Clinical trial NCT02975700
Conditions: Melanoma
Keywords: PLX3397 Kit-mutant Melanoma Unresectable or Metastatic KIT-mutated Melanoma Developmental Phase I/II
Sponsor: Daiichi Sankyo Co., Ltd.
Start date: 2017-01-31; Completion date: 2024-10-14
Enrollment: 6 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this Phase I/II study is to evaluate safety, pharmacokinetics, and preliminary efficacy of the investigational drug PLX3397 in subjects with unresectable or metastatic KIT-mutated melanoma.

Detailed description:

Arms: arm 1: Part 1: Open label, multicenter study includes a dose evaluation portion in which the safety profile of PLX3397 as a single oral agent will be evaluated

Part 2: An expansion cohort in which the efficacy and safety of PLX3397 administered at the recommended Phase 2 dose will be evaluated in patients with unresectable stage III or stage IV KIT-mutated melanoma.
Interventions: intervention 1: PLX3397
Intervention descriptions: intervention 1: 1000 mg/day (400 mg in the morning and 600 mg in the evening)

Protocol documents:
Prot_SAP_000.pdf: 
Daiichi Sankyo Co., Ltd. 
PLX3397 
Protocol PLX108-13 
Version 9.0, 25FEB2020 
CONFIDENTIAL/PROPRIETARY 
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CLINICAL STUDY PROTOCOL 
 
Protocol Number: 
PLX108-13 
Title: 
Phase I/II Open Label, Multicenter Study of PLX3397 in 
Patients with Unresectable or Metastatic KIT-mutated 
Melanoma 
Indication: 
Unresectable stage III or stage IV KIT-mutated melanoma 
Phase: 
I/II 
Sponsor: 
DAIICHI SANKYO CO., LTD. 
 
Protocol History: 
Date/Version: 
VERSION 9.0 25 FEB 2020 
VERSION 8.0 11 SEP 2018 
VERSION 7.0 27 DEC 2017 
VERSION 6.0 27 MAY 2017 
VERSION 5.0 (17 November 2016/Amendment 4) 
VERSION 4.0 (06 September 2016/Amendment 3) 
VERSION 3.0 (04 August 2016/Amendment 2) 
VERSION 2.0 (16 June 2016/Amendment 1) 
VERSION 1.0 (9 October 2014/Original) 
 
 
 
 
 
 
 
 
Confidentiality Statement 
INFORMATION CONTAINED IN THIS DOCUMENT IS PROPRIETARY TO DAIICHI 
SANKYO. THE INFORMATION IS PROVIDED TO YOU IN CONFIDENCE WHICH IS 
REQUESTED UNDER AN AGREED UPON AND SIGNED CONFIDENTIALITY AND 
DISCLOSURE AGREEMENT. DO NOT GIVE THIS DOCUMENT OR ANY COPY OF IT OR 
REVEAL ANY PROPRIETARY INFORMATION CONTAINED IN IT TO ANY THIRD PARTY 
(OTHER THAN THOSE IN YOUR ORGANIZATION WHO ARE ASSISTING YOU IN THIS 
WORK AND ARE BOUND BY THE CONFIDENTIALITY AND DISCLOSURE AGREEMENT) 
WITHOUT THE PRIOR WRITTEN PERMISSION OF AN AUTHORIZED REPRESENTATIVE 
OF DAIICHI SANKYO 


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PHASE I/II OPEN LABEL, MULTICENTER STUDY OF PLX3397 IN PATIENTS WITH 
UNRESECTABLE OR METASTATIC KIT-MUTATED MELANOMA 
Sponsor Approval: 
This clinical study protocol has been reviewed and approved by the Daiichi Sankyo representative listed below. 
 
Print Name 
Signature 
 
Clinical Study Lead 
 
  
 
Title 
Date (DD MMM YYYY) 
Investigator’s Signature: 
I have fully discussed the objectives of this study and the contents of this protocol with the 
Sponsor’s representative. 
I understand that information contained in or pertaining to this protocol is confidential and should 
not be disclosed, other than to those directly involved in the execution or the ethical review of the 
study, without written authorization from the Sponsor. It is, however, permissible to provide 
information to a subject in order to obtain consent. 
I agree to conduct this study according to this protocol and to comply with its requirements, subject 
to ethical and safety considerations and guidelines, and to conduct the study in accordance with the 
Declaration of Helsinki, International Council for Harmonisation guidelines on Good Clinical 
Practice (ICH E6), and applicable regional regulatory requirements. 
I agree to make available to Sponsor personnel, their representatives and relevant regulatory 
authorities, my subjects’ study records in order to verify the data that I have entered into the case 
report forms. I am aware of my responsibilities as a Principal Investigator as provided by the 
Sponsor. 
I understand that the Sponsor may decide to suspend or prematurely terminate the study at any time 
for whatever reason; such a decision will be communicated to me in writing. Conversely, should I 
decide to withdraw from execution of the study, I will communicate my intention immediately in 
writing to the Sponsor. 
 
<<Insert Name>> 
 
  
 
Print Name 
Signature 
 
<<Insert Title>> 
 
  
 
Title 
Date (DD MMM YYYY) 


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TABLE OF CONTENTS 
TABLE OF CONTENTS ................................................................................................................ 3 
1.0 
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS .................................... 6 
2.0 
PROTOCOL SYNOPSIS ............................................................................................... 8 
3.0 
BACKGROUND AND STUDY RATIONALE .......................................................... 18 
4.0 
STUDY OBJECTIVES ................................................................................................ 23 
5.0 
STUDY DESIGN ......................................................................................................... 23 
6.0 
STUDY POPULATION .............................................................................................. 26 
7.0 
STUDY TREATMENT ............................................................................................... 29 
8.0 
STUDY CONDUCT .................................................................................................... 37 
9.0 
STUDY ASSESSMENT SCHEDULE ........................................................................ 39 
10.0 
STUDY ENDPOINTS ................................................................................................. 54 
11.0 
STATISTICAL AND QUANTITATIVE ANALYSES ...............................................55 
12.0 
ETHICAL CONSIDERATIONS ................................................................................. 58 
13.0 
EVENTS OF SPECIAL INTEREST ............................................................................59 
14.0 
ADVERSE EVENTS ................................................................................................... 59 
15.0 
ADMINISTRATIVE REQUIREMENTS .................................................................... 64 
16.0 
ADDRESS LIST .......................................................................................................... 68 
17.0 
PUBLICATION POLICY ............................................................................................ 68 
18.0 
REFERENCES ............................................................................................................. 69 
19.0 
ATTACHMENT .......................................................................................................... 70 
ATTACHMENT 1:  LABORATORY TESTS ............................................................................. 70 
ATTACHMENT 2:  LIST OF COMMON CYP3A INHIBITORS AND INDUCERS ................71 
ATTACHMENT 3:  RECIST V1.1 CRITERIA ........................................................................... 72 
ATTACHMENT 4:  ECOG PERFORMANCE STATUS ............................................................84 
ATTACHMENT 5: ADDRESS LIST ......................................................................................... 85 
ATTACHMENT 6:  VERSION 2.0 (AMENDMENT 1 SUMMARY OF CHANGES) ............. 88 
ATTACHMENT 7:  VERSION 3.0 (AMENDMENT 2 SUMMARY OF CHANGES) ............. 91 
ATTACHMENT 8:  VERSION 4.0 (AMENDMENT 3 SUMMARY OF CHANGES) ........... 102 
ATTACHMENT 9:  VERSION 5.0 (AMENDMENT 4 SUMMARY OF CHANGES) ........... 106 
ATTACHMENT 10:  VERSION 6.0 SUMMARY OF CHANGES .......................................... 108 
ATTACHMENT 11:  VERSION 7.0 SUMMARY OF CHANGES .......................................... 109 
ATTACHMENT 12:  VERSION 8.0 SUMMARY OF CHANGES .......................................... 110 


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LIST OF TABLES 
Table 2-1:   Schedule of Events for Pilot Portion of Study ........................................................... 13 
Table 2-2:   Schedule of Events for Phase II Portion of Study...................................................... 15 
Table 7-1:   Dose Modification Guidelines for Treatment-emergent Toxicities ........................... 31 
Table 7-2:   Additional Liver Evaluation ...................................................................................... 32 
Table 7-3: Recommended Dosage Reductions for Pexidartinib with Concomitant Use of 
Moderate or Strong CYP3A Inhibitors or UGT Inhibitors ........................................ 35 
Table 9-1: Summary of Known KIT Mutations in Melanoma and Their Sensitivity to 
PLX3397 and Other Approved Drugs ....................................................................... 53 
Table 19-1: Time Point Response:  Patients with Targets (+/- Non-Target) Disease ................... 81 
Table 19-2: Time Point Response:  Patients with Non-Target Disease Only ............................... 82 
Table 19-3: Best Overall Response When Confirmation of CR and PR Required ....................... 82 
 
 
LIST OF FIGURES 
Figure 3-1: PLX3397 Causes Tumor Regression in a Patient-Derived Xenograft Model 
of Kit-Mutant Melanoma ........................................................................................... 19 
Figure 5-1: Overview of Study PLX3397 .................................................................................... 25 


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GLOBAL AMENDMENT, PROTOCOL VER 9.0 
Amendment Rationale: 
The main purpose of this amendment is to update the safety information for pexidartinib and to 
revise the dose modification criteria. 
Changes to the Protocol: 
Please refer to the comparison document for protocol version 8.0 (dated 11 Sep 2018) vs. 
protocol version 9.0 (dated 25 Jan 2020) for actual changes in-text. The summary of changes 
below is a top-line summary of major changes in the PLX108-13 clinical study protocol (Version 
9.0). 
 
DESCRIPTION OF EACH HIGH-LEVEL CHANGE 
1 
Updated dose modification guidelines. 
The following sections of the protocol were updated: 
Section 7.5 (Dose Modification Guidelines) 
2 
Updated guidelines for concomitant dosing of CYP3A inducers, CYP3A/UGT 
inhibitors, hormonal contraceptives, and proton-pump inhibitors. 
The following sections of the protocol were updated: 
Section 7.7.1 (CYP3A inducers) 
Section 7.7.2 (CYP3A and UGT Inhibitors) 
Section 7.7.3 (Hormonal Contraceptives) 
Section 7.7.4 (Acid-reducing Agents) 
Section 7.8 (Dosage Modification for Renal Impairment) 
3 
Updated list of common CYP3A inhibitors and inducers 
The following sections of the protocol were updated: 
ATTACHMENT 2: LIST OF COMMON CYP3A INHIBITORS AND 
INDUCERS 


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1.0 
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS 
 
Abbreviation or Term 
Definition/Explanation 
AE 
Adverse Event 
ALT 
Alanine aminotransferase 
AML 
Acute Myelogenous Leukemia 
ANC 
Absolute Neutrophil Count 
AST 
Aspartate aminotransferase 
AUC0-6 
Area Under the concentration-time Curve from time zero to 6 hrs post dosing 
AUCinf 
Area Under the concentration-time Curve from time zero to infinity 
BID 
Twice daily 
BUN 
Blood Urea Nitrogen 
Ca++ 
Calcium 
CBC 
Complete Blood Count 
CFDA 
China Food and Drug Administration 
CHF 
Congestive Heart Failure 
Cl- 
Chloride 
Cmax 
Maximum observed concentration 
CR 
Complete Response 
CRF 
Case Report Form 
Cr 
Creatinine 
CrCl 
Creatinine Clearance 
CRO 
Contract Research Organization 
CSD 
Chronically Sun Damaged 
CT 
Computed Tomography 
CTCAE 
Common Toxicity Criteria for Adverse Events 
ctDNA 
Circulating tumor DNA 
DLT 
Dose Limiting Toxicity 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EIU 
Exposure In Utero 
FDA 
Food and Drug Administration 
FFPE 
Formalin-Fixed Paraffin-Embedded 
GCP 
Good Clinical Practice 
GGT 
Gamma Glutamyl Transferase 
G-CSF 
Granulocyte-Colony Stimulating Factor 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
HBsAg 
Hepatitis B surface Antigen 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 


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Abbreviation or Term 
Definition/Explanation 
HIV 
Human Immunodeficiency Virus 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IHC 
Immunohistochemistry 
IRB 
Institutional Review Board 
LDH 
Lactate Dehydrogenase 
MedDRA 
Medical Dictionary for Drug Regulatory Activities 
MI 
Myocardial Infarction 
mm3 
Cubic millimeters 
MTD 
Maximum Tolerated Dose 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NOAEL 
No-Observed-Adverse-Effect Level 
NY 
New York 
OS 
Overall Survival 
PD 
Pharmacodynamic(s) or Progressive Disease 
PET 
Positron Emission Tomography 
PFS 
Progression Free Survival 
PK 
Pharmacokinetic(s) 
PPI 
Proton Pump Inhibitor 
PR 
Partial Response 
PT/INR 
Prothrombin Time/International Normalized Ratio 
QT 
Interval between the start of the Q wave and the end of the T wave 
QTc 
QT interval corrected 
QTcF 
QT interval corrected using Fredericia equation 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
Recommended Phase II Dose 
RR 
Respiratory Rate 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
Tmax 
Time of maximum observed concentration 
TEAE 
Treatment-Emergent Adverse Event 
ULN 
Upper Limit of Normal 
WBC 
White Blood Cell 


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2.0 
PROTOCOL SYNOPSIS 
 
Title: 
Phase I/II Open Label, Multicenter Study of PLX3397 in Patients with Unresectable or 
Metastatic KIT-mutated Melanoma 
Sponsor: 
Daiichi Sankyo Co., Ltd. 
Clinical Phase: 
I/II 
Indication(s): 
Unresectable stage III or stage IV KIT-mutated melanoma 
Objectives: 
The objectives of the Pilot portion of the study are: 
• To evaluate the safety profile of PLX3397 1000 mg per day when administered twice 
daily (BID) orally as a single agent to patients with unresectable or metastatic KIT- 
mutated melanoma 
• To determine the pharmacokinetics (PK) of PLX3397 
The objectives of the Phase II portion of the study are: 
• To determine the preliminary efficacy of PLX3397 
• To evaluate the safety profile of PLX3397 
The exploratory objectives are: 
• To evaluate the pharmacodynamics as well as the association between KIT mutation type 
and response to therapy (Pilot and Phase II portions of the study) 
• To evaluate tumor response by positron emission tomography (PET) scan on Day 1 of 
Cycle 2 compared to Baseline (Pilot portion and first 13 patients of the Phase II portion of 
the study) 
Study Design: 
This Phase I/II, open label, multicenter study includes a dose evaluation portion (Pilot 
phase) in which the safety profile of PLX3397 as a single oral agent will be evaluated, 
followed by an expansion cohort (Phase II) in which the efficacy and safety of PLX3397 
administered at the recommended Phase II dose (RP2D) will be evaluated in patients with 
unresectable stage III or stage IV KIT-mutated melanoma. 
The Pilot portion of the study follows a 3+3 design to determine if 1000 mg per day is the 
appropriate dose for the Phase II portion. Three patients are planned to be dosed initially. If 
0 or 1 of 3 patients at the 1000 mg dose level cohort experience a dose-limiting toxicity 
(DLT), 3 additional patients will be enrolled for a total of 6 patients. If ≥2 of 6 patients 
experience a DLT at the 1000 mg per day dose, the dose will be de-escalated to 800 mg per 
day. If 0 or 1 of 3 patients at the 800 mg per day dose level cohort experiences a DLT, 
3 additional patients will be enrolled for a total of 6 patients. If ≥2 of 6 patients experience a 
DLT at the 800 mg dose, the study will be terminated due to intolerability. Additional 
patients may be enrolled in a dose cohort based on safety and efficacy observations. The 
RP2D can be either 1000 mg per day or 800 mg per day based on discussions between the 
Sponsor and the investigators. The RP2D will be further evaluated in an expansion cohort 
during the Phase II portion of the study. 
In the Phase II portion of the study, an analysis of anti-tumor response will be carried out 
after approximately 13 patients have been treated. If 3 or more responses are seen (complete 
response (CR) and partial response (PR) based upon Response Evaluation Criteria in Solid 
Tumors (RECIST) v1.1 or PET imaging), an additional approximately 19 patients will be 
enrolled and treated. 
Number of 
Patients: 
Approximately 44 patients are planned for enrollment 
Pilot: Approximately 6-12 patients 
Phase II: Approximately 32 patients 
Study 
Procedures: 
Procedures include medical history, physical examination, vital sign assessment, 12-lead 
electrocardiography (ECG), clinical laboratory evaluations (serum chemistry, hematology, 
urinalysis), pregnancy testing, and eastern cooperative oncology group (ECOG) 


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performance status assessment. Concomitant medications and adverse events (AEs) will be 
monitored and recorded throughout the study. Radiographic tumor response assessment by 
computed tomography (CT) scan will be performed every 8 weeks × 3 (at the end of Cycles 
2, 4, 6), then every 12 weeks thereafter (e.g., at the end of Cycles 9, 12, 15, and onward). 
Information on qualified KIT mutation(s) will be collected, and archived tumor tissue will 
be collected at Screening. Fresh tumor tissue for the purpose of exploratory 
pharmacodynamics will be obtained at baseline (Day 1) and optionally also at Day 15 of 
Cycle 1 and End-of-treatment in the Pilot portion and first 13 patients of the Phase II 
portion. PET scan will be obtained at baseline (Day 1) and Day 1 of Cycle 2 in the Pilot 
portion and first 13 patients of the Phase II portion. 
Inclusion/ 
Exclusion 
Criteria: 
To be eligible for enrollment, patient must meet all inclusion and exclusion criteria. 
Inclusion Criteria: 
1. Age ≥18 years 
2. Unresectable stage III or stage IV melanoma which is histologically confirmed at the 
treating institution with KIT mutation(s) not known to be resistant to PLX3397 (see 
Table 9-1). 
Note: Patients with KIT exon 8, 9, 11, 13, and 14 mutations are the most likely to be 
sensitive to PLX3397. Patients with KIT exon 17 or 18 mutations D816V, Y823D, and 
A829P should not be enrolled as they are not sensitive to PLX3397. Other KIT exon 17 
or 18 mutations may be sensitive to PLX3397 and should be enrolled. 
3. No limit on prior systemic therapies for melanoma. Patients who have not received 
prior therapy are eligible if they have a potentially sensitive KIT mutation. 
4. Presence of measurable lesions by RECIST v1.1 
5. ECOG performance status 0, 1, or 2 
6. Life expectancy ≥3 months in the judgment of the investigator 
7. Adequate organ and bone marrow function 
a. 
Absolute neutrophil count (ANC) ≥1.5 X 109/L, Hgb ≥10 g/dL, platelet count ≥100 
X 109/L 
b. AST/ALT ≤2.5 X upper limit of normal (ULN) or <5 X ULN in the presence of 
liver metastases, total bilirubin ≤1.5 ULN (unless due to Gilbert’s Syndrome, in 
which case it must be ≤2.5 mg/dL), albumin ≥3.0 g/dL 
c. 
Serum creatinine ≤1.5 X ULN or calculated creatinine clearance (CrCl) 
>60 mL/min using the Cockcroft-Gault formula 
Patients may be transfused or receive granulocyte-colony stimulating factor (G-CSF) or 
growth factors. 
8. Women of child-bearing potential must have a negative serum pregnancy test at 
Screening and must agree to use an effective form of contraception from the time of the 
negative pregnancy test up to 3 months after the last dose of study drug. Effective forms 
of contraception include abstinence, hormonal contraceptive (injectable or implantable) 
in conjunction with a barrier method, or a double barrier method. Women of non-child- 
bearing potential must have been postmenopausal for ≥1 year or surgically sterile. 
9. Fertile men must agree to use an effective method of birth control during the study and 
for up to 3 months after the last dose of study drug. 
10. Willingness and ability to provide written informed consent prior to any study-related 
procedures and to comply with all study requirements 
Exclusion Criteria: 
1. Prior treatment with a KIT inhibitor for melanoma 
2. Known presence of NRAS or BRAF mutation 


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3. Exposure to any chemotherapy, antibody or antibody drug conjugate, small molecule 
TKI, immunotherapy (e.g., PD-1, PD-L1, or CTLA-4 inhibitors – either antibody or 
small molecule), investigational drug, or radiation therapy within 28 days prior to Cycle 
1 Day 1 (C1D1). 
4. Unresolved Grade >1 clinically significant (in the judgment of the investigator) adverse 
effects from previous therapy prior to C1D1 
5. Symptomatic brain metastases. Subjects with untreated brain metastasis ≤1 cm can be 
considered eligible if deemed asymptomatic by the investigator upon consultation with 
the medical monitor and do not require immediate radiation or steroids. Subjects with 
brain metastasis that is treated and stable for 1 month may be considered eligible if they 
are asymptomatic and on stable dose of steroids or if they do not require steroids 
following successful local therapy. 
6. History of another malignancy (within 2 years prior to first study drug administration) 
unless malignancy was treated with curative intent and likelihood of relapse is small 
(<5% in 2 years in the judgment of the investigator). Patients with a history of 
squamous or basal cell carcinoma of the skin or carcinoma in situ of the cervix may be 
enrolled. 
7. Concomitant treatment with other anti-neoplastic agents (hormonal therapy acceptable) 
8. Uncontrolled intercurrent or infectious illness 
9. Major surgical procedure or significant traumatic injury within 14 days of initiating 
study drug or anticipation of the need for major surgery during the study 
10. Previous radiotherapy to 25% or more of the bone marrow and/or radiation therapy 
within 28 days prior to C1D1 
11. Inability to swallow capsules, or refractory nausea and vomiting, malabsorption, an 
external biliary shunt, or significant bowel resection that would preclude adequate 
absorption 
12. Congestive heart failure (CHF) New York (NY) Heart Association class III or IV; 
unstable coronary artery disease (myocardial infarction [MI] more than 6 months prior 
to study entry is permitted); or serious cardiac arrhythmia 
13. Baseline QTcF ≥450 ms (males) or ≥470 ms (females) 
14. Known active or chronic infection with human immunodeficiency virus (HIV), hepatitis 
C virus (HCV), or hepatitis B virus (HBV). Active or chronic HBV infection is defined 
as being hepatitis B surface antigen (HBsAg) or HBV DNA-positive. Chronic HCV is 
defined as being anti-HCV or HCV RNA-positive 
15. Known chronic liver disease 
16. Women who are breast-feeding or pregnant 
Duration of 
Study: 
Screening Period: 
28 days 
Treatment Period: 
Subjects will receive study drug twice daily during each 28-day cycle. There is no limit to 
the number of treatment cycles that can be administered. The treatment will continue until 
disease progression, unacceptable toxicity, consent withdrawal, or a protocol violation. 
Subjects receiving clinical benefit from treatment (stable disease or better) will be offered 
the opportunity to continue therapy with pexidartinib in the extension phase of this protocol. 
Follow-up Period: 
All patients will undergo an End-of-Study evaluation within 28 days of the last dose of 
study drug and prior to the initiation of any new anti-cancer therapy (if applicable). 
Thereafter, patients will be contacted by phone every 3 months during year 1 and every 
6 months thereafter to obtain information about subsequent treatment(s) and survival status. 
Test Product, 
Dose, and 
PLX3397 will be supplied in 200 mg capsules and will be taken BID approximately 12 
hours apart. Each dose is to be taken with approximately 200 mL of water. Subject will fast 


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Mode of 
Administration: 
for at least one hour before and one hour after dosage. Each cycle of treatment will last 28 
days. 
During the Pilot portion of the study, 3 to 6 patients in sequential dose cohorts will be 
enrolled. The dose cohorts are as follows: 
• Cohort 1: 1000 mg/day (400 mg in the morning and 600 mg in the evening) 
• Cohort -1 (if required): 800 mg/day (400 mg BID) 
Cohort -1 will be carried out only if Cohort 1 is considered intolerable. Study treatment may 
be delayed up to 2 weeks to permit resolution of any treatment-related toxicity outside the 
DLT window. 
The dose level for the Phase II portion of the study will be the RP2D as determined from the 
Pilot phase. Study drug will be administered BID in a fasting state. 
Definition of 
Dose-limiting 
Toxicity (DLT): 
A DLT is defined as an AE assessed as being possibly or probably related to study drug 
administration that is: 
• Not due to the underlying malignancy; 
• Has no clear evidence of an alternative etiology; and 
• Meets one of the following CTCAE v. 4.03 criteria during the first 28 days of PLX3397 
administration: 
Any Grade ≥3 clinically significant hematologic toxicity except: 
Grade 3 lymphopenia 
Grade 3 neutropenia ≤7 days 
Any thrombocytopenia resulting in clinically significant bleeding 
Any Grade ≥3 clinically significant non-hematologic toxicity except: 
Nausea, vomiting, and/or diarrhea of Grade 3 severity that resolves to Grade ≤2 within 
7 days with optimal prophylaxis and/or treatment. 
Grade 3 fatigue that resolves to Grade ≤2 within 7 days. 
Grade ≥3 alkaline phosphatase that is related to underlying malignancy (e.g., bone 
metastasis) 
If, for any reason, either the Sponsor or principal investigator deems further dose reduction 
inappropriate. Final decisions on determination of DLTs will be made in consultation 
between the Sponsor and the principal investigator. 
Any dose reduction required during Cycle 1 due to potential toxicity. 
For the purposes of determining the DLT in Cycle 1, the use of G-CSF or other hematologic 
growth factors is not permitted during Cycle 1. If a patient develops a protocol defined 
hematologic DLT and requires the use of G-CSF or other hematologic growth factors, they 
may be used in accordance with local standard of care, and per Section 7.7. 
Stopping Rules: 
Pilot portion: 
• If ≥2 of 6 patients experience DLTs in cohort 1 (1000 mg/day), Cohort -1 (800 mg per 
day) will be activated 
• If ≥2 of 6 patients in Cohort -1 experience DLTs, the study will be terminated due to 
intolerability. 
Phase II: 
• Subjects will be discontinued from the study for reasons of disease progression, 
unacceptable toxicity, consent withdrawal, a protocol violation, or noncompliance (taking 
less than 80% of study drug). Noncompliant patients may be replaced. 
Patients will be discontinued from the study if they are off study drug for more than 
2 weeks, regardless of the reason, unless the patient has demonstrated a clinical benefit from 
therapy and would like to continue dosing with study drug after discussion between the 
investigator and the Sponsor. 


