Clinical trial NCT02452424
Conditions: Melanoma Non-small Cell Lung Cancer Squamous Cell Carcinoma of the Head and Neck Gastrointestinal Stromal Tumor (GIST) Ovarian Cancer
Sponsor: Daiichi Sankyo
Start date: 2015-07-02; Completion date: 2018-10-12
Enrollment: 78 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The goal of this clinical research study is to learn how PLX3397 and pembrolizumab work together to affect cancer cells.

PLX3397 is designed to target the receptor for CSF1 (CSF1R). Pembrolizumab is designed to block the interaction between the receptor PD-1 and molecules that bind PD-1. In this study, PLX3397 and pembrolizumab are being given together in order to study their combined effects on patients' immune responses to their tumors. Tumor-specific immune responses have been shown to kill cancer cells and/or to stop tumors from growing.

Part 1 of the study (dose-escalation phase) will establish the safest dose of PLX3397 to be given in combination with pembrolizumab. Part 2 of the study (expansion phase) will include an evaluation of efficacy of this combination in the following tumor types:

* Advanced melanoma: prior anti-PD-1/PD-L1 therapy but never responded
* Advanced melanoma: prior anti-PD-1/PD-L1 therapy and responded but later progressed as defined by irRECIST while on therapy
* Non-small cell lung cancer
* Ovarian cancer
* Gastrointestinal Stromal Tumor (GIST)
* Squamous cell cancer of the head and neck

Detailed description:

Arms: arm 1: Open-label, sequential PLX3397 dose escalation with a fixed dose of pembrolizumab in approximately 24 patients with advanced solid tumors.

(Enrollment complete- 33 enrolled) arm 2: Extension cohort at the RP2D of PLX3397 in combination with pembrolizumab in approximately 376 patients with advanced solid tumors

(Enrollment Complete- 45 enrolled)
Interventions: intervention 1: PLX3397 intervention 2: Pembrolizumab
Intervention descriptions: intervention 1: PLX3397 capsules, 200 mg intervention 2: Pembrolizumab, 200 mg, IV

Protocol documents:
Prot_SAP_000.pdf: 
Proprietary | Confidential 
 
CLINICAL STUDY PROTOCOL 
 
PHASE 1/2a STUDY OF DOUBLE-IMMUNE 
SUPPRESSION BLOCKADE BY COMBINING A 
CSF1R INHIBITOR (PLX3397) WITH AN ANTI-PD-1 
ANTIBODY (PEMBROLIZUMAB) TO TREAT 
ADVANCED MELANOMA AND OTHER SOLID 
TUMORS 
PROTOCOL NUMBER PLX108-14 
IND NUMBER 105,521 
AMENDMENT 6:  14 DECEMBER 2017 
AMENDMENT 5:  26 MAY 2017 
AMENDMENT 4:  10 FEBRUARY 2017 
AMENDMENT 3:  17 AUGUST 2016 
AMENDMENT 2:  9 MARCH 2016 
AMENDMENT 1:  15 OCTOBER 2015 
VERSION 1.0:  1 MAY 2015 
 
PLEXXIKON INC. 
91 BOLIVAR DRIVE 
BERKELEY, CA 94710, USA 
TELEPHONE:  +1 (510) 647-4000 
 
CONFIDENTIALITY STATEMENT 
Information contained in this document is proprietary to Plexxikon Inc. (Plexxikon). 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 Plexxikon. 




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PROTOCOL SYNOPSIS 
IND Number: 
105,521 
Protocol Number: 
PLX108-14 
Investigational 
Product: 
PLX3397 in combination with pembrolizumab 
Active Ingredient(s)/ 
International Non-
proprietary Name: 
PLX3397:  CSF1R inhibitor 
Pembrolizumab:  Humanized monoclonal antibody (mAb) 
that blocks the programmed cell death (PD-1) receptor 
Study Title: 
Phase 1/2a Study of Double-Immune Suppression Blockade 
by Combining a CSF1R Inhibitor (PLX3397) with an 
Anti-PD-1 Antibody (Pembrolizumab) to Treat Advanced 
Melanoma and Other Solid Tumors 
Study Phase: 
Phase 1/2a 
Indication Under 
Investigation: 
Dose-escalation Phase:  Advanced solid tumors, all comers 
Expansion Phase:  The following tumor types: 
• Melanoma (treatment-naïve) 
• Melanoma (primary progressive) 
• Melanoma (secondary progressive) 
• Non-small-cell lung cancer (NSCLC; non-
squamous; EGFR, ALK wild type) 
• Ovarian cancer 
• Triple-negative breast cancer (TNBC) 
• Squamous cell cancer of the head and neck 
• Clear cell renal cell carcinoma (CCRCC) 
• Pancreatic ductal adenocarcinoma 
• Gastric cancer 
• Glioblastoma multiforme (GBM) 
• Gastrointestinal stromal tumor (GIST) 
• 
High grade soft tissue sarcoma 
• 
Cholangiocarcinoma 


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Study Objectives: 
Primary Objectives 
• To establish the recommended phase 2 dose 
(RP2D) and schedule of PLX3397 for the 
combination of PLX3397 and pembrolizumab. 
• To determine the safety and tolerability of 
combination of the CSF-1R inhibitor PLX3397 and 
the anti-PD-1 antibody pembrolizumab. 
Secondary Objectives 
• To define the adverse event (AE) profile of the 
combination of PLX3397 and pembrolizumab and 
to determine the relationship of AEs to study 
treatment. 
• To evaluate objective response rate (ORR) by 
Response Evaluation Criteria in Solid Tumors, 
version 1.1 (RECISTv1.1) guidelines, relative to 
the assumed historical control rate for 
pembrolizumab, for each of the tumor types in 
subjects treated with the RP2D of PLX3397 for the 
combination of PLX3397 and pembrolizumab 
(Expansion Phase). Subjects with each of the tumor 
types will also by analyzed by RECISTv1.1 for 
progression-free survival (PFS). 
Exploratory Objectives for Dose-escalation and 
Expansion Phases 
• To evaluate biomarkers of drug effects on liver. 
• To evaluate biomarkers of treatment effects, 
including but not limited to myeloid-derived 
suppressor cell (MDSC) function. 
• To evaluate ORR by immune-related RECIST 
(irRECIST) guidelines, relative to the assumed 
historical control rate for pembrolizumab in 
subjects treated with the RP2D for the combination 
of PLX3397 and pembrolizumab (Expansion 
Phase). 
• 
To determine effects of the combination of 
PLX3397 and pembrolizumab on multiple 
biomarkers of disease or treatment, through 
analysis of available paired tumor biopsy samples 
using methods that include but are not limited to 
Nanostring and IHC of intratumoral CD68+ 
macrophages and CD8+ T-cells. Optional baseline 
and 28-day post-treatment biopsies will be 
collected in the Dose-escalation phase and will be 


