28 days. 
12 
Monitored throughout the study via safety assessments, observation, and participant reporting. 
13 
For all cycles after Cycle 1, a CBC with differential is required every 2 weeks (i.e., mid-cycle in addition to end 
of cycle). 
 


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TRIAL FLOW CHART – Extension Cohorts 
STUDY DAY► 
EVENT▼ 
Day –21 
to -1 1 
C1 
D1 
C1 
D15 
(±2 d) 
C2 
D1 
(±7 d) 
D1 of  
C3 to  C40 2 
(±7 d) 
D1 of  
C40, C43, C46, etc.+ 2 
(±7 d) 
End-of-Study/ 
Early Withdrawal3 
12-Week Follow-up 
(LD + 12 wk 
+4 wk) 4 
Informed Consent 
X 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
Weight 
X 
 
 
X 
X 
X (unless remote) 
X 
 
Physical Exam 
X 
 
X 
X 
X 
X (unless remote) 
X 
 
Chemistry, hematology, urinalysis 
X 
 
X5 
X5 
X5 
X5 
(no urinalysis) 
X 
 
ECG 
X 
 
X 
 
 
 
X 
 
Vital Signs 
X 
X 
X 
X 
X 
X (unless remote) 
X 
 
Plasma for PK 6 
 
X 
X 
X 
X 
 
 
 
Pregnancy Test 7 
X 
 
 
 
 
 
X 
 
ECOG Performance Status Assessment 
X 
 
 
X 
X 
 
X 
 
WOMAC Questionnaire 8 
 
X 
X 
X 
X 
X (unless remote) 
X 
 
Numeric Rating Scale (NRS) for PVNS 
Symptoms Questionnaire to Patient 8 
 
X 
X 
X 
X 
X (unless remote) 
X 
 
Dispense Numeric Rating Scale (NRS) 
for PVNS Symptoms Questionnaire for 
Outpatient Completion 9 
X 
 
X 
X 
X 
X (unless remote) 
 
 
Serum and Urine for Biomarker 
Assessment 10 
 
X 
 
X 
 
 
 
 
Radiographic Assessment of Tumor 
Burden 11 
X 
 
 
 
X 
X (every 6 months) 
X 
X 
Test Article Compliance 
 
X 
X 
X 
X 
X (unless remote) 
X 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
 
Adverse Events 12 
 
X 
X 
X 
X 
X 
X 
 
Collection of surgical data 13 
 
 
 
 
 
 
X 
X 
C = cycle; D = day; CxDx = Cycle x, Day x; LD = last dose; wk = week 


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1 
Screening window for radiographic assessment of tumor burden is 4 weeks. 
2 
If well tolerated and no tumor progression; clinic visits, laboratories at 1-month intervals with radiographic assessment performed every two cycles. Radiographic assessment 
of tumor status can be performed every four cycles in patients who complete 14 cycles of treatment (i.e., reached Cycle 15 visit) and have Cycle 13 and Cycle 15 MRI scans 
that indicate SD or better per local RECIST v1.1 reading. For patients beyond Cycle 40, clinic visits will transition to every 12 weeks/3 cycles (remote serum chemistry and 
hematology as well as a telephone check-in for AEs and con meds and to review remote safety laboratory data may be performed in lieu of an on-site visit for subjects without 
ongoing Grade 2 or greater related adverse events; regular procedures not performed remotely include Weight, PE, Vitals, WOMAC, NRS, and IP compliance), with on-site 
visit and radiographic assessments performed every 24 weeks/6 cycles. 
3 
End of Study or early withdrawal procedures should be completed 7-30 days after the last dose of study drug (or on the date of last dose of study drug for all subjects that 
enroll in the phase 4 continuation study) and prior to the initiation of any new anti-cancer therapy. If patient is starting commercially available drug then the end of study visit 
should be conducted before that transition. 
4 
Visit only conducted for subjects that don’t enroll in the phase 4 continuation study or transition immediately to commercial pexidartinib. For patients who miss the 30-day or 
12-week post-treatment follow-up MRI, post-treatment radiographic assessments from any source (e.g., primary care provider) within 24 weeks of the last dose are acceptable. 
5 
If there is a Grade 2 or higher ALT or AST elevation (i.e., >3 × ULN) at any time during treatment, the patient should be followed closely (see Section 14.7 for monitoring 
details). 
6 
On C1D1, obtain predose. On C1D15, obtain predose (AM) and 1, 2, 4 and 6 hours postdose. During continued dosing, obtain once every 4 weeks (predose). For patients with 
afternoon clinic visits, see Section 20.1. 
7 
For women of child-bearing potential. 
8 
Patients enrolled after the implementation of Amendment 8 will complete these two patient reported outcome (PRO) instruments predose at the clinic on C1D1, C1D15, 
C2D1, and monthly thereafter, and every 12 weeks after C40, while continuing study drug administration, and at the End of Study visit. 
9 
For patients enrolled after the implementation of Amendment 8, six (6) questionnaires will be dispensed at the indicated clinic visits with instructions and reminders to 
complete the questionnaire on an outpatient basis for 6 consecutive days (Day -6 to Day -1) prior to each monthly clinic visit on C1D1, C2D1, C3D1, etc. (or at every 12- or 
24-week visit after C40) while continuing study drug administration. The patient should return the completed questionnaires to site staff at each of the subsequent monthly 
clinic visits on C1D1, C2D1, C3D1, etc. 
10 
Morning urine NTX and CTX-II and the following serum markers:  IL-6, CSF-1. CD14+/CD16+ monocytes predose (AM) on C1D1 only. 
11 
This assessment will occur every 8 weeks during continued dosing, and every 24 weeks after C40, and (for subjects that don’t enroll in the phase 4 continuation study or 
transition to commercial pexidartinib) approximately 30 days and 12 weeks after the last dose of study drug; additional detail regarding MRI is included in footnote 2. For 
PVNS patients, the Sponsor will receive radiologic images for possible retrospective analysis of treatment response, to be performed by a central vendor. 
12 
Monitored throughout the study via safety assessments, observation, and participant reporting. 
13 
If surgical resection of the tumor is performed within 12 weeks of the last dose of study treatment, details of the surgery and its outcome should be obtained. Tumor biopsy 
tissue may be submitted for biomarker analysis. 
 


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6.0 
INTRODUCTION 
6.1 
Background 
Kinases play a ubiquitous role in the signaling pathways for proliferation, metastasis, and 
survival of most tumor types. Pexidartinib is a potent and selective inhibitor of Fms (the receptor 
for macrophage-colony stimulating factor, M-CSF), Kit (the receptor for stem cell factor, SCF) 
and oncogenic Flt3 (the receptor for Flt3 ligand). Therefore, it has the potential to treat cancers 
through multiple mechanisms. For example, somatic activation of Kit and Flt3 has been well-
documented in a number of cancers. Beyond the direct dependence of tumors on these oncogenic 
drivers, Fms and Kit are regulators of key components of the tumor microenvironment, namely 
macrophages, osteoclasts, and mast cells. Therefore, pexidartinib has effects on multiple aspects 
of tumorigenesis, including proliferation, intravasation, extravasation, and survival of metastases. 
The inhibition of these activities by pexidartinib has been characterized in cellular and in vivo 
assays. The pharmacologic efficacy demonstrated to date and the therapeutic promise support 
further development of pexidartinib as an anti-cancer therapeutic. 
Pexidartinib is a novel, orally active, small molecule inhibitor that targets Fms, Kit and 
oncogenic Flt3, but remains highly selective versus other kinases. The potent inhibition of these 
three kinases can be exploited to attach tumors via different mechanisms:  1) directly inhibiting 
oncogenic drivers such as oncogenic Kit and Flt3 mutant proteins, 2) inhibiting paracrine loops 
between stromal cells and tumors, 3) blocking migration and angiogenesis, and 4) disrupting 
osteolytic metastases. 
Tumor control due to blockade of Kit mutations has been validated in the clinic through the 
established efficacy of imatinib and sunitinib in gastrointestinal stromal tumors (Fletcher 2007). 
Clear tumor responses in patients with acute myelogenous leukemia (AML) using inhibitors of 
mutant Flt3 have also been reported, although none of these inhibitors has yet been approved to 
treat AML (Tam 2008). Pexidartinib may afford an advantage over other compounds in that very 
few ‘off-target’ kinases are inhibited. Indeed, pexidartinib preferentially inhibits oncogenic Flt3 
versus the wildtype protein, providing promise for a wider therapeutic potential. 
The efficacy of osteoclast antagonists such as bisphosphonates in preventing bone fractures and 
pain resulting from osteolytic metastases has been recognized for some time (Kohno 2008). 
Osteoclasts require the parallel activation of the RANK-L and Fms pathways for activity and 
survival. Recently, RANK-L antagonists have demonstrated efficacy to prevent bone destruction 
in preclinical models, and efforts to validate this in the clinic are well underway (Lipton 2008). 
As a potent inhibitor of Fms, the anti-osteoclast effects of pexidartinib that are seen in vitro and 
in vivo provide an alternative mechanism to block bone destruction and consequent pain. 
More recently, an important role for tumor infiltrating macrophages in tumor progression has 
pointed to Fms as a key target in multiple tumor types (Coffelt 2009). The pro-tumorigenic role 
of CSF-1 and Fms is strongly supported by a wealth of studies demonstrating that CSF-1 levels 
predict a poor outcome in a variety of oncology indications, including breast, ovarian, non-small 


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cell lung, and colorectal cancers. Further strengthening the fundamental tumorigenic role of Fms 
is a key study showing that mice defective in CSF-1 are protected against tumor metastases. 
Accordingly, treatment of breast cancer xenografts with anti-sense, antibodies or siRNA to 
CSF-1 suppresses tumor growth. The mechanism for this inhibition relates in part to a paracrine 
loop that links CSF-1 secreting tumor cells with EGF-secreting macrophages (Pollard 2008). 
Furthermore, a growing body of literature has now linked macrophages to angiogenesis 
(Coffelt 2009). One final aspect to tumorigenesis also implicates Fms, namely its role in the 
terminal differentiation of osteoclasts (Tanaka 2007). Coupled with the reported efficacy of 
bisphosphonates and RANK-L antagonists in tumor models, the anti-osteoclast activity of Fms 
inhibition should supplement the anti-macrophage mediated tumor suppressive potential. Taken 
together, this information provides a rationale for the role of Fms as a potentially important 
cancer target. 
Finally, mast cells also comprise an important faction of the microenvironment of certain tumors. 
For example, in plexiform neurofibromas that cause significant morbidity in patients with 
neurofibromatosis type 1, a paracrine loop between mast cells and Schwann cells has been 
demonstrated in preclinical models (Yang 2008). Subsequently, pexidartinib has shown 
preliminary efficacy to reduce development of plexiform tumors in a mouse model of NF1. 
6.2 
Pharmacodynamics 
In brief, biochemical data support Fms, Kit and oncogenic Flt3 as key targets of pexidartinib. 
Consequently, proliferation of cell lines that alternatively depend on M-CSF, SCF, or 
endogenous Flt3 that is oncogenically activated by internal tandem duplications (Flt3-ITD) is 
inhibited at IC50 values below 1 µM. Furthermore, M-CSF-induced autophosphorylation of Fms 
and SCF-induced autophosphorylation of Kit are potently inhibited by pexidartinib. By contrast, 
Flt3-ligand induced autophosphorylation of Flt3 and Flt3-ligand induced proliferation of cells are 
only weakly inhibited by pexidartinib, suggesting preferential inhibition of the oncogenically-
activated kinase. Finally, the RANK-L and M-CSF-dependent differentiation of osteoclasts 
precursors is also potently inhibited by pexidartinib. These in vitro effects translated to effects in 
a variety of in vivo models designed to test the effects of pexidartinib on Fms-dependent 
proliferation, Fms-dependent osteoclasts differentiation, and Flt3-ITD dependent tumor growth. 
6.2.1 
In Vitro Pharmacodynamics 
Pexidartinib shows significant selectivity versus a panel of over 200 kinases. Fms, Kit, and 
activated Flt3 appear to be the most sensitive target kinases, with IC50 vslues of 17, 12, and 
9 nM, respectively (see Table 1). 
Table 1: 
IC50 Values of Pexidartinib Against Selected Kinases 
Kinase 
Fms 
Kit 
Flt3 
Kdr 
Lck 
Flt1 
TrkC 
Pexidartinib 
17 nM 
12 nM 
9 nM 
213 nM 
860 nM 
880 nM 
890 nM 


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Kdr kinase activity is only modestly affected, and other kinases tested are even less sensitive to 
pexidartinib. While physiologic effects due to the inhibition of Fms and Kit are expected, the 
selectivity of pexidartinib suggests that minimal off-target effects should be observed. When 
screened against a broad panel of additional kinases, IC50 values were >1 µM for all, with the 
majority >10 µM. 
Pexidartinib also demonstrated negligible activity in a standard Novascreen panel screen. This is 
a screen for off-target activity against a broad array of 71 targets in 8 families (Neurotransmitter-
related, Steroids, Ion Channels, Nitric Oxide, Prostaglandins, Growth Factors, Brain/Gut 
Peptides, and Enzymes). At a concentration of 10 µM serum-free, all results were within 40% of 
Baseline, indicating no relevant off-target activity. 
M-NFS-60 cells and BAC1.2F5 cells are mouse cell lines that require M-CSF to proliferate, and 
Mo7E cells are human cells that require SCF to proliferate. The ligand dependent proliferation of 
these cells is inhibited by pexidartinib with IC50s of 0.33, 0.23 and 0.31 μM, respectively. In 
THP-1 cells, Fms autophosphorylation induced by M-CSF can be inhibited by 7 nM 
concentrations of pexidartinib. In Flt3-ITD-expressing MV4-11 cells, ligand-independent 
autophosphorylation of Flt3 is potently inhibited by pexidartinib with an IC50 of 26 nM. By 
contrast, in RS4:11 cells, Flt3 autophosphorylation can be induced by Flt3 ligand and this 
autophosphorylation requires high levels of pexidartinib (1500 nM) for inhibition. This weak 
inhibition of Flt3-ligand effects suggests that pexidartinib binds only weakly to unactivated Flt3. 
Finally, human osteoclast precursor cells can be induced to differentiate in to mature osteoclasts 
by the combination of RANK-L and M-CSF. Pexidartinib inhibits this osteoclast differentiation 
with an IC50 of 33 nM. 
6.2.2 
In Vivo Pharmacodynamics 
Models of Fms-dependent proliferation and Fms-dependent osteoclast activity can be 
inhibited by 5–10 mg/kg doses of pexidartinib in vivo. This was demonstrated in a Fms-
dependent splenomegaly model, a metastatic breast cancer model, and a murine collagen-
induced arthritis model. 
BaF3 cells are mouse pre-B cells that depend on interleukin-3 (IL-3) for survival. By engineering 
BaF3 cells to express BCR-activated Fms kinase activity, the dependence on IL-3 can be 
replaced. Consequently, these BCR-Fms expressing BaF3 cells are dependent on Fms kinase 
activity for survival. In vitro, proliferation of these cells can be potently inhibited by 
pexidartinib, with an IC50 of 7 nM. A corresponding BaF3 cell line expressing BCR-Kit is also 
quite sensitive to pexidartinib, with an IC50 of 130 nM. 
Injection of the BCR-Fms-expressing BaF3 cells into the tail vein of nude mice results in 
homing of these cells to the spleen and subsequent cellular proliferation that results in dramatic 


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splenomegaly over the course of 14–18 days. Oral dosing of pexidartinib for the final 8 days of 
this model results in dose-dependent inhibition of the splenomegaly. The ED50 of this effect is 
between 2 and 5 mg/kg. Therefore, we believe that a 5 mg/kg oral dose of pexidartinib in mice 
corresponds to an efficacious dose. Pharmacokinetic analysis reveals that this 5 mg/kg dose 
achieves an AUC0–24 of 99.8 μM•h, and a Cmax of 13.4 μM. We will use these values to 
define an efficacious exposure, and this will be used the denominator in calculations of 
therapeutic multiples. 
In a separate model, mice expressing the polyoma middle T antigen (PyMT) behind a mammary 
promoter develop breast cancer that metastasizes after several months. During the metastatic 
process, circulating tumor cells that express PyMT can be measured among circulating blood 
cells. Since Fms activity is a critical component of extravasation into the blood stream, reduction 
in the number of these circulating tumor cells can be a measure of anti-Fms activity. Within 
24 hours of a single oral dose of 40 mg/kg pexidartinib, a 10-fold decrease in these circulating 
tumor cells can be determined (see Figure 1). 
Figure 1: 
Pexidartinib-Induced Reduction of Circulating Tumor Cells in PyMT 
Mouse Model of Breast Cancer 
 
In order to determine effects of pexidartinib on osteoclastic activity in vivo, a murine collagen-
induced arthritis model was implemented. In this model, double immunization of the mice with 
collagen leads to progressive clinical symptoms resembling rheumatoid arthritis. Histology can 
be used to measure osteoclasts that contribute bone-destructive pathology in this model. 
Osteoclasts are measured using an osteoclast-specific marker, namely tartrate-resistant acid 
phosphatase 5B (TRAP 5B). Treatment of these mice with 50 mg/kg pexidartinib over the course 
of 24 days results in significant stabilization of disease, and this is accompanied by dramatic 
reductions in macrophages infiltrating the joints. Importantly, joint-infiltrating osteoclasts are 
also reduced by 10-fold, illustrating the potent anti-osteoclastic effects of pexidartinib. 