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The Pilot and Phase II portions of the study may be discontinued if the study is terminated 
by the Sponsor, the China Food and Drug Administration (CFDA), or other regulatory 
authorities. 
Safety and 
Tolerability 
Assessments: 
Physical examination, vital signs, 12-lead ECG, AEs, and clinical laboratory evaluations 
(hematology, serum chemistry, urinalysis). 
PK Parameters: 
The pharmacokinetic profile of plasma PLX3397 will be analyzed by measuring area under 
the plasma concentration–time curve (AUC0-6), peak concentration (Cmax), and time of 
maximum observed concentration (Tmax). 
PD Parameters: 
Histological/molecular analysis of paired fresh tumor biopsy, and PET scan evaluation on 
Day 1 of Cycle 2 compared to Baseline in the Pilot portion and the first 13 patients in the 
Phase II portion of the study will be performed. Exploratory tissue studies will include 
immunohistochemistry (IHC) for KIT, pERK, Ki67 and other markers of target or tumor 
evaluation. Other exploratory evaluations may include assessment of the tumor 
microenvironment by IHC or other methods for immune cell expression/number (e.g., PD- 
1). Exploratory blood studies will measure CSF-1 and circulating tumor DNA (ctDNA) 
(Phase II portion in Korea Only). 
Endpoints: 
The endpoints in the Pilot portion of the study include: 
• DLTs will define the RP2D (1000 mg per day or 800 mg per day) 
• Safety endpoints (i.e., AEs, clinical laboratory evaluations, ECGs, physical examinations, 
and vital sign measurements) 
• PK analysis 
• Serum/plasma tumor biomarkers including CSF-1 
The exploratory endpoints in the Pilot portion of the study include: 
• IHC and molecular analysis of archival and paired fresh tumor biopsy 
• PET scan evaluation on Day 1 of Cycle 2 compared to Baseline 
The primary endpoint in the Phase II portion of the study includes: 
• Objective response rate (ORR), which is the sum of CR and PR by RECIST v1.1 
The secondary endpoints in the Phase II portion of the study include: 
• Duration of response (DoR) 
• Progression free survival (PFS) 
• Overall survival (OS) 
• Safety endpoints (i.e., AEs, clinical laboratory evaluations, ECGs, physical examinations, 
and vital sign measurements) 
The exploratory endpoints in the Phase II portion of the study include : 
• IHC and molecular analysis of archival and paired fresh tumor biopsy 
• Serum/plasma tumor biomarkers including CSF-1. 
• ctDNA 
• PET scan evaluation on Day 1 of Cycle 2 compared to Baseline 
Statistical 
Considerations 
The Phase II portion of the study will follow a Simon two-stage design to compare a null 
ORR of 15% with an alternative ORR of 40% with 90% power and a one-sided type I error 
of 5%. With the assumption of 10% drop-out, the total sample size will be 32 patients to 
achieve 29 evaluable patients. Thirteen patients will be enrolled in the first stage, with at 
least three responses required to proceed to the second stage. Eight responses among 29 
evaluable patients are required for PLX3397 to be considered promising. 


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Table 2-1: 
Schedule of Events for Pilot Portion of Study 
 
Procedure 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 and 
Subsequent 
Cycles2 
Extension 
phase21 
(every 28 
days) 
End 
of 
Study3 
Post-Study 
Follow-up4 
Day –28 
to –11 
Day 1 Day 8 
± 3d 
Day15 
± 3d 
Day 22 
± 3d 
Day 1 
± 3d 
Day 8 
± 3d17 
Day 15 
± 3d 
Day 22 
± 3d17 
Day 1 
± 3d 
Day 1 
± 3d 
Consent 
X 
Medical history 
X 
Archival Tissue15 
X 
KIT mutation 
documentation5 
X 
Physical examination6, 
vital signs 
X 
X18 
X 
X 
X 
X 
X 
X 
Height 
X 
Weight 
X 
X 
ECOG Performance Status 
X 
X18 
X 
X 
X 
X 
X 
ECG7 
X 
X 
X 
X 
Hematology8 
X 
X18 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum chemistry20 
X 
X18 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis8 
X 
X18 
X 
X 
Coagulation Profile 
(PT/INR)8 
X 
Serum pregnancy test9 
X 
Blood sampling for PK10 
X 
X 
Blood sampling for PD16 
X 
X 
In-clinic study drug 
administration (am dose) 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug compliance19 
X 
X 
X 
X 
X 
CT chest, abdomen, pelvis12 
X 
X 12 
X22 
PET scan13 
X 
X 
Fresh tumor biopsy14 
X 
X 
X 
Phone interview 
X 


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1. Protocol-specified screening procedures that are performed as part of standard of care and within 28 days of Day 1 of Cycle 1 may be used for screening 
purposes. Clinical laboratory studies and baseline CT scan must be performed within the 14-day period before Day 1 of Cycle 1. 
2. If the study treatment is well tolerated and the patient experiences no disease progression, then the clinic visit, laboratory studies and other procedures indicated 
in the column (except CT chest/abdomen/pelvis – see footnote 11) will be performed every 4 weeks at the beginning of each cycle. 
3. The End-of-Study visit should be scheduled within the 28-day period after the last dose of study drug and before starting any new anti-neoplastic therapy. 
4. A post-study follow-up contact by phone by site staff will be conducted every 3 months during Year 1, then every 6 months thereafter to obtain information on 
any new anti-cancer therapy received and survival status. 
5. Documentation of KIT mutation(s) prior to enrollment to include submission of deidentified sequencing report and associated .scf, .ab1, or equivalent output 
files. 
6. A complete physical examination will be performed at screening. All subsequent physical examinations will be disease-specific. 
7. ECG will be performed after the patient has been in a supine position for at least 5 minutes. It will be performed at Screening, before and 2 hours (± 30 minutes) 
after the morning dose on Day 15 of Cycle 1, Day 1 of Cycle 2, and at the End-of-Study visit. 
8. A complete blood count (CBC) with a differential count and comprehensive chemistry will be performed every 7 days during Cycle 1, Cycle 2, at the beginning 
of each cycle starting with Cycle 3 and onward, and at the end of the study. Urinalysis will be performed at Screening and at the beginning of each cycle. 
PT/INR will be performed at Screening. 
9. For women of child-bearing potential, a screening serum pregnancy test must be negative within 7 days of Day 1 of Cycle 1. 
10. On Day 1 and Day 15 of Cycle 1 during the Pilot portion of the study, blood samples for pharmacokinetic (PK) analysis will be obtained pre-morning dose, and 
0.5, 1, 2, 4, and 6 hours post-morning dose (± 10 minutes at the 0.5- and 1-hour post-dose timepoints, and ± 30 minutes at the 2-, 4-, and 6-hour post-dose 
timepoints). 
11. Concomitant medications will include non-prescribed medications and any complementary/herbal supplements. 
12. CT with and without contrast to assess tumor status will be performed every 8 weeks during the first 24 weeks of study treatment, then every 12 weeks 
thereafter (e.g., at the end of Cycles 2, 4, 6, then at the end of Cycles 9, 12, 15 and onward). PET/CT scan may be used as well. 
13. PET scan will be performed at Day 1 (-3d) of Cycle 1 or before fresh tumor biopsy in screening and Day 1 (± 3d) of Cycle 2 for patients enrolled in the Pilot 
portion of the study. If a PET/CT scan is performed, then no additional PET scan is needed. 
14. Fresh tumor biopsy will be performed on Day 1 (-3d), Day 15 (±3d) (optional), and at the End-of-Study visit (optional) for subjects enrolled in the Pilot portion 
of the study. Biopsies must be core needle or excisional (not fine needle), and sufficient for 20 unstained slides of 5 micron thickness. If a Screening tumor 
biopsy was obtained (Day -28 to Day -1), and there was sufficient tissue from that sample for laboratory testing, then tumor biopsy on Day 1 is not required. All 
PET scans should be performed prior to biopsy collection procedures to avoid false positive results. 
15. Availability of archival tissue should be documented and at least 10 unstained slides of 5 micron thickness should be submitted to the central lab. 
16. On Day 1 and Day 15 of Cycle 1 during the Pilot portion of the study, blood samples for pharmacodynamics (PD) analysis will be obtained pre-morning dose. 
17. Assessments on these visits may be performed at a local hospital or testing facility for patient convenience. Results should be shared with the Principal 
Investigator within 48 hours. 
18. ECOG Performance Status, symptom-directed physical examination, hematology, serum chemistry, and urinalysis do not need to be repeated if these 
assessments from Screening occurred within 3 days of C1D1 unless a change in status is suspected. 
19. Drug Diary to be reviewed. Collection of completed drug diary and distribution of new diary to occur at beginning of each cycle. 
20. Serum chemistry could be more frequent if liver function test are elevated and reference the dose modification (Section 7.5). 
21. Subjects receiving clinical benefit from study treatment at the time of data cut-off, will be offered the opportunity to continue pexidartinib treatment in an 
extension phase. Subjects will continue until disease progression, unacceptable toxicity, or withdrawal of consent. 
22. CT with and without contrast to assess tumor status will be performed every 12 weeks. PET/CT scan may be used as well. 


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Table 2-2: 
Schedule of Events for Phase II Portion of Study 
 
Procedure 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 and 
Subsequent 
Cycles 2 
End 
of 
Study3 
Post- 
Study 
Follow- 
up4 
Day –28 
to –11 
Day 1 
Day 8 
± 3d 
Day15 
± 3d 
Day 22 
± 3d 
Day 1 
± 3d 
Day 8 
± 3d16 
Day 15 
± 3d 
Day 22 
± 3d16 
Day 1 
± 3d 
Consent 
X 
Medical history 
X 
Archival Tissue14 
X 
KIT mutation 
documentation5 
X 
Physical examination6, 
vital signs 
X 
X17 
X 
X 
X 
X 
X 
Height 
X 
Weight 
X 
X 
ECOG Performance Status 
X 
X17 
X 
X 
X 
X 
X 
ECG7 
X 
X 
X 
X 
Hematology8 
X 
X17 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum chemistry20 
X 
X17 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis8 
X 
X17 
X 
X 
Coagulation Profile 
(PT/INR)8 
X 
Serum pregnancy test9 
X 
Blood sampling for PD10 
X 
X 
In-clinic study drug 
administration (am dose) 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug compliance18 
X 
X 
X 
X 
CT chest, abdomen, pelvis12 
X 
X 12 
PET scan15 
X 
X 
Fresh tumor biopsy13 
X 
X 
X 


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Procedure 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 and 
Subsequent 
Cycles 2 
End 
of 
Study3 
Post- 
Study 
Follow- 
up4 
Day –28 
to –11 
Day 1 
Day 8 
± 3d 
Day15 
± 3d 
Day 22 
± 3d 
Day 1 
± 3d 
Day 8 
± 3d16 
Day 15 
± 3d 
Day 22 
± 3d16 
Day 1 
± 3d 
Circulating tumor DNA 
(ctDNA)19 (Korea sites only) 
X 
X 
X 
X 
Phone interview 
X 
1. Protocol-specified screening procedures that are performed as part of standard of care and within 28 days of Day 1 of Cycle 1 may be used for screening 
purposes. Clinical laboratory studies and baseline CT scan must be performed within the 14-day period before Day 1 of Cycle 1. 
2. If the study treatment is well tolerated and the patient experiences no disease progression, then the clinic visit, laboratory studies and other procedures indicated 
in the column (except CT chest/abdomen/pelvis – see footnote 11) will be performed every 4 weeks at the beginning of each cycle. 
3. The End-of-Study visit should be scheduled within the 28-day period after the last dose of study drug and before starting any new anti-neoplastic therapy. 
4. A post-study follow-up contact by phone by site staff will be conducted every 3 months during Year 1, then every 6 months thereafter to obtain information on 
any new anti-cancer therapy received and survival status. 
5. Documentation of KIT mutation(s) prior to enrollment to include submission of deidentified sequencing report and associated .scf, .ab1, or equivalent output 
files. 
6. A complete physical examination will be performed at screening. All subsequent physical examinations will be disease-specific. 
7. ECG will be performed after the patient has been in a supine position for at least 5 minutes. It will be performed at Screening, before and 2 hours (± 30 minutes) 
after the morning dose on Day 15 of Cycle 1, Day 1 of Cycle 2, and at the End-of-Study visit. 
8. CBC with a differential count and comprehensive chemistry will be performed every 7 days during Cycle 1, Cycle 2, at the beginning of each cycle starting with 
Cycle 3 and onward, and at the end of the study. Urinalysis will be performed at Screening and at the beginning of each cycle. PT/INR will be performed at 
Screening. 
9. For women of child-bearing potential, a screening serum pregnancy test must be negative within 7 days of Day 1 of Cycle 1. 
10. On Day 1 and Day 15 of Cycle 1 during the Phase II portion of the study, blood samples for pharmacodynamics (PD) analysis will be obtained pre-morning 
dose. 
11. Concomitant medications will include non-prescribed medications and any complementary/herbal supplements. 
12. CT with and without contrast to assess tumor status will be performed every 8 weeks during the first 24 weeks of study treatment, then every 12 weeks 
thereafter (e.g., at the end of Cycles 2, 4, 6, then at the end of Cycles 9, 12, 15 and onward). PET/CT scan may be used as well. 
13. Fresh tumor biopsy will be performed on Day 1 (-3d), Day 15 (-3d) (optional), and at the End-of-Study visit (optional) for first 13 patients enrolled in Phase II. 
Biopsies must be core needle or excisional (not fine needle), and sufficient for 20 unstained slides of 5 micron thickness. If a Screening tumor biopsy was 
obtained (Day −28 to Day −1), and there was sufficient tissue from that sample for laboratory testing, then tumor biopsy on Day 1 is not required. All PET scans 
should be performed prior to biopsy collection procedures to avoid false positive results. 
14. Availability of archival tissue should be documented and at least 10 unstained slides of 5 micron thickness should be submitted to the central lab. 
15. PET scan will be performed at Day 1 (-3d) of Cycle 1 or before fresh tumor biopsy in screening and Day 1 (± 3d) of Cycle 2 for the first 13 patients enrolled in 
the Phase II portion of the study. If a PET/CT scan is performed, then no additional PET scan is needed. 
16. Assessments on these visits may be performed at a local hospital or testing facility for patient convenience. Results should be shared with the Principal 
Investigator within 48 hours. 


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17. ECOG Performance Status, symptom-directed physical examination, hematology, serum chemistry, and urinalysis do not need to be repeated if these 
assessments from Screening occurred within 3 days of C1D1 unless a change in status is suspected. 
18. Drug Diary to be reviewed. Collection of completed drug diary and distribution of new diary to occur at beginning of each cycle. 
19. Korea sites only. Whole blood for circulating tumor DNA assessment to be done pre-dose and the End of Study visit. 
20. It could be more frequent if liver function test are elevated and reference the dose modification (Section 7.5). 


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3.0 
BACKGROUND AND STUDY RATIONALE 
3.1. 
Background 
The incidence of malignant melanoma continues to increase globally, and this includes Asia. Up 
to the end of 2010, the incidence of melanoma in Beijing, China was 8.9 per 100000 people 
(Si 2013). Melanomas can be generally classified into 4 subtypes: (1) melanomas that occur on 
skin without chronic sun-induced damage (non-CSD); (2) melanomas on skin with chronic sun- 
induced damage (CSD); (3) mucosal melanomas, and (4) acral melanomas. The incidence of 
these 4 subtypes differs significantly among different races and ethnicities (Kong 2011). In the 
Chinese and other Asian populations, acral and mucosal melanomas are the predominant 
subtypes, accounting for approximately 65% of all melanomas (Chi 2011). Five-year survival 
rates of Chinese patients with stage I, II, III, and IV diseases were 94.1%, 44.0%, 38.4%, and 
4.6%, respectively (Chi 2011). 
In a large analysis which comprised 502 samples from melanoma patients screened for KIT 
mutations at Peking Cancer Hospital & Institute, the overall mutation frequency was 10.8% 
(54/502), with the highest mutation frequency within the CSD subgroup (20.7%); in the acral and 
mucosal melanoma subtypes, the frequency of KIT mutations was 11.9% (23/193) and 9.6% 
(16/167), respectively. Importantly, the overall survival of melanoma patients with KIT 
mutations was significantly shorter than that of patients without such alterations (p = 0.001) 
(Kong 2011). 
Until recently, there had been no improvements in outcome for patients with advanced disease 
for several decades. The identification of an activating mutation in BRAF in 50% of melanoma 
patients (Davies 2002) led to the development of vemurafenib, a highly active targeted therapy 
that benefits approximately 80% of eligible patients, is associated with a significant survival 
benefit, and is now a standard of care in advanced disease (Chapman 2011). Apart from BRAF, 
KIT is the only other aberrant signaling molecule for which targeted drugs are available. Some 
evidence of efficacy for imatinib in KIT advanced melanoma has been reported in two Phase 
II trials (Guo 2011). However, KIT mutations are heterogeneous, and many do not respond to 
imatinib therapy (Si 2013; Carvajal 2011). To date, there has been no therapy approved for KIT 
mutated melanoma. 
PLX3397 is a novel, orally active, small molecule inhibitor that targets a variety of KIT 
mutations, as well as CSF1R (Fms), and oncogenic Flt3, but remains highly selective versus 
other kinases. Few preclinical models for Kit-mutant melanoma exist, but preliminary results 
from an ongoing study of PLX3397 in one model are promising. This model is based on a 
patient-derived tumor xenograft from a patient with sinal-nasal melanoma. This patient had been 
treated with the kinase inhibitor nilotinib and experienced partial tumor regression at 3 months. 
After 6 months a new subcutaneous lesion appeared and a biopsy of this lesion was removed and 
propagated in immunocompromised mice. Tumors in these mice grew to 100 mm3 in 12 days 
and treatment with PLX3397 (chow formulation, nominal strength of 46 mg/kg) was initiated. 
As shown in Figure 3-1 below, vehicle-treated animals (n = 12) were sacrificed at Week 7, while 
PLX3397 treatment resulted in tumor regression (n = 12). PLX3397 treatment was stopped at 
Week 13, and three of the 12 animals showed re-growth of the tumor. 


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Figure 3-1: 
PLX3397 Causes Tumor Regression in a Patient-Derived Xenograft 
Model of Kit-Mutant Melanoma 
 
It is now widely accepted that tumor-associated macrophages (TAMs) play a critical role in 
promoting tumor angiogenesis, metastasis and creating an immunosuppressive microenviroment 
for tumor growth (Hao 2012). PLX3397 targets these TAMs by blocking the Fms receptor on 
their surface. Pharmacology models show that PLX3397 blocks Fms activity in vivo, and 
significantly reduces the incidence of lymph node metastasis in the A2058 BRAF-mutant 
xenograft model. In addition, synergistic efficacy is demonstrated when PLX3397 is combined 
with BRAF inhibition in this same model, providing a possible explanation for the beneficial 
effect of FMS blockade in the tumor microenviroment. See the PLX3397 Investigator’s 
Brochure for further details. 
 
3.1.1. 
Nonclinical Experience 
Good Laboratory Practice (GLP) safety pharmacology studies (in vitro hERG, dog 
cardiovascular, rat central nervous system, and rat respiratory) did not identify any meaningful 
test article related effects. 
In the GLP 13-week rat oral gavage study at doses of 0.5, 4 and 20 mg/kg/day, there were no test 
article-related clinical observations or effects on body weights, food consumption, ophthalmic 
examinations, urinalysis, or macroscopic examinations. Systemic toxicity was observed at a 
dosage level of 20 mg/kg/day, as evidenced by anemia and mild to moderate generalized bone 
marrow depletion in both sexes, and minimal to moderate hepatocellular vacuolation associated 
with higher AST, ALT, and cholesterol values in males. The no-observed-adverse-effect level 
(NOAEL) was considered to be 4 mg/kg/day. 
In the GLP 13-week dog oral gavage study at doses of 1, 6, and 30 mg/kg/day, there were no test 
article-related macroscopic findings. Body weights, food consumption, ophthalmic, and 
electrocardiography parameters were unaffected by test article administration. Systemic toxicity 
was observed at the dosage level of 30 mg/kg/day, as evidenced by microscopic findings of 
generalized depletion of all germ cell populations in the testes, moderate hypospermatogenesis, 


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and moderate or severe hypospermia in the epididymides, which were consistent with observed 
lower absolute and relative testes weights and lower testicular volume in this group and sex. The 
NOAEL was considered to be 6 mg/kg/day for males. 
In GLP genotoxicity studies (Ames, chromosomal aberrations, and mouse bone marrow 
micronucleus), there was no evidence of mutagenic or clastogenic effects. 
See the PLX3397 Investigator’s Brochure for further details. 
 
3.1.2. 
Clinical Experience 
PLX3397 is being evaluated in both solid tumors and hematological malignancies. 
Approximately 345 patients have been exposed to PLX3397 doses ranging from 200 mg/day to 
5000 mg/day for up to 16 months. The recommended Phase II dose (RP2D) for solid tumors is 
1000 mg/day, and the RP2D for patients with Flt3-ITD AML (acute myelogenous leukemia) is 
3000 mg/day. 
No safety signals in vital signs, physical examinations, or electrocardiograms (ECGs) (including 
careful evaluation of potential electrocardiogram Interval between the start of the Q wave and the 
end of the T wave (QT) prolongation) have been identified. At doses of ≥600 mg/day, transient 
and reversible increases in aspartate aminotransferase (AST) and/or alanine aminotransferase 
(ALT) have been observed in approximately half of the patients. In addition, 1 case of liver 
enzyme elevation in association with an elevated bilirubin which was considered possibly drug- 
related was noted in study PLX108-04 (Phase II, single agent study in subjects with glioblastoma 
multiforme). Transient increases in AST and ALT were seen in the 13-week rat study, but not in 
the dog study. In addition to increased AST among solid tumor patients, the most common 
adverse events (AEs) have been fatigue, decreased appetite, nausea, vomiting, anemia, hair color 
change (depigmentation), and diarrhea. 
Details on the clinical experience with PLX3397 can be found in the Investigator’s Brochure. 
 
3.2. 
Rationale for Dose Selection and Study Design 
As summarized above (and discussed in detail in the Investigator’s Brochure), the safety of 
PLX3397 has been evaluated in patients with a range of tumor types, including solid tumors, 
hematologic malignancy, and in combination with chemotherapeutic agents. The selection of 
1000 mg per day as the initial dose to be evaluated in the Pilot portion of this study was based 
upon the safety data from PLX108-01, a dose-escalation study of PLX3397 in solid tumor 
patients followed by expansion cohorts of patients receiving PLX3397 at the RP2D. In the dose 
escalation portion of the study, 1000 mg per day was identified as the RP2D, and the safety of 
1000 mg per day was further evaluated in over 75 additional solid tumor patients. As this is the 
first time PLX3397 will be studied in melanoma patients, a Pilot portion of the study will 
confirm the safety and tolerability of 1000 mg per day in this patient population. A dose de- 
escalation option will allow dose reduction to 800 mg per day in the event that 1000 mg per day 
is not well tolerated. Doses below 800 mg per day are anticipated to result in reduced efficacy 
and will not be considered in this study. 