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mandatory in the Expansion Phase, unless deemed 
medically unsafe by the Investigator. 
Study Design: 
Phase 1/2a, 2-part, open-label clinical study comprised of a 
Dose-escalation Phase followed by an Expansion Phase. 
Dose-escalation Phase:  Up to 42 subjects with advanced 
solid tumors (any type) will be enrolled sequentially in up to 
7 cohorts of 3 to 6 subjects using a standard 3+3 design. 
Subjects will receive pembrolizumab 200 mg IV every 
3 weeks in combination with a starting dose of PLX3397 at 
600 mg/day (administered twice daily as a split dose of 
200 mg in the morning and 400 mg in the evening), with 
sequential escalations to 800 and 1000 mg/day. (If the 
600 mg/day dose of PLX3397 is not well tolerated, 
de-escalation to 400 mg/day will be allowed). The goal of 
this phase is to determine the RP2D of PLX3397 in 
combination with a fixed dose of pembrolizumab, defined as 
the maximum tolerated dose (MTD) or maximum 
administered dose of PLX3397. The MTD is defined as the 
dose level below the one at which more than 1 of 6 subjects 
experience DLT in Cycle 1 during the 42-day DLT window. 
If the MTD cannot be determined because of a lack of a DLT 
during the 42-day DLT window, the MAD of PLX3397 will 
be declared the RP2D. The MAD is defined as the maximum 
dose proposed to be administered during the study, i.e., 
PLX3397 administered orally at 1000 mg/day (as a split 
dose) in combination with pembrolizumab. The RP2D will 
be confirmed with at least 6 subjects. Subjects who complete 
the Dose-escalation Phase may continue in the study and 
receive treatment at the dose assigned to their cohort, 
assuming that dose is considered pharmacodynamically active, 
or these subjects can be titrated up to the RP2D at the 
discretion of the Investigator. The recommended phase 2 dose 
(RP2D) of PLX3397 in combination with pembrolizumab 
200 mg every 3 weeks is 600 mg/day (as a split dose, 200 mg 
in the morning and 400 mg in the evening) based on the 
incidence observed toxicities (i.e., ≥2 patients with DLT at a 
higher dose level) and overall tolerability. 
Expansion Phase:  The design of the expansion phase uses a 
truncated sequential probability ratio test for single-arm binary 
response studies. Subjects with advanced solid tumors of any 
1 of the tumor types will receive pembrolizumab 200 mg IV 
every 3 weeks in combination with the RP2D of PLX3397. 
Dosing will continue until a subject experiences disease 
progression as determined by irRECIST, unacceptable 


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toxicity, or meets any other discontinuation criterion such as 
meeting criteria for a complete response 
Dose Decrements:  Throughout the study, dose decrements 
of 200 mg/day of PLX3397 are permitted for management of 
toxicity. 
Study Duration: 
~12 months to complete the Dose-escalation Phase and up 
to 2 years to enroll subjects in and subsequently complete the 
Expansion Phase. 
Study Sites and 
Location: 
The Dose-escalation Phase will be conducted at up to 5 study 
sites in the US. Additional sites may be added for the 
Expansion Phase. 
Planned Sample Size: 
• Dose-escalation Phase:  Up to 42 subjects in up to 
7 cohorts, each a different dose or regimen. The 
number of subjects is not based on statistical power 
considerations. Three to 6 subjects will be accrued per 
dose level or regimen in order to insure the safety and 
tolerability. 
• 
Expansion Phase:  Up to 483 subjects, with the 
sample size for each of the tumor types based on a 
truncated sequential probability ratio test. The 
maximum sample size will be 28 to 48 subjects per 
tumor type, depending on the null response within 
each tumor type. 
Subject Eligibility — 
Inclusion Criteria: 
A subject must satisfy all of the following criteria to be 
considered for inclusion in the study: 
1. Be willing and able to provide written informed 
consent for the trial. 
2. Male or female ≥18 years old. 
3. Subjects with histologically or cytologically-confirmed 
diagnosis of cancer that is recurrent, metastatic, or 
persistent, who have relapsed from or are refractory to 
treatment, and who also meet the following 
corresponding requirements for the cohort or phase of 
the study they into which they will enroll: 
• Dose-escalation Phase:  Subjects with advanced 
solid tumors (any tumor type) considered to have 
no standard-of-care treatment for their 
malignancy with a curative intent, either as initial 
therapy or after progressing to prior therapies; 
subjects who have been treated previously with a 
CSF1R inhibitor or an anti-PD1/PDL1 inhibitor 


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may enroll. 
• Expansion Phase:  Subjects with 1 of the tumor 
types who have relapsed from or are refractory to 
standard treatment. Subjects with:   
i. NSCLC (non-squamous; EGFR and ALK wild-
type) and SCCHN cancer must show primary 
progression (i.e., no partial or complete 
response [PR or CR]) with anti-PD1/anti-PDL1 
therapy 
ii. Melanoma subgroups are as follows:  (a) anti-
PD-1 /PD-L1 naïve and CSF1R naïve; (b) at 
least 4 months of prior anti-PD-1 PD-L1 
therapy but never responded (i.e., no PR or 
CR); (c) prior anti-PD-1 /PD-L1 therapy and 
responded but later progressed as defined by 
irRECIST while on therapy 
iii. Ovarian includes primary peritoneal and 
fallopian tube cancers; (carcinosarcomas and 
low grade serous tumors are excluded) 
iv. Unresectable RCC with component of clear-cell 
histology and/or component of sarcomatoid 
histology 
v. World Health Organization Grade IV 
supratentorial malignant glioma (glioblastoma 
or gliosarcoma) following complete or partial 
surgical resection and radiation plus 
temozolomide 
vi. Gastrointestinal stromal tumor (GIST) cohort 
must have locally advanced or metastatic 
disease and have progressed on or have been 
intolerant to imatinib therapy 
vii. All tumor types must be naïve to 
anti-PD1/PDL1 inhibitors except as described 
in (i) and (ii). 
4. Subjects with melanoma must have a histologically 
confirmed diagnosis of stage III or stage IV disease 
not amenable to local therapy. Melanoma subjects 
may have received any number of prior lines of 
therapy for metastatic disease and must have 
measurable disease per RECISTv1.1. Cutaneous 
lesions and other superficial lesions that are 
detectable only by physical examination are not 