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Since pexidartinib permeates the blood-brain barrier and Fms-dependent microglia are likely 
mediators of pain transmission, pexidartinib was tested in a formalin-pain model. This formalin 
model measures both acute nociceptive and acute inflammatory pain responses. Pexidartinib 
showed reduction in both phases of the formalin pain response, suggesting that effects on both 
acute and inflammatory pain may be expected in further studies. 
As pexidartinib is a potent inhibitor of the proliferation of Flt3-ITD-dependent MV4-11 cells 
(cells derived from a patient with acute myelogenous leukemia) in vitro, the effect of 
pexidartinib treatment in an MV4-11 xenograft model was investigated. MV4-11 cells were 
implanted subcutaneously in the flank of male nude mice using matrigel as an adsorbing matrix. 
Once these tumors had been established to a size of >100 mm2, treatment with 10 and 
30 mg/kg/day oral doses of pexidartinib was initiated and continued for 3 weeks. This 
pexidartinib treatment was quite efficacious, resulting in tumor stabilization and some tumor 
regression at the 10 mg/kg dose and considerable tumor regression at the 30 mg/kg dose (see 
Figure 2). Indeed, half of the mice treated with 30 mg/kg pexidartinib had no palpable tumor at 
the end of 3 weeks of treatment. These data provide considerable rationale for testing for clinical 
efficacy of pexidartinib in acute myelogenous leukemia patients whose tumor cells bear Flt3-ITD 
mutations. 
Figure 2: 
Daily Oral Dosing of Pexidartinib Results in Dose-Dependent Tumor 
Suppression in MV4-11 Xenograft Model of Flt3-ITD Dependent 
Acute Myelogenous Leukemia 
 


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* p<0.05, ** p <0.005 
Please refer to the Investigator’s Brochure for updated information and detailed description of 
the nonclinical pharmacology data. 
6.3 
Nonclinical Metabolism and Pharmacokinetics 
Please refer to the Investigator’s Brochure for updated information and detailed description of 
the nonclinical metabolism and PK. 
Pexidartinib has low aqueous solubility and modest permeability. It is not a substrate or inhibitor 
of Pgp. Several studies in four species (mouse, rat, dog and monkey) evaluated formulations to 
optimize absorption and systemic exposure following oral administration. Pexidartinib was 
absorbed within two to three hours following oral administration. In several studies, plasma 
exposure (based on AUC values) was greater in females (up to 34% in rats). Elimination half-
lives ranged from 2 to 5 hours in these four species. A study conducted in cynomolgus monkeys 
showed that food does not inhibit or delay absorption of pexidartinib following oral (gavage) 
administration. 
The extent to which pexidartinib binds to the plasma proteins was evaluated in vitro using a 
Rapid Equilibrium Dialysis inverted method. Pexidartinib is strongly protein bound in plasma for 
all four species tested (mouse, rat, dog, and human). With regards to potential species 
differences, the binding in mouse, dog and human plasma at 75 µM was approximately equal 
(99.8%, 99.7%, and 99.8% respectively) while rat protein binding was marginally lower 
(98.3%). 
Two experiments evaluated the partitioning of pexidartinib between blood and brain, based on 
measurements of test article in brain tissue, cerebrospinal fluid and plasma. In one study, 
appreciable amounts of pexidartinib were recovered in whole blood (vs. plasma), suggesting that 
pexidartinib associates with cellular elements of blood. In experiments that quantified 
pexidartinib concentration in brain tissue and cerebrospinal fluid 4 and 6 hours following oral 
administration in rats, the brain:plasma ratio averaged 0.41 and 0.36, respectively - values close 
to that of antipyrene, a positive control (0.50 and 0.54). The ratios of CSF:plasma at these 
timepoints for pexidartinib, however, were lower (0.026 and 0.014) than those for antipyrene 
(1.06 and 0.92). 
A series of in vitro studies examined the metabolic stability of pexidartinib using either liver S9 
fraction or intact hepatocytes from several species, including rats and dogs, the two species used 
in toxicology studies, as well as humans. Studies with intact hepatocytes revealed that 
pexidartinib was very slowly metabolized in all three species, especially human liver cells. 
Although the exact molecular species were not identified, in the presence of human hepatocytes, 
several molecular species corresponding to glucuronide conjugates were detected, with minimal 
evidence of breakdown. These data, along with the high protein binding, suggests that the 
clearance of pexidartinib from human plasma may be slow. Another study was conducted to 


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evaluate the CYP450 phenotypes of pexidartinib metabolism in vitro. Of the five major CYP 
isoforms, 3A4 (BFC) may be involved in Phase I metabolism of pexidartinib, with possibly 
CYP1A2 playing a minor role. 
Pexidartinib does not appear to inhibit CYP drug-metabolizing enzymes to an important extent. 
Studies using human liver microsomes yielded enzyme inhibitory constant (Ki) values exceeding 
30 µM for CYP1A2 and 3A4 (testosterone substrate), ≥12 µM for 3A4 (midazolam substrate), 
2D6 and 2C9. A Ki value <10 µM was obtained for only one CYP isozyme:  2C19 
(Ki = 8.4 µM). It is worth noting that the latter experiment was conducted in the absence of HSA. 
When pexidartinib was evaluated for its ability to inhibit the major human CYP isozymes in the 
presence of 10 µM human serum albumin (HSA), IC50 values greater than 30 µM were 
uniformly obtained. 
In another series of experiments, pexidartinib was demonstrated not to induce the expression of 
genes that encode CYP enzymes and several other proteins involved in metabolism and 
transport. 
In aggregate, an extensive series of non-clinical studies evaluating pexidartinib reveal a 
metabolically stable drug that displays extensive protein binding. Clinically relevant drug-drug 
interactions are not anticipated based upon experimental evidence of negligible CYP inhibition 
or induction in vitro. 
6.4 
Summary of Nonclinical Toxicology and Safety Pharmacology 
After establishing dose-response systemic exposure data with gavage formulations of 
pexidartinib, the toxicology was evaluated in non-GLP repeat dose and GLP 28-day repeat-dose 
toxicity studies in Sprague-Dawley rats and Beagle dogs. Standard GLP batteries of genotoxicity 
and safety pharmacology studies were also performed. 
Results of the studies are presented below. In summary, a NOAEL for either species was not 
determined, based on body weight losses and several histological and/or gross morphological 
effects. However, the significant test article-related adverse effects (testes, ovaries, bone and 
bone marrow, hematology and lymphoid changes) are consistent with the pharmacological 
mechanism of action of pexidartinib. Importantly, all of these findings were partially or fully 
reversible. There were no safety findings in the genotoxicity and safety pharmacology studies. 
Please refer to the Investigator’s Brochure for a more detailed description of the non-clinical 
toxicology and safety pharmacology studies. 
6.4.1 
Repeat-Dose Toxicity in Rats 
In rats administered pexidartinib by oral gavage for 7 days at doses of 30, 100, and 
300 mg/kg/day, there were modest potential test article-related effects as follows:  decreased 
WBC and hemoglobin, increased AST, ALT, alkaline phosphatase, increased liver and decreased 


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spleen weights, bone marrow hematopoietic atrophy, and cystic corpora lutea. Under the 
conditions of this study the NOAEL was 30 mg/kg/day for males and females. 
In the subsequent GLP 28-day study with a 14-day recovery period, Sprague-Dawley rats were 
dosed at 20, 60, and 200 mg/kg/day. Exposure increased as dosage was increased over the 20 to 
200 mg/kg/day range for both sexes, with exposure in females tending to be modestly higher 
(9-34%, depending on dose) compared to males. 
Non-adverse lower body weights and food consumption were noted for the 200 mg/kg/day group 
females. Body and food consumption effects resolved during the recovery period. 
Changes in hematology parameters consisted of dose-related lower WBC, RBC, PT, aPTT, and 
lower reticulocyte counts in all test article-treated groups. At study day 43 recovery evaluation, 
the WBC counts had rebounded, the RBC mass partially recovered, reticulocyte counts were 
higher than the control group, and fibrinogen, PT, and APTT had resolved in the 200 mg/kg/day 
groups. Alterations in hematology are likely related to the mechanism of pexidartinib-mediated 
inhibition of Fms and Kit kinase. No effects on clinical chemistry were considered adverse. 
There were macroscopic findings of discoloration/red areas of the ovaries in the 60 and 
200 mg/kg/day females at primary necropsy, and soft/small testes in the 200 mg/kg/day group 
males at the recovery necropsy. Microscopic alterations included dose-related minimal to 
moderate subphyseal hyperostosis in the femur for the 60 and 200 mg/kg/day groups, minimal to 
moderate physeal hypertrophy in the femur for the 60 and 200 mg/kg/day groups, and dose-
related reduction in the density of hematopoietic cells of all lineages within the bone marrow 
(sternum and femur). Alterations in bone parameters are likely related to the mechanism of 
pexidartinib-mediated inhibition of Fms and Kit kinase. Dose-related hepatocellular centrilobular 
hypertrophy was noted for the 200 mg/kg/day groups and correlated with higher liver enzyme 
levels and higher liver weights, and a higher incidence and/or severity of chronic progressive 
nephropathy was noted for the 200 mg/kg/day groups. This finding is a normal spontaneous 
change in Sprague-Dawley rats and was noted in the vehicle control groups. Microscopic 
findings in the skin and lymphoid tissues included a dose-related higher incidence of minimal to 
mild myxomatous change in the skin/subcutis of all test article-treated groups, and lymphoid 
depletion of the cortex in the thymus in the 60 and 200 mg/kg/day groups. 
Microscopic findings in endocrine and reproductive tissues included dose-related higher 
incidence and severity of hemorrhagic corpora luteal cysts in the ovaries in the 60 and 
200 mg/kg/day females, dose-related higher incidence and/or severity of thyroid follicular cell 
hypertrophy in the 200 mg/kg/day groups. Minimal to moderate depletion of spermatogenic 
epithelium at study day 28/29 was noted in the 60 and 200 mg/kg/day group males, and the 
200 mg/kg/day group males were often completely devoid of spermatogonia and pachytene 
spermatocytes. Tubules in stages of elongation were frequently characterized by complete 
absence of prepachytene and pachytene spermatocytes and sertoli cell vacuolization was 
occasionally observed. At study day 43, the 200 mg/kg/day group males had depletion of 


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spermatogonic epithelium and mild to severe atrophy characterized by a depletion of spermatids, 
however there was an increase in the spermatogonial population, which is reflected by the 
presence of significant numbers of early prepachytene (leptotene and zygotene) spermatocytes. 
Alterations in testes and ovaries are likely related to the mechanism of pexidartinib-mediated 
inhibition of Fms and Kit kinase. 
The majority of alterations in morphologic pathology parameters, except for luteal cysts and 
chronic progressive nephropathy, partially or completely resolved following the recovery period. 
Luteal cysts reduced in severity but remained higher than the control group in the 200 mg/kg/day 
group females. On the basis of observations made in this GLP-compliant study, a no-observed 
adverse effect level (NOAEL) for oral (gavage) administration of pexidartinib was not 
determined. This study also did not establish a lethal dose in 50% of rats LD50 or severely toxic 
dose in 10% or rats (STD10). However, for the purposes of calculating a clinical starting dose 
for oncology, Plexxikon has assumed the highest dose tested in this study (200 mg/kg) to be 
the STD10. 
6.4.2 
Repeat-Dose Toxicity in Dogs 
In two pairs of Beagle dogs administered pexidartinib at a dose of 600 mg/kg BID 
(1200 mg/kg/day) for 7 days, findings included emesis and mild to moderate reduction of 
erythropoiesis in bone marrow. Mild body weight loss was likely secondary to emesis. 
In the subsequent GLP toxicity study, groups of Beagle dogs were administered pexidartinib for 
28 days at doses of 100, 300, and 1000 mg/kg/day which was then reduced to 50, 100, and 
300 mg/kg/day after the first week due to lethargy, weight loss, and lack of food consumption in 
several high dose animals. 
Mean exposure generally increased as dosage increased over the 50 to 1000 mg/kg/day range, 
but the range of exposure observed for individual animals within a dose group frequently 
overlapped between the dosages of 50 and 100 mg/kg/day and 300 and 1000 mg/kg/day doses. 
Exposure tended to be similar in males compared to females. 
There were no test-article-related ophthalmic or macroscopic findings or effects on urinalysis, 
ECG or organ weight parameters. 
Three dogs in the 1000/300 mg/kg/day group were euthanized in extremis on study days 8, 15, 
and 17 due to prostration, tremors, impaired coordination, and tachypnea. Emesis was noted in 
all groups with an increased incidence in the 300/100 and 1000/300 mg/kg/day groups. 
Modest body weight declines were observed for the 300/100 and 1000/300 mg/kg/day group; 
primarily from study week 0 to 1. These changes correlated with decreased food consumption 
and were reversible during the recovery period. 


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Changes in hematology parameters consisted of time- and dose-related declines in RBC mass 
and reticulocyte counts at 1000/300 and 300/100 mg/kg/day, which correlated with bone marrow 
hypocellularity resulting in a non-regenerative anemia at study week 2. The anemia increased in 
severity at study week 4, despite a rebound in absolute numbers of reticulocytes. These effects 
were considered adverse though reversible, based on partial recovery noted at study week 6. 
Higher fibrinogen levels were also noted in all dose groups. Alterations in hematology are likely 
related to the mechanism of pexidartinib-mediated inhibition of Fms and Kit kinase. 
There were no adverse test article related serum chemistry effects. Hypophosphatemia was noted 
in males at dosage levels >300/100 mg/kg/day and in females at doses >100/50 mg/kg/day. 
Elevated levels of PTH in the 300/100 and 1000/300 mg/kg/day groups may have contributed to 
the hypophosphatemia but was reversible and not severe enough to be considered adverse. 
Additionally, Fms inhibition can reduce osetoclast differentiation and function, resulting in 
decreased bone resorption and decreased serum phosphate. 
Pexidartinib caused significant, partially reversible testicular atrophy at all three doses. The 
earliest changes, noted in two 1000/300 mg/kg/day group males euthanized in extremis, were 
severe, with diffuse spermatocytes and spermatid degeneration. At study week 4, the atrophic 
tubules contained small numbers of retained spermatids and degenerate/multinucleate intra-
luminal spermatids. 
Pexidartinib-related alterations were less prominent in the ovary, possibly because most ovaries 
were immature. Follicular degeneration, characterized by large, distorted, antral follicles with 
extensive apoptosis of granulose cells and a peripheral stromal cell proliferation, was noted in 
two of three females administered 1000/300 mg/kg/day. There appeared to be an increased 
number of atretic follicles in one of two affected dogs. Alterations in testes and ovaries are likely 
related to the mechanism of pexidartinib-mediated inhibition of Fms and Kit kinase. 
Bone marrow exhibited a dose-related minimal to mild hypocellularity. Following a 14-day 
recovery, the bone marrow from the 1000/300 mg/kg/day group was minimally hypercellular, 
demonstrating recovery. In the spleens, minimal to mild increased extramedullary hematopoiesis 
was noted in all dose groups. The extramedullary hematopoiesis was an expected physiologic 
response to the decreased RBC mass and regenerative anemia. 
In the femur, minimal to moderate subphyseal hyperostosis was evident in dogs that received 
300/100 and 1000/300 mg/kg/day. Hyperostosis was not evident at study week 6. This lesion was 
characterized by a retention and elongation of the primary spongiosa beneath the physis and was 
considered a reversible consequence of pharmacologic effect on osteoclasts. 
Lymphoid depletion was evident in the thymus, lymph nodes, Peyer’s patches, and spleen more 
frequently, compared to vehicle controls. These effects were considered to be secondary to 
Pexidartinib-related nonspecific stress factors; however, an organ-specific test article-related 
effect on the lymphoid system cannot be excluded. 


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Minimal to mild valvular endocardiosis was occasionally noted in placebo- and pexidartinib-
treated dogs at study weeks 4 and 6. Because this finding can occur spontaneously and a clear 
dose-response was not observed, it was likely not a direct pexidartinib-related effect. 
Additionally, minimal subendothelial myxomatous change was noted in four dogs treated with 
pexidartinib at the primary necropsy. This alteration was characterized by focal increases in 
proteoglycans near the luminal surface of the aorta. While regional variation in proteoglycan 
content was considered within normal limits and the change could have been part of the normal 
spectrum, a pexidartinib-related effect cannot be ruled out. Importantly, no evidence of 
myxomatous change in the aorta was noted in the 28-day rat GLP toxicology study where high-
dose unbound pexidartinib exposure was 18-fold that seen at the high-dose in the dog study. 
In the kidneys, basophilic tubules were noted in the 100/50 (females only) 300/100 and 
1000/300 mg/kg/day groups with no clear relationship to the pexidartinib dose administered. 
Basophilic tubules are a common spontaneous finding in control group dogs. The incidence of 
findings was within the range of those noted in the database of historical control groups. Thus 
the kidney findings were considered of uncertain relationship to the test article. 
Based on the results of this study, systemic toxicity of pexidartinib administered orally by 
gavage twice daily for 28 consecutive days was observed at dosage levels of 300/100 and 
1000/300 mg/kg/day, as evidenced by mortality (1000/300 mg/kg/day), adverse clinical 
observations of emesis, and emesis-related findings, body weight losses with associated low food 
consumption, and microscopic findings of the testes, bone marrow, kidneys, spleen, and 
lymphoid depletion in the thymus. Therefore, a NOAEL was not determined. This study also did 
not establish a lethal dose in 50% of dogs LD50. For the purposes of calculating a clinical starting 
dose for oncology Plexxikon has defined the 300 mg/kg dose to be the highest nonseverely toxic 
dose (HNSTD) in dogs. 
6.4.3 
Genotoxicity 
No signs of genotoxicity were identified in a standard battery of tests (in vitro AMES and 
chromosomal aberration and in vivo micronucleus assays) conducted with pexidartinib. 
6.4.4 
Safety Pharmacology 
In GLP-compliant respiratory and central nervous system safety studies, the NOEL for 
pexidartinib was 200 mg/kg in rats. Additionally, three GLP-compliant safety pharmacology 
studies addressed the potential adverse cardiovascular or cardiac electrophysiological effects of 
pexidartinib. When evaluated in a serum free hERG study, pexidartinib was shown to bind to the 
channel (IC50 0.7 µM). However, in a follow-up cardiac Purkinje fiber study, no test article-
related effects on repolarization, AP amplitude or speed of cardiac depolarization were observed. 
Furthermore, in a dog in vivo GLP cardiovascular safety study, all electrocardiographic 
parameters were qualitatively and quantitatively within normal limits, demonstrating that 
pexidartinib does not prolong cardiac repolarization up to the highest dose tested (1000 mg/kg). 