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Once the RP2D is selected from the Pilot portion, the study will be expanded to include an 
additional 32 patients to evaluate the anti-tumor activity of PLX3397 in KIT-mutated melanoma. 
The Phase II portion of this study will enroll patients in two stages. Thirteen patients will be 
enrolled in the first stage, with at least three responses (23%) required to proceed to the second 
stage. With the assumption of 10% drop-out, the total sample size will be 32 patients to achieve 
29 evaluable patients. Eight responses (28%) among 29 evaluable patients are required for 
PLX3397 to be considered promising. In view of the fact that there is no effective and approved 
therapy for advanced KIT mutated melanoma, a response rate of >40% is considered worthy of 
further study. 
This study design will allow the step-wise evaluation of PLX3397 in patients with advanced 
KIT-mutated melanoma, with the Pilot portion evaluating the safety of the proposed RP2D of 
1000 mg per day and the Phase II Portion providing for an initial evaluation of efficacy (among 
the first 13 enrolled patients) prior to further enrollment of the full cohort. 
The Extension part of the study will allow subjects to continue pexidartinib treatment who 
demonstrate clinical benefit (SD, PR, or CR). The benefits of transitioning subjects into the 
extension part are to allow subjects to continue receiving the study drug and monitor for safety, 
but decrease the amount of procedures. 
 
3.3. 
Potential Risks and Benefits 
The safety of pexidartinib has been evaluated in subjects with a range of tumor types, including 
solid tumors, hematologic malignancy, and in combination with chemotherapeutic agents. The 
selection of 1000 mg per day as the initial dose to be evaluated in the several studies was based 
upon the safety data from Study PLX108-01 and the safety of 1000 mg per day was further 
evaluated in several clinical studies. 
In the GLP repeat-dose toxicology studies consisting of up to 13 weeks of pexidartinib dosing, 
test article-related AEs were noted in testes (testicular spermatogonia reduction), ovaries 
(ovarian follicular degeneration), liver, bone and bone marrow, hematology, and lymphoid 
changes; these changes are consistent with the pharmacological mechanism of action of 
pexidartinib. All test article-related findings were partially or fully reversible. Potential dose- 
related changes in bone marrow function can be monitored by peripheral blood cell count and 
differential counts. Because of the effects on reproductive organs, subjects will be monitored for 
changes in luteinizing hormone, follicle stimulating hormone, and other sex-specific hormone 
levels. 
Effects on embryo fetal development have been observed in both rat and rabbit toxicology 
studies. Subjects in the study will be required to use adequate birth control during the study and 
for 90 days after the last dose of study drug administered. 
Findings in the nonclinical canine safety pharmacology study suggest that pexidartinib may have 
a negative inotropic effect. Subjects will be monitored for changes in ejection fraction with 
cardiac echocardiograms. 
In the clinical evaluation to date, among solid tumor patients, the most common AEs (occurring 
in ≥20% of all patients treated with pexidartinib) observed have been fatigue, nausea, decreased 


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appetite, hair color change (depigmentation), vomiting, diarrhea, headache, and anemia. In the 
AML study, the most common AEs reported have been diarrhea, nausea, fatigue, febrile 
neutropenia, vomiting, decreased appetite, anemia, cough, hypokalemia, and increases in AST. 
In some instances, the increase in liver enzymes may require dose hold or modification. Dosing 
modification guidance is included within the protocol for AE monitoring. Liver function (serum 
chemistry), renal function (serum chemistry), and heart electrophysiology (QT interval corrected 
for heart rate [QTc] evaluation) will be monitored during this study. 
Based on the treatment emergent adverse event (TEAE) reports of increased INR observed in 
patients receiving concomitant warfarin, careful monitoring is required during treatment with 
pexidartinib. Warfarin doses should be adjusted if an increase in INR is noted. 
Updated hepatic safety risk information as of December 2017; please consult the IB for more 
information: Hepatotoxicity is an important adverse drug reaction. Elevations of liver 
transaminases and bilirubin have been observed in studies with pexidartinib, together with cases 
of drug induced cholestasis. Cases of cholestasis have been observed in the first 8 weeks, have 
generally resolved with treatment discontinuation, but in some cases have been severe, with a 
protracted course requiring liver dialysis and, in 1 case, transplantation. Hepatotoxicity may be 
fatal. One fatal case with ongoing cholestatic liver injury at the time of death has been reported. 
Monitor patients closely as defined in the protocol. Protocol defined dose reductions and 
discontinuations of pexidartinib, increased frequency of laboratory monitoring, and reporting of 
findings should be followed (refer to Section 7.5). In addition, rechallenge with pexidartinib 
should not be attempted without prior discussion with the Sponsor’s Medical Monitor. 
Pexidartinib is a novel, orally active, small molecule inhibitor that targets CSF1R, Kit, and 
oncogenic Flt3, but remains highly selective versus other kinases. The potent inhibition of these 
3 kinases can be exploited to attack tumors via multiple mechanisms. Pexidartinib has shown a 
potent inhibitor of the proliferation of these target dependent models. 


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4.0 
STUDY OBJECTIVES 
4.1. 
Pilot Portion Objectives 
The objectives of the Pilot portion of the study are: 
 
• To evaluate the safety profile of PLX3397 1000 mg per day when administered twice daily 
(BID) orally as a single agent to patients with unresectable or metastatic KIT-mutated 
melanoma 
• To determine the pharmacokinetics of PLX3397 
 
4.2. 
Phase II Objectives 
The objectives of the Phase II portion of the study are: 
 
• To determine the preliminary efficacy of PLX3397 
• To evaluate the safety profile of PLX3397 
 
4.3. 
Exploratory Objectives 
The exploratory objectives are: 
 
• To evaluate the pharmacodynamics as well as the association between KIT mutation type and 
response to therapy (Pilot and Phase II portions of the study) 
• To evaluate tumor response by positron emission tomography (PET) scan on Day 1 of Cycle 
2 compared to Baseline (Pilot portion and first 13 patients of the Phase II portion of the 
study). 
 
 
5.0 
STUDY DESIGN 
5.1. 
Overview of Study Design 
This Phase I/II, open label, multicenter study includes a dose evaluation portion (Pilot phase) in 
which the safety profile of PLX3397 as a single oral agent will be evaluated, followed by an 
expansion cohort (Phase II) in which the efficacy and safety of PLX3397 administered at the 
RP2D will be evaluated in patients with unresectable stage III or stage IV KIT-mutated 
melanoma (comprising mainly acral, mucosal or CSD forms of the disease). 
The Pilot portion of the study follows a 3+3 design to determine if 1000 mg per day is an 
appropriate dose for the Phase II portion. Three patients are planned to be dosed initially. If 0 or 


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1 of 3 patients at the 1000 mg dose level cohort experience dose-limiting toxicity (DLT), 
3 additional patients will be enrolled for a total of 6 patients. If ≥2 of 6 patients experience DLT 
at the 1000 mg dose, the dose will be de-escalated to 800 mg per day. If 0 or 1 of 3 patients at the 
800 mg dose level cohort experiences DLT, 3 additional patients will be enrolled for a total of 
6 patients. If ≥2 of 6 patients experience DLT at the 800 mg dose, the study will be terminated 
due to intolerability. Additional patients may be enrolled in a dose cohort based on safety and 
efficacy observations. The RP2D can be either 1000 mg per day or 800 mg per day based on 
discussions between the Sponsor and the investigators. The RP2D will be further evaluated in an 
expansion cohort during the Phase II portion of the study. 
In the Phase II portion of the study, an analysis of anti-tumor response will be carried out after 
approximately 13 patients have been treated. If 3 or more responses (23%) are seen (complete 
response (CR) and partial response (PR) based upon Response Evaluation Criteria in Solid 
Tumors (RECIST) v1.1 or PET imaging), an additional approximately 19 patients will be 
enrolled and treated. 
As of June 30 2018, 6 patients were enrolled in the Pilot portion of the study and received 1000 
mg per day dose. Two subjects are currently ongoing. Following a preliminary safety and 
efficacy assessment of these 6 patients, the sponsor decided to discontinue this study. The 
sponsor informed the 2 remaining subjects of study discontinuation and re-consented the subjects 
to continue in the extension part of the study. 
It is anticipated that a cut-off date will be established and that the data for the safety variables are 
considered to be mature. Subjects who benefit from therapy (stable disease or better) and remain 
on treatment without tumor progression at the time of cut-off will be allowed to continue 
treatment in an extension part of this study. Treatment will continue until disease progression, 
unacceptable toxicity, or consent withdrawal. 
A graphic overview of the study design is presented in Figure 5-1. 


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DOSE 
 
Pilot Portion - Determine Recommended Phase 2 Dose (RP2D) 
EVALUATION 
(Pilot Portion)n 
=12 
 
 
 
 
 
 
 
 
 
 
 
 
,, ,,.,-,. -  - 
-  
 
Recommended Phase 2 Dose 
- - ', 
''  ----------- <-
R2PD) = 1000 or 800 m2/da-
,· -- _,, 
.-. 
,,.J 
 
EXPANSION 
COHORT 
(Phase 2) n = 32 
Phase II - Efficacy & Safety of RP2D 
 
 
 
 
 
 
 
 
 
Figure 5-1: 
Overview of Study PLX3397 
If DLT for O or 1 of 
initial 3, 3 more enrolled 
Dose Cohort -I 
800 mg 
n = 6 
If DLT for 
2 of 6, 
study tenninated 
If DLT for 
2 of 6, begin 
Dose Cohort - 1 at 800 mg 
IfDLT for O or 1 of 
initial 3, 3 more enrolled 
Dose Coho11 l 
1000 mg 
n = 6 
n = 13{first stage) 
• Treated with PLX3397 at RP2D 
• Three or more responses [CR or PR] required to 
proceed to second stage) 
n = 19 {second stage) 
• Treated with PLX3397 at RP2D 
• Eight responses [CR or PR] out of29 evaluable 
patients required to consider PLX3397 promising 
Unresectable Stage III or Stage IV 
KIT-Mutated, Acral, Mucosa! or 
Clu·onicaly Sun Damaged Melanoma 


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5.2. 
Number of Subjects 
Up to approximately 44 patients are planned for enrollment. 
 
Pilot Portion: Approximately 6-12 patients 
 
Phase II: Approximately 32 patients 
 
 
5.3. 
Duration of Study 
Screening Period: 
 
The Screening period will be 28 days prior to the first dosing for each patient. 
 
Treatment Period: 
 
Subjects will receive study drug twice daily during each 28-day cycle. There is no limit to the 
number of treatment cycles that can be administered. The treatment will continue until disease 
progression, unacceptable toxicity, consent withdrawal, or a protocol violation. 
Those subjects deriving clinical benefit from therapy defined as stable disease or better at the 
cut-off date, will be offered the opportunity to continue therapy with pexidartinib in the 
extension phase of this protocol until disease progression, unacceptable toxicity, consent 
withdrawal, or a protocol violation. 
 
 
Follow-up Period: 
 
All patients will undergo an End-of-Study evaluation within 28 days of the last dose of study 
drug and prior to the initiation of any new anti-cancer therapy (if applicable [see Section 8.4]). 
Thereafter, patients will be contacted by phone every 3 months during year 1 and every 6 months 
thereafter to obtain information about subsequent treatment(s) and survival status. 
 
 
6.0 
STUDY POPULATION 
Patients must meet the inclusion and exclusion criteria to be enrolled in the study, unless a 
planned protocol deviation is granted by the Sponsor. 
6.1. 
Inclusion Criteria 
Each patient must meet all of the following inclusion criteria to be enrolled in the study to 
treatment: 


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1. Age ≥18 years 
2. Unresectable stage III or stage IV melanoma which is histologically confirmed at the treating 
institution with KIT mutation(s) not known to be resistant to PLX3397. 
Note: Patients with KIT exon 8, 9, 11, 13, and 14 mutations are the most likely to be 
sensitive to PLX3397. Patients with KIT exon 17 or 18 mutations D816V, Y823D, and 
A829P should not be enrolled as they are not sensitive to PLX3397. Other KIT exon 17 or 18 
mutations may be sensitive to PLX3397 and should be enrolled. 
3. No limit on prior systemic therapies for melanoma. Patients who have not received prior 
therapy are eligible if they have a potentially sensitive KIT mutation. 
4. Presence of measurable lesions by RECIST v1.1 
5. Eastern cooperative oncology group (ECOG) performance status 0, 1, or 2 
6. Life expectancy ≥3 months in the judgment of the investigator 
7. Adequate organ and bone marrow function 
a. Absolute neutrophil count (ANC) ≥1.5 X 109/L, Hgb ≥10 g/dL, platelet count ≥100 X 
109/L 
b. AST/ALT ≤2.5 X upper limit of normal (ULN) or <5 X ULN in the presence of liver 
metastases, total bilirubin ≤1.5 ULN (unless due to Gilbert’s Syndrome, in which case it 
must be ≤2.5 mg/dL), albumin ≥3.0 g/dL 
c. Serum creatinine ≤1.5 X ULN or calculated creatinine clearance (CrCl) >60 mL/min 
using the Cockcroft-Gault formula 
Patients may be transfused or receive granulocyte-colony stimulating factor (G-CSF) or 
growth factors. 
8. Women of child-bearing potential must have a negative serum pregnancy test at Screening 
and must agree to use an effective form of contraception from the time of the negative 
pregnancy test up to 3 months after the last dose of study drug. Effective forms of 
contraception include abstinence, hormonal contraceptive (injectable or implantable) in 
conjunction with a barrier method, or a double barrier method. Women of non-child-bearing 
potential must have been postmenopausal for ≥1 year or surgically sterile. 
9. Fertile men must agree to use an effective method of birth control during the study and for up 
to 3 months after the last dose of study drug. 
10. Willingness and ability to provide written informed consent prior to any study-related 
procedures and to comply with all study requirements 


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6.2. 
Exclusion Criteria 
Subjects meeting any of the following exclusion criteria are not to be enrolled in the study to 
treatment: 
 
1. Prior treatment with a KIT inhibitor for melanoma 
2. Known presence of NRAS or BRAF mutation 
3. Exposure to any chemotherapy, antibody or antibody drug conjugate, small molecule TKI, 
immunotherapy (e.g., PD-1, PD-L1, or CTLA-4 inhibitors – either antibody or small 
molecule), investigational drug, or radiation therapy within 28 days prior to Cycle 1 Day 1 
(C1D1). 
4. Unresolved Grade >1 clinically significant (in the judgment of the investigator) adverse 
effects from previous therapy prior to C1D1 
5. Symptomatic brain metastases. Subjects with untreated brain metastasis ≤1 cm can be 
considered eligible if deemed asymptomatic by the investigator upon consultation with the 
medical monitor and do not require immediate radiation or steroids. Subjects with brain 
metastasis that is treated and stable for 1 month may be considered eligible if they are 
asymptomatic and on stable dose of steroids or if they do not require steroids following 
successful local therapy. 
6. History of another malignancy (within 2 years prior to first study drug administration) unless 
malignancy was treated with curative intent and likelihood of relapse is small (<5% in 
2 years in the judgment of the investigator). Patients with a history of squamous or basal cell 
carcinoma of the skin or carcinoma in situ of the cervix may be enrolled. 
7. Concomitant treatment with other anti-neoplastic agents (hormonal therapy acceptable) 
8. Uncontrolled intercurrent or infectious illness 
9. Major surgical procedure or significant traumatic injury within 14 days of initiating study 
drug or anticipation of the need for major surgery during the study 
10. Previous radiotherapy to 25% or more of the bone marrow and/or radiation therapy within 
28 days prior to C1D1 
11. Inability to swallow capsules, or refractory nausea and vomiting, malabsorption, an external 
biliary shunt, or significant bowel resection that would preclude adequate absorption 
12. Congestive heart failure (CHF) New York (NY) Heart Association class III or IV; unstable 
coronary artery disease (myocardial infarction [MI] more than 6 months prior to study entry 
is permitted); or serious cardiac arrhythmia 
13. Baseline QTcF ≥450 ms (males) or ≥470 ms (females) 


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14. Known active or chronic infection with human immunodeficiency virus (HIV), hepatitis C 
virus (HCV), or hepatitis B virus (HBV). Active or chronic HBV infection is defined as 
being hepatitis B surface antigen (HBsAg) or HBV DNA-positive. Chronic HCV is defined 
as being anti-HCV or HCV RNA-positive 
15. Known chronic liver disease 
16. Women who are breast-feeding or pregnant 
 
 
7.0 
STUDY TREATMENT 
7.1. 
Study Drug Administration 
PLX3397 will be supplied in 200 mg capsules and will be taken BID approximately 12 hours 
apart. Each dose is to be taken with approximately 200 mL of water. Subject will fast for at least 
one hour before and one hour after dosage. Each cycle of treatment will last 28 days. 
The dose level for the Phase II portion of the study will be the RP2D as determined from the 
Pilot phase. Study drug will be administered BID in a fasting state for at least one hour before 
and one hour after administration. 
Missed doses (generally outside of a 2-hour dosing window) will be skipped and not 
administered as a double dose at the next administration. Patients who omit their dose will be 
instructed NOT to make up that dose. Doses that are vomited will not be replaced. 
 
7.2. 
Dose Levels for Pilot Portion of the Study 
7.2.1. 
Dose Evaluation 
During the Pilot portion of the study, 3 to 6 patients in sequential dose cohorts will be enrolled. 
The dose cohorts are as follows: 
• Cohort 1: 1000 mg/day (400 mg in the morning and 600 mg in the evening) 
• Cohort -1(if required): 800 mg/day (400 mg BID) 
 
Cohort -1 will be carried out only if Cohort 1 is considered intolerable. Study treatment may be 
delayed up to 2 weeks to permit resolution of any treatment-related toxicity outside the DLT 
window. 
 
7.3. 
Dose Reduction Rules 
Dose reduction will occur in accordance with the rules listed below. 
 
• The DLT window is 28 days. 


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• A minimum of 3 patients will be initially enrolled per cohort. 
• If 0 or 1 of the first 3 patients enrolled in a given cohort experiences a DLT, at least 
3 additional patients will be enrolled in that cohort. 
• If a DLT is observed in one-third or more of patients (e.g., 2 or more of up to 6 patients), the 
dose combination at which this occurs will be considered intolerable and the maximum 
tolerated dose (MTD) will have been exceeded and the next lower dose will be evaluated. 
• The highest dose level at which 0 or 1 out of 6 experiences a DLT will be declared the MTD. 
If only 3 patients were initially evaluated at that dose level, an additional 3 patients will be 
enrolled to evaluate for DLTs at that dose level. 
• After dosing has been completed in each cohort, safety and PK data (as applicable) will be 
reviewed by and dose reduction decisions made by the Sponsor, and investigators and study 
staff from all participating sites. 
 
7.4. 
Definitions of Dose-Limiting Toxicity 
In the Pilot portion of the study, DLTs will be assessed during a DLT assessment window of 
28 days in Cycle 1. However, if clinically relevant ≥Grade 3 cumulative toxicities are observed 
beyond Cycle 1, these should also be taken into account when assessing further dose reduction. 
There will be a 24 hour delay between the first and subsequent patients enrolled in each cohort to 
maximize the safety of enrolled patients. 
Patients who are withdrawn from the study prior to completing the DLT assessment window for 
any reason other than a DLT will be replaced. Patient numbers must not be re-used. 
Subjects who receive less than 80% of the planned dose during the DLT evaluation period will 
not be considered evaluable and need to be replaced. 
A DLT is defined as an AE assessed as being possibly or probably related to study drug 
administration that is: 
• Not due to the underlying malignancy; 
• Has no clear evidence of an alternative etiology; and 
• Meets one of the following CTCAE v. 4.03 criteria during the first 28 days of PLX3397 
administration: 
• Any Grade ≥3 clinically significant hematologic toxicity except: 
• Grade 3 lymphophenia 
• Grade 3 neutropenia ≤7 days 
• Any thrombocytopenia resulting in clinically significant bleeding 
• Any Grade ≥3 clinically significant non-hematologic toxicity except: 


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• Nausea, vomiting, and/or diarrhea of Grade 3 severity that resolves to Grade ≤2 
within 7 days with optimal prophylaxis and/or treatment. 
• Grade 3 fatigue that resolves to Grade ≤2 within 7 days. 
• Grade ≥3 alkaline phosphatase that is related to underlying malignancy (e.g., bone 
metastasis) 
• If, for any reason, either the Sponsor or principal investigator deems further dose 
reduction inappropriate. Final decisions on determination of DLTs will be made in 
consultation between the Sponsor and the principal investigator. 
• Any dose reduction required during Cycle 1 due to potential toxicity. 
• For the purposes of determining the DLT in Cycle 1, the use of G-CSF or other 
hematologic growth factors is not permitted during Cycle 1. If a patient develops a 
protocol defined hematologic DLT and requires the use of G-CSF or other hematologic 
growth factors, they may be used in accordance with local standard of care, and per 
Section 7.7. 
 
 
7.5. 
Dose-Modification Guidelines 
Toxicities that occur outside the DLT window will be taken into consideration when determining 
the RP2D. Reduction/interruption of dosing for AEs may take place at any time. Below are 
guidelines for dosage modification for PLX3397–related toxicities as well as guidelines for their 
management. Dose reductions should occur in increments of 200 mg/day, depending on the 
toxicity grade, as noted in Table 7-1 and Table 7-2. 
These parameters are only a guide and are not intended to supersede the clinical judgment of the 
treating physician. Medical Monitor should be notified of any dose adjustments. Dosing 
interruptions longer than 2 weeks for any reason 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 after discussion between the investigator and the Sponsor. 
Rechallenge with a reduced dose of pexidartinib may result in a recurrence of increased serum 
transaminases, bilirubin, or ALP. Monitor liver tests weekly for the first month after 
rechallenge. 
 
Table 7-1: 
Dose Modification Guidelines for Treatment-emergent Toxicities 
 
Adverse Reaction 
Severity 
Pexidartinib Dosage Modifications 
Increased ALT 
and/or AST 
Greater than 3 to 
5 times ULN 
• 
Withhold and monitor liver tests weekly. 
• 
If AST and ALT are less than or equal to 3 times 
ULN within 4 weeks, resume at reduced dose. 
• 
If AST or ALT is not less than or equal to 3 times 
ULN in 4 weeks, permanently discontinue 
pexidartinib. 


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Greater than 5 to 
10 times ULN 
• 
Withhold and monitor liver tests twice weekly. 
If AST and ALT are less than or equal to 3 times ULN 
within 4 weeks, resume at reduced dose. 
• 
If AST or ALT is not less than or equal to 3 times 
ULN in 4 weeks, permanently discontinue 
pexidartinib. 
Greater than 10 times 
ULN 
• 
Permanently discontinue pexidartinib. 
• 
Monitor liver tests twice weekly until AST or ALT 
is less than or equal to 5 times ULN, then weekly 
until less than or equal to 3 times ULN. 
Increased ALP and 
Gamma-glutamyl 
transpeptidase 
(GGT) 
ALP greater than 
2 times ULN with 
GGT greater than 
2 times ULN 
• 
Permanently discontinue pexidartinib. 
• 
Monitor liver tests twice weekly until ALP is less 
than or equal to 5 times ULN, then weekly until 
less than or equal to 2 times ULN. 
Increased bilirubin 
Total bilirubin greater 
than ULN to less than 
2 times ULN 
or 
Direct bilirubin 
greater than ULN and 
less than 1.5 times 
ULN 
• 
Withhold and monitor liver tests twice weekly. 
• 
If an alternate cause for increased bilirubin is 
confirmed and bilirubin is less than ULN within 
4 weeks, resume at reduced dose. 
• 
If bilirubin is not less than ULN in 4 weeks, 
permanently discontinue pexidartinib. 
Total bilirubin greater 
or equal to 2 times 
ULN 
or 
Direct bilirubin 
greater than 1.5 times 
ULN 
• 
Permanently discontinue pexidartinib. 
• 
Monitor liver tests twice weekly until bilirubin is 
less than or equal to ULN. 
Adverse reactions or 
other laboratory 
abnormalities 
Severe or intolerable 
• 
Withhold until improvement or resolution. 
• 
Resume at a reduced dose upon improvement or 
resolution. 
 