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considered measurable lesions for the purposes of this 
protocol, but may be considered as non-target lesions. 
Tumor lesions situated in a previously irradiated area 
are considered measurable if progression has been 
demonstrated in such lesions. Subjects with 
melanoma who have received prior treatment with a 
MEK/BRAF inhibitor are acceptable candidates. 
5. Expansion cohorts:  Subjects must have relapsed or 
been refractory to standard treatment and have 
measurable disease per RECISTv1.1, using computed 
tomography (CT) or magnetic resonance imaging 
(MRI), with [18F]-fluorodeoxyglucose (FDG) positron 
emission tomography-computer tomography 
(PET/CT) for GIST subjects only. They must have 
tumor accessible for sequential biopsy (core needle 
biopsy or excision required) and be willing to provide 
on-study tumor tissue biopsy. When possible, newly 
obtained tissue should be collected from a non-target 
lesion. Repeat samples may be required if adequate 
tissue is not provided. Subjects for whom newly 
obtained samples cannot be obtained (e.g., 
inaccessible or patient safety concern; glioblastoma 
tumor type) may submit an archived specimen only 
upon agreement from the Sponsor. 
6. Eastern Cooperative Oncology Group (ECOG) 
performance status 0 or 1. 
7. Women of childbearing potential must have a 
negative serum pregnancy test within 72 hours prior 
to initiation of dosing. 
8. Women of childbearing potential should be willing to 
use 2 methods of birth control or be surgically sterile, 
or abstain from heterosexual activity for the course of 
the study through 120 days after the last dose of study 
medication. Effective forms of contraception include 
abstinence, hormonal contraceptive in conjunction 
with a barrier method, or a double-barrier method. 
Women of non-child bearing potential may be 
included if they are either surgically sterile or have 
been postmenopausal for ≥1 year. 
9. Fertile men must agree to use an effective method of 
birth control starting with the first dose of study 
treatment through 120 days after the last dose of study 
treatment. 


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10. Adequate organ function as demonstrated by the 
laboratory values shown below. These laboratory tests 
should be performed within 10 days of the first dose 
of study treatment.  
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count 
(ANC) 
≥1.5 × 109/L 
Platelets  
≥100 × 109/L 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L  
Renal 
 
Creatinine OR 
Measured or calculateda 
creatinine clearance (crcl) 
(GFR can also be used in 
place of creatinine or crcl) 
≤1.5 × ULN OR 
≥60 mL/min for subject with 
creatinine levels >1.5 × institutional ULN 
Hepatic 
 
Total bilirubin 
≤1.25 × ULN (Gilbert’s syndrome allowed) 
AST and ALT  
≤1.5 × ULN  
Coagulation 
 
International normalized 
ratio or prothrombin time 
(PT) 
≤1.5 × ULN unless subject is receiving 
anticoagulant therapy as long as PT or PTT is 
within therapeutic range of intended use of 
anticoagulants 
Activated partial 
thromboplastin time 
(aPTT) 
≤1.5 × ULN unless subject is receiving 
anticoagulant therapy as long as PT or PTT is 
within therapeutic range of intended use of 
anticoagulants. 
aPTT = activated partial thromboplastin time; ALT = alanine 
aminotransferase; ANC = absolute neutrophil count; AST = aspartate 
aminotransferase; INR = International Normalized Ratio; 
PT = Prothrombin time; ULN = upper limit of normal 
a  Creatinine clearance should be calculated per institutional standard. 
Subject Eligibility — 
Exclusion Criteria: 
A subject who meets any of the following criteria will be 
disqualified from entering the study: 
1. Disease that is suitable for local therapy administered 
with curative intent. 
2. Diagnosis of immunodeficiency or is receiving 
systemic steroid therapy or any other form of 
immunosuppressive therapy within 7 days prior to the 
first dose of study treatment. The use of physiologic 
doses of corticosteroids may be approved after 
consultation with the Sponsor. 
3. Is currently participating and receiving study therapy 
or has participated in a study of an investigational 
agent and received study therapy or used an 


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investigational device within 28 days prior to the first 
dose of study treatment. 
4. Has had monoclonal antibody treatment for cancer 
within 28 days of first dose of study treatment or has 
not recovered from AEs due to agents administered 
more than 28 days earlier (i.e., AEs should be 
≤Grade 1 or ≤the value collected at baseline). 
5. Has had chemotherapy, targeted small molecule 
therapy, or radiation therapy >30 Gray within 14 days 
prior to first dose of study treatment or who has not 
recovered (i.e., AEs should be ≤Grade 1 or ≤the value 
collected at baseline) from AEs due to a previously 
administered intervention 
Note:  Subjects with ≤Grade 2 neuropathy or 
≤Grade 2 alopecia are an exception to this criterion 
and may qualify for the study. 
6. Has received transfusion of blood products (including 
platelets or red blood cells [RBC]) or administration 
of colony stimulating factors (including granulocyte 
colony-stimulating factor, granulocyte-macrophage 
colony-stimulating factor, or recombinant 
erythropoietin) within 28 days prior Day 1. 
7. Has a history of (non-infectious) pneumonitis that 
required steroids or current pneumonitis. 
8. Has a known additional malignancy that is 
progressing or requires active treatment. Exceptions 
include basal cell carcinoma of the skin, squamous 
cell carcinoma of the skin that has undergone 
potentially curative therapy, in situ cervical cancer 
and isolated elevation of prostate-specific antigen. 
Subjects with a completely treated prior malignancy 
with no evidence of disease for ≥2 years are eligible. 
9. Dose-escalation Cohort [-1]:  Patients with liver 
metastases; inclusion of patients with liver metastases 
in subsequent cohorts will be based upon clinical 
safety data. 
10. For Expansion cohort subjects who have previously 
received an anti-PD-1, anti-PD-L1, or anti-PD-L2 
agent or has previously participated in 
pembrolizumab clinical trials are excluded, except 
those tumor types listed under Inclusion Criteria #3. 
11. Has active autoimmune disease that has required 