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7.0 
RATIONALE 
This study will provide an assessment of the safety, tolerability, PK, and PD activity of 
ascending doses of pexidartinib in patients with solid tumors. Each of six Extension cohorts will 
evaluate the potential of pexidartinib to provide clinical responses in these disease settings. 
These diseases consist of the following:  mucoepidermoid carcinoma (MEC) of the salivary 
gland, pigmented villo-nodular synovitis (PVNS), gastrointestinal stromal tumor (GIST), 
anaplastic thyroid carcinoma (ATC), solid tumors with malignant effusions, and a cohort of 
miscellaneous tumors. The rationale for initiation of these Extension cohorts is based on clinical 
responses observed in the dose escalation phase of the study as well as available literature 
support and specific pharmacology data with pexidartinib. A favorable benefit-risk ratio in an 
Extension cohort is likely to result in additional clinical development of pexidartinib in that 
indication. 
For MEC of the salivary gland, tumor-associated macrophages (TAMs) are strongly associated 
with tumor grade and stage (Shieh 2009), high levels of CSF-1 are expressed in saliva, and a 
dose escalation patient with MEC of the salivary gland had a pronounced and confirmed PR 
during treatment with pexidartinib. For PVNS, CSF-1 translocations can result in overexpression 
of CSF-1; the majority of cells express Fms, suggesting a tumor-landscaping effect with aberrant 
CSF1 expression in the neoplastic cells, leading to the abnormal accumulation of non-neoplastic 
cells that form a tumorous mass (West 2006). For GIST, pexidartinib has potent activity on both 
wild type Kit as well as acquired Kit mutations in exon 13 that are resistant to both imatinib and 
sunitinib (Liegl 2008). For ATC, recent work has highlighted the role of TAMs in the 
progression of thyroid cancers, and ATC in particular harbors abundant TAM infiltration 
(Ryder 2008). In-house data support that pexidartinib significantly reduces TAM levels. 
Malignant effusions are associated with high levels of M2 inflammatory macrophages, CSF-1, 
and inflammatory mediators such as IL-6 (Kaczmarek 2011). Additionally, the dose escalation 
patient with MEC of the salivary gland had a profound decrease in her pleural effusions. 
7.1 
Dose Escalation 
The selection of the starting dose of 200 mg QD is based on in vivo data from nonclinical 
pharmacological models, toxicologic results, and estimated PK parameters for humans. 
In accordance with guidelines for starting dose selection for investigational agents in cancer 
patients, dose ratios were calculated using the severely toxic dose in 10% (STD10) in rats and 
non-rodent highest non-severely toxic dose (HNSTD). The rat 28-day repeated-dose toxicology 
study did not establish a lethal dose in 50% of animals (LD50) or a STD10. However for the 
purposes of calculating a clinical starting dose for oncology, Plexxikon has assumed the highest 
dose tested in the rat study (200 mg/kg) to be the STD10. The dog study also did not establish a 
LD50, and thus the 300 mg/kg dose was considered to be the HNSTD. Using this algorithm and 
estimating the rat 1/10 x STD10 to be 20 mg/kg, a maximum recommended starting dose 
(MRSD) of 200 mg (or ~120 mg/m2) is proposed. Based on a comparison the 1/10 x STD10 


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(after converting mg/kg dose to mg/m2) to either the efficacious dose in the mouse BaF3 model 
or the proposed human MRSD of 200 mg, dose ratios for the rat (vs. human) were 13 and 1, 
respectively. The dose ratios in the dog, based on these assumptions and estimating the dog 
1/6 x HNSTD to be 50 mg/kg, were 111 and 8. 
Safety margins were also calculated by comparing values for free drug exposure (AUC) in rats 
and dogs at their 1/10 STD or 1/6 HNSTD, respectively. Pexidartinib is strongly protein bound 
in plasma of dogs, rats, and humans thus the fraction of pexidartinib unbound is a more 
meaningful comparison. In the comparison of rat vs. human, this method yielded an exposure 
ratio of 72, based on the predicted AUC of 14 ng•hr/mL at the proposed MRSD of 200 mg. 
Applying the same method of comparison and assumptions, exposure ratios of 2.4 and 10 were 
obtained for dog vs. human. 
In the case of calculating safety margins based on free drug exposure, the safety margin based 
upon the maximum recommended starting dose in humans is 10 or above. Thus, based on either 
dose ratios or free drug exposure ratios, the proposed MRSD of 200 mg in humans should 
represent a minimally effective dose with only a limited safety risk. 
For dose escalation planning, the effects of pexidartinib on bone marrow appear to be the most 
predictive of Fms and Kit activity on normal tissue. In both rats and dogs, both the incidence and 
severity of bone marrow hypocellularity with resulting decreased peripheral WBC counts is 
approximately linear with increasing dose and systemic exposure. This supports the planned dose 
escalation design as proposed in Section 16.4. 
7.2 
Route and Regimen 
Oral dosing with pexidartinib is planned for this study. Adequate systemic exposure is expected 
by oral administration. The proposed regimen for the first cohort is once daily. A twice-daily 
dosing regimen may be instituted for subsequent cohorts after review of the PK data from the 
initial cohort. For the Extension cohorts, the dose regimen is BID. 
7.3 
Treatment Period 
The proposed treatment period of 28 days (initial phase) was initially supported by 28 days of 
GLP general toxicology studies in 2 species for the 200 mg starting dose. Pexidartinib will be 
offered to each patient as long as both the patient and investigator agree that it continues to be 
well tolerated, and there has been no evidence of clinical disease progression. 
8.0 
OBJECTIVES 
8.1 
Primary 
The primary objective for the dose escalation phase of this study is to evaluate the safety and PK 
of pexidartinib in patients with solid tumors. The primary objective of the Extension cohorts is to 
evaluate the potential of pexidartinib as a single agent to provide clinical benefit in patients with 


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specific malignancies, based on literature, pharmacology data, or responses in the dose escalation 
phase of the study. 
8.2 
Secondary 
The secondary objective is to measure the pharmacodynamic activity of pexidartinib via plasma 
and urine biomarkers of Fms activity (all cohorts). 
9.0 
DESIGN 
9.1 
Description 
Dose Escalation Cohorts: 
This is an open-label, ascending dose trial of daily oral doses of pexidartinib administered to 
patients with solid tumors at approximately 4 investigational sites. A cohort of 3 patients will be 
assigned to the first dose group to receive 200 mg QD of pexidartinib. PK samples will be 
obtained after the first dose (through 8 hours) on C1D1 and prior to the first dose on C1D2. 
Patients will return to the clinical site on C1D8 for assessment of adverse events, PK (predose), 
and clinical laboratory assessments. They will then return to the clinic on C1D15 for evaluation 
of safety (AEs, clinical laboratory assessments, vital signs, ECG) and PK. Each cycle is defined 
as 28 days. If adequate safety and tolerability have been demonstrated for one cycle of 28 days at 
this dose level, the next cohort of 3 patients will be enrolled and treated with pexidartinib once or 
twice daily in a similar fashion as the first cohort. Each cohort will return to the clinic after 
4 weeks of dosing for a repeat evaluation of safety. Three patients will be enrolled to each dose 
level in the absence of Grade 2 or greater drug-attributable toxicity. Dose escalations of 100% 
are planned until the occurrence of drug-attributable Grade 2 or greater toxicity. In the absence 
of DLT, dose escalation will proceed sequentially by 50% increments from that point forward. 
In selected cohorts, 3–6 patients will be treated with a pexidartinib dose of either 100 mg QD or 
200 mg QD during a one-week run-in period before increasing to the full dose for that cohort, in 
order to profile the pharmacodynamic (PD) dose response activity of pexidartinib at doses below 
300 mg QD. 
Assignment of patient study numbers and verification of dose selection will be coordinated by 
the CRO assigned by the Sponsor, in collaboration with the Sponsor. A teleconference attended 
by the participating investigators, the CRO personnel, and the Sponsor will be held weekly or as 
needed to assess cumulative safety data and jointly confirm a decision to expand a cohort or dose 
escalate, in accordance with the criteria set forth in Section 16.4. 
After the initial 4 weeks of dosing, all patients will be able to continue receiving pexidartinib at 
their assigned dose provided they meet the criteria described in Section 13.8. Patients will return 
for clinical evaluation every 28 days and will have radiographic assessments (solid tumors) for 
response and progression after every two months of drug administration. 


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Extension Cohorts: 
At the recommended Phase 2 dose of 1000 mg/day, a total of six Extension cohorts will be 
enrolled and followed for safety and tumor response as assessed by CT scan every 8 weeks (or, 
beyond Cycle 40, every 24 weeks). Participants will remain on treatment until tumor 
progression, as long as there are no unacceptable toxicities. 
9.2 
Number of Patients 
Up to 50 patients will participate in the study in the dose escalation phase of the study. 
Approximately 10 patients will be enrolled in each of the five disease-specific Extension cohorts 
and up to 20 patients can be enrolled in the miscellaneous Extension cohort, for a total of 
approximately 70 patients with the possibility of 30 additional patients in a specific cohort if 
necessary (Section 24.6). 
9.3 
Number of Study Centers 
For dose escalation, the study will be performed at approximately 4 investigational sites. For the 
extension cohorts, up to approximately 18 sites will participate. 
9.4 
Duration of Patient Participation 
Each patient in the dose escalation phase of the study will participate in the study for 4 weeks at 
the designated dose, and then will be offered continued dosing with pexidartinib if it is well 
tolerated and in the absence of tumor progression. Patients in the Extension cohorts will be 
offered continued dosing with pexidartinib if it is well tolerated and in the absence of tumor 
progression. 
9.5 
Duration of Study 
The duration of the study is contingent on the number of dose levels in the dose escalation phase. 
Each dose escalation cohort will take approximately 6 weeks (7 weeks for cohorts that include a 
one-week run-in period), including 2 weeks of recruitment. For the Extension cohorts, patients 
will be treated with study drug until progression or toxicity, until the phase 4 PVNS continuation 
study has been opened. Upon study termination, patients that don’t transition to the phase 4 
continuation study will be provided information regarding potential transition to commercial 
drug. 
10.0 
SELECTION OF STUDY POPULATION 
All patients must participate in the consent process. During the consent process, the person 
obtaining consent must inform the patient of all elements of informed consent. No protocol-
specific procedures, including screening procedures, are to be performed until the patient has 
signed and dated an institutional review board (IRB)/independent ethics committee (IEC)-


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approved informed consent form. The study begins with the signing and dating of the informed 
consent form. Patients must also meet the inclusion and exclusion criteria to be enrolled in the 
study. 
10.1 
Inclusion Criteria 
1. Male or female patients ≥18 years old 
2. For the dose escalation cohorts, patients with advanced, incurable, solid malignancies in 
which the target kinases are thought to be linked to disease pathophysiology and whose 
cancers are confirmed histologically. The tumors must fulfill BOTH of the following 
criteria:  a) refractory to standard therapy, OR standard or curative therapy does not exist 
or is not considered appropriate by the investigator, AND b) tumor proliferation or 
metastasis could be driven or promoted in part by Flt3, Kit, or Fms/CSF-1 activity. 
3. For the Extension cohorts, patients must have measurable disease by RECIST v1.1 
criteria and meet the following disease-specific criteria: 
a. For advanced or recurrent MEC of the salivary gland, patients must not be candidates 
for curative surgery or radiotherapy. 
b. For PVNS (including tenosynovial giant cell tumor), patients must have a 
histologically confirmed diagnosis of inoperable progressive or relapsing PVNS, or 
resectable tumor requiring mutilating surgery, as well as demonstrated progressive 
disease in the last 12 months. 
c. For GIST, patients must have failed previous therapy with imatinib and sunitinib. 
Patients with known PDGFR mutations are excluded, but mutation testing is not 
required for study entry. 
d. For ATC, patients must have histologically or cytologically diagnosed advanced 
ATC. 
e. For metastatic solid tumors with documented malignant pleural, pericardial, and/or 
peritoneal effusions, patients must not be receiving specific therapy for the effusion 
(other than periodic drainage by needle) or have an indwelling drain. 
f. Other solid tumor types can be included in a miscellaneous cohort, provided there is a 
clear scientific rationale for treatment with pexidartinib and upon approval by the 
Medical Monitor. 
4. Women of child-bearing potential must have a negative pregnancy test within 7 days of 
initiation of dosing and must agree to use an acceptable non-hormonal method of birth 
control from the time of the negative pregnancy test up to one month after the last dose of 
study drug, Women of non-childbearing potential may be included if they are either 
surgically sterile or have been postmenopausal for ≥1 year. Fertile men must also agree to 
use an acceptable method of birth control while on study drug and for one month after the 
last dose of study drug. 
5. All associated toxicity from previous or concurrent cancer therapy must be resolved (to 
≤Grade 1 or Baseline) prior to administration of pexidartinib. 


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6. Willing and able to provide written informed consent prior to any study related 
procedures and to comply with all study requirements. 
7. ECOG performance status 0 or 1. 
8. Life expectancy ≥3 months. 
9. Adequate hematologic, hepatic, and renal function (absolute neutrophil count 
≥1.5 x 109/L, Hgb >9 g/dL, platelet count ≥100 x 109/L, AST/ALT ≤2.5 x ULN or 
<5 x ULN in the presence of liver metastases, albumin ≥3 g/dL, creatinine ≤1.5 x ULN or 
calculated CrCl >60 mL/min using Cockcroft-Gault formula). 
 
10.2 
Exclusion Criteria 
1. Specific anti-cancer therapy within 3 weeks prior to study drug administration. 
2. Investigational drug use within 28 days of the first dose of pexidartinib. 
3. Uncontrolled intercurrent illness. 
4. Refractory nausea and vomiting, malabsorption, external biliary shunt, or significant 
small bowel resection that would preclude adequate absorption. 
5. QTcF ≥450 msec (for males) or ≥470 msec (for females) at screening. 
6. The presence of a medical or psychiatric condition that, in the opinion of the Principal 
Investigator, makes the patient inappropriate for inclusion in this study. 
 
10.3 
Screen Failures 
Patients who sign an informed consent form, are not assigned to a treatment, and do not receive 
test article are defined as screen failures. For all screen failures, the investigator is to maintain a 
screening log that documents the screening number, patient initials, and reason(s) for screen 
failure. A copy of this log should be retained in the investigator's study files. 
11.0 
PRIOR TREATMENT 
Reasonable efforts will be made to determine all relevant treatment received by the patient 
within 1 month before administration of the test article and within 14 days before test article 
administration for over-the-counter drugs. All previous treatments for the solid tumor should be 
recorded. Relevant information must be recorded on the patient's case report form (CRF). This 
should include the name of the procedure or drug and other information required on the CRF. 
12.0 
CONCOMITANT TREATMENT 
Concomitant treatment is permitted if the medication is not expected to interfere with the 
evaluation of safety or efficacy of the study drug. During the study, if the use of any concomitant 
treatment becomes necessary (e.g., for treatment of an adverse event), the treatment must be 


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recorded on the CRF, including the reason for treatment, generic name of the drug, dosage, route, 
and date and time of administration. 
12.1 
CYP3A and UGT Inhibitors 
Although pexidartinib does not appear to inhibit CYP drug-metabolizing enzymes to an 
important extent, caution is warranted when administering pexidartinib to subjects taking drugs 
that are highly dependent on CYP3A4 for metabolism and have a narrow therapeutic index. It is 
not known whether systemic exposure to these medications will demonstrate an increase while 
patients are receiving pexidartinib. 
Of the five major CYP isoforms, 3A4 (BFC) may be involved in Phase I metabolism of 
pexidartinib, with possibly CYP1A2 playing a minor role (see Attachment 5 for a list of common 
CYP3A4 inhibitors and inducers). In general, strong inducers of CYP3A4 should be avoided 
unless clinically necessary. These include anticonvulsants, mycin antimicrobials, and 
antiretrovirals. Some common examples include inducers such as rifampicin, carbamazepine, 
phenytoin, efavirenz, and nevirapine. 
Avoid concomitant use of pexidartinib with moderate or strong CYP3A inhibitors or uridine 
diphosphate glucuronosyltransferase (UGT) inhibitors.  If concomitant use with a moderate or 
strong CYP3A inhibitor or UGT inhibitor cannot be avoided, reduce the pexidartinib dose 
according to the recommendations in Table 2. If concomitant use of a moderate or strong 
CYP3A inhibitor or UGT inhibitor is discontinued, increase the pexidartinib dose (after 3 plasma 
half-lives of the moderate or strong CYP3A inhibitor or UGT inhibitor) to the dose that was used 
before starting the inhibitor. 
Table 2: 
Recommended Dosage Reductions for Pexidartinib with Concomitant 
Use of Moderate or Strong CYP3A Inhibitors or UGT Inhibitors 
Current Total Daily Dose 
Modified Total Daily Dose 
Administration of Modified Total Daily Dose 
800 mg 
400 mg 
200 mg twice daily 
600 mg 
400 mg 
200 mg twice daily 
400 mg 
200 mg 
200 mg once daily 
 
12.2 
Hormonal Contraceptives 
Pexidartinib has been indicated to be a moderate CYP3A4 inducer, as concurrent administration 
of pexidartinib decreased the AUC0-∞ of the CYP3A4 substrate midazolam by 57%. As the 
hormonal contraceptive ethinyl estradiol is a CYP3A4 substrate, there is a potential that exposure 
of ethinyl estradiol may decrease on concurrent administration with pexidartinib. As pexidartinib 
may cause embryo-fetal harm when administered to a pregnant woman, females of reproductive 
potential should be advised to use an effective, non-hormonal method of contraception during 
treatment with pexidartinib and for one month after the last dose. Males with female partners of 
reproductive potential should be advised to use an effective method of contraception during 


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treatment with pexidartinib and for one month after the last dose. Female partners of male 
patients should concurrently use effective contraceptive methods (hormonal or non-hormonal). 
12.3 
Acid-reducing Agents 
Avoid the concomitant use of proton pump inhibitors (PPIs) while taking pexidartinib. As an 
alternative to a PPI, administer pexidartinib 2 hours before or 2 hours after taking a locally-
acting antacid, or if using a histamine 2 (H2)-receptor antagonist, administer pexidartinib at least 
2 hours before or 10 hours after taking an H2-receptor antagonist. 
13.0 
PROCEDURES (DOSE ESCALATION COHORTS) 
13.1 
Screening Evaluation 
Within 21 days (28 days for the one-week run-in patients) before test article administration on 
study C1D1 (28 days for assessment of tumor burden), all patients will have a screening 
evaluation that includes the following: 
1. Sign and date an IRB/IEC-approved informed consent form before any study-specific 
screening procedures are performed.  
2. Medical history including ethnic origin (Hispanic or non-Hispanic) and race (white, 
black, Asian, or other). 
3. Physical examination including weight (kg) and height (cm). 
4. Vital signs (sitting blood pressure, pulse rate, and respiratory rate, and oral temperature 
[°F]). 
5. Standard 12-lead ECG (in triplicate 2 minutes apart) to determine the mean QTc, which 
must be <450 msec). 
6. Recording of concomitant medications. 
7. Clinical laboratory evaluation (hematology, chemistry, coagulation, urinalysis, TSH, 
serum pregnancy test (women of child-bearing potential); see Attachment 1). 
8. ECOG Performance status assessment. 
9. Baseline assessment of tumor burden (see Attachment 4). 
10. Tumor biopsy and/or FDG-PET scan [OPTIONAL]. 
A patient who meets all of the inclusion criteria will be assigned a patient number. Each patient 
should fast for 1 hour before and 1 hour after test article administration. 
13.2 
Run-In Period (Selected Cohorts) – Cycle 1 Day(-7), Day(-6), and Day(-4) 
1. All 3 days:  Recording of concomitant medications and adverse events. 