 
 
 
Table 7-2: 
Additional Liver Evaluation 
 
Evaluation 
Comments 
Increase frequency of testing liver chemistries to 
twice per week, 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. 


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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. 
 
For suspected cases of cholestatic liver injury, eg, 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. 
 
7.6. 
Stopping Rules 
Following are the stopping rules for the Pilot portion of the study: 
 
• If ≥2 of 6 patients experience DLTs in cohort 1 (1000 mg/day), Cohort -1 (800 mg per day) 
will be activated. 
• If ≥2 of 6 patients in Cohort -1 experience DLTs, the study will be terminated due to 
intolerability. 
 
Following are the stopping rules for the Phase II portion of the study: 
 
• Subjects will be discontinued from the study for reasons of AE, clinically significant disease 
progression, patient request, investigator decision, protocol violation, patient noncompliance, 
and study termination by the Sponsor or institutional review board (IRB)/independent ethics 
committee (IEC). See Section 7.5 for guidance on dose reduction and discontinuation of 
therapy for safety concerns. Noncompliant patients may be replaced. 
Patients will be discontinued from the study if they are off study drug for more than 2 weeks, 
regardless of the reason, unless the patient has demonstrated a clinical benefit from therapy and 


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would like to continue dosing with study drug after discussion between the investigator and the 
Sponsor. 
The Pilot and Phase II portions of the study may be discontinued if the study is terminated by the 
Sponsor, the China Food and Drug Administration (CFDA), or other regulatory authorities. 
 
7.7. 
Concomitant Medications (and Procedures) 
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 AE), the treatment must be recorded on 
the electronic case report form (eCRF), including the reason for treatment, generic name of the 
drug, dosage, route, and start and stop dates of administration. 
For the purposes of determining the DLT in Cycle 1, the use of G-CSF or other hematologic 
growth factors is not permitted during Cycle 1. If a patient develops a protocol defined 
hematologic DLT and requires the use of G-CSF or other hematologic growth factors, they may 
be used in accordance with local standard of care. 
Patients enrolled in studies with PLX3397 who are also receiving concomitant warfarin should 
have their anti-coagulation status carefully monitored, especially shortly after initiation of 
PLX3397, for the potential need to make adjustments in warfarin dosing. In particular, INR 
should be obtained just prior to initiation of PLX3397, within 1 to 2 weeks after initiation, and 
periodically thereafter. Dose adjustments of warfarin should be made as medically indicated. 
Patients are discouraged from taking proton pump inhibitors or other strong anti-acids (e.g., H-2 
antagonists) as these may interfere with the reliable identification of the R2PD. 
 
 
7.7.1. 
CYP3A inducers 
 
Avoid the concomitant use of strong CYP3A inducers, including St John’s wort (see 
ATTACHMENT 2, a list of common CYP3A inhibitors and inducers). 
 
7.7.2. 
CYP3A and UGT inhibitors 
Although pexidartinib does not appear to inhibit cytochrome P450 (CYP) drug-metabolizing 
enzymes to an important extent, caution is warranted when administering pexidartinib to subjects 
taking drugs that are highly dependent on CYP for metabolism and have a narrow therapeutic 
index. It is not known whether systemic exposure to these medications will increase while 
subjects are receiving pexidartinib. 
Of the five major CYP isoforms, 3A4 (BFC) may be involved in Phase 1 metabolism of 
PLX3397, with possibly CYP1A2 playing a minor role (see ATTACHMENT 2 for a list of 
common CYP3A inhibitors and inducers). In general, strong inducers of CYP3A4 should be 
avoided unless absolutely clinically necessary. These include anticonvulsants, mycin, 


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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 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 7.3. 
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 7-3: 
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 
 
 
7.7.3. 
Hormonal Contraceptives 
Pexidartinib has been indicated to be a moderate CYP3A4 inducer, as concurrent administration 
of pexidartinib decreased the AUCinf of the CYP3A4 substrate midazolam by 57%. As the 
hormonal contraceptive ethinyl estradiol is a CYP3A4 substrate, there is a potential that exposure 
of ethinyl estradiol may decrease on concurrent administration with pexidartinib.  As 
pexidartinib may cause embryo-fetal harm when administered to a pregnant woman, females of 
reproductive potential should be advised to use an effective, non-hormonal method of 
contraception during treatment with pexidartinib and for 1 month after the last dose. Males with 
female partners of reproductive potential should be advised to use an effective method of 
contraception during treatment with pexidartinib and for 1 month after the last dose. Female 
partners of male patients should concurrently use effective contraceptive methods (hormonal or 
non-hormonal). 
 
7.7.4. 
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. 


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7.8. 
Dosage Modification for Renal Impairment 
The recommended dosage of pexidartinib for patients with mild to severe renal impairment 
(CLcr 15 to 89 mL/min estimated by Cockcroft-Gault using actual body weight) is 200 mg in the 
morning and 400 mg in the evening. 
 
7.9. 
Precautions and Restrictions 
Because pexidartinib is a substrate for CYP3A4/5 and some fruits are CYP3A4/5 inhibitors, 
foods or beverages containing CYP3A4/5 inhibiting fruits (eg, grapefruit, pomelo, star fruit, and 
pomegranate) should be avoided throughout the study. 
 
7.10. 
Management of Clinical Events 
All necessary support care will be available to patients. For dose-modification guidelines, see 
Section 7.5. 
 
7.11. 
Blinding and Unblinding 
Blinding methods will not be employed; PLX3397 will be administered in open-label fashion. 
 
 
7.12. 
Preparation, Reconstitution, and Dispensation 
PLX3397 is an anticancer drug, and as with other potential toxic compounds, caution should be 
exercised when handling PLX3397 (see Section 7.14). Specific instructions on preparation, 
reconstitution, and dispensation will be provided in the PLX108-13 Pharmacy Manual. 
 
7.13. 
Packaging and Labeling 
PLX3397 capsules (200 mg strength) are manufactured, packaged, and labeled according to 
Good Manufacturing Practice (GMP) and GCP at the following address: 
Catalent Pharma Solutions 
10245 Hickman Mills Drive 
Kansas City, MO 64137, USA 
 
7.14. 
Storage, Handling, and Accountability 
PLX3397 capsules will be stored at the clinical site, as indicated on the study drug label, 
i.e., room temperature, between 15º–30ºC (59º–86ºF). Patients will be requested to store the 
study drug at the recommended storage conditions noted on the label, out of the reach of children 
or other cohabitants. 


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Daiichi Sankyo, Inc. 
211 Mount Airy Road Basking Ridge, NJ 07920, US 
Medical Monitor 
(Sponsor) 
 
The Study drug provided in accordance with this Protocol will be kept in a secure place, and will 
only be supplied to Subjects participating in this Study. The Principal Investigator is accountable 
for all Study drug supplied by the Sponsor in accordance with this Protocol. In addition, the 
Principal Investigator must keep accurate and up-to-date dispensation records. Any Study drug 
accidently or deliberately destroyed must be recorded in a timely fashion, including an 
explanation for the destruction in writing. Any discrepancies between the amounts of Study drug 
dispensed and returned must also be explained in writing. All such records of drug accountability 
must be entered on the corresponding Subject CRF’s. 
All unused and partially used Study drug must be returned to the designee as instrusted by the 
Sponsor, or destroyed on Site in accordance with the established procedures for drug destruction, 
and with approval by the Principal Investigator or his/her designee. Details of destruction, 
including, but not limited to, the number of boxes destroyed, batch number, and the date and 
method of destruction must be recorded on the Study drug destruction logs. 
 
7.15. 
Other Protocol-Specified Materials 
There are no other supplies or materials required by the Protocol. 
 
 
8.0 
STUDY CONDUCT 
8.1. 
Study Personnel and Organizations 
The contact information for the Medical Monitor for this study is presented below. The contact 
information for the central and any additional clinical laboratories, the coordinating investigator 
for each member state/country, and CRO can be found in the Study Manual. A full list of 
investigators is available in the sponsor’s investigator database. 
 
 


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8.2. 
Arrangements for Recruitment of Subjects 
Recrnitment and enrollment strategies for this study may include recrnitment from the 
investigator's local practice or refe1rnls from other physicians. If adveitisements become pa1t of 
the recrnitment strategy, they will be reviewed by IRB and/or IEC. Subjects will be compensated 
for their paiticipation in this study. 
 
8.3. 
Treatment Group Assignments 
This is an open-label, sequential dose-escalation study with an expansion coho1t. The initial dose 
level of PLX3397 will be 1000 mg/day administered BID. Thereafter, dose de-escalation will 
occm as described in Section 7.2.1. The expansion cohort will be enrolled at the RP2D according 
to inclusion and exclusion criteria (Section 6.1 and Section 6.2). 
 
8.4. 
Withdrawal of Patients from Drug Treatment, Study and Patient 
Replacement 
The Medical Monitor will monitor safety data throughout the course of the study. The Medical 
Monitor will review SAEs within timeframes mandated by company procedmes and will review 
trends, laborato1y data, and AEs at periodic inte1vals and provide for interim safety analyses if 
appropriate. 
The reasons a patient may discontinue or be withdrawn from the study include, but are not 
limited to, AE, clinically significant disease progression, patient request, investigator decision, 
The investigator will ensme that the SAE repo1ting 
fo1m is completed and E-mailed/eFaxed to the 
following address within 24 homs of learning of the 
occmTence: 
• 
SAE 
• 
Hepatic events meeting combination 
abno1malities [ALT or AST 3 X ULN with 
simultaneous total bilirnbin 2 X ULN] 
(potential Hy's Law case), both serious and 
nonserious (see Section 13.0 for details) 
Name: DSI CSPV Safety 
Phone: 
Fax: 
Email: 
SAE and Potential 
Hy's Law case 
Reporting Contact: 


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protocol violation, patient noncompliance, and study termination by the Sponsor or IRB/IEC. 
When a patient discontinues or is withdrawn, the investigator will notify the Sponsor and should 
perform the procedures indicated in the End of Study column in the Schedule of Events within 
28 days after discontinuation of study drug and before 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 for reasons other than toxicity or clinically significant disease 
progression (e.g., protocol violation or noncompliance) may be replaced at the discretion of the 
medical monitor and the investigator. Study drug administration may be discontinued due to an 
AE or at the discretion of the investigator. 
The consequence of withdrawal of consent by a patient will be that no new information will be 
collected from that patient and added to the existing data or any database. However, every effort 
will be made to follow all patients for safety. 
 
8.5. 
Study Compliance 
The study drug PLX3397 will be provided only to eligible patients under the supervision of the 
investigator or identified sub-investigator(s). The appropriate study personnel will maintain 
records of study drug receipt and dispensing. Any discrepancy regarding the dose administered 
and the reason for the discrepancy will be recorded in the eCRF. At each clinic visit, patients will 
be questioned about their compliance with study drug administration, and their dosing diary 
should be reviewed. 
 
 
9.0 
STUDY ASSESSMENT SCHEDULE 
Event schedules are summarized in Table 2-1 and Table 2-2. 
All patients must provide written informed consent. During the consent process, the person 
obtaining consent must inform the patient of all elements of the study. No protocol-specific 
procedures, including screening procedures, are to be performed until the patient has signed and 
dated an IRB/IEC-approved informed consent form. The study begins with the signing and 
dating of the informed consent form. 
A patient will be considered enrolled in the study once all inclusion and exclusion criteria have 
been met, and the completed patient enrollment form has been submitted to the CRO, signed by 
the appropriate representative, and returned to the investigative site. 
Screening procedures are to be performed within 28 days before C1D1 of study therapy. 
The end of the study is defined as the date of the last dose of PLX3397 (see Section 8.4 for 
reasons for discontinuation or withdrawal of a patient from the study). 


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9.1. 
Pilot Portion—All Cohorts 
The schedule of events for patients in all cohorts in the Pilot portion is summarized in Table 2-1 
and detailed in the subsections below. 
9.1.1. 
Screening Visit (Day –28 to Day –1) 
• Informed consent 
• Medical history 
• Height and weight 
• Complete physical examination 
• Vital signs, including blood pressure, respiratory rate, pulse rate, and body temperature 
• 12-lead ECG 
• ECOG performance status evaluation 
• Serum chemistry, including sodium, potassium, chloride, CO2, calcium, phosphorus, glucose, 
blood urea nitrogen (BUN), creatinine, uric acid, total protein, albumin, total and direct 
bilirubin, AST, ALT, alkaline phosphatase, gamma glutamyl transferase (GGT), lactate 
dehydrogenase (LDH), and prothrombin time/international normalized ratio (PT/INR) 
• Hematology: hemoglobin, hematocrit, white blood cell count with a differential, platelet 
count 
• Urinalysis, including pH, protein/albumin, glucose, nitrites, ketones/acetone, and 
hemoglobin/blood 
• Documentation of archival tissue availability 
• KIT mutation documentation 
• Computed Tomography (CT) chest, abdomen, and pelvis (PET/CT scan may be used as well) 
• Adverse event assessment 
 
9.1.2. 
Screening Visit (Day –7 to Day –1) 
• Pregnancy test (for women of childbearing potential). For women of child-bearing potential, 
a serum pregnancy test at Screening must be negative. 
• Concomitant medications 
 
9.1.3. 
Cycle 1, Day 1 
 
Procedures to be performed before the morning dose: 


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• Fresh tumor biopsy (may be performed within 3 days prior to the study visit) 
• Blood sampling for PK analysis 
• Blood sampling for PD analysis 
• Physical examination (symptom-directed) 
• Serum chemistry, including sodium, potassium, chloride, CO2, calcium, phosphorus, glucose, 
BUN, creatinine, uric acid, total protein, albumin, total and direct bilirubin, AST, ALT, 
alkaline phosphatase, GGT, and LDH 
• Hematology: hemoglobin, hematocrit, white blood cell count with a differential, platelet 
count 
• Urinalysis, including pH, protein/albumin, glucose, nitrites, ketones/acetone, and 
hemoglobin/blood 
• Vital signs, including blood pressure, respiratory rate, pulse rate, and body temperature 
• ECOG performance status 
• PET scan (–3-day window) (If a PET/CT scan is performed, then no additional PET scan is 
needed.) 
• Adverse event assessment 
• Concomitant medications 
 
Procedures to be performed after the morning dose: 
 
• Blood sampling for PK analysis (0.5, 1, 2, 4, and 6 hours post-dose [± 10 minutes at the 
0.5- and 1-hour post-dose timepoints, and ± 30 minutes at the 2-, 4-, and 6-hour post-dose 
timepoints]) 
 
9.1.4. 
Cycle 1, Day 8 ± 3 days 
• Serum chemistry, including sodium, potassium, chloride, CO2, calcium, phosphorus, glucose, 
BUN, creatinine, uric acid, total protein, albumin, total and direct bilirubin, AST, ALT, 
alkaline phosphatase, GGT, and LDH 
• Hematology: hemoglobin, hematocrit, white blood cell count with a differential, platelet 
count 
• Adverse event assessment 
• Concomitant medications 


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9.1.5. 
Cycle 1, Day 15 ± 3 days 
 
Procedures to be performed before the morning dose: 
 
• Fresh tumor biopsy (optional, and may be performed within 3 days prior to the study visit) 
• Blood sampling for PK analysis 
• Blood sampling for PD analysis 
• 12-lead ECG 
• Physical examination (symptom-directed) 
• Serum chemistry, including sodium, potassium, chloride, CO2, calcium, phosphorus, glucose, 
BUN, creatinine, uric acid, total protein, albumin, total and direct bilirubin, AST, ALT, 
alkaline phosphatase, GGT, and LDH 
• Hematology: hemoglobin, hematocrit, white blood cell count with a differential, platelet 
count 
• Vital signs, including blood pressure, respiratory rate, pulse rate, and body temperature 
• ECOG performance status assessment 
• Adverse event assessment 
• Concomitant medications 
• Study drug compliance via study drug diary review and accountability 
Procedures to be performed after the morning dose: 
• Blood sampling for PK analysis (0.5, 1, 2, 4, and 6 hours post-dose [± 10 minutes at the 
0.5- and 1-hour post-dose timepoints, and ± 30 minutes at the 2-, 4-, and 6-hour post-dose 
timepoints]) 
• 12-lead ECG (2 hours (± 30 minutes) post-dose) 
 
9.1.6. 
Cycle 1, Day 22 ± 3 days 
• Serum chemistry, including sodium, potassium, chloride, CO2, calcium, phosphorus, glucose, 
BUN, creatinine, uric acid, total protein, albumin, total and direct bilirubin, AST, ALT, 
alkaline phosphatase, GGT, and LDH 
• Hematology: hemoglobin, hematocrit, white blood cell count with a differential, platelet 
count 
• Adverse event assessment 


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• Concomitant medications 
 
9.1.7. 
Cycle 2, Day 1 ± 3 days 
 
Procedures to be performed before the morning dose: 
 
• Physical examination (symptom-directed) 
• Vital signs, including blood pressure, respiratory rate, pulse rate, and body temperature 
• 12-lead ECG 
• Serum chemistry, including sodium, potassium, chloride, CO2, calcium, phosphorus, glucose, 
BUN, creatinine, uric acid, total protein, albumin, total and direct bilirubin, AST, ALT, 
alkaline phosphatase, GGT, and LDH 
• Hematology: hemoglobin, hematocrit, white blood cell count with a differential, platelet 
count 
• Urinalysis, including pH, protein/albumin, glucose, nitrites, ketones/acetone, and 
hemoglobin/blood 
• ECOG performance status 
• Adverse event assessment 
• PET scan (±3-day window) (If a PET/CT scan is performed, then no additional PET scan is 
needed.) 
• Concomitant medications 
• Study drug compliance via study drug diary review and accountability 
Procedures to be performed after the morning dose: 
• 12-lead ECG (2 hours (± 30 minutes) post-dose) 
 
9.1.8. 
Cycle 2, Day 8 ± 3 days 
• Serum chemistry, including sodium, potassium, chloride, CO2, calcium, phosphorus, glucose, 
BUN, creatinine, uric acid, total protein, albumin, total and direct bilirubin, AST, ALT, 
alkaline phosphatase, GGT, and LDH 
• Hematology: hemoglobin, hematocrit, white blood cell count with a differential, platelet 
count 


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9.1.9. 
Cycle 2, Day 15 ± 3 days 
• Physical examination (symptom-directed) 
• Vital signs, including blood pressure, respiratory rate, pulse rate, and body temperature 
• ECOG performance status 
• Serum chemistry, including sodium, potassium, chloride, CO2, calcium, phosphorus, glucose, 
BUN, creatinine, uric acid, total protein, albumin, total and direct bilirubin, AST, ALT, 
alkaline phosphatase, GGT, and LDH 
• Hematology: hemoglobin, hematocrit, white blood cell count with a differential, platelet 
count 
• Adverse event assessment 
• Concomitant medications 
• Study drug compliance via study drug diary review and accountability 
 
9.1.10. 
Cycle 2, Day 22 ± 3 days 
• Serum chemistry, including sodium, potassium, chloride, CO2, calcium, phosphorus, glucose, 
BUN, creatinine, uric acid, total protein, albumin, total and direct bilirubin, AST, ALT, 
alkaline phosphatase, GGT, and LDH 
• Hematology: hemoglobin, hematocrit, white blood cell count with a differential, platelet 
count 
 
9.1.11. 
Cycle 3+, Day 1 ± 3 days 
Patients will continue treatment beyond Cycle 2 if they tolerate the drug well and experience no 
disease progression. 
Procedures to be performed before the morning dose: 
• Physical examination (symptom-directed) 
• Serum chemistry, including sodium, potassium, chloride, CO2, calcium, phosphorus, glucose, 
BUN, creatinine, uric acid, total protein, albumin, total and direct bilirubin, AST, ALT, 
alkaline phosphatase, GGT, and LDH; 
• Hematology: hemoglobin, hematocrit, white blood cell count with a differential, platelet 
count 
• Urinalysis, including pH, protein/albumin, glucose, nitrites, ketones/acetone, and 
hemoglobin/blood 
• Vital signs, including blood pressure, respiratory rate, pulse rate, and body temperature; 


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• ECOG performance status assessment 
• Adverse event assessment 
• Concomitant medications 
• Study drug compliance via study drug diary review and accountability 
• CT chest, abdomen, and pelvis (performed every 8 weeks during the first 24 weeks of study 
treatment, then every 12 weeks thereafter [e.g., at the end of Cycles 4, 6, then 9, 12, 15, and 
onward]) (PET/CT scan may be used as well) 
 
 
9.1.12. 
Extension phase 
Subjects receiving clinical benefit (SD, PR, or CR) from study treatment at the time of data cut- 
off of the main study, will be offered the opportunity to continue pexidartinib treatment in an 
extension phase. 
Procedures to be performed before the morning dose in the extension phase include: 
• 
Physical examination (symptom-directed) 
• 
Serum chemistry: sodium, potassium, chloride, CO2, calcium, phosphorus, glucose, BUN, 
creatinine, uric acid, total protein, albumin, total and direct bilirubin, AST, ALT, alkaline 
phosphatase, GGT, and LDH; 
• 
Hematology: hemoglobin, hematocrit, white blood cell count with a differential, platelet 
count 
• 
Vital signs: blood pressure, respiratory rate, pulse rate, and body temperature; 
• 
Adverse event assessment 
• 
Study drug compliance via study drug diary review and accountability 
• 
CT chest, abdomen, and pelvis (performed every 12 weeks) (PET/CT scan may be used as 
well) 
Subjects will continue in the extension phase until disease progression, unacceptable toxicity or 
withdrawal of consent. 
 
9.1.13. 
End-of-Study visit 
The End-of-Study visit is scheduled within the 28-day period after the last dose of study drug 
and before starting any new anti-neoplastic therapy. 
Procedures to be performed: 
• Fresh tumor biopsy (optional) 
• Weight 


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• Physical examination (complete) 
• 12-lead ECG 
• Serum chemistry, including sodium, potassium, chloride, CO2, calcium, phosphorus, glucose, 
BUN, creatinine, uric acid, total protein, albumin, total and direct bilirubin, AST, ALT, 
alkaline phosphatase, GGT, and LDH; 
• Hematology: hemoglobin, hematocrit, white blood cell count with a differential, platelet 
count 
• Vital signs, including blood pressure, respiratory rate, pulse rate, and body temperature; 
• ECOG performance status assessment 
• Adverse event assessment 
• Concomitant medications 
 
9.1.14. 
Post-Study Follow-up 
Telephone contact by study staff will be conducted every 3 months during Year 1, then every 6 
months thereafter to obtain information on survival status and any new anti-cancer therapies 
received. 
 