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systemic treatment in past 2 years (i.e., with use of 
disease modifying agents, corticosteroids or 
immunosuppressive drugs). Replacement therapy 
(e.g., thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary 
insufficiency) is not considered a form of systemic 
treatment. 
12. Has an active infection requiring systemic therapy. 
13. Has known central nervous system metastases and/or 
carcinomatous meningitis. Note:  Subjects with 
previously treated brain metastases may participate if 
they meet the following criteria:  1) are stable (i.e., no 
evidence of progression per irRECIST [see the 
irRECIST Tip Sheet, provided in the Study Reference 
Manual] determined by imaging, using the identical 
imaging modality for each assessment, either MRI or 
CT scan) for at least 35 days prior to the first dose of 
study treatment and if all neurologic symptoms 
returned to baseline, 2) have no evidence of new or 
enlarging brain metastases, and 3) have not been 
using steroids for at least 7 days prior to first dose of 
study treatment. This exception does not include 
carcinomatous meningitis, which is excluded 
regardless of clinical stability. 
14. Uncontrolled intercurrent illness. 
15. Refractory nausea and vomiting, malabsorption, 
external biliary shunt, or significant small bowel 
resection that would preclude adequate absorption. 
16. QT interval corrected using Fridericia’s formula 
(QTc) ≥450 msec (males) or ≥470 msec (females) at 
Screening. 
17. Congenital long QT syndrome or patients taking 
concomitant medications known to prolong the QT 
interval. A list of drugs known to prolong the QT 
interval can be found in Appendix 17.1. 
18. Major surgery within 28 days prior to first dose of 
study treatment. 
Note:  If subject received major surgery, he or she 
must have recovered adequately from the toxicity 
and/or complications from the intervention prior to 
starting study treatment. 
19. History of active ethanol abuse. 


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20. Has received a live vaccine administered within 
30 days of planned treatment start or while 
participating in the trial. Seasonal flu vaccines that do 
not contain live virus are permitted. 
21. Has a history or current evidence of any condition, 
therapy, or laboratory abnormality that might 
confound the results of the trial, interfere with the 
subject's participation for the full duration of the trial, 
or is not in the best interest of the subject to 
participate, in the opinion of the treating Investigator. 
22. Has a known history of Human Immunodeficiency 
Virus (HIV) (HIV 1/2 antibodies), has known active 
Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., 
HCV RNA [qualitative] is detected). 
23. Any of the following within 48 weeks (~1 year) prior 
to first dose of study treatment:  myocardial infarction, 
uncontrolled angina, coronary/peripheral artery bypass 
graft, symptomatic congestive heart failure, 
cerebrovascular accident or transient ischemic attack. 
24. Imprisoned or under legal guardianship. 
25. Is pregnant or breastfeeding, or expecting to conceive 
or father children within the projected duration of the 
trial, starting with the screening visit through 
120 days after the last dose of trial treatment. 
26. Has known psychiatric or substance abuse disorders 
that would interfere with cooperation with the 
requirements of the trial. 
27. Has had prior exposure to PLX3397. 
28. Has had hypersensitivity (≥Grade 3) reaction to 
pembrolizumab and/or any of its excipients. 
Dosage Form, Dose 
and Route of 
Administration: 
Dose-escalation Phase:  Subjects receive pembrolizumab 
200 mg IV every 3 weeks in combination with a starting dose 
of PLX3397 at 600 mg/day, with sequential escalations to 
800 and 1000 mg/day. (If the 600 mg/day dose of PLX3397 
is not well tolerated, de-escalation to 400 mg/day will be 
allowed.) If 400 mg/day is tolerated (i.e., no DLTs in 
3 subjects or ≤1 DLT in 6 subjects), then re-escalation to 600 
mg/day may be considered within the hepatic laboratory test 
limits in inclusion #10. Further dose escalation will be 
considered depending upon safety and tolerability of each 
cohort. PLX3397 is administered orally twice daily as a split 


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dose. 
An intermediate dose level may be studied and may comprise 
alternative dosing regimens such as intermittent dosing (e.g., 
1 week off and 2 weeks on for PLX3397 doses during the 
3-week pembrolizumab dosing interval) and/or the same 
dose level with a run in period of PLX3397 for two weeks 
prior to starting pembrolizumab. 
Subjects who complete the Dose-escalation Phase may 
continue in the study at the dose determined for their cohort, 
assuming that dose is considered pharmacodynamically 
active. Also, these subjects can be titrated up to the RP2D, at 
the discretion of the Investigator. 
Expansion Phase:  Subjects with any 1 of the tumor types 
will receive pembrolizumab 200 mg IV every 3 weeks in 
combination with oral PLX3397 administered as a split dose 
at the RP2D of PLX3397. 
Study Endpoints: 
Primary Endpoint 
• To establish the recommended RP2D and schedule of 
the combination of pembrolizumab and PLX3397, i.e., 
the MTD or MAD, for future trials. The MTD is defined 
as the dose level below the one at which more than 1 of 
6 subjects experience DLT in Cycle 1 (1 cycle = 
42 days). The planned MAD is defined as PLX3397 
administered orally at 1000 mg/day as a split dose. 
Secondary Endpoints 
• To evaluate the safety and tolerability of the 
combination of pembrolizumab and PLX3397, based on 
the incidence of AEs, as graded by National Cancer 
Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE). 
• To evaluate ORR by RECISTv1.1 guidelines, relative to 
the assumed historical control rate for pembrolizumab, 
for each of the tumor types in subjects treated with the 
RP2D of PLX3397 for the combination of PLX3397 and 
pembrolizumab (Expansion Phase). Subjects with each 
of the tumor types will also be analyzed by RECISTv1.1 
for PFS. 
Exploratory Endpoints 
• To evaluate ORR by irRECIST guidelines, relative to 
the assumed historical control rate for pembrolizumab, 
for each of the tumor types in subjects treated with the 