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2. All 3 days:  Vital signs (sitting blood pressure, pulse rate, and respiratory rate and oral 
temperature [°F]). 
3. All 3 days:  Pre-dose blood sample collection for PK analysis and response biomarkers. 
4. C1D(-7):  Post-dosing blood collection for PK analysis. 
 
13.3 
Pre-Treatment (Baseline):  Cycle 1 Day 1 
Patients will return to the clinic on C1D1 and will undergo the following procedures: 
1. Recording of concomitant medications. 
2. Vital signs (sitting blood pressure, pulse rate, and respiratory rate and oral temperature 
[°F]). 
3. Standard 12-lead ECG in triplicate 2 minutes apart. 
4. Pre-dose blood sample collection for PK analysis and response biomarkers. 
5. Pre-dose morning urine collection for response biomarkers. 
 
13.4 
Post-Treatment:  Cycle 1 Day 1 and Cycle 1 and Day 2 
On C1D1, each patient will receive the assigned dose of test article. AE monitoring will be 
continuous. Vital signs, ECGs, laboratory evaluations, and PK sample collections will be 
completed at designated times during the study (see Trial Flow Charts). The blood sample for PK 
analysis should be collected at the scheduled time, within the windows noted in the PK section. 
ECG in triplicate will be repeated at 2, 4, and 6 hours after administration of study drug. Pulse 
and blood pressure will be repeated at 1 and 4 hours post administration of study drug on C1D1. 
Patients will return to the clinic on the morning of C1D2 prior to dosing on that day for 
evaluation and blood draw to obtain the predose PK time-point (approximately 12 hours after the 
previous evening dose for a BID dosing regimen). 
13.5 
Cycle 1 Day 8 ± 1 Day 
Patients will return for evaluation of AEs, concomitant meds, vital signs, physical exam, clinical 
laboratory values, and collection of serum and morning urine for biomarker assessments. A 
predose blood sample for PK and as well as predose blood samples for response biomarkers will 
be obtained, as well as a predose morning urine for response biomarkers (see Trial Flow Charts, 
pp. 16–20). 
13.6 
Cycle 1 Day 15 and Cycle 1 Day 16 (± 2 Days) 
At the C1D15 visit, AEs, concomitant meds, vital signs, physical exam, and clinical laboratory 
values will be recorded. Triplicate ECGs will be obtained 2, 4, and 6 hours postdose, and PK 


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evaluation performed as on C1D1 (see Trial Flow Charts, pp. 16–20). Patients will return to the 
clinic on the morning of C1D16 prior to dosing on that day for evaluation and blood draw to 
obtain the predose PK time-point (approximately 12 hours after the previous evening dose for a 
BID dosing regimen). An on-treatment tumor biopsy and/or FDG-PET scan may be obtained in 
selected patients. 
13.7 
Cycle 2 Day 1 (± 7 Days) 
On C2D1, evaluations will consist of AEs, concomitant meds, physical exam with vital signs, 
ECOG performance status assessment, clinical laboratory values, a predose PK time-point, 
serum/urine collection for biomarkers, and blood collection for circulating tumor cells. 
13.8 
Continued Dosing 
Pexidartinib, at the assigned dose, will be offered to each patient as long as both the patient and 
investigator agree that it continues to be well tolerated, and there has been no evidence of disease 
progression. Study visits will occur at approximately 4 week (± 7 days) intervals for assessment 
of safety (AEs, concomitant meds, physical exam with vital signs, and clinical laboratory 
values), PK, and ECOG status, and 8 week (± 7 days) intervals (or as clinically indicated) for 
assessment of tumor response or progression. In addition, in the dose escalation phase, 
hematology (CBC with differential) will be measured every two weeks after Cycle 1. The mid-
cycle values may be provided from a local laboratory. 
13.9 
Dose Modification (Dose Escalation Cohorts) 
Reduction/interruption of dosing for adverse events may take place any time. Below are general 
guidelines for dosage modification for pexidartinib–related toxicities as well as guidelines for 
their management. 
For toxicities which are considered by the investigator unlikely to develop into serious or life-
threatening events (e.g., alopecia, altered taste, etc.), treatment should be continued at the same 
dose without reduction or interruption. In addition, if any Grade 1 toxicity occurs, treatment 
should be continued at the original dose without interruption. If drug-related Grade 2 toxicity 
occurs, the Sponsor should be notified, and the investigator may discontinue or interrupt 
treatment with pexidartinib if it is considered to be medically appropriate. If dosing is 
interrupted, treatment at the same dose may be resumed once toxicity is ≤Grade 1. 
If Grade 3 or 4 drug-related toxicity occurs, immediate treatment interruption will be followed 
by a selective dose reduction depending on the types of toxicity, and based on discussion and 
agreement between the investigator and Sponsor after recovery of the toxicity to at least Grade 1. 
pexidartinib re-challenge after interruption of dosing may occur only if the investigator and 
Sponsor agree that it is in the best interest of the patient. In addition, the patient’s ECOG 
performance status must be 0–2. Following re-challenge at a modified dose, study visits will 
occur at approximately one month intervals for assessment of safety and PK, and two month 


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intervals for assessment of tumor response or progression. Dosing interruptions longer than 
3 weeks should generally result in discontinuation from the study, unless the patient has 
demonstrated a clinical benefit from therapy and would like to continue dosing with study drug. 
All adjustments should be made in consultation with the Medical Monitor. 
If treatment with pexidartinib is interrupted due to bone marrow toxicity in Cycle 2 and beyond, 
growth factors may be used. However, growth factors should not be used concomitant with study 
drug dosing, as it will interfere with the assessment of drug toxicity. 
14.0 
PROCEDURES (EXTENSION COHORTS) 
14.1 
Screening Evaluation 
Within 21 days before test article administration on study C1D1 (28 days for assessment of 
tumor burden), all patients will have a screening evaluation that includes the following: 
1. Sign and date an IRB/IEC-approved informed consent form before any study-specific 
screening procedures are performed. 
2. Medical history including ethnic origin (Hispanic or non-Hispanic) and race (white, 
black, Asian, or other). 
3. Physical examination including weight (kg) and height (cm).Vital signs (sitting blood 
pressure, pulse rate, and respiratory rate, and oral temperature [°F]). 
4. Standard 12-lead ECG to determine the QTcF, which must be <450 msec (for males) or 
<470 msec (for females). 
5. Recording of concomitant medications. 
6. Clinical laboratory evaluation (hematology, chemistry, urinalysis, serum pregnancy test 
(women of child-bearing potential) 
7. ECOG Performance status assessment. 
8. Baseline assessment of tumor burden (see Attachment 4). 
9. Obtaining archival tumor tissue [OPTIONAL] – this can occur anytime during or after 
the Screening visit 
10. Tumor biopsy and/or FDG-PET scan [OPTIONAL]. 
11. For patients in the malignant effusion Extension cohort, recording of the number of 
effusion removal procedures and volume, if appropriate (e.g. paracentesis or 
thoracentesis) required over the previous 6 months. 
12. For the GIST cohort, tumor genotyping results for Kit and PDGFR from a CLIA-certified 
laboratory should be provided if available. 


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13. For patients enrolled after the implementation of Amendment 8, dispense six (6) Numeric 
Rating Scale (NRS) for PVNS Symptoms questionnaires with instructions and reminders 
to complete the daily questionnaire on an outpatient basis for the 6 consecutive days 
(Day -6 to Day -1) prior to the next scheduled study visit on C1D1 and to bring the 
completed questionnaires back at that visit. NOTE:  At each of the applicable visits, sites 
should refrain from providing any interpretation of how the questions should be answered 
by the patient. 
A patient who meets all of the inclusion criteria will be assigned a patient number. Each patient 
should fast for 1 hour before and 1 hour after test article administration. 
14.2 
Pre-Treatment (Baseline):  Cycle 1 Day 1 
Patients will return to the clinic on C1D1 and will undergo the following procedures: 
1. Recording of concomitant medications. 
2. Vital signs (sitting blood pressure, pulse rate, and respiratory rate and oral 
temperature [°F]). 
3. Pre-dose blood sample collection for PK analysis and response biomarkers. 
4. Pre-dose morning (second void, between approximately 7 AM and 10 AM) urine 
collection for response biomarkers. 
5. For patients enrolled after the implementation of Amendment 8, collect the six (6) 
completed NRS for PVNS Symptoms questionnaires and give the patient another one of 
the questionnaires to complete predose. NOTE:  the NRS for PVNS Symptoms 
questionnaire to be completed in the clinic is exactly the same as the other 6 daily 
questionnaires. 
6. For patients enrolled after the implementation of Amendment 8, then give the patient the 
Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) 
questionnaire to complete predose. NOTE:  At each of the applicable visits, sites should 
refrain from providing any interpretation of how the questions should be answered by 
the patient. 
 
14.3 
Post-Treatment:  Cycle 1 Day 1 
On C1D1, each patient will receive the assigned dose of test article. AE monitoring will be 
continuous. 
14.4 
Cycle 1 Day 15 (± 2 days) 
At the C1D15 visit, AEs, concomitant meds, vital signs, physical exam, test article compliance, 
and clinical laboratory values will be recorded. An ECG will be obtained, and PK blood samples 


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will be obtained predose (AM) and at 1, 2, 4 and 6 hours postdose (for patients who have an 
afternoon clinic visit, the documentation of dosing and PK sampling times is described in 
Section 20.1). If obtained at the pre-dose Baseline, a repeat tumor biopsy and/or FDG-PET scan 
may be obtained. 
For patients enrolled after the implementation of Amendment 8, give the patient the NRS for 
PVNS Symptoms questionnaire to complete predose. Then give the patient the WOMAC 
questionnaire to complete predose. Then dispense six (6) NRS for PVNS Symptoms 
questionnaires with instructions and reminders to complete the daily questionnaire on an 
outpatient basis for the 6 consecutive days (Day -6 to Day -1) prior to the C2D1 study visit and 
to bring the completed questionnaires back at that visit. 
14.5 
Cycle 2 Day 1 (± 7 days) 
On C2D1, evaluations will consist of AEs, concomitant meds, compliance, physical exam with 
vital signs, weight, ECOG performance status assessment, clinical laboratory values, a predose 
PK time-point, and serum/urine collection for biomarkers. 
For patients enrolled after the implementation of Amendment 8, collect the six (6) completed 
NRS for PVNS Symptoms questionnaires and give the patient another one of the questionnaires 
to complete predose. Then give the patient the WOMAC questionnaire to complete predose. 
Once all other C2D1 procedures have been completed, dispense six (6) NRS for PVNS 
Symptoms questionnaires with instructions and reminders to complete the daily questionnaire on 
an outpatient basis for the 6 consecutive days (Day -6 to Day -1) prior to the next scheduled 
study visit and to bring the completed questionnaires back at that visit. 
14.6 
Continued Dosing 
14.6.1 
Visits through Cycle 40 
Pexidartinib, at the assigned dose, will be offered to each patient as long as both the patient and 
investigator agree that it continues to be well tolerated, and there has been no evidence of disease 
progression. Study visits will occur at 4-week (± 7 days) intervals for assessment of safety (AEs, 
concomitant meds, physical exam with weight and vital signs, PK, and clinical laboratory 
values), compliance, and ECOG status, and 8-week intervals (or as clinically indicated) for 
radiographic assessment of tumor response or progression. Radiographic assessment of tumor 
status can be performed every four cycles in patients who complete 15 cycles of treatment and 
have Cycle 13 and Cycle 15 MRI scans that indicate SD or better per local RECIST v1.1 reading 
(cycle 19, 23, 27…). For PVNS patients, the Sponsor will receive radiologic images for possible 
retrospective analysis of treatment response, to be performed by a central vendor. For the 
malignant effusion cohort, the frequency and volume of on-study fluid removal procedures 
should be recorded. 


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For patients enrolled after the implementation of Amendment 8, every four weeks collect the 
six (6) completed NRS for PVNS Symptoms questionnaires and give the patient another one of 
the questionnaires to complete predose. Then give the patient the WOMAC questionnaire to 
complete predose. Once all other procedures have been completed at the visit, dispense six (6) 
NRS for PVNS Symptoms questionnaires with instructions and reminders to complete the daily 
questionnaire on an outpatient basis for the 6 consecutive days (Day -6 to Day -1) prior to the 
next scheduled study visit 4 weeks later and to bring the completed questionnaires back at that 
visit. 
14.6.2 
Visits after Cycle 40 
Pexidartinib, at the assigned dose, will be offered to each patient as long as both the patient and 
investigator agree that it continues to be well tolerated, and there has been no evidence of disease 
progression. Study visits will occur at 12-week (± 7 days) intervals (i.e., every 3 cycles) for 
assessment of safety (AEs, concomitant meds, physical exam with weight and vital signs, 
hematology, and chemistry), compliance, and 24-week intervals (i.e., every 6 cycles, or as 
clinically indicated) for radiographic assessment of tumor response or progression. For patients 
without ongoing Grade 2 or greater related adverse events, frequency of on-site visits may be 
extended to every 24 weeks, with remote serum chemistry and hematology as well as a telephone 
check-in for AEs and con meds and to review remote safety laboratory data performed 12 weeks 
after each on-site visit; Weight, PE, Vitals, WOMAC, NRS, and IP compliance will not be 
performed remotely). For PVNS patients, the Sponsor will receive radiologic images for possible 
retrospective analysis of treatment response, to be performed by a central vendor. 
At every on-site visit the six (6) completed NRS for PVNS Symptoms questionnaires will be 
collected and the patient will be given another one of the questionnaires to complete predose. 
Then the patient will be given the WOMAC questionnaire to complete predose. Once all other 
procedures have been completed at the visit, six (6) NRS for PVNS Symptoms questionnaires 
will be given to the patient with instructions and reminders to complete the daily questionnaire 
on an outpatient basis for the 6 consecutive days (Day -6 to Day -1) prior to the next scheduled 
study visit 12 weeks later and to bring the completed questionnaires back at that visit. 
14.7 
Dose Modification (Extension Cohorts) 
Reduction/interruption of dosing for adverse events may take place at any time during the study 
according to guidelines in Table 3. Dose reductions should occur in increments of 200 mg/day, 
depending on the toxicity grade, as noted in Table 3. 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. Interruptions due to toxicity 


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lasting >3 weeks require treatment discontinuation unless the medical monitor approves 
continuation. 
Table 3: 
Dose Modifications 
Event 
Severity 
Pexidartinib Dosage Modifications 
Hepatoxicity 
Increased ALT 
and/or AST 
>3 to 5 × ULN 
Withhold and monitor liver tests weekly. 
If AST and ALT ≤3 × ULN within 4 weeks, resume at reduced 
dose. 
If AST or ALT not ≤3 × ULN in 4 weeks, permanently 
discontinue pexidartinib. 
>5 to 10 × ULN 
Withhold and monitor liver tests twice weekly. 
If AST and ALT ≤3 × ULN within 4 weeks, resume at reduced 
dose. 
If AST or ALT not ≤3 × ULN in 4 weeks, permanently 
discontinue pexidartinib. 
>10 × ULN 
Permanently discontinue pexidartinib. 
Monitor liver tests twice weekly until AST or ALT ≤5 × ULN, 
then weekly until ≤3 × ULN. 
Increased ALPa 
and GGT 
ALP >2 × ULN with reflex 
test of GGT >2 × ULN 
Permanently discontinue pexidartinib.  Monitor liver tests 
including GGT twice weekly until ALP ≤5 times ULN, then 
weekly until ≤2 × ULN. 
Increased 
bilirubin 
TB >ULN to <2 × ULN 
or 
DB >ULN and <1.5 × ULN 
Withhold and monitor liver tests twice weekly. 
If an alternate cause for increased bilirubin is confirmed and 
bilirubin <ULN within 4 weeks, resume at reduced dose. 
If bilirubin not <ULN in 4 weeks, permanently discontinue 
pexidartinib. 
TB ≥2 × ULN 
or 
DB >1.5 × ULN 
Permanently discontinue pexidartinib. 
Monitor liver tests twice weekly until bilirubin ≤ULN. 
Adverse Reactions or Other Laboratory Abnormalities 
Any 
Severe or intolerable 
Withhold until improvement or resolution. 
Resume at a reduced dose upon improvement or resolution. 
ALT = alanine aminotransferase; ALP = alkaline phosphatase; AST = aspartate aminotransferase;  
DB = direct bilirubin; GGT = gamma-glutamyl transferase; TB = total bilirubin; ULN = upper limit of normal 
a 
Confirm ALP elevations as liver isozyme fraction. 
 