9.2. 
Phase II - Expansion Cohort 
The schedule of events for patients in the Phase II portion of the study is summarized in Table 2- 
2 and detailed in the subsections below. 
9.2.1. 
Screening Visit (Day –28 to Day –1) 
• Informed consent 
• Medical history 
• Height and weight 
• Complete physical examination 
• Vital signs, including blood pressure, respiratory rate, pulse rate, and body temperature 
• 12-lead ECG 
• ECOG performance status evaluation 
• Serum chemistry: including sodium, potassium, chloride, CO2, calcium, phosphorus, 
glucose, BUN, creatinine, uric acid, total protein, albumin, total and direct bilirubin, AST, 
ALT, alkaline phosphatase, GGT, LDH, and PT/INR 


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• Hematology: hemoglobin, hematocrit, white blood cell count with a differential, platelet 
count 
• Urinalysis, including pH, protein/albumin, glucose, nitrites, ketones/acetone, and 
hemoglobin/blood 
• Documentation of archival tissue availability 
• KIT mutation documentation 
• CT chest, abdomen pelvis (PET/CT scan may be used as well) 
• Adverse event assessment 
 
9.2.2. 
Screening Visit (Day –7 to Day –1) 
• Pregnancy test (for women of childbearing potential). For women of child-bearing potential, 
a serum pregnancy test at Screening must be negative. 
• Concomitant medications 
 
9.2.3. 
Cycle 1, Day 1 
 
Procedures to be performed before the morning dose: 
 
• Blood sampling for PD analysis 
• Whole blood for circulating tumor DNA (ctDNA) (Korea sites only) 
• Fresh tumor biopsy (first 13 patients enrolled in Phase II; –3-day window) 
• Physical examination (symptom-directed) 
• Serum chemistry, including sodium, potassium, chloride, CO2, calcium, phosphorus, glucose, 
BUN, creatinine, uric acid, total protein, albumin, total and direct bilirubin, AST, ALT, 
alkaline phosphatase, GGT, and LDH 
• Hematology: hemoglobin, hematocrit, white blood cell count with a differential, platelet 
count 
• Urinalysis, including pH, protein/albumin, glucose, nitrites, ketones/acetone, and 
hemoglobin/blood 
• Vital signs, including blood pressure, respiratory rate, pulse rate, and body temperature 
• ECOG performance status 
• Adverse event assessment 
• PET scan (–3-day window) (If a PET/CT scan is performed, then no additional PET scan is 
needed) 


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• Concomitant medications 
 
9.2.4. 
Cycle 1, Day 8 ± 3 days 
• Serum chemistry, including sodium, potassium, chloride, CO2, calcium, phosphorus, glucose, 
BUN, creatinine, uric acid, total protein, albumin, total and direct bilirubin, AST, ALT, 
alkaline phosphatase, GGT, and LDH 
• Hematology: hemoglobin, hematocrit, white blood cell count with a differential, platelet 
count 
• Adverse event assessment 
• Concomitant medications 
 
9.2.5. 
Cycle 1, Day 15 ± 3 days 
 
Procedures to be performed before the morning dose: 
 
• Blood sampling for PD analysis 
• Fresh tumor biopsy (optional, first 13 patients enrolled in Phase II; –3-day window) 
• 12-lead ECG 
• Physical examination (symptom-directed) 
• Serum chemistry, including sodium, potassium, chloride, CO2, calcium, phosphorus, glucose, 
BUN, creatinine, uric acid, total protein, albumin, total and direct bilirubin, AST, ALT, 
alkaline phosphatase, GGT, and LDH 
• Hematology: hemoglobin, hematocrit, white blood cell count with a differential, platelet 
count 
• Vital signs, including blood pressure, respiratory rate, pulse rate, and body temperature 
• ECOG performance status assessment 
• Adverse event assessment 
• Concomitant medications 
• Study drug compliance via study drug diary review and accountability 
Procedures to be performed after the morning dose: 
• 12-lead ECG (2 hours (± 30 minutes) post-dose) 


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9.2.6. 
Cycle 1, Day 22 ± 3 days 
• Serum chemistry, including sodium, potassium, chloride, CO2, calcium, phosphorus, glucose, 
BUN, creatinine, uric acid, total protein, albumin, total and direct bilirubin, AST, ALT, 
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alkaline phosphatase, GGT, and LDH; 
• Hematology: hemoglobin, hematocrit, white blood cell count with a differential, platelet 
count 
• Adverse event assessment 
• Concomitant medications 
 
9.2.7. 
Cycle 2, Day 1 ± 3 days 
 
Procedures to be performed before the morning dose: 
 
• Physical examination (symptom-directed) 
• 12-lead ECG 
• Whole blood for ctDNA (Korea sites only) 
• Serum chemistry, including sodium, potassium, chloride, CO2, calcium, phosphorus, glucose, 
BUN, creatinine, uric acid, total protein, albumin, total and direct bilirubin, AST, ALT, 
alkaline phosphatase, GGT, and LDH 
• Hematology: hemoglobin, hematocrit, white blood cell count with a differential, platelet 
count 
• Urinalysis, including pH, protein/albumin, glucose, nitrites, ketones/acetone, and 
hemoglobin/blood 
• Vital signs, including blood pressure, respiratory rate, pulse rate, and body temperature 
• ECOG performance status 
• Adverse event assessment 
• PET scan (±3-day window) (If a PET/CT scan is performed, then no additional PET scan is 
needed) 
• Concomitant medications 
• Study drug compliance via study drug diary review and accountability 
Procedures to be performed after the morning dose: 
• 12-lead ECG (2 hours (± 30 minutes) post-dose) 


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9.2.8. 
Cycle 2, Day 8 ± 3 days 
• Serum chemistry, including sodium, potassium, chloride, CO2, calcium, phosphorus, glucose, 
BUN, creatinine, uric acid, total protein, albumin, total and direct bilirubin, AST, ALT, 
alkaline phosphatase, GGT, and LDH 
• Hematology: hemoglobin, hematocrit, white blood cell count with a differential, platelet 
count 
 
9.2.9. 
Cycle 2, Day 15 ± 3 days 
• Physical examination (symptom-directed) 
• Vital signs, including blood pressure, respiratory rate, pulse rate, and body temperature 
• ECOG performance status 
• Serum chemistry, including sodium, potassium, chloride, CO2, calcium, phosphorus, glucose, 
BUN, creatinine, uric acid, total protein, albumin, total and direct bilirubin, AST, ALT, 
alkaline phosphatase, GGT, and LDH 
• Hematology: hemoglobin, hematocrit, white blood cell count with a differential, platelet 
count 
• Adverse event assessment 
• Concomitant medications 
• Study drug compliance via study drug diary review and accountability 
 
9.2.10. 
Cycle 2, Day 22 ± 3 days 
• Serum chemistry, including sodium, potassium, chloride, CO2, calcium, phosphorus, glucose, 
BUN, creatinine, uric acid, total protein, albumin, total and direct bilirubin, AST, ALT, 
alkaline phosphatase, GGT, and LDH 
• Hematology: hemoglobin, hematocrit, white blood cell count with a differential, platelet 
count 
 
9.2.11. 
Cycle 3+, Day 1 ± 3 days 
 
Patients will continue treatment beyond Cycle 2 if they tolerate the drug well and experience no 
disease progression. 
 
Procedures to be performed before the morning dose: 
 
• Physical examination (symptom-directed) 


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• Whole blood for ctDNA (Korea sites only) 
• Serum chemistry, including sodium, potassium, chloride, CO2, calcium, phosphorus, glucose, 
BUN, creatinine, uric acid, total protein, albumin, total and direct bilirubin, AST, ALT, 
alkaline phosphatase, GGT, and LDH; 
• Hematology: hemoglobin, hematocrit, white blood cell count with a differential, platelet 
count 
• Urinalysis, including pH, protein/albumin, glucose, nitrites, ketones/acetone, and 
hemoglobin/blood 
• Vital signs, including blood pressure, respiratory rate, pulse rate, and body temperature; 
• ECOG performance status assessment 
• Adverse event assessment 
• Concomitant medications 
• Study drug compliance via study drug diary review and accountability 
• CT chest, abdomen pelvis (performed every 8 weeks during the first 24 weeks of study 
treatment, then every 12 weeks thereafter [e.g., at the end of Cycles 4, 6, then 9, 12, 15, and 
onward]) (PET/CT scan may be used as well) 
 
9.2.12. 
End-of-Study visit 
The End-of-Study visit is scheduled within the 28-day period after the last dose of study drug 
and before starting any new anti-neoplastic therapy. 
Procedures to be performed: 
• Fresh tumor biopsy (optional, first 13 patients enrolled in Phase II; –3-day window) 
• Weight 
• Physical examination (complete) 
• 12-lead ECG 
• Whole blood for ctDNA Korea sites only. 
• Serum chemistry, including sodium, potassium, chloride, CO2, calcium, phosphorus, glucose, 
BUN, creatinine, uric acid, total protein, albumin, total and direct bilirubin, AST, ALT, 
alkaline phosphatase, GGT, and LDH; 
• Hematology: hemoglobin, hematocrit, white blood cell count with a differential, platelet 
count 
• Vital signs, including blood pressure, respiratory rate, pulse rate, and body temperature; 
• ECOG performance status assessment 


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• Adverse event assessment 
• Concomitant medications 
 
9.2.13. 
Post-Study Follow-up 
Telephone contact by study staff will be conducted every 3 months during Year 1, then every 
6 months thereafter to obtain information on survival status and any new anti-cancer therapies 
received. 
 
9.3. 
Study Procedures 
9.3.1. 
Electrocardiograms 
Patients should rest in the supine position for at least 5 minutes before each 12-lead ECG 
recording is started. The ECGs should be reviewed, signed, and dated by a qualified physician 
(or qualified physician’s assistant or nurse practitioner) and any clinically important finding 
recorded on the appropriate eCRF. The investigator is responsible for providing the 
interpretation of all ECGs. The results will include heart rate, respiratory rate (RR), PR interval, 
QRS interval, QT interval, and QTcF interval. 
 
9.3.2. 
KIT Mutation Documentation 
KIT mutation(s) must be documented prior to enrollment. Patients with KIT exon 8, 9, 11, 13, 
and 14 mutations are the most likely to be sensitive to PLX3397. Patients with KIT exon 17 or 
18 mutations D816V, Y823D, and A829P should not be enrolled as they are not sensitive to 
PLX3397. Other KIT exon 17 or 18 mutations may be sensitive to PLX3397 and should be 
enrolled. 


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Table 9-1: 
Summary of Known KIT Mutations in Melanoma and Their 
Sensitivity to PLX3397 and Other Approved Drugs 
 
Exon Mutation Be08a 
Be08- 
citedb 
Total 
Imatinib 
PLX3397 
Sunitinib 
Dasatinib 
Sorafenib 
11 
Y553N 
1 
1 
S 
11 
W557R 
1 
1 
2 
S 
11 
K558N 
1 
1 
S 
11 
V559A 
1 
2 
3 
S 
11 
V559D 
1 
1 
0.063 
(Gu07) 
S 
0.027 
(Gu07) 
0.066 
(Gu07) 
11 
V560A 
1 
1 
S 
11 
V560D 
1 
1 
0.1 (He08) 
S (V560G 
<0.016) 
11 
V569G 
1 
1 
S 
11 
L576P 
5 
7 
12 
poor 
S 
13 
K642E 
9 
9 
S 
17 
D816H 
2 
2 
2.6 
0.1 
0.1 
0.002 
17 
Y823D 
1 
1 
R 
R 
R (He08) 
18 
A829P 
1 
1 
2 
~0.2 
(He08) 
R 
R (He08) 
Total 
13 
24 
37 
Note: IC50 (µM) is listed if available (either from literature or sponsor’s own assay data); otherwise sensitivity is 
indicated qualitatively by S (sensitive) or R (resistant). In the latter case, the sensitivity for each mutation was 
deduced based on 1) structure-based prediction of the effect of the mutation on the binding of PLX3397 to KIT 
and/or 2) the activity of other inhibitors (e.g., dasatinib) with analogous binding mode(s). 
a 
Beadling 2008. 
b 
Other studies cited in Beadling 2008. 
 
 
9.3.3. 
Fresh Tissue Biopsy Samples (Pilot Portion and First 13 Patients of Phase II 
Portion of the Study) 
A pre-dose tumor biopsy of a progressive lesion will be obtained in patients with accessible 
tissue. Formalin-Fixed Paraffin-Embedded (FFPE) tissue slides will be collected and stored for 
subsequent evaluation using project-specific tumor assays to be performed at one or more central 
laboratories. 
 
9.3.4. 
PET Scans (Pilot Portion and First 13 Patients of Phase II Portion of the Study) 
18FDG-PET scans will be obtained at Day 1 of Cycle 1 and at Day 1 of Cycle 2. Patients 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 levels will be 
determined before administration of 18FDG to document euglycemia. 


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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. 
 
 
10.0 
STUDY ENDPOINTS 
10.1. 
Pilot Portion 
The endpoints in the Pilot portion of the study include: 
 
• DLTs will define the RP2D (1000 mg per day or 800 mg per day) 
• Safety endpoints (i.e., AEs, clinical laboratory evaluations, ECGs, physical examinations, 
and vital sign measurements) 
• Pharmacokinetic (PK) analysis 
• Serum/plasma tumor biomarkers including CSF-1 
 
The exploratory endpoints in the Pilot portion of the study include: 
 
• Immunohistochemistry (IHC) and molecular analysis of archival and paired fresh tumor 
biopsy 
• PET scan evaluation on Day 1 of Cycle 2 compared to Baseline 
 
10.2. 
Phase II 
The primary endpoint in the Phase II portion of the study includes: 
 
• Objective response rate (ORR), which is the sum of CR and PR by RECIST v1.1 
The secondary endpoints in the Phase II portion of the study include: 
• Duration of response (DoR) 
• Progression free survival (PFS) 
• Overall survival (OS) 
• Safety endpoints (i.e., AEs, clinical laboratory evaluations, ECGs, physical examinations, 
and vital sign measurements) 


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The exploratory endpoints in the Phase II portion of the study include: 
 
• IHC and molecular analysis of archival and paired fresh tumor biopsy 
• Serum/plasma tumor biomarkers including CSF-1 
• Positron emission tomography (PET) scan evaluation on Day 1 of Cycle 2 compared to 
Baseline 
 
 
11.0 
STATISTICAL AND QUANTITATIVE ANALYSES 
11.1. 
Determination of Sample Size 
The Pilot portion of this study will determine if 1000 mg PLX3397 is an appropriate dose for the 
Phase II portion of the study. Traditional 3+3 design will be utilized to determine RP2D. 
Eligible patients will enter the study in sets of three. Dose-limiting toxicity (DLT) is defined in 
Section 7.4. If 0 or 1 of 3 patients at the 1000 mg dose level cohort experience DLT, 3 additional 
patients will be enrolled for a total of 6 patients. If ≥2 of 6 patients experience DLT at the 
1000 mg dose, the dose will be de-escalated to 800 mg per day. If 0 or 1 of 3 patients at the 
800 mg dose level cohort experiences DLT, 3 additional patients will be enrolled for a total of 
6 patients. If ≥2 of 6 patients experience DLT at the 800 mg dose, the study will be terminated 
due to intolerability. Each cohort of patients will be observed for toxicity for 28 days in order to 
allow time to identify all acute effects of PLX3397. Between 6 and 12 patients will be accrued 
for the Pilot portion of this study. 
The primary objective of the Phase II portion of this study is to evaluate the objective response 
rate (ORR) at the RP2D. The RP2D will be either the MTD or the alternate dose level below the 
MTD determined by sponsor and investigator. A true response rate of 40% or more will be 
considered promising while 15% or lower will not be considered as evidence of activity. 
A Simon two-stage design with 90% targeted power and one-sided type I error of 5% will be 
employed for this study. With the assumption of 10% drop-out, the total sample size will be 
32 patients to achieve 29 evaluable patients. During stage one, 13 evaluable patients will be 
enrolled. If there are 3 or more responses (CR+PR) observed, then the study will continue to the 
second stage of accrual, and 16 evaluable patients will be enrolled in the second stage. If there 
are 8 or more responses observed among 29 evaluable patients, the treatment will be considered 
promising. 
With this design, the probability of terminating the study after 13 patients is 69% if the true 
response rate is 15%. The probability that the treatment will be considered promising is 5%, if 
the true response rate is 15%, and 90.7% if the true response rate is 40%. Allowing for a 10% 
unevaluability rate, the overall accrual goal will be 32 patients for the Phase II portion of this 
study. 


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11.2. 
Randomization and Stratification 
No randomization or stratification of patients is planned for this study. 
 
 
11.3. 
Populations for Analysis 
The primary population for safety will consist of patients who signed the informed consent and 
have any follow-up data after receiving at least one dose of study drug. The primary population 
for efficacy will consist of the modified ITT population, i.e., patients who a) fulfill 
inclusion/exclusion criteria, b) have a baseline CT scan at screening, and c) have at least one on- 
study CT scan to assess tumor response to study drug, or early progression of disease or death 
prior to first tumor assessment during treatment period. 
The main study will be closed at the cut-off date and the data will be followed in ongoing 
subjects in the extension part. Data collected in the extension part will be reported separately 
from the clinical study report. 
 
11.4. 
Procedures for Handling Missing, Unused, and Spurious Data 
All available efficacy and safety data will be included in the data listings and tabulations. No 
imputation of values for missing data will be performed. 
 
11.5. 
General Methodology 
Summary of tabulations will be presented by treatment group displaying the number of 
observations, mean, standard deviation, median, minimum, and maximum for continuous 
variables, and the number and percent per category for categorical data. 
 
11.6. 
Baseline Comparisons 
Demographic and baseline characteristics will be summarized by treatment group. 
 
11.7. 
Efficacy Analysis 
The Phase II portion of the study will follow a Simon two-stage design to compare a null ORR of 
15% with an alternative ORR of 40% with 90% power and a one-sided type I error of 5%. The 
total sample size will be 29 evaluable patients. Thirteen patients will be enrolled in the first 
stage, with at least three responses required to proceed to the second stage. Eight responses 
among 29 patients are required for PLX3397 to be considered promising. See Section 11.10 for 
discussion of interim analysis. 
Object tumor response to treatment will be evaluated using investigator-determined RECIST 
v1.1 (ATTACHMENT 3). PFS, OS and duration of response will be evaluated as secondary 
efficacy endpoints. PFS will be calculated for each patient as the number of days from study 


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enrollment to the date of the first documented disease progression or date of death from any 
cause, whichever occurs first. Overall survival is defined as the time from study enrollment to 
death from any cause, censoring at the date of last contact or the end of the study. Duration of 
response (DoR) is defined as the time from the first documentation of objective tumor response 
(CR or PR) that is subsequently confirmed to the first documentation of disease progression or to 
death due to any cause, whichever occurs first. DoR will only be calculated for the subgroup of 
patients with a confirmed objective tumor response. Sponsor may request imaging data for the 
confirmation of the tumor response. 
The Kaplan-Meier method will be used to estimate the median PFS, OS and DoR. 
 
 
11.8. 
Pharmacokinetics/Pharmacodynamics/Biomarkers 
11.8.1. 
Pharmacokinetic Analysis 
The PK profile of plasma PLX3397 will be analyzed by measurement of area under the plasma 
concentration-time curve (AUC0-6), peak concentration (Cmax), and time of maximum observed 
concentration (Tmax). To evaluate plasma exposure accumulation after repeated dosing, 
accumulation ratios of Day 15 to Day 1 for AUC0-6 and Cmax (Robs and RCmax, respectively) will 
be determined. 
 
11.8.2. 
Pharmacodynamic Analysis 
No formal statistical analysis of PD endpoints will be performed. PD data from each assay will 
be listed, and possible relationships between clinical response and PD variables will be explored. 
Any biological activity will be described. 
 
11.8.3. 
Tissue Evaluation 
At least 10 unstained FFPE slides of 5 µm thickness from the archival tissue should be submitted 
on all participants in the study. The archival tissue may be from the original diagnosis, or from a 
biopsy obtained after a previous therapy. Slides should be air-dried (NOT baked) onto positively 
charged slides. A representative paraffin block can also be provided, which will be returned to 
the study site after sectioning. For patients undergoing paired fresh biopsy, at least 10 sections 
are also requested, and at least 20 unstained FFPE slides of 5 µm thickness from the fresh tissue 
should be submitted (Phase I and first 13 patients enrolled in Phase II). 
Exploratory tissue studies will include IHC for KIT, pERK, Ki67. Tissue may also be used for 
KIT or other oncogene mutation sequencing confirmation. Other exploratory evaluations may 
include assessment of the tumor microenvironment by IHC or other methods for immune cell 
expression/number (e.g., PD-1). Exploratory blood studies will measure CSF-1 and ctDNA 
(Phase II portion in Korea only). Planned biomarkers are listed in ATTACHMENT 1. 


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11.9. 
Safety Analysis 
Safety variables to be assessed will include AEs, laboratory test results (hematology, serum 
chemistry, and urinalysis), ECG, weight, and vital signs. 
Adverse event terms recorded on the eCRFs will be mapped to preferred terms using the Medical 
Dictionary for Drug Regulatory Activities (MedDRA®) version 17.0 or later. All AEs will be 
summarized 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 patients), worst 
reported severity, and relationship to study drug for each preferred term per patient. SAEs 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. 
Laboratory variables will be examined using mean change in value from baseline to scheduled 
time points. Laboratory values will also be categorized according to their CTCAE (version 4.03) 
toxicity grade and tabulated by worst on-study toxicity grade. The baseline value of a variable is 
defined as the last value obtained on or before the date and time of the first PLX3397 dose. 
ECG, weight, and vital signs will also be summarized by changes from baseline to scheduled 
time points using descriptive statistics. Changes in QTcF will also be evaluated for the 
proportion of patients with absolute values >500 msec and change from baseline >60 msec. 
 
11.10. 
Interim Analysis 
The Phase II portion of the study will follow a Simon two-stage design to compare a null ORR of 
15% with an alternative ORR of 40% with 90% power and a one-sided type I error of 5%. The 
total sample size will be 29 evaluable patients. Thirteen patients will be enrolled in the first stage 
before triggering an interim analysis. At least three responses are required to proceed to the 
second stage. Eight responses among 29 patients are required for PLX3397 to be considered 
promising. 
 
 
12.0 
ETHICAL CONSIDERATIONS 
The study will be conducted in accordance with ethical principles founded in the Declaration of 
Helsinki. The IRB/IEC will review all appropriate study documentation in order to safeguard the 
rights, safety and well-being of the patients. The study will only be conducted at sites where 
IRB/IEC approval has been obtained. The protocol, Investigator Brochure, informed consent 
form, advertisements (if applicable), written information given to the patients (including diary 
cards), safety updates, annual progress reports, and any revisions to these documents will be 
provided to the IRB/IEC by the investigator or the sponsor, as allowable by local regulations. 


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13.0 
EVENTS OF SPECIAL INTEREST 
13.1. 
Combined Elevations of Aminotransferases and Bilirubin 
Combined elevations of aminotransferases and bilirubin, either serious or nonserious and 
whether or not causally related, meeting the laboratory criteria of a potential Hy’s Law case 
(ALT or AST ≥3×ULN with simultaneous total bilirubin ≥2×ULN) should always be 
reported to the Sponsor using a SAE reporting form along with the investigator’s assessment of 
seriousness, causality, and a detailed narrative. These events should be reported within 24 h of 
the investigator’s awareness of the events. 
If the subject discontinues the study drug due to liver enzyme abnormalities, the subject will 
have additional clinical and laboratory evaluations in order to determine the cause and severity of 
the potential liver injury. 
 
 
14.0 
ADVERSE EVENTS 
14.1. 
Definitions 
14.1.1. 
Adverse Event Definition 
An adverse event (AE) is any untoward medical occurrence in a patient administered a 
pharmaceutical product, which does not necessarily have a causal relationship with the treatment. 
An AE can be any unfavorable and unintended sign (e.g., including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of the study drug, whether or 
not it is considered to be study drug related. This includes any newly occurring event or previous 
condition that has increased in severity or frequency since the administration of study drug. Clear 
progression of the underlying cancer and hospitalizations due to the progression of cancer should 
not be reported as an AE, or a SAE. 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 
study drug, whether accidental or intentional. 
• An AE occurring from abuse (e.g., use for nonclinical reasons) of a study drug. 
• An AE that has been associated with the discontinuation of the use of a study drug. 
 
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 eCRF: 
• Accompanied by clinical symptoms 
• Leading to a change in study medication (e.g., dose modification, interruption or permanent 
discontinuation) 


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• 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) 
 
Adverse events will be graded in severity according to CTCAE v4.03 criteria. 
 
 
14.1.2. 
Serious Adverse Event Definition 
 
A SAE is any AE, occurring at any dose and regardless of causality that: 
 
• Results in death 
• Is life-threatening. Life-threatening means that the patient was at immediate risk of death 
from the reaction as it occurred, i.e., it does not include a reaction which hypothetically 
might have caused death had it occurred in a more severe form. 
• Requires inpatient hospitalization or prolongation of existing hospitalization (see 
clarification in the paragraph below on planned hospitalizations). 
• Results in persistent or significant disability/incapacity. Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions. 
• Is a congenital anomaly/birth defect 
• Is an important medical event. An important medical event is an event that may not result in 
death, be life-threatening, or require hospitalization but may be considered an SAE when, 
based upon appropriate medical judgment, it may jeopardize the patient and may require 
medical or surgical intervention to prevent one of the outcomes listed in the definitions for 
SAEs. Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug abuse. 
Clarification should be made between the terms “serious” and “severe” because they ARE NOT 
synonymous. The term “severe” is often used to describe the intensity (severity) of a specific 
event (as in mild, moderate, or severe myocardial infarction); the event itself, however, may be 
of relatively minor medical significance (such as a severe headache). This is NOT the same as 
“serious,” which is based on patient/event outcome or action criteria described above and are 
usually associated with events that pose a threat to a patient’s life or functioning. A severe AE 
does not necessarily need to be considered serious. For example, persistent nausea of several 
hours duration may be considered severe nausea but not an SAE. On the other hand, a stroke 
resulting in only a minor degree of disability may be considered mild, but would be defined as an 
SAE based on the above noted criteria. Seriousness (not severity) serves as a guide for defining 
regulatory reporting obligations. 