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RP2D of PLX3397 for the combination of PLX3397 and 
pembrolizumab (Expansion Phase). Subjects with each 
of the tumor types will also be analyzed by irRECIST 
for PFS. 
• To evaluate ORR and PFS by RECISTv1.1 guidelines 
descriptively by cohort for subjects in the Dose-
escalation Phase. 
• To determine effects of the combination of PLX3397 
and pembrolizumab on multiple biomarkers of disease 
or treatment, through analysis of available paired tumor 
biopsy samples using methods that include but are not 
limited to Nanostring and IHC of intratumoral CD68+ 
macrophages and CD8+ T-cells. Optional baseline and 
28-day post-treatment biopsies will be collected in the 
Dose-escalation phase and will be mandatory in the 
Expansion Phase, unless deemed medically unsafe by 
the Investigator. 
Statistical Analyses: 
The Dose-escalation Phase of the study will employ a 
standard 3+3 design in order to determine the R2PD for 
PLX3397 when administered with pembrolizumab 200 mg 
IV every 3 weeks. The DLT-window is 1 cycle (42 days). Up 
to seven dose levels or regimens of PLX3397 will be 
investigated. Subjects will be treated in cohorts of 3 to 6, and 
the dose level will be escalated if the clinical toxicity is 
acceptable. 
The safety and tolerability of the combination of 
pembrolizumab and PLX3397 will be assessed by the 
incidence of AEs as graded by the NCI CTCAE. 
For the Expansion Phase, efficacy will be evaluated 
separately within each cohort based on tumor type. A 
truncated sequential probability ratio test for single-arm 
binary response studies will be employed in each of these 
cohorts (DOD RAC 2005). This sequential monitoring 
procedure establishes continuous boundary conditions to stop 
enrollment for either efficacy or futility at any time up to the 
total prescribed sample size. 
Disease response will be evaluated using RECISTv1.1 
criteria on the Efficacy Analysis Set. Overall response rate 
(ORR), defined as the proportion of subjects who achieve a 
best disease response of either CR or PR, will be evaluated. 
Patients who discontinue study therapy due to clinical 
progression, radiographic progression or death without the 
required tumor assessments will be considered to be non-
responders in the ORR calculation. The efficacy analysis will 


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include all subjects with baseline tumor measurements who 
received at least on dose of study treatment. The point 
estimate, confidence interval, and adjusted p-values for 
testing whether the observed ORR is statistically greater than 
the specified null rate will be provided for each cohort. Exact 
methods for binary, sequential data will be employed for the 
analysis. A one-sided alpha of 0.05 and 80% power will be 
used for all tumor types for calculating stopping boundary 
conditions.  
 


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TABLE OF CONTENTS 
PROTOCOL NUMBER PLX108-14................................................................................1 
INVESTIGATOR AGREEMENT ...................................................................................2 
PROTOCOL SYNOPSIS ..................................................................................................3 
TABLE OF CONTENTS ................................................................................................16 
LIST OF IN-TEXT TABLES .........................................................................................22 
LIST OF IN-TEXT FIGURES .......................................................................................22 
LIST OF ABBREVIATIONS .........................................................................................23 
1. 
INTRODUCTION AND BACKGROUND INFORMATION ..........................26 
1.1. 
Investigational Product .......................................................................................26 
1.1.1. PLX3397 .....................................................................................................26 
1.1.2. Intended Use Under Investigation ...............................................................26 
1.2. 
Nonclinical Studies .............................................................................................26 
1.2.1. Nonclinical Studies with PLX3397 .............................................................26 
1.2.2. Nonclinical Studies with PLX3397 and PD-1 Antibody .............................27 
1.3. 
Clinical Experience .............................................................................................27 
1.3.1. PLX3397 Clinical Pharmacokinetics ..........................................................27 
1.3.2. PLX3397 Clinical Safety .............................................................................28 
1.3.3. Pembrolizumab in Clinical Trials ................................................................29 
1.4. 
Study Rationale ...................................................................................................29 
1.5. 
Benefits and Risks for Study Subjects ................................................................30 
2. 
STUDY OBJECTIVES AND HYPOTHESIS ....................................................30 
2.1. 
Study Objectives .................................................................................................30 
2.1.1. Primary Objectives ......................................................................................30 
2.1.2. Secondary Objectives ..................................................................................31 
2.1.3. Exploratory Objectives for Dose-escalation and Expansion Phases ...........31 
2.2. 
Study Hypothesis ................................................................................................31 
3. 
STUDY DESIGN ...................................................................................................32 
3.1. 
Overview of the Study Plan ................................................................................32 
3.1.1. Design and Treatments ................................................................................32 
3.1.1.1. 
Dose-escalation Phase .....................................................................33 
3.1.1.2. 
Expansion Phase .............................................................................34 


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3.1.1.3. 
Dose Decrements ............................................................................35 
3.1.2. Study Sites ...................................................................................................35 
3.1.3. Study Population .........................................................................................35 
3.1.4. Study Endpoints ..........................................................................................36 
3.1.4.1. 
Primary Endpoint ............................................................................36 
3.1.4.2. 
Secondary Endpoints .......................................................................36 
3.1.4.3. 
Exploratory Endpoints ....................................................................36 
3.1.5. Duration of the Study ..................................................................................36 
3.1.6. Duration of Subject Participation ................................................................37 
3.1.7. Modifications and Rules During the Dose-escalation Phase (i.e., 
the 42-day DLT Observation Period) ..........................................................37 
3.1.7.1. 
Dose-Limiting Toxicities ................................................................37 
3.1.7.2. 
Rules for Dose Escalation ...............................................................38 
3.1.7.3. 
Maximum Tolerated Dose...............................................................39 
3.1.8. Dosing Interruptions During Both Phases of the Study ..............................39 
3.1.9. Guidelines for Management of Potential Toxicities Associated with 
PLX3397 and Pembrolizumab ....................................................................39 
3.1.9.1. 
Potential PLX3397 Toxicities and Guidelines for 
Management ....................................................................................39 
3.1.9.2. 
Potential Pembrolizumab Toxicities and 
Dose Modifications (Escalation/Titration/Other) ...........................44 
3.1.10. Radiologic Disease Progression:  Assessment and Treatment 
During Dose-escalation and Expansion Phases ...........................................49 
3.1.10.1. 
Assessment of Radiologic Disease Progression ..............................49 
3.1.10.2. 
Procedure and Treatment After Initial Evidence of 
Radiologic Disease Progression ......................................................50 
3.2. 
Selection of Doses...............................................................................................51 
3.2.1. PLX3397 .....................................................................................................51 
3.2.2. Rationale for Pembrolizumab Dose Selection .............................................52 
3.2.3. Missed or Vomited Doses ...........................................................................53 
4. 
STUDY POPULATION ........................................................................................53 
4.1. 
Enrollment...........................................................................................................53 
4.1.1. Inclusion Criteria .........................................................................................54 
4.1.2. Exclusion Criteria ........................................................................................56 