Dose interruptions for Grade 2 non-hematologic toxicity for up to 1 week can be implemented at 
the discretion of the treating physician to manage intolerable or clinically significant toxicity. No 
dose reduction is required when resuming treatment. 
Liver enzyme abnormalities, including increased transaminase values, have occurred with 
pexidartinib and should also be managed as described in Table 4. 


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PROPRIETARY 
Re-challenge with a reduced dose of pexidartinib may result in a recurrence of increased serum 
transaminases, bilirubin, or ALP. Monitor liver tests weekly for the first month after re-
challenge. 
Table 4: 
Additional Liver Evaluation 
Evaluation 
Comments 
Increase frequency of testing liver chemistries to twice per 
week (if Grade 3+), 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 days. 
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 (e.g., aminotransferase increase concurrent with 
hyperbilirubinemia, or liver biopsy suggesting cholestasis and/or ductopenia), patients will be 
followed to assess long-term outcome. Additional diagnostic and follow-up procedures might be 
implemented as appropriate to fully assess the event. 
14.7.1 
Renal Impairment 
A reduced dose of 600 mg/day (200 mg in the morning and 400 mg in the evening) is 
recommended in study subjects with mild to severe renal impairment (creatinine clearance [CLcr] 
15 to 89 mL/min estimated by Cockcroft-Gault using actual body weight). 


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14.8 
End of Study/Early Withdrawal (last dose for subjects that enroll in phase 4 
continuation study or immediately transition to commercial pexidartinib; last 
+ 30 ± 7 days for all other subjects) 
Note: In order to be eligible to participate in the phase 4 PVNS continuation study, subjects must 
not be withdrawn from PLX108-01 until they are ready to begin screening in the phase 4 
continuation study. Screening for the phase 4 continuation study may occur prior to withdrawal 
from PLX108-01. 
Following the last dose of drug, all patients will have the following evaluations: 
1. Physical examination including weight (kg) and vital signs (sitting blood pressure, pulse 
rate, and respiratory rate, and oral temperature [°F]). 
2. Standard 12-lead ECG to determine QTcF. 
3. Clinical laboratory evaluation (hematology, chemistry, urinalysis, serum pregnancy test 
(women of child-bearing potential). 
4. ECOG Performance status assessment. 
5. For patients enrolled after the implementation of Amendment 8, collect the six (6) 
completed NRS for PVNS Symptoms questionnaires and give the patient another one of 
the questionnaires to complete predose. NOTE:  the NRS for PVNS Symptoms 
questionnaire to be completed in the clinic is exactly the same as the other 6 daily 
questionnaires. 
6. For patients enrolled after the implementation of Amendment 8, then give the patient the 
Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) 
questionnaire to complete predose. NOTE:  At each of the applicable visits, sites should 
refrain from providing any interpretation of how the questions should be answered by the 
patient. 
7. Radiographic assessment of tumor burden. 
8. Test article compliance. 
9. Concomitant medications. 
10. Collection of surgical data - If surgical resection of the tumor is performed within 30 
days of the last dose of study treatment, details of the surgery and its outcome should be 
obtained. 
 
14.9 
Twelve-week Follow-up (last dose + 12 weeks [+4-week window]) 
Within +12 weeks (+4 week window) of the last dose of study drug, all patients that don’t enroll 
in the phase 4 continuation study or transition immediately to commercial pexidartinib will have 
the following study evaluations: 


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1. Radiographic assessment of tumor burden 
2. Collection of surgical data - If surgical resection of the tumor is performed within 
12 weeks of the last dose of study treatment, details of the surgery and its outcome should 
be obtained. 
For patients who miss the 30-day and 12-week post-treatment follow-up visit, post-treatment 
radiographic assessments from any source (e.g., primary care provider) within 24 weeks of last 
dose are acceptable. 
15.0 
DISCONTINUATION OF TREATMENT AND WITHDRAWAL OF PATIENTS 
The reasons a patient may discontinue or be withdrawn from the study include, but are not 
limited to, adverse event, disease progression, patient request, protocol violation, patient 
noncompliance, study termination by the Sponsor, and subject transition to commercial 
pexidartinib (TuralioTM). When a patient discontinues or is withdrawn, the investigator will 
notify the Sponsor and should perform the procedures indicated in the End of Study visit column 
in the study flow chart 7–30 days after the last dose of study drug and prior to initiation of any 
new anti-cancer therapy. Follow-up information will be obtained for patients who discontinue 
their participation in or are withdrawn from the study. Patients withdrawn from the study will be 
replaced at the discretion of the medical monitor and the investigator. Test article administration 
may be discontinued for an adverse event or at the discretion of the investigator. 
16.0 
TEST ARTICLE 
16.1 
Test Article Administration 
Test article (study drug) will be administered only to patients who have signed and dated an 
informed consent form. Test article will be administered on days 1 through 28 or longer in the 
fasting state with 240 mL (8 oz.) of room-temperature water. The patient should fast at least 
2 hours before administration and 1 hour after administration of the test article. Patients will be 
permitted to eat a low-fat snack (e.g., crackers, toast, tea) during the fasting period if needed. 
Test article will be taken orally by swallowing the capsules. For patients with tumors of the head 
and neck area who may have difficulty swallowing capsules, test article may be administered by 
emptying the contents of the dose (e.g., 3 x 200 mg capsules in the morning, and 2 x 200 mg 
capsules in the evening for a total daily dose of 1000 mg/day) into an empty glass. 
Approximately 6 ounces of orange juice, apple juice, or cola should be added to the glass, stirred 
vigorously with a spoon and the patient should drink the contents, add 2 additional ounces to the 
glass, stir again and drink the remaining contents. The entire dose should be consumed within 
30 minutes and the capsule shells should be discarded in a bio-disposable hazard bag provided 
by the site. NOTE:  The Plexxikon Medical Monitor must be consulted prior to implementation 
of this alternative method of test article administration. 


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Test article administration will start on C1D1 and should be taken once daily for the initial 
cohort. Subsequent cohorts may utilize a twice daily dosing regimen, with study drug being 
administered at approximately 12-hour intervals. On PK collection C1D1 and C1D15, the 
patients will be administered pexidartinib capsules at the clinical site. The time of the 
administration will be recorded. On non-PK collection days, patients will administer the study 
drug at home. Missed doses (i.e., outside of a + 2-hour window) should be skipped and not 
administered as a double dose at the next administration. Patients who vomit their dose should be 
instructed to NOT to make up that dose. Patients should take precautions to prevent accidental 
ingestion of or exposure to investigational drug by family members or other cohabitants. 
Food-Effect Assessment: 
Once the optimal dose has been identified at steady state (C1D15) in the fasted state, a subset of 
patients may be studied in this trial to assess the effect of food on pexidartinib exposure. For 
active patients who consent to this optional procedure, the food-effect assessment will only be 
initiated on or after the C1D15 visit. C1D15 will remain a fasted PK analysis visit, i.e., PK 
samples should be obtained in the fasted state at predose (AM) and 1, 2, 4 and 6 hours postdose. 
After electing to participate in this optional procedure, at their next clinic visit these patients will 
have PK samples drawn prior to the morning dose and then 2 and 4 hours post-dose in the fasting 
state (with a low-fat snack if needed, as above). This will serve as a baseline steady state PK 
assessment of pexidartinib administered in the fasting state. The patients should then be 
instructed to begin dosing study drug with meals, beginning with the evening dose on the day of 
this visit (if a BID dosing regimen is being used). Each pexidartinib dose should be taken with 
food (for example breakfast and dinner). The dose should be administered within 30 minutes of 
beginning the meal, but not before the meal. The patients will be asked to return to the clinic  
2–4 weeks after the food-effect assessment has begun. At this visit, a total of 3 blood samples 
(predose that morning, 2 and 4 hours post-dosing with a meal) will be drawn for analysis of 
pexidartinib exposure. 
After the effect of food on pexidartinib exposure has been determined, all patients in this trial 
will be informed whether or not to take study drug with meals. 
16.2 
Packaging and Labeling 
Pexidartinib-HCl capsules (100 mg or 200 mg strength of the active free base of pexidartinib) are 
manufactured, packaged, and labeled according to GMP and GCP. 
16.3 
Storage and Stability 
Pexidartinib-HCl capsules will be stored at the clinical site, as indicated on the study drug label, 
i.e., room temperature (not above 25°C). 
Patients will be requested to store the pexidartinib at the recommended storage conditions noted 
on the label out of the reach of children or other cohabitants. 


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16.4 
Dose Escalation 
At least three and up to six patients will be enrolled in each dose level using 100% dose 
increments for each level in the absence of Grade 2 or greater drug-attributable toxicity. In each 
cohort (and following the one-week run-in period for applicable patients), the first patient will be 
observed for at least one week before additional patients in that cohort are treated with 
pexidartinib. Following the one-week run-in period for applicable patients, upon the occurrence 
of Grade 2 or greater toxicity, in the absence of DLT, dose escalation will proceed sequentially 
by up to 50% increments. Following the one-week run-in period for applicable patients, if 
one DLT is observed in one of the first 3 patients during the first cycle in a given cohort, at least 
6 patients will be treated at that dose. Following the one-week run-in period for applicable 
patients, if DLT is observed in 2 or more of 6 patients at a dose level, then the next lower dose 
level will be expanded or an intermediate dose level will be introduced. Dose escalation will only 
be permitted if adequate safety and tolerability have been demonstrated at the previous lower 
dose for 28 days for the first 3 patients. The DLTs observed in all patients in the first cycle will 
be taken into account when evaluating the safety of a given dose level to support dose escalation 
or selection of a recommended Phase 2 dose. Dose escalation decisions will be made during 
teleconferences attended by the medical monitor and appropriate personnel from all participating 
sites. 
Dose Limiting Toxicities during the first 28 days of treatment are defined as follows: 
 Any CTCAE (version 4) Grade 4 toxicity (Grade 4 neutropenia for ≥3 days) 
 Any CTCAE Grade 3 toxicity other than Grade 3 lymphopenia 
 CTCAE Grade 2 vomiting within 2 hours of study drug administration on 3 consecutive 
days despite optimal anti-emetic therapy 
 If, for any reason, either the Principal Investigator or Sponsor deems further dose 
escalation inappropriate 
The specific criterion for Grade 2 vomiting is based on the observations in the dog toxicity 
studies; vomiting may preclude adequate oral absorption of study drug. The justification for the 
exemption of Grade 3 lymphopenia is based on the following:  a) modest lymphopenia of 
uncertain mechanism was observed in the 28-day GLP rat repeat dose toxicology study, but only 
at significant dose and exposure multiples vs. the clinic, b) asymptomatic and clinically 
nonsignificant lymphopenia is a common finding in patients with advanced solid tumors, 
c) patients may exhibit continuing or even worsening asymptomatic lymphopenia during clinical 
trials with no clinical consequence, and d) the clinical risk of G3 lymphopenia, in the absence of 
concurrent atypical infections, is minimal. 
The MTD is defined as the dose at which ≤1 of 6 patients experience a DLT during Cycle 1, with 
the next higher dose having at least 2 of the up to 6 patients experiencing a DLT during Cycle 1. 


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No dose reductions are to be made during Cycle 1, which is the primary evaluation period for 
safety. Dosing will be discontinued based on DLT criteria noted above. If a patient has a 
documented objective clinical benefit despite having an individual DLT, continued dosing at a 
reduced dose may be allowed, after consultation with the FDA. 
16.5 
Test Article Accountability, Reconciliation, and Return 
The investigator is accountable for all test article supplied by the Sponsor. The designated copies 
of the completed dispensing and inventory record will be returned to the Sponsor after the 
Sponsor has performed accountability procedures. 
All test articles must be returned to the Sponsor or contract distribution center with the 
appropriate form. Unused test article may also be destroyed and documented at the investigative 
site in accordance with GCP and site SOPs. 
16.6 
Test Article Compliance 
Test article should be administered at each scheduled clinic visit. At each clinic visit, patients 
will be questioned about their compliance with study drug administration. 
17.0 
MEASURES TO MINIMIZE/AVOID BIAS 
Patients are numbered sequentially. Each patient will be assigned a unique number and will keep 
this number for the duration of the study. Patient numbers will not be reassigned or reused for 
any reason. Patients should be identified to the Sponsor only by their assigned number, initials, 
date of birth, and sex. The investigator must maintain a patient master log. 
18.0 
SAFETY EVALUATION 
Routine safety and tolerability will be evaluated from the results of reported signs and 
symptoms, scheduled physical examinations, vital sign measurements, 12-lead ECGs (including 
QTc intervals), and clinical laboratory test results. 
Safety data will be reviewed by the investigator and the medical monitor. Safety of pexidartinib 
will be established after 28 days of dosing at the previous dosage group before the next higher 
dose is initiated. 
More frequent safety evaluations may be performed if clinically indicated or at the discretion of 
the investigator. All AEs will be recorded from the time the patient receives the first dose of 
study drug until the patient’s End of Study visit. 
18.1 
Physical Examination 
Physical examinations will be performed by a licensed physician, physician’s assistant, or nurse 
practitioner. 


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18.2 
Vital Signs 
Vital signs will be measured at the study days and times as noted in the flow charts. 
18.3 
Electrocardiograms 
12-lead ECGs will be recorded at screening to assess study eligibility. Please refer to the flow 
charts for study days and times. For the dose escalation cohorts only, triplicate ECGs will be 
obtained. Patients should rest in the supine position for at least 5 minutes before the ECG 
recording is started. The ECGs should be reviewed promptly by a qualified physician (or 
physician’s assistant, nurse practitioner) and any clinically important finding recorded on the 
appropriate CRF. The investigator is responsible for providing the interpretation of all ECGs. 
The results will include heart rate, PR interval, QRS interval, QT interval, and QTc interval. 
18.4 
Safety Laboratory Determinations 
Laboratory evaluations will be performed at each participating site at the study visits as noted 
in the flow charts. For the dose escalation cohorts, blood for CBC values should be obtained 
mid-cycle after Cycle 1. Please see Attachment 1 for the specific laboratory tests to be 
performed. 
19.0 
BIOMARKER SAMPLES 
Plasma and spot urine samples will be obtained as noted in the study flow charts. 
Details on the preparation, handling, and shipping of blood samples are covered in the 
Laboratory Manual. 
20.0 
PHARMACOKINETIC EVALUATION 
20.1 
Blood Collection 
Venous blood samples will be collected in lithium heparin to measure concentrations of 
pexidartinib for each PK blood collection. 
For QD dosing in the dose escalation cohorts, PK samples will be obtained on C1D1 and C1D15 
within 30 minutes before dose administration (predose, time 0) and at 30 minutes, 1, 2, 4, and 
8 hours post-dosing. For BID dosing, PK samples will be obtained on C1D1 and C1D15 predose 
(AM) and 1, 2, 4, and 7 hours postdose. The second dose will be administered, and a PK sample 
will be obtained 1 hour post the second dose (8 hours post the first dose). Predose samples will 
be obtained on C1D2, C1D8, and C1D16, and then every 4 weeks during continued dosing. 
Patients should be informed to refrain from taking study drug until they arrive in the clinic. If a 
patient experiences a DLT or SAE, a single blood sample for PK analysis should be obtained 
within 48 hours of the event. Samples will be collected and processed according to the 
instructions in Attachment 2 and Attachment 3. 


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In the Extension cohorts, PK samples should be obtained pre-dose on C1D1. On C1D15, the 
samples should be obtained pre-dose and 1, 2, 4, and 6 hours postdose. During continued dosing, 
PK samples should be obtained once every 4 weeks (predose). PK sampling will no longer occur 
beyond C40. 
Blood samples for PK analysis should be collected at the requested time but the following 
sample collection windows will be allowed:  ±5 minutes for the 30-minute postdose sample; 
±10 minutes for the hour 1 through 4–8 postdose samples; within ±30 minutes of dosing on 
C1D2, C1D8, and C1D16. The exact time of collection should be noted in the CRFs. 
If a patient has an afternoon clinic visit, the patient should be instructed to take his or her AM 
and PM dose as usual. When the patient arrives at the clinic, the PK blood sample should be 
obtained even though it will be drawn after the patient’s AM dose. The time of the AM dose 
should be entered on the PK CRF, and a comment should be added to the comment field of the 
CRF to indicate that the PK sample was collected after the AM dose. 
Biological specimen samples for pharmacokinetic analysis must be identified with labels 
provided by the Sponsor. 
20.2 
Bioanalytical Methodology 
The plasma samples will be analyzed for pexidartinib by using a validated method (high 
performance liquid chromatography (HPLC) with tandem quadrupole mass spectrometric 
detection) of appropriate specificity and sensitivity. 
21.0 
MEASUREMENT OF RESPONSE USING 18FDG PET SCANNING 
Patients who consent to PET scanning should be instructed to fast for at least 6 hours (if feasible) 
prior to 18FDG administration to maintain basal levels of plasma glucose and insulin. They are 
encouraged to keep drinking water to maintain hydration and limit radiation to the urinary tract. 
Plasma glucose or glucometer levels will be determined before administration of 18FDG to 
document euglycemia. 
The dose of 18FDG will be administered intravenously according to weight (0.15 mCi/kg, 
ranging from 3 to 16 mCi) and images will be acquired after approximately 60 minutes 
distribution time. Images will be obtained over the entire body from the base of the skull to 
mid-thigh, including brain and extremities when clinically relevant. 
18FDG PET emission images will be corrected for attenuation. 18FDG PET scanning should be 
performed prior to biopsy collection procedure to avoid false positive results. 