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14.1.3. 
Disease Progression 
Clear progression of the underlying cancer and hospitalizations due to the progression of cancer 
should not be reported as an AE, or a SAE. Sudden and unexplained death should be reported as 
an SAE. If there is any uncertainty about a finding being due solely to progression of underlying 
cancer, the finding should be reported as an AE or SAE as appropriate. 
 
14.2. 
Procedures for Recording and Reporting Adverse Events and 
Serious Adverse Events 
All AEs spontaneously reported by the patient and/or in response to an open question from study 
personnel or revealed by observation, physical examination or other diagnostic procedures will 
be recorded on the appropriate page of the CRF. Any clinically relevant deterioration in 
laboratory assessments or other clinical finding is considered an AE and must be recorded on the 
appropriate pages of the CRF. When possible, signs and symptoms indicating a common 
underlying pathology should be noted as 1 comprehensive event. 
All SAEs that occur during the course of the study, as defined in Section 14.3, must be reported 
by the investigator to the sponsor or designee by faxing or e-mail the SAE Form immediately 
after the investigator becomes aware of the SAE. In addition, all SAEs including all deaths that 
occur up to and including 21 ± 7 days after administration of the last dose of study drug or prior 
to the administration of any new anti-cancer therapy, whichever occurs first, must be reported to 
DSI CSPV Safety within 24 hours of site awareness of the event. ALL SAEs and deaths must be 
reported whether or not considered causally related to the study drug. The SAE Form, created 
specifically by the sponsor, will be provided to each clinical study site. The information collected 
will include a minimum of the following: patient number; a narrative description of the event; 
and an assessment by the investigator as to the intensity of the event and relatedness to study 
drug. A sample of the SAE Form may be found in the Study Manual. Follow-up information on 
the SAE may be requested by the sponsor. SAEs reported to DSI CSPV Safety must match the 
data provided on the CRF. 
Planned hospital admissions or surgical procedures for an illness or disease which existed before 
the patient was enrolled in the trial or before study drug was given are not to be considered AEs 
unless the condition deteriorated in an unexpected manner during the trial (e.g., surgery was 
performed earlier or later than planned). 
For both serious and non-serious AEs, the investigator must determine both the intensity of the 
event and the relationship of the event to study drug administration. 
Oncology Studies: Intensity for each AE, including any lab abnormality, will be determined by 
using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI 
CTCAE), Version 4.03, as a guideline, wherever possible. The criteria are provided in the Study 
Manual and also are available online at http://ctep.cancer.gov/reporting/ctc.html. In those cases 
where the NCI CTC criteria do not apply, intensity should be defined according to the following 
criteria: 


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Mild 
Awareness of sign or symptom, but easily tolerated 
 
 
Moderate 
Discomfort enough to cause interference with normal daily activities 
 
 
Severe 
Inability to perform normal daily activities 
 
Relatedness to study drug administration will be determined by the investigator responding to 
the question, ‘Is there a reasonable possibility that the AE is associated with the study drug?’ 
Relatedness to study drug administration will be graded as “probably,” “possibly,” or “not 
related,” as follows: 
 
Not Related Another cause of the event is most plausible; or, 
 
Clinically plausible temporal sequence is inconsistent with the onset of the 
event and the study treatment administration; or, 
 
A causal relationship is considered biologically implausible. 
 
 
Possibly 
Related 
An event that follows a reasonable temporal sequence from administration 
of the study treatment or a known or expected response pattern to the 
suspected drug, but that could readily have been produced by a number of 
other factors. 
 
 
Probably 
Related 
An event that follows a reasonable temporal sequence from administration 
of the study treatment, and, 
 
There is a biologically plausible mechanism for study treatment causing or 
contributing to the AE, and, 
 
The event could not be reasonably explained by the known characteristics 
of the patient’s clinical state. 
 
In addition, the relationship may be confirmed by improvement on 
stopping the study treatment and reappearance of the event on repeated 
exposure. 


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14.3. 
Monitoring of Adverse Events and Period of Observation 
Adverse events, both serious and non-serious, and deaths will be recorded on the CRFs up to and 
including the last visit within 28 days after administration of the last dose of study drug and prior 
to the administration of any new anti-cancer therapy. All SAEs should be monitored until they 
are resolved or are clearly determined to be due to a patient’s stable or chronic condition or inter- 
current illness(es). The AE collection period will begin when the patient signs informed consent. 
Any SAE that occurs at any time after completion of the study and the designated follow-up 
period, which the investigator considers to be related to study drug, must be reported to the 
sponsor. 
 
14.4. 
Procedures for Reporting Drug Exposure during Pregnancy and 
Birth Events 
Daiichi Sankyo must be notified of any female patient or any male patient whose female partner 
becomes pregnant while receiving or within 3 months of discontinuing the study drug. Reporting 
after follow-up visit or early termination is done voluntarily by the Investigator. 
Although pregnancy is not technically an AE, all pregnancies must be followed to conclusion to 
determine their outcome. This information is important for both drug safety and public health 
concerns. It is the responsibility of the Investigator or designee to report any pregnancy in a 
female patient or a male patient’s female partner to DSI CSPV Safety using the Exposure In 
Utero (EIU) Reporting Form. The Investigator should make every effort to follow the patient 
until completion of the pregnancy and complete the EIU Reporting Form with complete 
pregnancy outcome information, including normal delivery and induced abortion. Any adverse 
pregnancy outcome, either serious or nonserious, should be reported in accordance with study 
procedures. If the outcome of pregnancy meets the criteria for immediate classification as an 
SAE (ie, postpartum complications, spontaneous or induced abortion, stillbirth, neonatal death, 
or congenital anomaly, including that in an aborted fetus), the Investigator should follow the 
procedures for reporting SAEs outlined in Section 8.1. For reports of pregnancy in the female 
partner of a male patient, the EIU Reporting Form should be completed with the patient’s 
enrollment number, initials, and date of birth, and details regarding the female partner should be 
entered. 


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15.0 
ADMINISTRATIVE REQUIREMENTS 
15.1. 
Good Clinical Practice 
The study will be conducted in accordance with the international conference on harmonization 
(ICH) Guideline for GCP and the appropriate regulatory requirement(s). The investigator will be 
thoroughly familiar with the appropriate use of the study drug as described in the protocol and 
the Investigator’s Brochure. 
 
15.2. 
Data Quality Assurance 
The investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each study patient. 
Study data will be entered into an eCRF by site personnel using a secure, validated web-based 
electronic data capture (EDC) application. The sponsor will have access to all data upon entry in 
the EDC application. 
Study monitors will discuss instances of missing or un-interpretable data with the investigator for 
resolution. Any changes to study data will be made to the eCRF and documented via an 
electronic audit trail associated with the affected eCRF. 
 
15.3. 
Electronic Case Report Form Completion 
The sponsor or CRO designee will provide the study sites with secure access to and training on 
the EDC application, sufficient to permit site personnel to enter or correct information in the 
eCRFs for the patients for which they are responsible. 
eCRFs will be completed for each study patient. It is the investigator’s responsibility to ensure 
the accuracy, completeness, clarity, and timeliness of the data reported in the patient’s eCRF. 
The investigator, or designated representative, should complete the eCRF as soon as possible 
after information is collected. 
The audit trail entry will show the user’s identification information, and the date and time of the 
correction. The investigator must provide through the EDC application formal approval of all the 
information in the eCRFs and changes to the eCRFs to endorse the final submitted data for the 
patients for which he is responsible. 
The sponsor, or a CRO designee, will retain the eCRF data and corresponding audit trails. A 
copy of the final archival eCRF in the form of a compact disk (CD) or other electronic media 
will be placed in the investigator’s study file. 
 
15.4. 
Study Monitoring 
Monitoring and auditing procedures developed or approved by the sponsor will be followed, in 
order to comply with GCP guidelines. 


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All information recorded on the eCRFs for this study must be consistent with the patient’s source 
documentation. During the course of the study, the study monitor will make study site visits to 
review protocol compliance, verify eCRFs against source documentation, assess drug 
accountability, and ensure that the study is being conducted according to pertinent regulatory 
requirements. The review of medical records will be performed in a manner to ensure that 
patient confidentiality is maintained. 
 
15.5. 
Subject Information and Informed Consent 
After the study has been fully explained, written informed consent will be obtained from either 
the patient or his/her guardian or legal representative prior to study participation. The method of 
obtaining and documenting the informed consent and the contents of the consent is to comply 
with ICH-GCP and all applicable regulatory requirement(s). 
 
15.6. 
Subject Confidentiality 
In order to maintain patient privacy, all eCRFs, study drug accountability records, study reports 
and communications will identify the patient by initials where permitted and/or by the assigned 
patient number. The patient’s confidentiality will be maintained and will not be made publicly 
available to the extent permitted by the applicable laws and regulations. 
 
15.7. 
Investigator Compliance 
The investigator will conduct the trial in compliance with the protocol provided by the sponsor, 
and given approval/favorable opinion by the IRB/IEC and the appropriate regulatory 
authority(ies). Modifications to the protocol are not to be made without agreement of both the 
investigator and the sponsor. Changes to the protocol will require written IRB/IEC 
approval/favorable opinion prior to implementation, except when the modification is needed to 
eliminate an immediate hazard(s) to patients. The sponsor, or a CRO designee, will submit all 
protocol modifications to the appropriate regulatory authority(ies) in accordance with the 
governing regulations. 
When immediate deviation from the protocol is required to eliminate an immediate hazard(s) to 
patients, the investigator will contact the sponsor, or a CRO designee, if circumstances permit, to 
discuss the planned course of action. Any departures from the protocol must be documented. 
 
15.8. 
Supply of New Information Affecting the Conduct of the Study 
When new information becomes available that may adversely affect the safety of subjects or the 
conduct of the study, the Sponsor will inform all Investigators involved in the clinical study, 
ECs/IRBs, and regulatory authorities of such information, and when needed, will amend the 
protocol and/or subject information. 


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The Investigator should immediately inform the subject whenever new information becomes 
available that may be relevant to the subject’s consent or may influence the subject’s willingness 
to continue participation in the study. The communication should be documented on medical 
records, for example, and it should be confirmed whether the subject is willing to remain in the 
study. 
If the subject information is revised, it must be re-approved by the IEC/IRB. The Investigator 
should obtain written informed consent to continue participation with the revised written 
information even if subjects were already informed of the relevant information. The Investigator 
or other responsible personnel who provided explanations and the subject should sign and date 
the revised ICF. 
 
15.9. 
On-site Audits 
Regulatory authorities, the IEC/IRB, and/or the sponsor may request access to all source 
documents, eCRFs, and other study documentation for on-site audit or inspection. Direct access 
to these documents must be guaranteed by the investigator, who must provide support at all times 
for these activities. 
 
15.10. 
Investigator and Site Responsibility for Drug Accountability 
Accountability for the study drug at the trial site is the responsibility of the investigator. Drug 
accountability records indicating the drug’s delivery date to the site, inventory at the site, use by 
each patient, and amount returned to the sponsor, or a CRO designee, (or disposal of the drug, if 
approved by the sponsor) will be maintained by the clinical site. The sponsor or its CRO 
designee will review drug accountability at the site on an ongoing basis. 
All material containing study drug will be treated and disposed of as hazardous waste in 
accordance with governing regulations. 
 
15.11. 
Product Complaints 
A product complaint is any dissatisfaction with a product which may be attributed to the identity, 
quality, durability, reliability, or safety of the product. Individuals who identify a potential 
product complaint situation should immediately report the event. Whenever possible, the 
associated product should be maintained in accordance with the label instructions pending 
further guidance from the sponsor quality representative. 
For Product Complaints, refer to the Study Pharmacy Manual for instructions and details. 
 
15.12. 
Adjudication Committee 
An Adjudication Committee was established for the purpose of assessing hepatic safety and 
tolerability of the subjects. The Adjudication Committee meetings will be held to discuss subject 
safety as needed. Detailed procedures of the Adjudication Committee will be specified in the 


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Adjudication Committee Charter. 
 
15.13. 
Closure of the Study 
Within 90 days of the end of the study the sponsor will notify the competent authorities and the 
IECs in all member states where the study is being carried out that the study has ended. 
Within 1 year of the end of the study, a summary of the clinical trial results will be submitted to 
the competent authorities and IECs in all member states involved in the study. 
Study participation by individual sites or the entire study may be prematurely terminated, if in 
the opinion of the investigator or the sponsor, there is sufficient reasonable cause. Written 
notification documenting the reason for study termination will be provided to the investigator or 
the sponsor by the terminating party. 
Circumstances that may warrant termination include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to patients 
• Failure to enter patients at an acceptable rate 
• Insufficient adherence to protocol requirements 
• Insufficient, incomplete, and/or un-evaluable data 
• Determination of a lack of efficacy based on interim analysis 
• Plans to modify, suspend or discontinue the development of the study drug 
Should the study be closed prematurely, the site will no longer be able to access the EDC 
application, will not have a right to use the EDC application, and will cease using the password 
or access materials once their participation in the study has concluded. In the event that any 
access devices for the EDC application have been provided, these will be returned to the sponsor 
once the site’s participation in the study has concluded. 
Within 15 days of premature closure, the sponsor must notify the competent authorities and IECs 
of any member state where the study is being conducted, providing the reasons for study closure. 
 
15.14. 
Finance and Insurance 
15.14.1. 
Finances 
Prior to starting the study, the investigator and/or institution will sign a clinical study agreement 
with CRO. This agreement will include the financial information agreed upon by the parties. 
 
15.14.2. 
Reimbursement, Indemnity, and Insurance 
The sponsor provides insurance for study subjects to make available compensation in case of 
study-related injury. 


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Reimbursement, indemnity, and insurance shall be addressed in a separate agreement on terms 
agreed upon by the parties. 
 
15.15. 
Record Retention 
The Investigator and study staff are responsible for maintaining a comprehensive and centralized 
filing system (Trial Master File) of all study-related (essential) documentation, suitable for 
inspection at any time by representatives from the sponsor and/or applicable regulatory 
authorities. Essential documents contained in the Trial Master File include: 
• Subject files containing completed CRFs, informed consent forms, and supporting 
copies of source documentation (if kept). 
• Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of relevant essential documents required prior to commencing a clinical study, 
and all correspondence to and from the EC/IRB and the Sponsor. 
• Records related to the study drug(s) including acknowledgment of receipt at study 
site, accountability records and final reconciliation and applicable correspondence. 
In addition, all original source documents supporting entries in the CRFs must be maintained and 
be readily available 
The investigator will maintain all study records according to ICH-GCP and applicable regulatory 
requirement(s). Records will be retained for at least 2 years after the last marketing application 
approval or 2 years after formal discontinuation of the clinical development of the investigational 
product or according to applicable regulatory requirement(s). If the investigator withdraws from 
the responsibility of keeping the study records, custody must be transferred to a person willing to 
accept the responsibility and the sponsor must be notified. 
 
16.0 
ADDRESS LIST 
Please refer to ATTACHMENT 5 for the address list of various stakeholders involved in this 
study. 
 
17.0 
PUBLICATION POLICY 
All information regarding PLX3397 supplied by the sponsor to the investigator is privileged and 
confidential information. The investigator agrees to use this information to accomplish the study 
and will not use it for other purposes without consent from the sponsor. It is understood that 
there is an obligation to provide the sponsor with complete data obtained during the study. The 
information obtained from the clinical study will be used towards the development of PLX3397 
and may be disclosed to regulatory authority(ies), other investigators, corporate partners, or 
consultants as required. 
A study site may not publish results of a study until after a coordinated multicenter publication 
has been submitted for publication. Therefore, the study site will have the opportunity to publish 
the results of the study, provided that Daiichi Sankyo has had the opportunity to review and 


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comment on the study site’s proposed publication prior to its being submitted for publication 
with the prior advice of DS Legal Affairs (intellectual property council) and with proper regard 
to the protection of subjects’ identities. 
 
18.0 
REFERENCES 
Beadling C, Jacobson-Dunlop E, Hodi FS, et al. KIT gene mutations and copy number in 
melanoma subtypes. Clin Cancer Res. 2008;14(21):6821-6828. 
 
Carvajal RD, Antonescu CR, Wolchok JD. KIT as a therapeutic target in metastatic melanoma. 
JAMA. 2011;305(22):2327-2334. 
 
Chapman PB, Hauschild A, Robert C. Improved survival with vemurafenib in melanoma with 
BRAF V600E mutation. N Engl J Med. 2011;364:2507-2516. 
 
Chi Z, Li S, Sheng X, Si L, et al. Clinical presentation, histology, and prognoses of malignant 
melanoma in ethnic Chinese: A study of 522 consecutive cases. BMC Cancer. 2011;11:85. 
 
Davies H, Bignell GR, Cox C. Mutations of the BRAF gene in human cancer. Nature. 
2002;417(6892):949-954. 
 
Guo J, Si L, Kong Y, Flaherty KT, Xu X, Zhu Y, et al. Phase II, open-label, single-arm trial of 
imatinib mesylate in patients with metastatic melanoma harboring c-Kit mutation or 
amplification. J Clin Oncol. 2011;29(21):2904-2909. 
 
Hao NB, Lü MH, Fan YH, et al. Macrophages in tumor microenvironments and the progression 
of tumors. Clin Dev Immunol. 2012;2012:948098. 
 
Kong Y, Si L, Zhu Y, et al. Large-scale analysis of KIT aberrations in Chinese patients with 
melanoma. Clin Cancer Res 2011;17:1684-1691. 
 
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity 
and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 
1982;5:649-55. 
 
PLX3397 Investigator’s Brochure. 
 
Si L, Guo J. C-kit-mutated melanomas: the Chinese experience. Curr Opin Oncol. 
2013;25(2):160-165. 


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19.0 
ATTACHMENT 
 
 
ATTACHMENT 1: LABORATORY TESTS 
Hematology 
Hemoglobin and hematocrit 
White blood cell count with differential 
 
 
 
 
Platelet count 
 
Serum Chemistry 
Sodium 
Potassium 
Chloride 
CO2 
Calcium 
Phosphorus 
Glucose 
 
Blood urea nitrogen (BUN)* 
Creatinine (Creatinine clearance 
(CrCl)**) 
Uric acid 
Total protein 
Albumin 
 
Total and direct bilirubin 
Aspartate aminotransferase (AST) 
Alanine aminotransferase (ALT) 
Alkaline phosphatase (ALP) 
Lactate dehydrogenase (LDH) 
Gamma glutamyl transferase (GGT) 
*Urea to BUN conversions will be calculated using following formula (if need). 
Urea (mmol/l) = BUN (mg/dl)* 0.357 
**CrCl will be calculated using following formula (Cockcroft-Gault). 
CrCl={((140–age) x weight (kg))/(72 x serum creatinine (mg/dl))} (x 0.85 if female) 
 
Coagulation: PT/INR 
 
Urinalysis 
pH 
Protein/albumin 
Glucose/sugar 
White blood cells (WBCs) 
Nitrites 
Ketones/acetone 
Hemoglobin/blood 
Casts or other microscopic findings 
 
Serum Pregnancy Test (β-HCG): women of child-bearing potential 
• The Screening serum pregnancy test must be negative within 7 days of initiating study 
drug. 
Urine Pregnancy Test 
• Urine pregnancy test per PI discretion, or institutional policy 
Plasma Samples for PK 
 
Blood Response Biomarkers 
CSF-1, ctDNA 
 
Biopsy Tissue Response Biomarkers 
IHC for KIT, pERK, and Ki67 
Tumor oncogene mutation sequencing 


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ATTACHMENT 2: LIST OF COMMON CYP3A INHIBITORS AND INDUCERS 
 
 
Strong Inhibitors 
Moderate inhibitors 
Strong Inducers 
• Boceprevir 
• Aprepitant 
• Carbamazepine 
• Clarithromycin 
• Cimetidine 
• Enzalutamide 
• Cobicistat 
• Ciprofloxacin 
• Mitotane 
• Danoprevir and ritonavir 
• Crizotinib 
• Phenytoin 
• Elvitegravir and ritonavir 
• Cyclosporine 
• Rifampin 
• Grapefruit juice 
• Dronedarone 
• St. John’s wort 
• Idelalisib 
• Erythromycin 
• Indinavir and ritonavir 
• Fluconazole 
• Itraconazole 
• Fluvoxamine 
• Ketoconazole 
• Imatinib 
• Lopinavir and ritonavir 
• Tofisopam 
• Nefazodone 
• Verapamil 
• Nelfinavir 
• Paritaprevir and ritonavir 
and (ombitasvir and/or 
dasabuvir) 
• Posaconazole 
• Ritonavir 
• Saquinavir and ritonavir 
• Telithromycin 
• Tipranavir and ritonavir 
• Troleandomycin 
• Voriconazole 
Source: Food and Drug Administration (FDA) web site: Drug Development and Drug Interactions: Table of 
Substrates, Inhibitors and Inducers (3 Dec 2019). Available from: https://www fda.gov/drugs/drug-interactions- 
labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers 


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ATTACHMENT 3: RECIST V1.1 CRITERIA 
 
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 patiented 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, 


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imaging evaluation should be undertaken since it is more objective and may also be reviewed at 
the end of the study. 
 
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 patient 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 


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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. 
 
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 
tumors, where known residual benign tumors 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. 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. 


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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 
short axis of the node is the diameter normally used by radiologists to judge if a node is involved 
by solid tumor. Nodal size is normally reported as two dimensions in the plane in which the 
image is obtained (for CT scan this is almost always the axial plane; for MRI the plane of 
acquisition may be axial, sagittal or coronal). The smaller of these measures is the short axis. For 
example, an abdominal node which is reported as being 20 mm 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. 


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• 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. 
 
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. 


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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’. 
 
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 3 
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. 


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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 
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: 


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• 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. 
 
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 19-1 
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 19-2 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. 


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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. 
 
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 19-1: 
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 


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Table 19-2: 
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-PD* 
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 
If a CR is truly met at the 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. 
 
 
Table 19-3: 
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 19-1, Table 19-2, and Table 19-3. 
 
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 4: ECOG PERFORMANCE STATUS 
 
These scales and criteria are used by doctors and researchers to assess how a patient's disease is 
progressing, assess how the disease affects the daily living abilities of the patient, and determine 
appropriate treatment and prognosis. They are included here for health care professionals to 
access. 
 
ECOG PERFORMANCE STATUS* 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up 
and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair 
5 
Dead 
* As published in Oken 1982. 


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!!!IP 
 
ATTACHMENT 5: ADDRESS LIST 
 
1. Sponsor 
• 
Medical Monitor 
 
 
211 Mount Ai.I Road, Basking Ridge, NJ 07920, US 
 
 
• 
Project Leader / Clinical Study Leader 
 
Asia Development Department, R&D Division, Daiichi Sankyo Co., Ltd, 
1-2-58, Hiromachi, Shinagawa-ku, Tokyo, 140-8710, Japan 
 
 
• 
Delivery Lead 
 
Asia Development Department, R&D Division, Daiichi Sankyo Co., Ltd, 
1-2-58, Hiromachi, Shinagawa-ku, Tokyo, 140-8710, Japan 
 
• 
Data Management 
• 
Biostatistician 
 
2. 
CRO 
2.1. Hangzhou Tigermed Consulting Co., Ltd. (China and overall study coordination) 
Floor 17 East, Baoyichuangyi Plaza, No.3760 Nanhuan Road, Binjiang District, Hangzhou, 
Zhejiang Prov., 310053, P/R. China 
 


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• 
CRO Project manager 
 
Floor 17 East, Baoyichuangyi Plaza, No.3760 Nanhuan Road, Binjiang District, Hangzhou, 
Zhejiang Prov., 310053, P/R. China 
 
 
2.2. DreamCIS (Korea study coordination) 
l0F, Jeokseon H 
dai BID, 130, Sajik-ro, Jongno-gu, Seoul, Korea 
 
 
• 
Korea PM (Lead contact in Korea) 
 
dai BID, 130, Sajik-ro, Jongno-gu, Seoul, Korea 
 
 
 
2.3. EDC Vendor 
2.3.1. Medidata Solutions Inc. 
350 Hudson Street, 9th Floor, New York, New York 10014, USA 
 
 
2.4. Biological Specimens 
 
2.4.1. COVANCE Inc. (Sample management, PK and PD assessment) 
 
210 Carnegie Center, Princeton, NJ 08540-6233 USA 
lllliiiiiion: 
Global Study Manager, Global Project Management 
Covance (Asia) Pte. Limited 
1 International Business Park, #01-01 The Synergy, Singapore 609917 
 
 
Covance Central Lab APAC contact Regional Study Coordinator 
Covance Phaimaceutical Research and Development (Shanghai) Co. Limited 
1st Floor, No. 6 Building, No. 151 Li Bing Road, Zhangjiang Hi-Tech Park, Shanghai 201203, 


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China 
 
 
2.4.2. WuXi NextCODE (Shanghai) (Genomics) 
 
#288 FuTe Zhong Road, Shanghai, China, 
Contact erson: 
 
 
 
2.4.3. Guardant Health (ctDNA) 
 
505 Penobscot Dr, RedwoodCity, CA 94063, US 
 


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ATTACHMENT 6: VERSION 2.0 (AMENDMENT 1 SUMMARY OF CHANGES) 
 
Note: Minor grammatical changes are not listed. Text inserted is shown in bold while text deleted is shown with strikethrough. 
 