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4.2. 
Removal of Subjects From Therapy ...................................................................59 
4.2.1. Reasons for Withdrawal/Early Discontinuation ..........................................59 
4.2.2. Withdrawal Procedures ...............................................................................59 
4.2.3. Subject Replacement ...................................................................................59 
4.2.4. Subject Rescreening Procedures .................................................................60 
4.2.5. Discontinuation of Study Treatment after Complete Response ..................60 
5. 
TREATMENTS ADMINISTERED ....................................................................60 
5.1. 
Investigational Products ......................................................................................60 
5.1.1. Pembrolizumab ............................................................................................60 
5.1.2. PLX3397 .....................................................................................................60 
5.2. 
Method of Assigning Subjects to Treatments .....................................................61 
5.3. 
Method of Assessing Treatment Compliance .....................................................61 
5.4. 
Labeling and Packaging ......................................................................................61 
5.4.1. Preparation and Administration ...................................................................62 
5.4.1.1. 
Pembrolizumab ...............................................................................62 
5.4.1.2. 
PLX3397 .........................................................................................62 
5.4.2. Storage and Stability ...................................................................................63 
5.4.3. Investigator and Site Responsibility for Drug Accountability ....................63 
5.4.4. Product Complaints .....................................................................................63 
5.5. 
Concomitant Medications and Therapies ............................................................63 
5.5.1. Concomitant Medications and Therapies Related to PLX3397 ..................64 
5.5.2. Concomitant Medications/Vaccinations Related to Pembrolizumab 
(Allowed & Prohibited) ...............................................................................64 
5.5.2.1. 
Acceptable Concomitant Medications with Pembrolizumab ..........64 
5.5.2.2. 
Prohibited Concomitant Medications with Pembrolizumab ...........64 
6. 
STUDY PROCEDURES FOR THE DOSE-ESCALATION AND 
EXPANSION PHASES .........................................................................................65 
6.1. 
Screening (Day -28 to Day -1) ............................................................................66 
6.2. 
Randomization ....................................................................................................66 
6.3. 
Run-in Period ......................................................................................................66 
6.4. 
Treatment Period .................................................................................................66 
6.4.1. Cycle 1 (-2 days for assessments on Day 1; ± 3 days for 
assessments other than Day 1) .....................................................................66 


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6.4.2. Cycle 2 (± 3 days) .......................................................................................67 
6.4.3. Cycle 3 (± 3 days) .......................................................................................68 
6.4.4. Cycle 4 and Beyond (± 3 days) ...................................................................69 
6.5. 
End of Treatment (+3 days) ................................................................................69 
6.6. 
Follow-up ............................................................................................................70 
6.6.1. Safety Follow-up (28 days ± 7 days) ...........................................................70 
6.6.2. SAE Follow-Up (± 7 days) ..........................................................................71 
6.7. 
Follow-up ............................................................................................................71 
6.7.1. Safety Follow-up (28 days ± 7 days) ...........................................................71 
7. 
PROTOCOL DEVIATIONS ................................................................................71 
8. 
EFFICACY ASSESSMENTS ...............................................................................71 
8.1. 
Primary Efficacy Variable:  Dose-escalation Phase ...........................................71 
8.2. 
Secondary Efficacy Variable:  Expansion Phase ................................................72 
9. 
PHARMACOKINETIC/PHARMACODYNAMIC ASSESSMENTS .............73 
9.1. 
Pharmacokinetic Variables .................................................................................73 
9.2. 
Pharmacodynamic Variables ..............................................................................73 
9.3. 
Biomarker and Exploratory Variables ................................................................73 
9.4. 
Timing of Assessments .......................................................................................74 
9.4.1. Routine Assessments ...................................................................................74 
9.4.2. Additional Pharmacokinetic Assessments ...................................................77 
10. 
SAFETY ASSESSMENTS....................................................................................77 
10.1. General Procedures for Assessing and Recording Adverse Events ....................77 
10.1.1. Definitions ...................................................................................................78 
10.1.1.1. 
Adverse Event .................................................................................78 
10.1.1.2. 
Progression of Cancer .....................................................................78 
10.1.1.3. 
Serious Adverse Event ....................................................................78 
10.1.2. Adverse Event Severity ...............................................................................79 
10.1.3. Causality Assessment ..................................................................................79 
10.1.4. Action Taken Regarding the Study Product ................................................80 
10.1.5. Adverse Event Outcome ..............................................................................80 
10.1.6. Other Action Taken for Event .....................................................................81 
10.2. Serious Adverse Event Reporting–Procedure For Investigators ........................81 


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10.2.1. Notifying Regulatory Authorities, Investigators, IRB/EC, and 
Competent Authorities ................................................................................82 
10.3. Contraception ......................................................................................................82 
10.4. Pregnancy and Lactation and Reporting Requirements to Plexxikon ................82 
10.5. Use in Nursing Women .......................................................................................83 
10.6. Events of Clinical Interest (ECI).........................................................................83 
10.7. Clinical Laboratory Evaluations .........................................................................83 
10.8. Vital Signs ...........................................................................................................84 
10.9. Electrocardiograms .............................................................................................84 
10.10. Physical Findings and ECOG Performance Status .............................................84 
10.11. Overdose and Reporting of Overdose to Plexxikon ...........................................84 
11. 
STATISTICAL METHODS .................................................................................85 
11.1. Analysis Sets .......................................................................................................85 
11.2. General Statistical Considerations ......................................................................85 
11.2.1. Dose-escalation Phase .................................................................................85 
11.2.2. Expansion Phase ..........................................................................................85 
11.2.3. Efficacy Analyses ........................................................................................87 
11.2.4. Power and Sample Size ...............................................................................88 
11.2.5. Subjects Who Continue From the Dose-escalation Phase ...........................88 
11.2.6. Study Population Data .................................................................................89 
11.3. Analyses ..............................................................................................................89 
11.3.1. Analysis of Primary Endpoint .....................................................................89 
11.3.2. Analyses of Secondary Endpoints ...............................................................89 
11.3.3. Analysis of Exploratory Endpoints .............................................................90 
11.3.3.1. 
Safety and Tolerability ....................................................................90 
11.3.3.2. 
Evaluation of the Objective Response Rate in the 
Expansion Phase .............................................................................90 
11.3.4. Exploratory Pharmacology Studies of Drug Activity .................................91 
11.3.5. Clinical Laboratory Evaluation Analyses ....................................................91 
11.3.6. Vital Sign Analyses .....................................................................................91 
11.3.7. Electrocardiogram Analyses ........................................................................91 
11.3.8. Physical Finding Analyses ..........................................................................91 
11.4. Interim Analyses .................................................................................................92 