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22.0 
TUMOR AND RELATED TISSUE COLLECTION 
For patients who consent to this tumor and related tissue collection procedure, paired biopsies 
(where applicable) will be obtained to assess the effect of pexidartinib on PD endpoints and 
possibly pexidartinib concentration in the tissue (PK). The tumor lesions or fluids amenable to 
biopsy or extraction should not be target lesions. Patients will not be excluded from the study on 
the basis of consenting to biopsy. For patients’ safety, soft tissue lesions such as skin or 
subcutaneous metastases will be preferentially selected for biopsy. Liver metastases will also be 
eligible for biopsy provided that it is considered feasible and safe in the opinion of a staff 
interventional radiologist. If there is a change in dose or clinical status after C1D15, one or more 
additional biopsies may be obtained to assess PD and PK information, in consultation with the 
Sponsor. If surgical resection of the tumor is performed within 12 weeks of the last dose of study 
treatment, details of the surgery and its outcome should be obtained. Tumor biopsy tissue may be 
submitted for biomarker analysis. 
Where applicable, core biopsy samples should be obtained with an 18-gauge true-cut needle core 
biopsy device under ultrasound or computed tomography guidance. For cutaneous or 
subcutaneous lesions, a punch biopsy may be performed in place of a core biopsy. The tissue 
samples should be submitted fresh to the surgical pathology laboratory. If feasible, one half 
should be fixed in 10% buffered formalin and routinely embedded in paraffin, while the other 
half is to be snap-frozen to –70°C. 
For samples including but not limited to pleural, peritoneal, cerebrospinal, or other fluids and 
tissues, please refer to the Sample Handling and Logistics Manual as well as Attachment 2 and 
Attachment 3. 
For patients who consent to archival tumor tissue acquisition, the sample(s) will be obtained to 
generate baseline or historical evidence of target relevance. 
23.0 
PATIENT REPORTED OUTCOME (PRO) QUESTIONNAIRES 
Patients enrolled after the implementation of Amendment 8 will complete two patient 
reported outcome (PRO) instruments:  the Western Ontario and McMaster Universities 
Osteoarthritis Index (WOMAC®) and the Numeric Rating Scale (NRS) for PVNS Symptoms 
questionnaire. These will be completed predose at the clinic on C1D1, C1D15, C2D1, and 
monthly thereafter (and at every 12-week visit after C40) while continuing study drug 
administration, and at the End of Study visit. In addition, these patients will complete the NRS 
for PVNS Symptoms questionnaire on an outpatient basis for 6 consecutive days (Day -6 to 
Day -1) prior to each monthly clinic visit on C1D1, C2D1, C3D1, etc. (and at every on-site visit 
after C40) while continuing study drug administration. 


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The PRO questionnaires will be used to help understand which PVNS symptoms may be most 
meaningful in terms of improvement for a patient, which symptoms did improve with 
pexidartinib, and which questions might help best detect between-group differences. 
23.1 
PRO Instruments 
Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC®) 
The WOMAC (Attachment 7) is a self-administered 24-item instrument assessing pain, stiffness 
and difficulty performing daily activities. The WOMAC is focused on assessing issues 
associated with lower extremity conditions, mainly the knee and hip. All items include a  
0–10 point NRS scale; the scale for the pain items (5 items) is 0 “no pain” to 10 “extreme pain”, 
the scale for the stiffness items (2) is 0 “no stiffness” to 10 “extreme stiffness”, and the scale for 
the difficulty performing daily activity items (17) is 0 “no difficulty” to 10 “extreme difficulty.” 
Numeric Rating Scale (NRS) for PVNS Symptoms 
The NRS for PVNS Symptoms instrument is a 5-item self-administered questionnaire to assess 
the “worst” of each of the symptoms pain, swelling, stiffness, instability and limited motion in 
the last 24 hours (Attachment 6). A 0–10 NRS is provided for each symptom. For pain, 
0 indicates “no pain” and 10 indicates “pain as bad as you can imagine,” For the other four 
symptoms, 0 indicates “no (symptom)” and 10 indicates “(symptom) worst imaginable”, 
e.g., “swelling – worst imaginable.” 
24.0 
STATISTICAL ANALYSIS 
24.1 
Safety Analysis 
All patients in all cohorts who received study medication will be considered evaluable for safety 
regardless of their duration of treatment. 
The objective of the dose escalation is to determine a dose of pexidartinib for which the rate of 
DLTs is less than 33%. Safety variables to be analyzed are AEs, laboratory test results 
(hematology, clinical chemistry, coagulation parameters, and urinalysis), ECG, and vital signs. 
Adverse event terms recorded on the CRFs will be mapped to preferred terms using the Medical 
Dictionary for Drug Regulatory Activities (MedDRA®) version 7.1 or higher. All AEs will be 
summarized for each dose group according to the system organ class and preferred term within 
the organ class. Adverse events will be tallied for overall frequency (number and percentage of 
subjects), worst reported severity, and relationship to study drug for each preferred term per 
subject. Serious adverse events will be similarly summarized. Listings of deaths, SAEs, and AEs 
leading to early termination of study treatment or premature withdrawal from study will also be 
provided. In addition, all events meeting the criteria of a DLT will be tabulated as a separate 
listing by subject and dose group. Laboratory variables will be examined using mean change in 
value from baseline to scheduled time points for each pexidartinib dose group. Laboratory values 


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will also be categorized according to their CTCAE (version 4) toxicity grade and tabulated by 
worst on-study toxicity grade and pexidartinib dose group. The baseline value of a variable is 
defined as the last value obtained on or before the date and time of the first pexidartinib dose. 
Concomitant medications will also be summarized. 
ECG/QT Analysis: 
All ECG information will be listed by patient, including change from baseline for numeric ECG 
parameters (based on means of the triplicate assessments). Summaries by time-point will be 
provided for absolute and change from baseline numeric ECG parameters (including categorical 
summaries for QTc absolute and change from baseline). Plots of mean ECG data and their 
change from baseline over time will be provided. For each of the time points, the available 
triplicate QTc values will be averaged for all analyses. 
The primary study variable for the QT evaluation will be the study specifically corrected QT 
interval (QTcS or QTcF or QTcB) change from baseline. The correction formulae for QTc will 
be estimated based on linear or non-linear regression of predose QT interval data and RR data. 
In addition, change from baseline for other ECG variables (QT, RR, heart rate, PR, QRS) will be 
summarized. 
Corrected mean changes from baseline in QTc together with one-sided upper 95% confidence 
intervals will be derived for each timepoint to interpret the effect of pexidartinib on the QT 
interval. 
The following criteria on baseline measurements will be considered in the analysis of the QT 
interval. Patients who fall within these criteria may bias the interpretation of pexidartinib effect 
on QT interval. Data from these patients may be analyzed separately from the general patient 
population. 
 Heart rate (HR) greater than 90 or less than 45 beats per minute 
 Sustained systolic blood pressure measurements <90 or >140 mmHg or diastolic blood 
pressure measurements <50 or >90 mmHg at screening or Day -1 
 Any concomitant medications that prolong QT/QTcF interval 
 History and/or family history of congenital long QT syndrome or sudden death 
 Clinically significant abnormal ECG (e.g., marked QT/QTcF prolongation) 
 More than 30 msec difference in two extreme, highest and lowest reads of any baseline 
QTcF at a specific time point 
 Short QTcF (<300 msec) at screening or baseline 
 Screening or baseline ECG evidence of atrial fibrillation, atrial flutter, complete right or 
left bundle branch block, WPW-syndrome, or cardiac pacemaker 


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 QRS and/or T-wave judged to be unfavorable for a consistently accurate 
QT measurement at baseline (e.g., indistinct QRS onset, low amplitude T-wave, 
merged T- and U-waves, prominent U-waves) 
24.2 
Efficacy Analysis 
All patients with measurable disease by RECIST version 1.1 criteria at Baseline who complete at 
least one post-baseline radiographic assessment or discontinue study medication early due to 
disease progression will be considered evaluable for efficacy. 
Response to treatment according to the RECIST criteria will be reported via descriptive statistics 
by dose level. The absolute and percent change from baseline for the extent of disease (sum of 
the longest diameters) will be summarized at each scheduled evaluation using descriptive 
statistics. 
For PVNS patients, the Sponsor will receive radiologic images for possible retrospective analysis 
of treatment response, to be performed by a central vendor. Methodology of assessment will 
include RECIST 1.1 and development of other techniques for descriptive and exploratory 
analysis. 
All patients who are eligible for efficacy analyses will be evaluable for progression–free 
survival, regardless of the presence or absence of measurable disease. Progression-free survival 
will be calculated for each subject. Progression-free survival is defined as the number of days 
from the first day of treatment to the date of the first documented disease progression or date of 
death, whichever occurs first. 
For each subject with a response to therapy, duration of response will be calculated. The duration 
of response is defined as number of days from the date of initial response (confirmed at least 
28 days later) to the date of first documented disease progression or death, whichever occurs 
first. If the information is available, the pre-study stability of disease will also be recorded to 
assist the interpretation of the on-treatment progression-free survival. 
In the event no disease progression or death is documented prior to study termination, analysis 
cutoff, or the start of confounding anticancer therapy, progress-free survival and duration of 
response will be censored at the date of last evaluable tumor assessments. In addition, 
relationships between antitumor activity, pharmacodynamic markers, and drug exposure levels 
will be explored. 
For the malignant effusion cohort, the frequency of effusion removal procedures (e.g., 
paracentesis or thoracentesis) prior to study entry will be compared to the frequency of on-study 
fluid removal procedures. The volume of fluid removed by on-study procedures for each patient 
will be plotted as appropriate. Puncture-free survival (Seimetz 2011) will be calculated for each 
patient. Puncture-free survival is defined as the number of days from the first day of treatment to 
the date of the first need for therapeutic puncture or death. 


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24.3 
Pharmacokinetic Analysis 
A noncompartmental method of analysis will be used to analyze the plasma concentrations of 
pexidartinib. Cmax and the time to attain the Cmax (tmax) will be determined directly from the 
observed data. The following PK parameters will be estimated, based on available data: 
 Clearance 
 Volume of distribution 
 Area under the plasma/serum concentration-time curve (AUC) 
 Elimination half-life 
Pharmacokinetic assessments will be measured for each dose cohort of patients with correlations 
of Cmax and AUC to any SAEs. Dose-response trends in Cmax and AUC will be analyzed within 
each patient group for any suggestion of drug accumulation or alterations in PK based on 
concomitant medications. 
24.4 
Pharmacodynamic Analysis 
No formal statistical analysis of pharmacodynamic endpoints will be performed. 
Pharmacodynamic data from each assay will be listed by dose. Possible relationships between 
PK and pharmacodynamic variables will be explored, as appropriate. Any biological activity will 
be described. 
24.5 
Statistical Analyses 
Statistical analyses will be descriptive in general. Limited statistical comparisons for a dose 
effect may be made using analysis of variance. The dependent variables for assessing dose 
proportionality will be estimates of selected PK parameters. 
No formal statistical analysis of data from the PRO instruments will be performed. Results for 
each instrument will be listed by dose. Change from baseline may be calculated, as appropriate. 
WOMAC data from patients with only upper extremity disease (e.g., PVNS of the elbow) may 
be excluded since WOMAC focuses on lower extremity function. 
24.6 
Sample Size and Power 
The primary objective of the study is to assess the safety of pexidartinib in a limited number of 
patients with solid tumors. The number of patients is not based on statistical power 
considerations. 
For the dose escalation phase of the study, 3 to 6 patients will be accrued per dose level in order 
to ensure the safety and tolerability. The probabilities of detecting DLTs in this study are shown 
in Table 5 and Table 6. 


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Table 5: 
Probabilities of Detecting DLTs (3 Patients) 
Number DLTs in a Cohort of 3 Patients 
Incidence of DLTs in Patient Population 
0.10 
0.20 
0.30 
0.40 
0.50 
0 a 
0.729 
0.512 
0.343 
0.216 
0.125 
1 b 
0.243 
0.384 
0.441 
0.432 
0.375 
2 or more c 
0.028 
0.104 
0.216 
0.352 
0.500 
a 
Number of DLTs leads to advancing to the next cohort. 
b 
Number of DLTs leading to enrolling an additional 3 patients in the Cohort. 
c 
Number of DLTs leading to stopping the study and defining the MTD. 
 
Table 6: 
Probabilities of Detecting DLTs (6 Patients) 
Number DLTs in a Cohort of 6 Patients 
Incidence of DLTs in Patient Population 
0.10 
0.20 
0.30 
0.40 
0.50 
0  
NA 
NA 
NA 
NA 
NA 
1 a 
0.177 
0.197 
0.151 
0.093 
0.047 
2 or more b 
0.066 
0.187 
0.290 
0.339 
0.328 
a 
Number of DLTs leading to advancing to the next cohort [Prob (1 in first 3 and 0 in second 3)]. 
b 
Number of DLTs leading to stopping the study and defining the MTD [Prob (1 in first 3 and 1 in second 3) + 
Prob (1 in first 3 and 2 in second 3)]. 
 
For the five disease-specific Extension cohorts, a sample size of 10 patients is considered the 
minimum sample size required to test the hypothesis that single agent pexidartinib can provide a 
clinical benefit in this patient population. For each Extension cohort, we plan to test the 
hypothesis of no clinical benefit against the hypothesis that at least 30% of patients achieve a 
clinical benefit. With a sample size of 10 patients per group, we will have 85% power at a 
0.10 significance level to declare pexidartinib worthy of further study if at least 2 patients 
achieve clinical benefit. For this study, clinical benefit is defined as either CR/PR or PFS 
≥6 months. If fewer than 2 patients achieve clinical benefit within a disease group, pexidartinib 
will not be considered worth of further study within that disease. Depending on the response in 
the 10-patient cohort, the sample size for a specific cohort may be increased by 30 additional 
patients (to approximately 40 patients total) if those data are determined to be necessary to 
design additional studies in that indication. 
For the miscellaneous Extension cohort, a sample size of 20 patients will be used, as the tumor 
types are anticipated to be rare. The sample size is not determined by any statistical power 
considerations. Accordingly, the potential clinical benefit will be evaluated on a per-patient 
basis. If one or more partial responses are observed in patients in the miscellaneous cohort, 
additional patients (up to 20 total additional patients) may be recruited if needed to profile the 
tumor responses in the specific (or related) indications. 


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25.0 
PRECAUTIONS 
There is no previous experience with pexidartinib in humans. Although major adverse events are 
not anticipated, the investigator must proceed with utmost caution. Equipment, supplies, and 
properly skilled medical personnel must be immediately available for emergency use in the event 
of an unexpected reaction. Patients must be carefully selected and closely monitored. 
For a complete description of preclinical studies reported during clinical studies with 
pexidartinib, please refer to the pexidartinib Investigator’s Brochure. 
26.0 
ADVERSE EVENTS 
For safety information on pexidartinib, refer to the most recent version of the Investigator’s 
Brochure. 
26.1 
Definitions 
An adverse event (AE) is any untoward, undesired, or unplanned event in the form of signs, 
symptoms, disease, or laboratory or physiologic observations occurring in a person given a test 
article in a clinical study. The event does not need to be causally related to the test article. An AE 
includes, but is not limited to, the following: 
 Any clinically significant worsening of a preexisting condition. 
 An AE occurring from overdose (i.e., a dose higher than that indicated in the protocol) of 
a test article, whether accidental or intentional. 
 An AE occurring from abuse (e.g., use for nonclinical reasons) of a test article. 
 An AE that has been associated with the discontinuation of the use of a test article. 
Any treatment-emergent abnormal laboratory result which is clinically significant, i.e., meeting 
one or more of the following conditions, should be recorded as a single diagnosis on the adverse 
event page in the CRF: 
 Accompanied by clinical symptoms 
 Leading to a change in study medication (e.g., dose modification, interruption or 
permanent discontinuation) 
 Requiring a change in concomitant therapy (e.g., addition of, interruption of, 
discontinuation of, or any other change in a concomitant medication, therapy or 
treatment) 
A serious adverse event is an AE that: 
 Results in death (NOTE:  death is an outcome, not an event) 
 Is life-threatening. 


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 Requires inpatient hospitalization or prolongation of an existing hospitalization. 
 Results in a persistent or significant disability or incapacity. 
 Results in a congenital anomaly or birth defect. 
 Additionally, important medical events that may not result in death, be life-threatening, 
or require hospitalization may be considered SAEs when, based on appropriate medical 
judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such 
events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias or convulsions that do not result in hospitalization, or 
development of drug dependency or drug abuse. 
Disease progression is a study end point and clear progression or worsening of neoplasia 
should not be reported as an adverse event or serious adverse event. Findings that are clearly 
consistent with the expected progression of the underlying cancer should not be reported as an 
adverse event, and hospitalizations due to the progression of cancer do not necessarily qualify for 
a serious adverse event. Sudden and unexplained death should be reported as an SAE. If there is 
any uncertainty about a finding being due solely to progression of neoplasia, the finding should 
be reported as an adverse event or serious adverse event as appropriate. 
Life-threatening refers to immediate risk of death as the event occurred per the reporter. A life-
threatening experience does not include an experience, had it occurred in a more severe form, 
which might have caused death, but as it actually occurred, did not create an immediate risk of 
death. For example, hepatitis that resolved without evidence of hepatic failure would not be 
considered life-threatening, even though hepatitis of a more severe nature can be fatal. Similarly, 
an allergic reaction resulting in angioedema of the face would not be life-threatening, even 
though angioedema of the larynx, allergic bronchospasm, or anaphylaxis can be fatal. 
Hospitalization is official admission to a hospital. An Emergency Room visit lasting longer than 
24 hours should be considered a hospitalization. Hospitalization or prolongation of a 
hospitalization constitutes criteria for an AE to be serious; however, it is not in itself considered 
a serious adverse event (SAE). In absence of an AE, a hospitalization or prolongation of a 
hospitalization should not be reported as an SAE. This is the case in the following situations: 
 The hospitalization or prolongation of hospitalization is needed for a procedure required 
by the protocol. Day or night survey visits for biopsy or surgery required by the protocol 
are not considered serious. 
 The hospitalization or prolongation of hospitalization is part of a routine procedure 
followed by the center (e.g., stent removal after surgery). This should be recorded in the 
study file. 
 Hospitalization for survey visits or annual physicals falls in the same category. 