Section(s) 
Previous 
Amendment 1 
Rationale 
Title Page/Protocol 
Title; Signature Page, 
4.0 Synopsis 
Phase 2 Open Label, Multicenter Study of 
PLX3397 in Patients with Unresectable or 
Metastatic KIT-mutated Melanoma 
Phase 1/2 Open Label, Multicenter Study of 
PLX3397 in Patients with Unresectable or Metastatic 
KIT-mutated Melanoma 
Due to lack of Phase 1 
clinical data, modified the 
title to reflect the 
2 portions of the study 
4.0 Synopsis/Inclusion 
and Exclusion Criteria; 
8.2 Exclusion Criteria 
13. Active or chronic infection with human 
immunodeficiency virus (HIV), hepatitis C 
virus (HCV), or hepatitis B virus (HBV) 
13. Active or chronic infection with human 
immunodeficiency virus (HIV), hepatitis C 
virus (HCV), or hepatitis B virus (HBV). Active or 
chronic HBV infection is defined as being HBsAg 
or HBV DNA-positive. Chronic HCV is defined as 
being anti-HCV or HCV RNA-positive. 
Clarification of definitions 
of HIV, HCV, and HBV- 
positive 
4.0 Test Product, Dose, 
and Mode of 
Administration; 
9.1 Study Drug 
Administration 
PLX3397 will be supplied in 200 mg capsules 
and will be taken twice daily (BID) 
approximately 12 hours apart. Each dose is to 
be taken with approximately 8 ounces of water. 
PLX3397 will be supplied in 200 mg capsules and 
will be taken twice daily (BID) approximately 
12 hours apart. Each dose is to be taken with 
approximately 8 ounces 200 mL of water. 
Clarification using 
relevant unit of measure 
Table 4-1: Schedule of 
Events for Pilot Portion 
of Study, footnote #14 
14. Fresh tumor biopsy will be performed on 
Day 1 (-3d), Day 15 (-3d), and at the End-of- 
Study visit (-3d) for patients enrolled in the 
Pilot portion of the study. A PET scan should 
be performed prior to biopsy collection 
procedures to avoid false positive results. 
14. Fresh tumor biopsy will be performed on Day 1 
(-3d), Day 15 (-3d), and at the End-of-Study visit 
(-3d) for patients enrolled in the Pilot portion of the 
study. If a Screening tumor biopsy was obtained 
(Day -28 to Day -1), and there was sufficient tissue 
from that sample for laboratory testing, then 
tumor biopsy on Day 1 is not required. A PET scan 
should be performed prior to biopsy collection 
procedures to avoid false positive results. 
Added to clarify that if 
sufficient tissue is 
available from Screening 
biopsy, a second biopsy at 
Day 1 is not required. 


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.•- 
= - 
Section(s) 
Previous 
Amendment 1 
Rationale 
Table 4-2: Schedule of 
Events for Phase 2 
Portion of Study, 
footnote #13 
13. Fresh tumor biopsy will be perfonned on 
Day 1 (-3d), Day 15 (-3d), and at the End-of­ 
Study visit (-3d) for patients enrolled in the 
Pilot portion of the study. A PET scan should 
be perfo1med prior to biopsy collection 
procedures to avoid false positive results. 
13. Fresh tumor biopsy will be perfonned on Day 1 
(-3d), Day 15 (-3d), and at the End-of-Study visit 
(-3d) for patients enrolled in the Pilot portion of the 
study. If a Screening tumo1· biop sy was obtain e d 
(Da y -28 to Da y -1 ), and there was sufficient tissue 
from that sample for laboratory testing, then 
tumor biopsy on Day 1 is not required. A PET scan 
should be perf01med prior to biopsy collection 
procedures to avoid false positive results. 
Added to clarify that if 
sufficient tissue is 
available from Screening 
biopsy, a second biopsy at 
Day 1 is not required. 
5.1 Backgt"Ound 
Apart from BRAF, KIT is the only other 
aben-ant signaling molecule for which targeted 
drugs are available. Some evidence of efficacy 
for imatinib in KIT advanced melanoma has 
been repo1t ed in two Phase 2 trials (Jun et al. 
2011) 
Apart from BRAF, KIT is the only other aben-ant 
signaling molecule for which targeted dmgs are 
available. Some evidence of efficacy for imatinib in 
KIT advanced melanoma has been reported in two 
Phase 2 trials (JYB et al.Guo 2011 ) 
Con-ected reference 
7.1 Overview of Study 
Design 
This Phase 2, open label, multicenter study 
includes a dose evaluation po1tion (Pilo t phase) 
in which the safety profile of PLX3397 as a 
single oral agent will be evaluated, followed by 
an expansion cohort (Phase 2) in which the 
efficacy and safety of PLX3397 administered at 
the recommended Phase 2 dose (RP2D). .. 
This Phase 1/2, open label, multicenter study includes 
a dose evaluation p01tion (Pilot phase) in which the 
safety profile of PLX3397 as a single oral agent will 
be evaluated, followed by an expansion coho1t 
(Pha se 2) in which the efficacy and safety of 
PLX3397 administered at the recommended Phase 2 
dose (RP2D).. . 
Due to lack of Phase 1 
clinical data, modified the 
study design description to 
reflect the 2 portions of the 
study 
10.1 Study Personnel 
and Organizations, SAE 
Reporting Contact 
The inves tigator will ensure that the SAE 
repo1ting form is completed and E­ 
mailed/eFaxed to the following address with.in 
24 hour s of learning of the occulTence of any 
SAE: 
The investigator will ensure that the SAE rep01t ing 
fonn is completed and E-mailed/eFaxed to the 
following address v.rithin 24 hour s of learning of the 
occulTence of any SAE : 
Na me: SynteractHCR Safety SAE Facsimile 
Updated to reflect CUil'ent 
SAE reporting contact 
• 
T o ll-fr 
ee 
US fax number: 


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Section(s) 
Previous 
Amendment 1 
Rationale 
10.2 Arrangements for 
Recruitment of Subjects 
Recruitment and enrollment strategies for this 
study may include recruitment from the 
investigator’s local practice or referrals from 
other physicians. If advertisements become part 
of the recruitment strategy, they will be 
reviewed by the institutional review board 
(IRB) and/or independent ethics committee 
(IEC). 
Recruitment and enrollment strategies for this study 
may include recruitment from the investigator’s local 
practice or referrals from other physicians. If 
advertisements become part of the recruitment 
strategy, they will be reviewed by the institutional 
review board (IRB) and/or independent ethics 
committee (IEC). Subjects will be compensated for 
their participation in this study. 
Added for clarity 


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ATTACHMENT 7: VERSION 3.0 (AMENDMENT 2 SUMMARY OF CHANGES) 
 
Note: Changes throughout the protocol that are repetitive, self-evident or grammatical may not be individually listed in this Summary 
of Changes. Text inserted is shown in bold while text deleted is shown with strikethrough. 
 
Section(s) 
Previous 
Amendment 2 
Rationale 
Title Page 
IND Number: TBD 
Eudra CT Number: TBD 
IND Number: TBD 
Eudra CT Number: TBD 
To reflect that the protocol 
will not have an IND or 
Eudra CT Number. 
Protocol Synopsis – 
Objectives; 
Section 6.3 Exploratory 
Objectives; Section 
11.1.7 Cycle 2, Day 1 
(Pilot Portion); 
Section 11.2.7 Cycle 2, 
Day 1 (Phase II); 
Section 11.3.4 Study 
Procedures 
To evaluate tumor response by PET scan on 
Day 15 compared to Baseline (Pilot portion of 
the study) 
To evaluate tumor response by PET scan on Day 15 
Day 1 of Cycle 2 compared to Baseline (Pilot portion 
and first 13 patients of the Phase II portion of the 
study) 
To include PET scans for 
the first 13 patients 
enrolled in the phase II 
portion of the study. 
Protocol Synopsis – 
Number of Patients; 
Section 7.2 Number of 
Subjects 
Pilot: Up to 12 patients 
Pilot: Up to Approximately 6-12 patients 
To more accurately reflect 
planned study schema. 
Protocol Synopsis, Study 
Procedures; 
Section 11.3.3 Study 
Procedures 
Fresh tumor tissue for the purpose of 
exploratory pharmacodynamics as well as PET 
scan will be obtained at baseline (Day 1) and 
Day 15 of Cycle 1 in patients of the Phase 1 
portion. 
Fresh tumor tissue for the purpose of exploratory 
pharmacodynamics will be obtained at baseline 
(Day 1) and optionally also at Day 15 of Cycle 1 
and End-of-treatment in the Pilot portion and first 
13 patients of the Phase II portion. as well as PET 
scan will be obtained at baseline (Day 1) and Day 15 
of Cycle 1 Day 1 of Cycle 2 in patients of the Phase 1 
portion in the Pilot portion and first 13 patients of 
the Phase II portion. 
To indicate that fresh 
tumor tissue biopsy is 
optional at Cycle 1 Day 15 
and End-of-treatment and 
to specify that the first 13 
subjects enrolled in the 
Phase II portion and on 
Pilot portion will have a 
PET scan and Fresh 
Tumor Biopsy 


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Section(s) 
Previous 
Amendment 2 
Rationale 
Protocol Synopsis – PK 
Parameters 
The pharmacokinetic profile of plasma 
PLX3397 will be analyzed by measuring area 
under the plasma concentration–time curve 
(AUC0-6, AUC0-∞), peak concentration (Cmax), 
time to peak concentration (Tmax), half-life 
(T½), and terminal elimination rate constant 
(Kel). 
Dose proportionality following study dosing 
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. 
The pharmacokinetic profile of plasma PLX3397 will 
be analyzed by measuring area under the plasma 
concentration–time curve (AUC0-6, AUC0-∞), peak 
concentration (Cmax), time to peak concentration 
(Tmax), and half-life (T½). , and terminal elimination 
rate constant (Kel). 
Dose proportionality following study dosing 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. 
To make consistent with 
Section 13.1.8.1 
Pharmacokinetic Analysis 
Protocol Synopsis – PD 
Parameters 
Histological/molecular analysis of paired fresh 
tumor biopsy, and positron emission 
tomography (PET) scan evaluation on Day 15 
compared to Baseline in the first 13 patients in 
the Phase 2 portion of the study will be 
performed. Exploratory tissue studies will 
include IHC for KIT, pERK, Ki67 and other 
markers of target or tumor evaluation. 
Exploratory blood studies in the Phase 2 
portion of the study will measure CSF-1 and 
other markers of target inhibition and tumor 
evaluation. 
Histological/molecular analysis of paired fresh tumor 
biopsy, and positron emission tomography (PET) 
scan evaluation on Day 15 Day 1 of Cycle 2 
compared to Baseline in the first 13 patients in the 
Phase 2II portion of the study will be performed. 
Exploratory tissue studies will include IHC for KIT, 
pERK, Ki67 and other markers of target or tumor 
evaluation. Exploratory blood studies in the Phase 2II 
portion of the study will measure CSF-1 and other 
markers of target inhibition and tumor evaluation. 
To make consistent with 
rest of protocol. 


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Section(s) 
Previous 
Amendment 2 
Rationale 
Protocol Synopsis – 
Endpoints; 
Section 12.1 Pilot 
Portion; 
Section 12.2 Phase II 
The endpoints in the Pilot portion of the study 
include: 
… 
• 
Serum/plasma tumor biomarkers include 
but not limited to CSF-1, and whole blood 
CD14/16 mononuclear cell counts 
The endpoints in the Pilot portion of the study 
include: 
… 
• 
Serum/plasma tumor biomarkers include but not 
limited to including CSF-1, and whole blood 
CD14/16 mononuclear cell counts 
To reflect that CD14/16 
testing is not found to be 
operationally feasible. 
The exploratory endpoints in the Pilot portion 
of the study include: 
The exploratory endpoints in the Pilot portion of the 
study include: 
• 
Immunohistochemistry and molecular 
analysis of paired fresh tumor biopsy 
• 
Immunohistochemistry and molecular analysis of 
archival and paired fresh tumor biopsy 
To make consistent with 
rest of protocol. 
• 
Positron emission tomography (PET) scan 
evaluation on Day 15 compared to Baseline 
• 
Positron emission tomography (PET) scan 
evaluation on Day 15 Day 1 of Cycle 2 compared to 
Baseline 
… 
… 
The exploratory endpoints in the Phase 2 
portion of the study include: 
The exploratory endpoints in the Phase 2II portion of 
the study include: 
To make consistent with 
rest of protocol. 
• 
Serum/plasma tumor biomarkers including 
but not limited to CSF-1, whole blood 
CD14/16 mononuclear cell counts 
• 
Immunohistochemistry and molecular 
analysis of archival and paired fresh tumor biopsy 
• 
Serum/plasma tumor biomarkers including but 
not limited to CSF-1, whole blood CD14/16 
mononuclear cell counts 
• 
Positron emission tomography (PET) scan 
evaluation on Day 1 of Cycle 2 compared to 
Baseline 
Table 4-1: Schedule of 
Events for Pilot Portion 
of Study 
N/A 
N/A 
Archival tissue – Screening 
Blood sampling for PD – Cycle 1 Day 1 and Day 15 
To add archival tissue 
collection at screening. 
To make consistent with 
study endpoints. 
PET scan – Cycle 1 Day 15 
PET scan – Cycle 2 Day 1 
To spread study 
procedures apart for 
patient convenience. 


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Table 4-1: Schedule of 
Events for Pilot Portion 
of Study (footnotes) 
Footnote 5. Qualified KIT mutation(s) must be 
documented prior to enrollment (see Table 11- 
1). 
Footnote 5. Qualified Documentation of KIT 
mutation(s) must be documented prior to enrollment 
(see Table 11 1) to include submission of 
deidentified sequencing report and associated .scf 
output files. 
To clarify documentation 
required based on 
discussion with 
investigators. 
Footnote 13. PET scan will be performed on at 
Screening (-3d) and Day 15 (-3d) of Cycle 1 
for patients enrolled in the Pilot portion of the 
study. 
Footnote 14. Fresh tumor biopsy will be 
performed on Day 1 (-3d), Day 15 (-3d), and at 
the End-of-Study visit (-3d) for subjects 
enrolled in the Pilot portion of the study. If a 
Screening tumor biopsy was obtained (Day -28 
to Day -1), and there was sufficient tissue from 
that sample for laboratory testing, then tumor 
biopsy on Day 1 is not required. A PET scan 
should be performed prior to biopsy collection 
procedures to avoid false positive results. 
N/A 
N/A 
Footnote 13. PET scan will be performed on at 
Screening Day 1 (-3d) and Day 15 Day 1 (-3d) of 
Cycle 1 2 for patients enrolled in the Pilot portion of 
the study. 
Footnote 14. Fresh tumor biopsy will be performed 
on Day 1 (-3d), Day 15 (-3d) (optional), and at the 
End-of-Study visit (-3d) (optional) for subjects 
enrolled in the Pilot portion of the study. Biopsies 
must be core needle or excisional (not fine needle), 
and sufficient for 20 unstained slides of 4-5 micron 
thickness. If a Screening tumor biopsy was obtained 
(Day -28 to Day -1), and there was sufficient tissue 
from that sample for laboratory testing, then tumor 
biopsy on Day 1 is not required. A All PET scans 
should be performed prior to biopsy collection 
procedures to avoid false positive results. 
Footnote 15. Availability of archival tissue should be 
documented and at least 10 unstained slides of 5 
micron thickness should be submitted to the central 
lab. 
Footnote 16. On Day 1 and Day 15 of Cycle 1 
during the Pilot portion of the study, blood 
samples for pharmacodynamics (PD) analysis will 
be obtained pre-morning dose. 
To make consistent with 
study endpoints. 
To specify the sampling 
requirements for biopsies 
and indicate that fresh 
tumor biopsies are 
optional at Cycle 1 Day 15 
and End-of-Study. 
To specify procedure for 
collecting archival tissue. 
To make consistent with 
study endpoints. 
Table 4-2: Schedule of 
Events for Phase II 
Portion of Study 
N/A 
N/A 
Archival tissue - Screening 
PET Scan – Cycle 1 Day 1, Cycle 2 Day 1 
To add archival tissue 
collection at screening. 
To make consistent with 
study endpoints. 


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Section(s) 
Previous 
Amendment 2 
Rationale 
Table 4-2: Schedule of 
Events for Phase II 
Portion of Study 
(footnotes) 
Footnote 5. Qualified KIT mutation(s) must be 
documented prior to enrollment (see Table 11- 
1). 
Footnote 5. Qualified Documentation of KIT 
mutation(s) must be documented prior to enrollment 
(see Table 11 1) to include submission of 
deidentified sequencing report and associated .scf 
output files. 
To clarify documentation 
required based on 
discussion with 
investigators. 
Footnote 13. Fresh tumor biopsy will be 
performed on Day 1 (-3d), Day 15 (-3d), and at 
the End-of-Study visit (-3d) for first 13 patients 
enrolled in Phase 2. If a Screening tumor 
biopsy was obtained (Day 28 to Day 1), and 
there was sufficient tissue from that sample for 
laboratory testing, then tumor biopsy on Day 1 
is not required. A PET scan should be 
performed prior to biopsy collection procedures 
to avoid false positive results. 
Footnote 13. Fresh tumor biopsy will be performed 
on Day 1 (-3d), Day 15 (-3d) (optional), and at the 
End-of-Study visit (-3d) (optional) for first 13 patents 
subjects enrolled in Phase II. Biopsies must be core 
needle or excisional (not fine needle), and 
sufficient for 20 unstained slides of 4-5 micron 
thickness. If a Screening tumor biopsy was obtained 
(Day -28 to Day -1), and there was sufficient tissue 
from that sample for laboratory testing, then tumor 
biopsy on Day 1 is not required. A All PET scans 
should be performed prior to biopsy collection 
procedures to avoid false positive results. 
To specify the sampling 
requirements for biopsies 
and indicate that fresh 
tumor biopsies are 
optional at Cycle 1 Day 15 
and End-of-Study. 
N/A 
Footnote 14. Availability of archival tissue should 
be documented and at least 10 unstained slides of 5 
micron thickness should be submitted to the 
central lab. 
To specify procedure for 
collecting archival tissue. 
N/A 
Footnote 15. PET scan will be performed at Day 1 
(-3d) of Cycle 1 and Day 1 (-3d) of Cycle 2 for the 
first 13 patients enrolled in the Phase II portion of 
the study.. 
To make consistent with 
study endpoints. 
Section 9.2.1 Dose 
Evaluation 
Cohort 2 will be carried out only if Cohort 1 is 
considered intolerable. Study treatment may be 
delayed up to 2 weeks to permit resolution of 
any treatment-related toxicity outside the DLT 
window. 
Cohort 2 -1 will be carried out only if Cohort 1 is 
considered intolerable. Study treatment may be 
delayed up to 2 weeks to permit resolution of any 
treatment-related toxicity outside the DLT window. 
To make consistent with 
the dose cohort levels. 


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Section 9.3 Dose 
Escalation Rules 
9.3 Dose Escalation Rules 
Dose escalation will occur in accordance with 
the rules listed below. 
… 
• 
After dosing has been completed in each 
cohort, safety and PK data (as applicable) will 
be reviewed by and dose escalation decisions 
made by the Sponsor, and investigators and 
study staff from all participating sites. 
9.3 Dose Escalation Reduction Rules 
Dose escalation reduction will occur in accordance 
with the rules listed below. 
… 
• 
After dosing has been completed in each cohort, 
safety and PK data (as applicable) will be reviewed 
by and dose escalation reduction decisions made by 
the Sponsor, and investigators and study staff from all 
participating sites. 
To make language 
consistent with study 
schema. 
Section 9.4 Definitions of 
Dose-Limiting Toxicity 
In the Pilot portion of the study, DLTs will be 
assessed during a DLT assessment window of 
28 days in Cycle 1. However, if clinically 
relevant ≥Grade 3 cumulative toxicities are 
observed beyond Cycle 1, these should also be 
taken into account when assessing further dose 
escalation. 
… 
If, for any reason, either the Sponsor or 
principal investigator deems further dose 
escalation inappropriate. Final decisions on 
determination of DLTs will be made in 
consultation between the Sponsor and the 
principal investigator. 
In the Pilot portion of the study, DLTs will be 
assessed during a DLT assessment window of 28 
days in Cycle 1. However, if clinically relevant 
≥Grade 3 cumulative toxicities are observed beyond 
Cycle 1, these should also be taken into account when 
assessing further dose escalation reduction. 
… 
If, for any reason, either the Sponsor or principal 
investigator deems further dose escalation reduction 
inappropriate. Final decisions on determination of 
DLTs will be made in consultation between the 
Sponsor and the principal investigator. 
To make language 
consistent with study 
schema. 
Table 9-1: 
Recommended PLX3397 
Dose Modifications 
– Grade 3 or 4 
Neutropenia 
– Grade 4 
Thrombocytopenia 
If not recovered to ANC ≥1 X 109/L after 
7 days, reduce dose by 1 dose level 
If not recovered to ANC ≥1 X 109/L after 
7 days, reduce dose by 2 dose levels. 
If not recovered to PLT ≥75 x 109/L after 
7 days, reduce dose by 2 dose levels. 
If not recovered to ANC ≥1 X 109/L after 7 days, 
reduce dose by 1 dose level (200 mg). 
If not recovered to ANC ≥1 X 109/L after 7 days, 
reduce dose by 2 dose levels an additional dose level 
(200 mg). 
If not recovered to PLT ≥75 x 109/L after 7 days, 
reduce dose by an additional 2 dose levels. 
To specify the dose level 
reduction of 200 mg. 
To specify the additional 
dose level reduction at the 
2nd appearance of Grade 3 
or 4 Neutropenia. 
To specify the additional 
dose level reduction at the 
2nd appearance of Grade 4 
Thrombocytopenia. 


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Section(s) 
Previous 
Amendment 2 
Rationale 
Section 9.6 Stopping 
Rules 
The Pilot and Phase 2 portions of the study 
may be discontinued if the study is terminated 
by the Sponsor, the Food and Drug 
Administration (FDA) or the China Food and 
Drug Administration (CFDA), or other 
regulatory authorities. 
The Pilot and Phase 2 II portions of the study may be 
discontinued if the study is terminated by the 
Sponsor, the Food and Drug Administration (FDA) or 
the China Food and Drug Administration (CFDA), or 
other regulatory authorities. 
To reflect that the protocol 
will not be conducted 
under a FDA IND. 
Section 9.13 Storage, 
Handling, and 
Accountability 
All unused and partially used Study drug must 
be sealed and returned to the Principal 
Investigator or his/her designee, or destroyed 
on Site in accordance with the established 
procedures for drug destruction, and with 
approval by the Principal Investigator or 
his/her designee. 
All unused and partially used Study drug must be 
sealed and returned to the Principal Investigator or 
his/her designee Sponsor, or destroyed on Site in 
accordance with the established procedures for drug 
destruction, and with approval by the Principal 
Investigator or his/her designee. 
To clarify Study drug 
handling procedures. 
Section 11.1.1 Screening 
Visit (Day -28 to Day -1) 
N/A 
• Documentation of archival tissue availability 
To add archival tissue 
collection at screening. 
Section 11.1.3 Cycle 1, 
Day 1 
N/A 
• Blood sampling for PD analysis 
To make consistent with 
study endpoints. 
Section 11.1.5 Cycle 1, 
Day 15 
N/A 
• Fresh tumor biopsy (may be performed 
within 3 days prior to the study visit) 
• PET scan (–3-day window) 
• Blood sampling for PD analysis 
• Fresh tumor biopsy (optional, and may be 
performed within 3 days prior to the study visit) 
• PET scan ( 3 day window) [moved to Cycle 2 Day 
1] 
To make consistent with 
study endpoints. 
To spread study 
procedures apart for 
patient convenience. 
Section 11.1.7 Cycle 2, 
Day 1 ± 3 days; 
N/A 
On this day, the patient will take the morning 
and evening does of study medication with 
food. 
N/A 
• PET scan (–3-day window) [moved from Cycle 1 
Day 15] 
On this day, the patient will take the morning and 
evening does of study medication with food. 
Procedures to be performed after the morning 
dose: 
• 12-lead ECG (2 hours post-dose) 
To spread study 
procedures apart for 
patient convenience. 
To make consistent with 
Section 9.1 Study Drug 
Administration. 
To make consistent with 
the Schedule of Events. 
Section 11.2.1 Screening 
Visit (Day -28 to Day -1) 
N/A 
• Documentation of archival tissue availability 
To add archival tissue 
collection at screening. 