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11.5. Data Monitoring Committee (DMC) ..................................................................92 
11.5.1. Dose-escalation Phase .................................................................................92 
11.5.2. Expansion Phase ..........................................................................................92 
12. 
DATA INTEGRITY AND QUALITY ASSURANCE .......................................93 
12.1. Monitoring and Inspections ................................................................................93 
12.2. Data Collection ...................................................................................................94 
12.3. Data Management ...............................................................................................94 
12.4. Study Documentation and Storage......................................................................94 
12.5. Record Keeping ..................................................................................................95 
13. 
COMPLIANCE STATEMENT, ETHICS AND REGULATORY 
COMPLIANCE .....................................................................................................95 
13.1. Subject Confidentiality .......................................................................................95 
13.2. Informed Consent Procedure ..............................................................................96 
13.3. Regulatory Compliance ......................................................................................96 
14. 
PUBLICATION POLICY ....................................................................................97 
15. 
STUDY ADMINISTRATIVE INFORMATION ................................................97 
15.1. Protocol Amendments .........................................................................................97 
16. 
REFERENCES ......................................................................................................98 
17. 
APPENDICES .......................................................................................................99 
17.1. Drugs Clearly Associated with the Risk of Torsades de Pointes and QT 
Prolongation ......................................................................................................100 
17.2. CYP3A4 Inhibitors and Inducers ......................................................................101 
17.3. Eastern Cooperative Oncology Group Performance Status ..............................102 
17.4. Response Evaluation Criteria for Solid Tumors, version 1.1 ...........................103 
17.5. Clinical Laboratory Evaluations .......................................................................114 
17.6. Schedule of Events for Protocol PLX108-14:  Dose-escalation and 
Expansion Phases ..............................................................................................116 
17.7. Schedule of Events for Protocol PLX108-14:  Dose-escalation and 
Expansion Phase:  Cohort Intermittent PLX3397 Administration ...................119 
17.8. Schedule of Events for Protocol PLX108-14:  Run-in with PLX3397 
Before Combination with Pembrolizumab (C1D1) ..........................................122 
 


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LIST OF IN-TEXT TABLES 
Table 1. 
Treatments During the Dose-escalation Phase of Study 
PLX108-14 .................................................................................................34 
Table 2. 
Tumor Types Investigated in the Expansion Phase of PLX108-14 ...........35 
Table 3. 
PLX3397-related Toxicities and Guidelines for Management, 
Excluding Hepatic Toxicities .....................................................................40 
Table 4. 
Dose Modification Guidelines for Liver Function Abnormalities .............42 
Table 5. 
Additional Liver Evaluation ......................................................................43 
Table 6. 
Dose Modification Guidelines for Adverse Events Related to 
Pembrolizumab ..........................................................................................45 
Table 7. 
Treatment Guidelines for Infusion Reactions Associated with 
Pembrolizumab ..........................................................................................48 
Table 8. 
Imaging and Treatment After First Radiologic Evidence of 
Disease Progression ...................................................................................51 
Table 9. 
Pembrolizumab Product Description .........................................................61 
Table 10. 
Pharmacokinetic and Pharmacodynamic Assessments in 
Study PLX108-14:  Dose-escalation and Expansion Phases .....................75 
Table 11. 
Sequential Monitoring Approach During Expansion Phase:  
Study PLX108-14 ......................................................................................86 
Table 12. 
Probabilities of Dose Escalation Based on True DLT Risk in the 
3+3 Design:  Statistical Basis for Dose Escalation ....................................89 
Table 13. 
Time Point Response:  Patients with Target (+/- Non-target) 
Disease .....................................................................................................111 
Table 14. 
Time Point Response:  Patients with Non-target Disease Only ...............111 
Table 15. 
Best Overall Response When Confirmation of CR and PR is 
Required ...................................................................................................112 
 
LIST OF IN-TEXT FIGURES 
Figure 1: 
Graphic Representation of Intermittent Dosing with Optional 
PLX3397 Run-in ........................................................................................32 
Figure 2: 
Stopping Conditions for Null Response Rate of 20% versus Target 
Rate of 40%:  Expansion Phase .................................................................87 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE  
Adverse event 
ALK 
Anaplastic Lymphoma Kinase 
ALT  
Alanine aminotransferase 
AP 
Alkaline phosphatase  
aPTT 
Activated partial thromboplastin time 
AST  
Aspartate aminotransferase 
AUC  
Area under the plasma concentration–time curve 
AUC0-6 
Area under the plasma concentration–time curve from time zero to 
6 hours 
β-hCG 
beta human chorionic gonadotropin 
BID  
Twice daily 
BRAF 
V-Raf murine sarcoma viral oncogene homolog B 
CCRCC 
Clear cell renal carcinoma 
CI 
Confidence interval 
crcl 
Creatinine clearance 
Cmax  
Peak plasma concentration 
CR 
Complete response 
CRF 
Case report form 
CRO 
Contract research organization 
CSF1 
Colony stimulating factor 1 
CSF1R 
Receptor for colony stimulating factor 1 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P450 
CYP3A4 
Cytochrome P450 3A4 
DLT 
Dose-limiting toxicity 
EAS 
Efficacy Analysis Set 
ECG 
Electrocardiogram 
ECI 
Events of clinical interest 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EGFR 
Epidermal Growth Factor Receptor 
FDA 
US Food and Drug Administration 
FDG-PET 
FDG-PET= [18F]-fluorodeoxyglucose (FDG) positron emission 
tomography-computer tomography (PET/CT) 
FMS 
(See CSF1R) 