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In addition, hospitalizations planned before the start of the study, for a preexisting condition that 
has not worsened, do not constitute an SAE. 
Disability is defined as a substantial disruption in a person’s ability to conduct normal life 
functions. 
If there is any doubt about whether the information constitutes an SAE, the information is treated 
as an SAE. 
Relatedness to study medication will be graded as either “probably”, “possibly”, or “unlikely”, as 
follows: 
Probably—The adverse event: 
 Follows a reasonable temporal sequence from drug administration 
 Abates upon discontinuation of the drug 
 Cannot be reasonably explained by the known characteristics of the patient’s clinical state 
Possibly—The adverse event: 
 Follows a reasonable temporal sequence from drug administration 
 Could have been produced by the patient’s clinical state or by other modes of therapy 
administered to the patient: 
Unlikely—The adverse event: 
 Does not follow a reasonable sequence from drug administration 
 Is readily explained by the patient’s clinical state or by other modes of therapy 
administered to the patient 
A protocol-related adverse event is an AE occurring during a clinical study that is not related 
to the test article, but is considered by the investigator or the medical monitor (or designee) to be 
related to the research conditions, i.e., related to the fact that a patient is participating in the 
study. For example, a protocol-related AE may be an untoward event occurring during a washout 
period or an event related to a medical procedure required by the protocol. 
Other Reportable Information:  certain information, although not considered an AE, must be 
recorded, reported, and followed up as indicated for an AE. This includes: 


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 A case involving a pregnancy exposure to a test article, unless the product is indicated for 
use during pregnancy, e.g., prenatal vitamins. Information about use in pregnancy 
encompasses the entire course of pregnancy and delivery and perinatal and neonatal 
outcomes, even if there were no abnormal findings. If a pregnancy is confirmed, test 
article must be discontinued immediately in female patients. All reports of pregnancy 
must be followed for information about the course of the pregnancy and delivery, as well 
as the condition of the newborn. When the newborn is healthy, additional follow-up is not 
needed. Pregnancies occurring up to 3 months after completion of the study treatment 
must also be reported to the investigator. 
 Overdose (e.g., a dose at least 40% higher than that indicated in the protocol). An 
overdose or incorrect administration of study drug is not an AE unless it results in 
untoward medical effects. Any study drug overdose or incorrect administration of study 
drug should be noted on the study drug administration CRF. 
 Abuse (e.g., use for nonclinical reasons) with or without an AE. 
 Inadvertent or accidental exposure with or without an AE. 
 Device malfunction with or without an AE. 
 
26.2 
Recording and Reporting 
A patient’s AE or SAE can occur from the time the patient receives the first dose of study drug 
until the patient’s End of Study visit. 
The investigator must follow-up on all drug-related AEs, SAEs, and other reportable information 
until the events have subsided, returned to baseline, the patient has initiated any other anticancer 
treatment, or in case of permanent impairment, until the condition stabilizes. 
All AE and SAEs must be recorded on source documents. All AEs and SAEs for patients who 
are not screen failures will be recorded in the CRFs. 
AEs should be based on the signs or symptoms detected during the physical examination and on 
clinical evaluation of the patient. In addition to the information obtained from those sources, the 
patient should be asked the following nonspecific question:  "How have you been feeling since 
your last visit?" Signs and symptoms should be recorded using standard medical terminology. 
Any unanticipated risks to the patients must be reported promptly to the IRB/IEC. 
26.3 
Serious Adverse Event Reporting 
Regardless of causality, all SAEs and follow-up information must be reported to the Synteract 
safety group within 24 hours of learning of the event by completing the study-specific SAE 
report form and faxing or e-mailing to the contact information on the form. In the case that fax or 
e-mail is unavailable, the SAE can be reported to the Medical Monitor (see Section 3.1). As a 


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reminder, all SAEs should also be promptly entered onto the appropriate eCRF form within 
SynCapture. 
Plexxikon (or designee) will process and evaluate all SAEs as soon as the reports are received. 
For each SAE received, Plexxikon will make a determination as to whether the criteria for 
expedited reporting have been met. 
Plexxikon (or designee) is responsible for reporting relevant SAEs to the relevant regulatory 
authorities and participating investigators, in accordance with FDA regulations 21 CFR 312.32, 
ICH guidelines, European Clinical Trials Directive (Directive 2001/20/EC), and/or local 
regulatory requirements. 
Reporting of SAEs by the investigator to the Institutional Review Board (IRB) or Ethics 
Committee (EC) will be done in accordance with the standard operation procedures and policies 
of the IRB/EC. Adequate documentation must be maintained showing that the IRB/EC was 
properly notified. 
27.0 
STUDY SUSPENSION, TERMINATION, AND COMPLETION 
The Sponsor may suspend or terminate the study or any part of the study at any time for any 
reason. If the investigator suspends or terminates the study, the investigator will promptly inform 
the Sponsor and the IRB/IEC and provide them with a detailed written explanation. The 
investigator will also return all test article, containers, and other study materials to the Sponsor, 
or destroy the materials at the investigative site. Upon study completion, the investigator will 
provide the Sponsor, IRB/IEC, and regulatory agency with final reports and summaries as 
required by regulations. For IND studies, the investigator must submit a written report to the 
Sponsor and the IRB/IEC within 3 months after the completion or termination of the study. 
28.0 
INFORMED CONSENT 
The investigator will provide for the protection of the patients by following all applicable 
regulations. These regulations are available upon request from the Sponsor. The informed 
consent form used during the informed consent process must be reviewed by the Sponsor and 
approved by the IRB/IEC. 
Before any procedures specified in the protocol are performed, a patient must: 
 Be informed of all pertinent aspects of the study and all elements of informed consent. 
 Be given time to ask questions and time to consider the decision to participate. 
 Voluntarily agree to participate in the study. 
 Sign and date an IRB/IEC approved informed consent form. 
 


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29.0 
PROTOCOL AMENDMENTS 
Any significant change in the study requires a protocol amendment. An investigator must not 
make any changes to the study without IRB/IEC and Sponsor approval except when necessary to 
eliminate apparent immediate hazards to the patients. A protocol change intended to eliminate an 
apparent immediate hazard to patients may be implemented immediately, but the change must 
then be documented in an amendment, reported to the IRB/IEC within 5 working days, and 
submitted to the appropriate regulatory agency in the required time frame. All protocol 
amendments must be reviewed and approved following the same process as the original protocol. 
30.0 
QUALITY CONTROL AND ASSURANCE 
The Sponsor performs quality control and assurance checks on all clinical studies that it 
sponsors. Before enrolling any patients in this study, Sponsor personnel and the investigator 
review the protocol, the investigator’s brochure, the CRFs and instructions for their completion, 
the procedure for obtaining informed consent, and the procedure for reporting AEs and SAEs. A 
qualified representative of the Sponsor will monitor the conduct of the study. During these site 
visits, information recorded in the CRFs is verified against source documents. 
31.0 
DIRECT ACCESS, DATA HANDLING, AND RECORD KEEPING 
31.1 
Investigator 
The investigator will permit study-related monitoring, audits, IRB/IEC review, and regulatory 
inspections by providing direct access to source data and documents. 
All information will be recorded on source documents. All required data will be recorded in the 
CRFs. All CRF data must be submitted to the Sponsor throughout and at the end of the study. 
If an investigator retires, relocates, or otherwise withdraws from conducting the study, the 
investigator must notify the Sponsor to agree upon an acceptable storage solution. Regulatory 
agencies will be notified with the appropriate documentation. 
31.2 
Sponsor 
The CRF data is stored in a database and processed electronically. The data are reviewed for 
legibility, completeness, and logical consistency. Automated validation programs identify 
missing data, out-of-range data, and other data inconsistencies. The lab data will be processed 
electronically. Requests for data clarification are forwarded to the investigative site for 
resolution. 
32.0 
PRE-STUDY DOCUMENTATION 
The investigator must provide the Sponsor with the following documents BEFORE enrolling any 
patients: 


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 Completed and signed Form 1572. 
 All applicable country-specific regulatory forms. 
 Current signed and dated curricula vitae for the investigator, subinvestigators, and other 
individuals having significant investigator responsibility who are listed on the Form 1572 
or equivalent, or the clinical study information form. 
 Copy of the IRB/IEC approval letter for the protocol and informed consent. All 
advertising, recruitment, and other written information provided to the patient must be 
approved by the IRB/IEC. Written assurance of continuing approval (at least annually) as 
well as a copy of the annual progress report submitted to the IRB/IEC must also be 
provided to the Sponsor. 
 Copy of the IRB/IEC-approved informed consent document to be used. 
 Where applicable, a list of the IRB/IEC members and their qualifications, and a 
description of the committee’s working procedure. 
 Copy of the protocol sign-off page signed by the investigator. 
 Copy of the current medical license of the principal Investigator and any 
subinvestigators. 
 Fully executed Clinical Trial Agreement. 
 Where applicable, a financial disclosure form. 
 A written document containing the name, location, certification number, and date of 
certification of the laboratory to be used for laboratory assays and those of other facilities 
conducting tests. This document should be returned along with the statement of 
investigator form. The Sponsor must be notified if the laboratory is changed or if any 
additional laboratory is to be used. 
 List of normal laboratory values and units of measure for all laboratory tests required by 
the protocol. This is required for each laboratory to be used during the study. The 
Sponsor must be notified if normal values or units of measurement change. 
 
33.0 
RECORDS RETENTION 
The investigator shall retain and preserve 1 copy of all data generated in the course of the study, 
specifically including but not limited to those defined by GCP as essential, for the longer of:  
(i) 2 years after the last marketing authorization for the study drug has been approved or the 
Sponsor has discontinued its research with respect to such drug or (ii) such longer period as 
required by applicable global regulatory requirements. At the end of such period, the investigator 
shall notify the Sponsor in writing of its intent to destroy all such material. The Sponsor shall 
have 30 days to respond to the investigator’s notice, and the Sponsor shall have a further 
opportunity to retain such materials at the Sponsor’s expense. 


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REFERENCES 
Plexxikon Pexidartinib (PLX3397) Investigator’s Brochure. 
Coffelt, S. B., Hughes, R., and Lewis, C. E. (2009). Tumor-associated macrophages:  Effectors 
of angiogenesis and tumor progression. Biochim Biophys Acta. 
Fletcher, J. A., and Rubin, B. P. (2007). KIT mutations in GIST. Curr Opin Genet Dev 17, 3-7. 
Kaczmarek, M. et al. (2011). Evaluation of the phenotype pattern of macrophages isolated from 
malignant and non-malignant pleural effusions. Tumour Biol Aug. 7 epub ahead of print. 
Kohno, N. (2008). Treatment of breast cancer with bone metastasis:  bisphosphonate treatment - 
current and future. Int J Clin Oncol 13, 18-23. 
Liegl, B. et al. (2008). Heterogeneity of kinase inhibitor resistance mechanisms in GIST. J Pathol 
216, 64-74. 
Lipton, A., and Jun, S. (2008). RANKL inhibition in the treatment of bone metastases. Curr Opin 
Support Palliat Care 2, 197-203. 
Pollard, J. W. (2008). Macrophages define the invasive microenvironment in breast cancer. J 
Leukoc Biol 84, 623-630. 
Ryder, M. et al. (2008). Increased density of tumor-associated macrophages is associated with 
decreased survival in advanced thyroid cancer. Endocr Relat Cancer. 15, 1069-1074. 
Seimetz D. (2011). Novel monoclonal antibodies for cancer treatment:  The trifunctional 
antibody catamaxomab (Removab). J Cancer 2, 309-316. 
Shieh, Y.S. et al. (2009). Tumor-associated macrophage correlated with angiogenesis and 
progression of mucoepidermoid carcinoma of salivary glands. Ann Surg Oncol 16, 751-760. 
Tam, W. F., and Gary Gilliland, D. (2008). Can FLT3 inhibitors overcome resistance in AML? 
Best Pract Res Clin Haematol 21, 13-20. 
Tanaka, S. (2007). Signaling axis in osteoclast biology and therapeutic targeting in the 
RANKL/RANK/OPG system. Am J Nephrol 27, 466-478. 
West, R.B. et al. (2006). A landscaping effect in tenosynovial giant-cell tumor from activation of 
CSF1 expression by a translocation in a minority of cells. Proc Natl Acad Sci 17;103, 690-695. 
Yang, F. C., Ingram, D. A., Chen, S., Zhu, Y., Yuan, J., Li, X., Yang, X., Knowles, S., Horn, W., 
Li, Y., et al. (2008). Nf1-dependent tumors require a microenvironment containing Nf1+/-- and 
c-kit-dependent bone marrow. Cell 135, 437-448. 


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ATTACHMENT 1:  LABORATORY TESTS 
Hematology 
Red blood cell count 
White blood cell count with differential 
Platelet count 
Hemoglobin 
Hematocrit 
 
Blood Chemistry 
Sodium 
Potassium 
Chloride 
CO2 
Calcium 
Phosphorus 
Glucose* 
Blood urea nitrogen 
Creatinine 
Total protein 
Albumin 
 
*Fasting is recommended but not required 
Triglycerides* 
Total cholesterol* 
HDL-cholesterol* 
LDL-cholesterol* 
Uric acid 
Total and direct bilirubin 
Aspartate aminotransferase (AST) 
Alanine aminotransferase (ALT) 
Alkaline phosphatase (AP) 
Lactate dehydrogenase (LDH) 
 
 
Urinalysis (microscopic) 
pH 
Protein/albumin 
Glucose/sugar 
Nitrites 
Ketones/acetone 
Hemoglobin/blood 
Coagulation (dose escalation cohorts):  Protime (PT), partial thromboplastin time (PTT), and 
international normalized ratio (INR) 
TSH (dose escalation cohorts) 
Pregnancy test (-HCG):  women of child-bearing potential 
Urine Response Biomarkers (all cohorts):  Morning N-Telopeptide of Type I Collagen (NTX) 
to assess bone mineralization and C-Telopeptide of Type II Collagen (CTX-II) to assess cartilage 
formation 
Serum Response Biomarkers (dose escalation cohorts): 
 Bone mineralization:  C-Telopeptide of Type I Collagen (CTX), Procollagen Type I 
Intact N-Terminal Propeptide (P1NP), bone-specific alkaline phosphatase (BAP) 


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 Macrophage and mast cell activity:  Tartrate-resistant acid phosphatase (TRAP 5b), 
Interleukin-6 (IL-6), Interleukin-1β (IL-1β), Matrix Metallopeptidase-3 (MMP-3), 
Erythrocyte Sedimentation Rate (ESR), C-Reactive Protein (CRP), CSF-1 
Serum Response Biomarkers (Extension cohorts): 
 IL-6 and CSF-1 
Blood Response Biomarkers (dose escalation cohorts): 
 Circulating Tumor Cells (CTCs) 
 CD14+/CD16+ monocytes (extension cohorts too) 
Because the identification of new response prediction or early response biomarkers of disease 
activity is a rapidly developing field, the definitive list of analyses remains to be determined, but 
may include additional markers of inflammatory cells such as macrophages, mast cells, and 
osteoclasts, in addition to inflammation biomarkers that may be related to Fms or Kit inhibition. 
Liver Effect Biomarkers 
If there is a Grade 2 or higher ALT or AST elevation (i.e., >3 × ULN) at any time during 
treatment, the patient should be followed closely as determined by the investigator and Medical 
Montor. The following liver effect biomarkers are required to be obtained at a frequency 
determined by the Investigator and Medical Monitor. 
 mir122, cytokeratin 18 (full-length and caspase-cleaved), and HMGB1 (native and 
acetylated) 
 


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ATTACHMENT 2:  COLLECTION, PREPARATION, AND LABELING OF PLASMA 
AND OTHER SAMPLES BEING COLLECTED 
Please consult the study-specific laboratory manual. 
 
 


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ATTACHMENT 3:  INSTRUCTIONS FOR SHIPPING FROZEN SAMPLES 
Please consult the study-specific laboratory manual. 
 
 


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ATTACHMENT 4:  RECIST CRITERIA VERSION 1.1 
Measurability of Tumor at Baseline 
Definitions 
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows. 
Measurable tumor lesions 
Tumor lesions must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of: 
 10 mm by CT scan (CT scan slice thickness no greater than 5 mm) 
 10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable) 
 20 mm by chest X-ray 
Malignant lymph nodes:  To be considered pathologically enlarged and measurable, a lymph 
node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will 
be measured and followed. See also section below on ‘Baseline documentation of target and non-
target lesions’ for information on lymph node measurement. 
Non-measurable tumor lesions 
Non-measurable tumor lesions encompass small lesions (longest diameter <10 mm or 
pathological lymph nodes with ≥10 to <15 mm short axis) as well as truly non-measurable 
lesions. Lesions considered truly non-measurable include:  leptomeningeal disease, ascites, 
pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or 
lung, peritoneal spread, abdominal masses/abdominal organomegaly identified by physical exam 
that is not measurable by reproducible imaging techniques. 
Special considerations regarding lesion measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment: 
Bone lesions: 
 Bone scan, PET scan or plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 


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 Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross sectional imaging techniques such as CT or MRI can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above. 
 Blastic bone lesions are non-measurable. 
Cystic lesions: 
 Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, 
by definition, simple cysts 
 ‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions 
Lesions with prior local treatment: 
 Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion. Study protocols should detail the conditions 
under which such lesions would be considered measurable. 
 
Specifications by methods of measurements 
Measurement of lesions 
All measurements should be recorded in metric notation, using calipers if clinically assessed. All 
baseline evaluations should be performed as close as possible to the treatment start and never 
more than 4 weeks before the beginning of the treatment. 
Method of assessment 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation should 
always be done rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
Clinical lesions:  Clinical lesions will only be considered measurable when they are superficial 
and ≥10 mm diameter as assessed using calipers (e.g., skin nodules). For the case of skin lesions, 
documentation by color photography including a ruler to estimate the size of the lesion is 
suggested. As noted above, when lesions can be evaluated by both clinical exam and imaging, 
imaging evaluation should be undertaken since it is more objective and may also be reviewed at 
the end of the study. 