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Section 11.2.3 Cycle 1, 
Day 1 
N/A 
• PET scan (–3-day window) 
To make consistent with 
study endpoints. 
Section 11.2.4 Cycle 1, 
Day 8 ± 3 days 
Urinalysis, including PH, protein/albumin, 
glucose, nitrates, ketones/acetones, and 
hemoglobin/blood 
Urinalysis, including PH, protein/albumin, glucose, 
nitrates, ketones/acetones, and hemoglobin/blood 
To make consistent with 
the Schedule of Events. 
Section 11.2.5 Cycle 1, 
Day 15 ± 3 days 
• Fresh tumor biopsy (first 13 patients 
enrolled in Phase 2; –3-day window) 
N/A 
• Fresh tumor biopsy (optional, first 13 patients 
enrolled in Phase 2II; –3-day window) 
Procedures to be performed after the morning 
dose: 
12-lead ECG (2 hours post-dose) 
To make consistent with 
the Schedule of Events. 
Section 11.2.7 Cycle 2, 
Day 1 ±3 days 
On this day, the patient will take the morning 
and evening does of study medication with 
food. 
On this day, the patient will take the morning and 
evening does of study medication with food. 
• PET scan (–3-day window) [moved from Cycle 1 
Day 15] 
Procedures to be performed after the morning 
dose: 
• 12-lead ECG (2 hours post-dose) 
To make consistent with 
Section 9.1 Study Drug 
Administration. 
N/A 
To spread study 
procedures apart for 
patient convenience. 
N/A 
To make consistent with 
the Schedule of Events. 
Section 11.2.10 End-of- 
Study Visit 
• Fresh tumor biopsy (first 13 patients 
enrolled in Phase 2; –3-day window) 
Urinalysis, including PH, protein/albumin, 
glucose, nitrates, ketones/acetones, and 
hemoglobin/blood 
• Fresh tumor biopsy (optional, first 13 patients 
enrolled in Phase 2II; –3-day window) 
Urinalysis, including PH, protein/albumin, glucose, 
nitrates, ketones/acetones, and hemoglobin/blood 
To make consistent with 
the Schedule of Events. 
Section 11.3.3 Fresh 
A pre-dose tumor biopsy of a progressive 
A pre-dose tumor biopsy of a progressive lesion will 
To specify the type of 
Tissue Biopsy Samples 
lesion will be obtained in patients with 
be obtained in patients with accessible tissue. 
assay that will be 
(Pilot Portion and First 
accessible tissue. Paraffin-fixed tissue slides 
Paraffin-fixed tissue slides will be collected and 
performed on fresh tissue 
13 Patients of Phase II 
will be collected and stored for subsequent 
stored for subsequent evaluation using a project- 
Biopsy. 
Portion of the Study) 
evaluation using a project-specific companion 
specific companion diagnostic assay tumor assays to 
diagnostic assay to be performed at one or 
be performed at one or more central laboratories. 
more central laboratories. Biopsy tissues will 
Biopsy tissues will interrogated for biomarkers of 
interrogated for biomarkers of KIT mutation. 
KIT mutation. 


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Section 11.3.4 PET Scans 
(Pilot Portion and First 
13 Patients of Phase II 
Portion of the Study) 
18FDG-PET scans will be obtained during 
Screening and Day 1 and at Day 15 of Cycle 1. 
18FDG-PET scans will be obtained at Cycle 1 during 
Screening and Day 1 and at Cycle 2 Day 1Day 15 of 
Cycle 1. 
To specify the timepoint 
for the PET scan. 
Section 13.1.7 Efficacy 
Analysis 
Thirteen patients will be enrolled in the first 
stage, with at least two responses required to 
proceed to the second stage. Eight responses 
among 29 patients are required for PLX3397 to 
be considered promising. 
Thirteen patients will be enrolled in the first stage, 
with at least threewo responses required to proceed to 
the second stage. Eight responses among 29 patients 
are required for PLX3397 to be considered 
promising. See Section 13.1.10 for discussion of 
interim analysis. 
To add reference to 
discussion of interim 
analysis plan. 
Section 13.1.8.3 Tissue 
Evaluation 
Exploratory tissue studies will include IHC for 
KIT, pERK, Ki67 and other markers of target 
or tumor evaluation. Tissue may also be used 
for KIT or other oncogene mutation sequencing 
confirmation. Blood biomarker analysis 
Exploratory studies in the Phase 2 part of the 
study will measure CSF-1 and other markers of 
target inhibition and tumor evaluation. Planned 
biomarkers are listed in Attachment 1.Safety 
Analysis 
Exploratory tissue studies will include IHC for KIT, 
pERK, Ki67 and other markers of target or tumor 
evaluation. Tissue may also be used for KIT or other 
oncogene mutation sequencing confirmation. Blood 
biomarker analysis 
Exploratory studies in the Phase 2II part of the study 
will measure CSF-1 and other markers of target 
inhibition and tumor evaluation. Planned biomarkers 
are listed in Attachment 1.Safety Analysis 
To specify the target 
biomarkers. 
Section 13.1.10 Interim 
Analysis 
No formal interim analysis is planned. 
No formal interim analysis is planned. The Phase II 
portion of the study will follow a Simon two-stage 
design to compare a null ORR of 15% with an 
alternative ORR of 40% with 90% power and a 
one-sided type I error of 5%. The total sample size 
will be 29 evaluable patients. Thirteen patients will 
be enrolled in the first stage before triggering an 
interim analysis. At least three responses are 
required to proceed to the second stage. Eight 
responses among 29 patients are required for 
PLX3397 to be considered promising. 
To specify the interim 
analysis plans for the 
study. 


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Section(s) 
Previous 
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Section 15.1.1 Adverse 
Event Definition 
This includes any newly occurring event or 
previous condition that has increased in 
severity or frequency since the administration 
of study drug. An AE includes, but is not 
limited to, the following… 
This includes any newly occurring event or previous 
condition that has increased in severity or frequency 
since the administration of study drug. Clear 
progression of the underlying cancer and 
hospitalizations due to the progression of cancer 
should not be reported as an adverse event, or a 
serious adverse event. An AE includes, but is not 
limited to, the following… 
To further clarify the 
definition of the 
reportability of an adverse 
event. 
Section 15.2.1 Studies 
Conducted Within the 
European Community 
Section 15.2.1 Studies Conducted Within the 
European Community 
In accordance with the European Clinical Trial 
Directive (Directive 2001/20/EC), suspected, 
unexpected serious adverse reactions 
(SUSARs) associated with the use of any study 
drug (Plexxikon and non-Plexxikon) will be 
processed with the following responsibilities. 
Section 15.2.1 Studies Conducted Within the 
European Community 
In accordance with the European Clinical Trial 
Directive (Directive 2001/20/EC), suspected, 
unexpected serious adverse reactions (SUSARs) 
associated with the use of any study drug (Plexxikon 
and non Plexxikon) will be processed with the 
following responsibilities. 
To remove the section 
15.2.1 as this protocol will 
not be conducted in the 
EU. 
Plexxikon (or its agent) will notify, in an 
expedited manner, the appropriate competent 
authorities, the IEC, and the reporting 
investigator of the SUSARs for all Plexxikon 
sponsored studies. In addition, Plexxikon (or its 
agent) will send out a monthly line-listing of all 
SUSAR associated with study drug(s) to the 
IECs, all investigators, and all competent 
authorities for member states where the studies 
are being conducted. 
Plexxikon (or its agent) will notify, in an expedited 
manner, the appropriate competent authorities, the 
IEC, and the reporting investigator of the SUSARs 
for all Plexxikon sponsored studies. In addition, 
Plexxikon (or its agent) will send out a monthly line 
listing of all SUSAR associated with study drug(s) to 
the IECs, all investigators, and all competent 
authorities for member states where the studies are 
being conducted. 
Section 16.12 Closure of 
the Study 
Determination of efficacy based on interim 
analysis 
Determination of a lack of efficacy based on interim 
analysis 
To clarify closure of study 
rules. 


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Section(s) 
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Rationale 
ATTACHMENT 1: 
LABORATORY TESTS 
Blood Response Biomarkers 
Paired Biopsy Tissue Response Biomarkers 
Blood Response Biomarkers 
CSF-1 
Paired Biopsy Tissue Response Biomarkers 
To specify the target 
biomarkers in biopsy 
tissue and blood samples. 
pERK and Ki67 
KIT, pERK, and Ki67 
RNA sequencing 
RNA Tumor oncogene mutation sequencing 
Other response or resistance biomarkers as 
appropriate 
Other response or resistance biomarkers as 
appropriate 
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, and may include additional 
markers of macrophage activity, in addition to 
anti-tumor biomarkers that may be related to 
PLX3997 treatment. 
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, and may include additional 
markers of macrophage activity, in addition to anti 
tumor biomarkers that may be related to PLX3997 
treatment. 


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ATTACHMENT 8: VERSION 4.0 (AMENDMENT 3 SUMMARY OF CHANGES) 
 
Note: Changes throughout the protocol that are repetitive, self-evident or grammatical may not be individually listed in this Summary 
of Changes. Text inserted is shown in bold while text deleted is shown with strikethrough. 
 
Section(s) 
Previous 
Amendment 3 
Rationale 
Protocol Synopsis; 
Section 9.4 Definitions of 
Dose-Limiting Toxicity 
• Any Grade ≥3 hematologic toxicity except: 
• Grade 3 lymphopenia 
• Grade 3 neutropenia ≤7 days 
• Any thrombocytopenia resulting in clinically 
significant bleeding 
• Any Grade ≥3 non-hematologic toxicity 
except: 
• Nausea, vomiting, and/or diarrhea of Grade 
3 severity that resolves within 7 days with 
optimal prophylaxis and/or treatment. 
… 
• If, for any reason, either the Sponsor or 
principal investigator deems further dose 
escalation inappropriate. Final decisions on 
determination of DLTs will be made in 
consultation between the Sponsor and the 
principal investigator 
• Any Grade ≥3 clinically significant hematologic 
toxicity except: 
• Grade 3 lymphopenia 
• Grade 3 neutropenia ≤7 days 
• Any thrombocytopenia resulting in clinically 
significant bleeding 
• Any Grade ≥3 clinically significant non- 
hematologic toxicity except: 
• Nausea, vomiting, and/or diarrhea of Grade 3 
severity that resolves within 7 days with optimal 
prophylaxis and/or treatment. 
… 
• If, for any reason, either the Sponsor or principal 
investigator deems further dose reduction 
escalation inappropriate. Final decisions on 
determination of DLTs will be made in 
consultation between the Sponsor and the principal 
investigator. 
• For the purposes of determining the DLT in 
Cycle 1, the use of G-CSF or other hematologic 
growth factors is not permitted during Cycle 1. 
If a patient develops a protocol defined 
hematologic DLT and requires the use of G- 
CSF or other hematologic growth factors, they 
may be used in accordance with local standard 
of care, and per Section 9.7. 
To clarify DLT definition 
and include rules on G- 
CSF use during the DLT 
period. 


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Section(s) 
Previous 
Amendment 3 
Rationale 
Protocol Synopsis; 
Section 9.6 Stopping 
Rules 
The Pilot and Phase II portions of the study 
may be discontinued if the study is terminated 
by the Sponsor, the Food and Drug 
Administration (FDA) or the China Food and 
Drug Administration (CFDA), or other 
regulatory authorities. 
The Pilot and Phase II portions of the study may be 
discontinued if the study is terminated by the 
Sponsor, the Food and Drug Administration (FDA) or 
the China Food and Drug Administration (CFDA), or 
other regulatory authorities. 
To make consistent with 
study region. 
Table 9-1: 
Recommended PLX3397 
Dose Modifications – 
Grade 3 or 4 
Neutropenia 
1st appearance: 
If not recovered to ANC ≥1 X 109/L after 
7 days, reduce dose by 1 dose level (200 mg). 
2nd appearance: 
If recovered to ANC ≥1 X 109/L in ≤7 days, 
reduce dose by 1 dose level. 
1st appearance: 
If not recovered to ANC ≥1 X 109/L after 7 days, 
reduce dose by 1 dose level (200 mg). 
2nd appearance: 
If recovered to ANC ≥1 X 109/L in ≤7 days, reduce 
dose by 1 dose level 200 mg. 
To specify the dose level 
reductions of 200 mg. 
If not recovered to ANC ≥1 X 109/L after 
7 days, reduce dose by an additional dose level 
(200 mg). 
If not recovered to ANC ≥1 X 109/L after 7 days, 
reduce dose by an additional dose level (200 mg). 
3rd appearance: 
3rd appearance: 
If recovered to ANC ≥1 X 109/L in ≤7 days, 
reduce dose by 1 dose level. 
If recovered to ANC ≥1 X 109/L in ≤7 days, reduce 
dose by 1 dose level 200 mg. 
Table 9-1: 
Recommended PLX3397 
Dose Modifications – 
Grade 3 or 4 
Febrile Neutropenia 
1st appearance: 
If recovered to ANC ≥1 X 109/L and T ≤38°C 
in ≤ 7 days, reduce dose by 1 dose level. 
2nd appearance: 
If recovered to ANC ≥1 X 109/L and T ≤38°C, 
reduce dose by an additional 1 dose level. 
1st appearance: 
If recovered to ANC ≥1 X 109/L and T ≤38°C in ≤ 
7 days, reduce dose by 1 dose level 200 mg. 
2nd appearance: 
If recovered to ANC ≥1 X 109/L and T ≤38°C, reduce 
dose by an additional 1 dose level 200 mg. 
To specify the dose level 
reductions of 200 mg. 


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Section(s) 
Previous 
Amendment 3 
Rationale 
Table 9-1: 
Recommended PLX3397 
Dose Modifications – 
1st appearance: 
If not recovered to PLT ≥75 x 109/L after 7 
days, reduce dose by 1 dose level. 
1st appearance: 
If not recovered to PLT ≥75 x 109/L after 7 days, 
reduce dose by 1 dose level 200 mg. 
To specify the dose level 
reductions of 200 mg. 
Grade 4 
Thrombocytopenia 
2nd appearance: 
If recovered to PLT ≥75 x 109/L in ≤7 days, 
reduce dose by 1 dose level. 
2nd appearance: 
If recovered to PLT ≥75 x 109/L in ≤7 days, reduce 
dose by 1 dose level 200 mg. 
If not recovered to PLT ≥75 x 109/L after 7 
days, reduce dose by an additional dose level. 
If not recovered to PLT ≥75 x 109/L after 7 days, 
reduce dose by an additional dose level 200 mg. 
3rd appearance: 
3rd appearance: 
If recovered to PLT ≥75 x 109/L in ≤7 days, 
reduce dose by 1 dose level. 
If recovered to PLT ≥75 x 109/L in ≤7 days, reduce 
dose by 1 dose level 200 mg. 
Table 9-1: 
Recommended PLX3397 
Dose Modifications – 
Non-Hematologic 
Grade 3 (excluding 
transaminase increases) 
1st appearance: 
If symptoms persist for >5 days despite 
supportive management, reduce by 1 dose 
level. 
2nd appearance: 
If recovered <5 days, reduce dose by 1 dose 
level. 
1st appearance: 
If symptoms persist for >5 days despite supportive 
management, reduce by 1 dose level 200 mg. 
2nd appearance: 
If recovered <5 days, reduce dose by 1 dose level 
200 mg. 
To specify the dose level 
reductions of 200 mg. 
Table 9-1: 
Recommended PLX3397 
Dose Modifications – 
1st appearance: 
If recovered <5 days, reduce dose by 1 dose 
level. 
1st appearance: 
If recovered <5 days, reduce dose by 1 dose level 
200 mg. 
To specify the dose level 
reductions of 200 mg. 
Non-Hematologic 
Grade 4 (excluding 
transaminase increases) 
Section 9.7 Concomitant 
Medications (and 
Procedures) 
N/A 
For the purposes of determining the DLT in Cycle 
1, the use of G-CSF or other hematologic growth 
factors is not permitted during Cycle 1. If a 
patient develops a protocol defined hematologic 
DLT and requires the use of G-CSF or other 
hematologic growth factors, they may be used in 
accordance with local standard of care. 
To define G-CSF use on 
study. 


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Section(s) 
Previous 
Amendment 3 
Rationale 
Section 10.1 Study 
Personnel and 
Organizations -
Medical Monitor:  (Emergency Contacts) 
Medical Monitor:  (Emergency Contacts) 
Chief Medical Officer 
Plexxikon Inc. 
Plexxikon Inc. 
91 Bolivar Drive, Berkeley, CA 11710 
91 Bolivar Drive, Berkeley, CA 94710 
Phone: 
Phone: 
To update the Medical 
Monitor contact. 
 
Section 11.1.3 Cycle 1, 
Se1umche1nistry, including sodium, potassium, 
Day 1 
chloride, CO2, calcium, phosphoms, glucose, 
BUN, creatinine, uric acid, total protein, 
albumin, total and direct bilimbin, AST, ALT, 
alkaline phosphatase, LDH, and PT/INR 
Senun chemistry, including sodium, potassium, 
chloride, CO2, calcium, phosphorus, glucose, BUN, 
creatinine, uric acid, total protein, albmnin, total and 
direct bilimbin, AST, ALT, alkaline phosphatase, 
and LDH, ana PT'DT-R 
To make consistent with 
Schedule of Events. 
Section 11.2.10 End-of­ 
The End-of-Study visit is scheduled within the 
Study Visit 
 28-day period after the last dose of study dmg 
or before sta1t ing any new anti-neoplastic 
therapy. 
The End-of-Study visit is scheduled within the 28-day 
period after the last dose of study dmg and el' before 
sta1ting any new anti-neoplastic therapy. 
To make consistent with 
Protocol Synopsis. 


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ATTACHMENT 9: VERSION 5.0 (AMENDMENT 4 SUMMARY OF CHANGES) 
• Inclusion criteria added to define prior cancer history treatment. 
Rationale: To clarify the eligible study population. 
• Inclusion criteria for adequate organ and bone marrow function clarified. 
Rationale: To further define eligible lab values. 
• Exclusion criteria amended for required washout period before starting on study to include 
chemotherapy, antibody or antibody drug conjugate, small molecule TKI, immunotherapy, 
investigational drug, or radiation therapy. 
Rationale: To clarify the eligible study population. 
• Exclusion criteria for resolution of adverse effects from prior treatment amended. 
Rationale: To more clearly define parameters of unresolved adverse effects for study 
eligibility. 
• Exclusion criteria for history of another malignancy amended. 
Rationale: To more clearly define parameters of prior cancer history for study eligibility. 
• Dose-limiting toxicity (DLT) criteria amended to indicate that Grade 3 nausea, vomiting, 
and/or diarrhea that resolves to Grade ≤2 within 7 days will not be considered a DLT. 
Rationale: To clarify the rule regarding the resolution of Grade 3 nausea, vomiting, and/or 
diarrhea for purposes of a DLT determination. 
• Dose-limiting toxicity (DLT) rule added to include that any dose reduction required during 
Cycle 1 due to potential toxicity is a DLT. 
Rationale: To clarify that any dose reduction during the DLT period is considered a DLT. 
• Additional study assessments were added to the Schedule of Events for Pilot and Phase II 
Portions of Study (Table 4-1 and Table 4-2 at Cycle 2 Day 8, Cycle 2 Day 15, and Cycle 2 
Day 22) to obtain hematology, serum hematology, and additional safety assessments. 
Rationale: To increase monitoring of liver function and safety during the first 8 weeks of 
PLX3397 therapy due to updated safety information. 
• Assessments on Cycle 2 Day 8 and Cycle 2 Day 22 may be performed at a local facility. 
Rationale: To ease patient travel burden to the clinical site. 
• Some Cycle 1 Day 1 assessments made optional at the judgment of the investigator if these 
assessments from Screening occurred within 2 days of Cycle 1 Day 1. 
Rationale: To reduce number of required assessments on Cycle 1 Day 1. 
• PET/CT clarified as an imaging modality. 
Rationale: To indicate that PET/CT is an acceptable imaging modality for the study. 
• Gamma glutamyl transferase (GGT) added as part of serum chemistry assessment. 
Rationale: To include GGT as a safety assessment. 


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• Concomitant medication precautions added for patients on proton pump inhibitors and/or 
warfarin. 
Rationale: To include precautions due to potential drug-drug interactions. 
Additional minor changes have been made to improve clarity and consistency. 


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• Sponsor name was changed. 
Rationale: To change the sponsor from Plexxikon to Daiichi Sankyo. 
• Inclusion criteria 2 added to define KIT mutation. 
Rationale: To clarify the eligible study population with KIT mutation. 
• Additional study assessment (whole blood sample collection) was added to the Schedule of 
Events for Phase II Portions. 
Rationale: To assess ctDNA in Phase 2 portion (only in Korea). 
• Potential Risks and Benefits added. 
Rationale: To update potential risks and benefits based on safety data of other clinical 
studies. 
• Additional criteria was added in DLT evaluation. 
Rationale: To clarify the DLT evaluation criteria for non-compliance (less than 80% of the 
planned dose). 
• Recommended PLX3397 Dose Modifications was revised. 
Rationale: To update the Recommended PLX3397 Dose Modifications based on safety data 
of other clinical studies. 
• Medical Monitor (Sponsor) was changed. 
Rationale: To change Medical Monitor based on the sponsor change. 
• Hy’s Law case was added to Event of special interest (Chapter 13) and emergency reporting. 
Rationale: To add the Hy’s Law case for emergency reporting based on safety data of other 
clinical studies. 
• Summary of Known KIT Mutations in Melanoma and Their Sensitivity to PLX3397 and 
Other Approved Drugs (Table) was updated. 
Rationale: To update based on latest information. 
• An Adjudication Committee was added. 
Rationale: To assess hepatic safety and tolerability of the subjects, the judicationCommittee 
meetings will be held as needed. 
• Finance and insurance (15.15) was added. 
Rationale: To clarify the sponsor’s responsibility for finance and insurance. 
• Address list was added in Attachment 5. 
Rationale: To clarify the contact person. 
 
Additional minor changes have been made to improve clarity and consistency. 


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• Inclusion criteria 9, exclusion criteria 14 and 15 were revised. 
Rationale: To mitigate the risk of liver function abnormalities for patients enrolled in the 
study. 
• Foot note was added into Schedule of Events for Pilot Portion of Study (Table 2-1) and 
Schedule of Events for Phase II Portion of Study (Table 2-2). 
Rationale: To reference the frequency of liver function test based on the revision of 
Recommended PLX3397 Dose Modifications for Liver Function Abnormalities (Table 7-2). 
• Recommended PLX3397 Dose Modifications (Table 7-1) was revised and added Table 7-2 
(Recommended PLX3397 Dose Modifications for Liver Function Abnormalities) and Table 
7-3 (Additional Liver Evaluation). 
Rationale: To mitigate the risk to patients of increased aminotransferases with or without 
associated hyperbilirubinemia. 
• The contact information for the Medical Monitor and safety reporting was changed. 
Rationale: To replace the Medical Monitor and safety reporting information. 
• Address list was revised (ATTACHMENT 5) 
Rationale: To update or replace the medical monitor, CRO person, and Vender persons. 


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• Updated study information and design 
Rationale: the Sponsor decided to discontinue this study, and evaluate the study procedures. 
The Sponsor added an extension part in the study to allow subjects to continue receiving 
study drug, monitor for safety, and decrease the amount of procedures.