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Chest X-ray:  Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new 
lesions. However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung. Still, non-contrast CT is preferred over chest X-ray. 
CT, MRI:  CT is the best currently available and reproducible method to measure lesions selected 
for response assessment. This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less. When CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. 
MRI is also acceptable in certain situations (e.g., for body scans). 
If prior to enrolment it is known that a patient is not able to undergo CT scans with IV contrast 
due to allergy or renal insufficiency, the decision as to whether a non-contrast CT or MRI (with 
or without IV contrast) will be used to evaluate the subject at baseline and follow-up, should be 
guided by the tumor type under investigation and the anatomic location of the disease. For 
patients who develop contraindications to contrast after baseline contrast CT is done, the 
decision as to whether non-contrast CT or MRI (enhanced or non-enhanced) will be performed, 
should also be based on the tumor type, anatomic location of the disease and should be optimized 
to allow for comparison to the prior studies if possible. Each case should be discussed with the 
radiologist to determine if substitution of these other approaches is possible and, if not, the 
patient should be considered not evaluable from that point forward. 
Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT or 
MRI is advised. If there is concern about radiation exposure at CT, MRI may be used instead of 
CT in selected instances. 
Endoscopy, laparoscopy:  The utilization of these techniques for objective tumor evaluation is 
not advised. However, they can be useful to confirm complete pathological response when 
biopsies are obtained or to determine relapse in trials where recurrence following complete 
response or surgical resection is an endpoint. 
Tumor markers:  Tumor markers alone cannot be used to assess objective tumor response. If 
markers are initially above the upper normal limit, however, they must normalize for a patient to 
be considered in complete response. Because tumor markers are disease specific, instructions for 
their measurement should be incorporated into protocols on a disease specific basis. Specific 
guidelines for both CA-125 response (in recurrent ovarian cancer) and PSA response (in 
recurrent prostate cancer), have been published. In addition, the Gynecologic Cancer Intergroup 
has developed CA125 progression criteria which are to be integrated with objective tumor 
assessment for use in first-line trials in ovarian cancer. 


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Cytology, histology:  These techniques can be used to differentiate between PR and CR in rare 
cases if required by protocol (for example, residual lesions in tumor types such as germ cell 
tumours, where known residual benign tumours can remain). When effusions are known to be a 
potential adverse effect of treatment (e.g., with certain taxane compounds or angiogenesis 
inhibitors), the cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment can be considered if the measurable tumor has met criteria for response 
or stable disease in order to differentiate between response (or stable disease) and progressive 
disease. 
Tumor response evaluation 
Assessment of overall tumor burden and measurable disease 
To assess objective response or future progression, it is necessary to estimate the overall tumor 
burden at baseline and use this as a comparator for subsequent measurements. Only patients with 
measurable disease at baseline should be included in protocols where objective tumor response is 
the primary endpoint. Measurable disease is defined by the presence of at least one measurable 
lesion (as detailed above in this Attachment 4). In studies where the primary endpoint is tumor 
progression (either time to progression or proportion with progression at a fixed date), the 
protocol must specify if entry is restricted to those with measurable disease or whether patients 
having non-measurable disease only are also eligible. 
Baseline documentation of ‘target’ and ‘non-target’ lesions 
When more than one measurable lesion is present at baseline all lesions up to a maximum of 
five lesions total (and a maximum of two lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline. 
This means in instances where patients have only one or two organ sites involved a maximum of 
two (one site) and four lesions (two sites), respectively, will be recorded. Other lesions in that 
organ will be recorded as non-measurable lesions (even if size is greater than 10 mm by CT 
scan). 
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest lesion which 
can be measured reproducibly should be selected. 
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
≥15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. The 


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short axis of the node is the diameter normally used by radiologists to judge if a node is involved 
by solid tumor. Nodal size is normally reported as two dimensions in the plane in which the 
image is obtained (for CT scan this is almost always the axial plane; for MRI the plane of 
acquisition may be axial, saggital or coronal). The smaller of these measures is the short axis. 
For example, an abdominal node which is reported as being 20 mm x 30 mm has a short axis of 
20 mm and qualifies as a malignant, measurable node. In this example, 20 mm should be 
recorded as the node measurement. All other pathological nodes (those with short axis ≥10 mm 
but <15 mm) should be considered non-target lesions. Nodes that have a short axis <10 mm are 
considered non-pathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease. 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal 
progression.’ In addition, it is possible to record multiple non-target lesions involving the same 
organ as a single item on the case report form (e.g., ‘multiple enlarged pelvic lymph nodes’ or 
‘multiple liver metastases’). 
Response criteria 
This section provides the definitions of the criteria used to determine objective tumor response 
for target lesions. 
Evaluation of target lesions 
 Complete Response (CR):  Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to <10 mm. 
 Partial Response (PR):  At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters. 
 Progressive Disease (PD):  At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if 
that is the smallest on study). In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm. (Note:  the appearance of one or 
more new lesions is also considered progression). 
 Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on study. 


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Special notes on the assessment of target lesions 
Lymph nodes:  Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline examination), 
even if the nodes regress to below 10 mm on study. This means that when lymph nodes are 
included as target lesions, the ‘sum’ of lesions may not be zero even if complete response criteria 
are met, since a normal lymph node is defined as having a short axis of <10 mm. Case report 
forms or other data collection methods may therefore be designed to have target nodal lesions 
recorded in a separate section where, in order to qualify for CR, each node must achieve a short 
axis <10 mm. For PR, SD and PD, the actual short axis measurement of the nodes is to be 
included in the sum of target lesions. 
Target lesions that become ‘too small to measure’:  while on study, all lesions (nodal and non-
nodal) recorded at baseline should have their actual measurements recorded at each subsequent 
evaluation, even when very small (e.g., 2 mm). However, sometimes lesions or lymph nodes 
which are recorded as target lesions at baseline become so faint on CT scan that the radiologist 
may not feel comfortable assigning an exact measure and may report them as being ‘too small to 
measure’. When this occurs it is important that a value be recorded on the case report form: 
 If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm. If the lesion is believed to be present and is 
faintly seen but too small to measure, a default value of 5 mm should be assigned and 
BML (below measurable limit) should be ticked (Note:  It is less likely that this rule will 
be used for lymph nodes since they usually have a definable size when normal and are 
frequently surrounded by fat such as in the retroperitoneum; however, if a lymph node is 
believed to be present and is faintly seen but too small to measure, a default value of 
5 mm should be assigned in this circumstance as well and BML should also be ticked). 
This default value is derived from the 5 mm CT slice thickness (but should not be changed with 
varying CT slice thickness). The measurement of these lesions is potentially non-reproducible, 
therefore providing this default value will prevent false responses or progressions based upon 
measurement error. 
To reiterate, however, if the radiologist is able to provide an actual measure, that should be 
recorded, even if it is below 5 mm and in that case BML should not be ticked. (BML is 
equivalent to a less than sign <) 
Lesions that split or coalesce on treatment:  when non-nodal lesions ‘fragment’, the longest 
diameters of the fragmented portions should be added together to calculate the target lesion sum. 
Similarly, as lesions coalesce, a plane between them may be maintained that would aid in 
obtaining maximal diameter measurements of each individual lesion. If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest diameter in this 
instance should be the maximal longest diameter for the ‘coalesced lesion’. 


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Evaluation of non-target lesions 
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions. While some non-target lesions may actually be measurable, they 
need not be measured and instead should be assessed only qualitatively at the time points 
specified in the protocol. 
Complete Response (CR):  Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
Progressive Disease (PD):  Unequivocal progression of existing non-target lesions. (Note:  the 
appearance of one or more new lesions is also considered progression). 
Special notes on assessment of progression of non-target disease 
The concept of progression of non-target disease requires additional explanation as follows: 
When the patient also has measurable disease:  in this setting, to achieve ‘unequivocal 
progression’ on the basis of the non-target disease, there must be an overall level of 
substantial worsening in non-target disease in a magnitude that, even in presence of SD or 
PR in target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy. A modest ‘increase’ in the size of one or more non-target lesions is 
usually not sufficient to qualify for unequivocal progression status. The designation of overall 
progression solely on the basis of change in non-target disease in the face of SD or PR of target 
disease will therefore be extremely rare. 
When the patient has only non-measurable disease:  this circumstance arises in some phase III 
trials when it is not a criterion of study entry to have measurable disease. The same general 
concepts apply here as noted above, however, in this instance there is no measurable disease 
assessment to factor into the interpretation of an increase in non-measurable disease burden. 
Because worsening in non-target disease cannot be easily quantified (by definition:  if all lesions 
are truly non-measurable) a useful test that can be applied when assessing patients for 
unequivocal progression is to consider if the increase in overall disease burden based on the 
change in non-measurable disease is comparable in magnitude to the increase that would be 
required to declare PD for measurable disease:  i.e., an increase in tumor burden representing an 
additional 73% increase in ‘volume’ (which is equivalent to a 20% increase diameter in a 
measurable lesion). Examples include an increase in a pleural effusion from ‘trace’ to ‘large’, an 
increase in lymphangitic disease from localized to widespread, or may be described in protocols 
as ‘sufficient to require a change in therapy’. If ‘unequivocal progression’ is seen, the patient 
should be considered to have had overall PD at that point. While it would be ideal to have 


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objective criteria to apply to non-measurable disease, the very nature of that disease makes it 
impossible to do so; therefore the increase must be substantial. 
New lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some comments 
on detection of new lesions are important. There are no specific criteria for the identification of 
new radiographic lesions; however, the finding of a new lesion should be unequivocal:  i.e., not 
attributable to differences in scanning technique, change in imaging modality or findings thought 
to represent something other than tumor (for example, some ‘new’ bone lesions may be simply 
healing or flare of pre-existing lesions). This is particularly important when the patient’s baseline 
lesions show partial or complete response. For example, necrosis of a liver lesion may be reported 
on a CT scan report as a ‘new’ cystic lesion, which it is not. 
A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. An example of this is 
the patient who has visceral disease at baseline and while on study has a brain CT or MRI 
ordered which reveals metastases. The patient’s brain metastases are considered to be evidence 
of PD even if he/she did not have brain imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm there 
is definitely a new lesion, then progression should be declared using the date of the initial scan. 
(18)F-Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) 
While FDG-PET response assessments need additional study, it is sometimes reasonable to 
incorporate the use of FDG-PET scanning to complement CT scanning in assessment of 
progression (particularly possible ‘new’ disease). New lesions on the basis of FDG-PET imaging 
can be identified according to the following algorithm: 
 Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
 No FDG-PET at baseline and a positive FDG-PET at follow-up: 
 If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed 
by CT, this is PD. 
 If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan). 
 If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on 
CT that is not progressing on the basis of the anatomic images, this is not PD. 


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Evaluation of best overall response 
The best overall response is the best response recorded from the start of the study treatment until 
the end of treatment taking into account any requirement for confirmation. On occasion a 
response may not be documented until after the end of therapy so protocols should be clear if 
post-treatment assessments are to be considered in determination of best overall response. 
Protocols must specify how any new therapy introduced before progression will affect best 
response designation. The patient’s best overall response assignment will depend on the findings 
of both target and non-target disease and will also take into consideration the appearance of new 
lesions. Furthermore, depending on the nature of the study and the protocol requirements, it may 
also require confirmatory measurement. Specifically, in non-randomised trials where response is 
the primary endpoint, confirmation of PR or CR is needed to deem either one the ‘best overall 
response’. This is described further below. 
Time point response 
It is assumed that at each protocol specified time point, a response assessment occurs. Table 7 
provides a summary of the overall response status calculation at each time point for patients who 
have measurable disease at baseline. 
When patients have non-measurable (therefore non-target) disease only, Table 8 is to be used. 
Missing assessments and not-evaluable designation 
When no imaging/measurement is done at all at a particular time point, the patient is not 
evaluable at that time point. If only a subset of lesion measurements are made at an assessment, 
usually the case is also considered not evaluable at that time point, unless a convincing argument 
can be made that the contribution of the individual missing lesion(s) would not change the 
assigned time point response. This would be most likely to happen in the case of PD. 
For example, if a patient had a baseline sum of 50 mm with three measured lesions and at 
follow-up only two lesions were assessed, but those gave a sum of 80 mm, the patient will have 
achieved PD status, regardless of the contribution of the missing lesion. 
If one or more target lesions were not assessed either because the scan was not done, or could not 
be assessed because of poor image quality or obstructed view, the Response for Target Lesions 
should be “Unable to Assess” since the patient is not evaluable. Similarly, if one or more non-
target lesions are indicated as ‘not assessed’, the response for non-target lesions should be 
“Unable to Assess” (except where there is clear progression). Overall response would be 
“Unable to Assess” if either the target response or the non-target response is “Unable to Assess” 
(except where this is clear evidence of progression) as this equates with the case being not 
evaluable at that time point. 


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Best overall response:  all time points 
The best overall response will be determined by statistical programming once all the data for the 
patient is known. 
Table 7: 
Time Point Response:  Patients with Targets (+/- Non-Target) Disease 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, NE = inevaluable 
 
Table 8: 
Time Point Response:  Patients with Non-Target Disease Only 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/Non-PD 
No 
Non-CR/non-PDa 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, NE = inevaluable 
a 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used as 
endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be measured is 
not advised. 


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Table 9: 
Best Overall Response When Confirmation of CR and PR Required 
Overall Response  
First Time Point 
Overall Response  
Subsequent Time Point 
BEST Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD or PRa 
CR 
SD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
CR 
PD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
CR 
NE 
SD provided minimum criteria for SD duration met, 
otherwise, NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
PR 
NE 
SD provided minimum criteria for SD duration met, 
otherwise, NE 
NE 
NE 
NE 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, NE = inevaluable 
a 
If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting 
PR criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after 
CR). Best response would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ 
may be claimed when subsequent scans suggest small lesions were likely still present and in fact the patient had 
PR, not CR at the first time point. Under these circumstances, the original CR should be changed to PR and the 
best response is PR. 
 


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Special notes on response assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to ‘normal’ 
size (<10 mm), they may still have a measurement reported on scans. This measurement should 
be recorded even though the nodes are normal in order not to overstate progression should it be 
based on increase in size of the nodes. As noted earlier, this means that patients with CR may not 
have a total sum of ‘zero’ on the case report form (CRF). 
In trials where confirmation of response is required, repeated ‘NE’ time point assessments may 
complicate best response determination. The analysis plan for the trial must address how missing 
data/assessments will be addressed in determination of response and progression. For example, 
in most trials it is reasonable to consider a patient with time point responses of PR-NE-PR as a 
confirmed response. 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
‘symptomatic deterioration’. Every effort should be made to document objective progression 
even after discontinuation of treatment. Symptomatic deterioration is not a descriptor of an 
objective response:  it is a reason for stopping study therapy. The objective response status of 
such patients is to be determined by evaluation of target and non-target disease as shown in 
Table 7, Table 8, and Table 9. 
Conditions that define ‘early progression, early death and non-evaluability’ are study specific 
and should be clearly described in each protocol (depending on treatment duration, treatment 
periodicity). 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends upon this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) before assigning a status of 
complete response. FDG-PET may be used to upgrade a response to a CR in a manner similar to 
a biopsy in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring. The use of FDG-PET in this circumstance should be prospectively described in the 
protocol and supported by disease specific medical literature for the indication. However, it must 
be acknowledged that both approaches may lead to false positive CR due to limitations of 
FDG-PET and biopsy resolution/sensitivity. 
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic changes 
or necrosis in existing lesions), treatment may continue until the next scheduled assessment. If at 
the next scheduled assessment, progression is confirmed, the date of progression should be the 
earlier date when progression was suspected. 


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ATTACHMENT 5:  CYP3A4 INHIBITORS AND INDUCERS 
Common CYP3A4 Inhibitors 
The following lists describe medications and foods which are common inhibitors of CYP3A4. 
This list should not be considered all-inclusive. Consult individual drug labels for specific 
information on a compound’s propensity to inhibit CYP3A4. 
HIV Protease Inhibitors 
Others 
indinavir 
nelfinavir 
ritonavir 
saquinavir 
amiodarone 
cimetidine 
clarithromycin 
erythromycin 
fluoxetine 
fluvoxamine 
itraconazole 
ketoconazole 
mibefradil 
nefazodone 
troleandomycin 
verapamil 
Food/Juice 
grapefruit juice 
 
Common CYP3A4 Inducers 
The following lists describe medications which are common inducers of CYP3A4. This list 
should not be considered all-inclusive. Consult individual drug labels for specific information on 
a compound’s propensity to induce CYP3A4. 
HIV Antivirals 
Others 
efavirenz 
nevirapine 
barbiturates 
carbamazepine 
glucocorticoids 
modafinil 
Phenobarbital 
phenytoin 
rifampin 
St. John's wort 
troglitazone 
rifabutin 
 


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ATTACHMENT 6:  NUMERIC RATING SCALE (NRS) FOR PVNS SYMPTOMS 
 
 
 


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NUMERIC RATING SCALE (NRS) FOR PVNS SYMPTOMS 
The following question asks about pain at the site of your tumor. 
Please rate your pain by circling the one number that best describes your pain at its worst 
in the last 24 hours. 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No 
pain 
 
 
 
 
 
 
 
 
 
Pain as bad 
as you can 
imagine 
 
 
The following questions ask about specific symptoms at the site of your tumor. 
Please rate your swelling by circling the one number that best describes your swelling at its worst 
in the last 24 hours. 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No 
swelling  
 
 
 
 
 
 
 
 
 
Worst 
imaginable 
Please rate your stiffness by circling the one number that best describes your stiffness at its worst 
in the last 24 hours. 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No 
stiffness 
 
 
 
 
 
 
 
 
 
Worst 
imaginable 
Please rate your instability (e.g., giving way, loss of balance) by circling the one number that 
best describes your instability at its worst in the last 24 hours. 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No 
instability 
 
 
 
 
 
 
 
 
 
Worst 
imaginable 
Please rate your limited motion (e.g., can’t bend or extend at site of tumor ) by circling the one 
number that best describes your limited motion at its worst in the last 24 hours. 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No 
limited 
motion 
 
 
 
 
 
 
 
 
 
Worst 
imaginable 
 
 
 


Pexidartinib (PLX3397) 
 
Protocol PLX108-01 
 
 
Amendment 12 
 
CONFIDENTIAL 
88 
Plexxikon Inc. 
PROPRIETARY 
ATTACHMENT 7:  WESTERN ONTARIO AND MCMASTER UNIVERSITIES 
OSTEOARTHRITIS INDEX (WOMAC) QUESTIONNAIRE