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Abbreviation 
Definition 
GBM 
Glioblastoma multiforme 
GGT 
Gamma-Glutamyl Transferase 
GIST 
Gastrointestinal stromal tumor 
GCP 
Good Clinical Practice(s)  
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent ethics committee 
IHC 
Immunohistochemistry 
INR 
International normalized ratio 
[int] 
Intermittent 
ITD 
Internal tandem duplications 
IRB 
Institutional review board 
irRECIST 
Immune-related RECIST 
MAD 
Maximum administered dose 
MDSC 
Myeloid-derived suppressor cells 
MRI 
Magnetic resonance imaging 
msec  
Millisecond 
MTD 
Maximal tolerated dose 
NA 
Not applicable 
NCI 
National Cancer Institute 
NE 
Not evaluated 
NSCLC 
Non-small cell lung cancer 
ORR 
Objective response rate 
PD  
Progressive disease 
PDA 
Pancreatic ductal adenocarcinoma 
PEG tube 
Percutaneous endoscopic gastrostomy tube 
PFS 
Progression-free survival 
PK 
Pharmacokinetic(s)  
PO 
Oral 
PR 
Partial response 
PT 
Prothrombin time 
QD 
Once daily 
QPCR 
Quantitative polymerase chain reaction 
QTc  
QT interval corrected for heart rate 
QTcF  
QT interval corrected using Fridericia’s formula 


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Abbreviation 
Definition 
RBC 
Red blood cell 
RP2D 
Recommended phase 2 dose 
RECISTv1.1 
Response Evaluation Criteria in Solid Tumors, version 1.1 
RT 
Radiation therapy  
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SCCHN 
Squamous cell carcinoma of the head and neck 
SCF 
Stem cell factor 
SD  
Stable disease 
Tmax 
Time to peak plasma concentration 
TNBC 
Triple Negative Breast Cancer 
ULN 
Upper limit of normal 
WBC 
White blood cell 
 
 


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1. 
INTRODUCTION AND BACKGROUND INFORMATION 
1.1. 
Investigational Product 
1.1.1. 
PLX3397 
PLX3397 is a novel, orally active, small molecule inhibitor intended for oral 
administration that targets 3 kinases:  1) FMS (also referred to as CSF1R, the receptor for 
colony stimulating factor 1 [CSF1, also known as macrophage-colony stimulating factor] 
as well as the ligand interleukin 34 [IL-34]); 2) Kit, the receptor for stem cell factor 
(SCF); and 3) oncogenic Flt3, the receptor for Flt3 ligand. However, it otherwise remains 
highly selective in terms of impact on the activity of other receptors and kinases. The 
potent inhibition of these 3 kinases can be exploited to attack tumors through a variety of 
mechanisms:  1) direct inhibition of inhibiting oncogenic drivers such as oncogenic Kit 
and Flt3 mutant proteins; 2) inhibition of paracrine loops between stromal cells and 
tumors; 3) blockade of migration and angiogenesis, 4) blockage of CSF1-dependent 
myeloid-derived suppressor cells; and 5) disruption of osteolytic metastases. 
An important role for tumor-infiltrating macrophages in tumor progression has pointed to 
FMS as a key target in multiple tumor types (Coffelt 2009). The pro-tumorigenic role of 
CSF1 and FMS is supported by a wealth of studies demonstrating that CSF1 levels 
predict a poor outcome in a variety of oncology indications, including breast, ovarian, 
non-small cell lung, and colorectal cancers. Further strengthening the fundamental 
tumorigenic role of FMS is a key study showing that mice defective in CSF1 are 
protected against tumor metastases (Lin 2001). For details, please refer to the 
PLX3397 Investigator’s Brochure. 
1.1.2. 
Intended Use Under Investigation 
PLX3397, a CSR-1R inhibitor, in combination with pembrolizumab, an anti-PD-1 
antibody, is under investigation for the treatment of subjects with advanced melanoma 
and other solid tumors. 
1.2. 
Nonclinical Studies 
1.2.1. 
Nonclinical Studies with PLX3397 
The effects of PLX3397 on multiple aspects of tumorigenesis have been characterized in 
cellular and in vivo assays. The proliferation of cell lines that depend on CSF1, SCF, or 
endogenous Flt3-ITD (internal tandem duplications) is inhibited by 50% (IC50) at drug 
concentrations of less than 1 µM. Furthermore, CSF 1 induced autophosphorylation of 
FMS and SCF-induced autophosphorylation of Kit are potently inhibited by PLX3397. 
Finally, the RANK-L- and CSF 1 dependent differentiation of osteoclast precursors is 
also potently inhibited by PLX3397. These in vitro results translate to PLX3397 effects in 
a variety of in vivo models for FMS-dependent proliferation, FMS-dependent osteoclast 
differentiation, Flt3-ITD dependent tumor growth, and Kit-dependent mast cell 
proliferation. 


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While pharmacologic effects due to the inhibition of FMS, Kit and oncogenic Flt3 are 
expected, the relative selectivity of PLX3397 against other kinases suggests that off-
target effects against other kinases should be limited. 
Additional detailed information regarding the nonclinical pharmacology and toxicology 
of PLX3397 can be found in the PLX3397 Investigator’s Brochure. 
1.2.2. 
Nonclinical Studies with PLX3397 and PD-1 Antibody 
Mobilizing the body’s immune system to fight cancer is a promising approach to induce 
durable responses. In particular, cytotoxic T-cells play a central role in immune-mediated 
control of cancer. By recognizing tumor specific antigens, T-cells are able to specifically 
detect and eliminate cancer cells. Thus, immune escape, the multiple mechanisms a 
tumor uses to escape from immune-mediated rejection, is one of the hallmarks of cancer. 
In recent clinical trials, agents that block the inhibitory receptors (e.g., PD-1 and CTLA4) 
on T-cells have demonstrated survival benefit in a subset of cancer patients, despite 
advanced disease. The immunosuppressive nature of the tumor microenvironment is a 
factor that limits wider clinical benefit of immune checkpoint blockade. Harnessing the 
full potential of cancer immunotherapy requires coordinated strategies to mitigate 
immunosuppression. The main drivers of immune escape include tumor-associated 
macrophages (TAM) and myeloid-derived suppressor cells. These cells not only mediate 
immune suppression but also promote metastasis and induce resistance to chemotherapy 
and radiation. However, inhibition of FMS, the pivotal myeloid growth factor receptor, 
can functionally reprogram the tumor microenvironment to eliminate tumor infiltrating 
macrophages and promote productive antitumor T-cell responses. 
This potential synergy between CSF1R inhibitor (PLX3397) and immune checkpoint 
inhibitors has been evaluated in a mouse model of pancreatic ductal adenocarcinoma 
(PDAC) (Zhu 2014). PD-1 and CTLA4 antagonists have shown limited efficacy as single 
agents to suppress PDAC growth. However, combining these agents with PLX3397 and 
other FMS blockades has potently elicited tumor regression. As expected, CSF1R 
inhibition decreases myeloid responses in the stromal compartment and alters the 
function of TAMs and dendritic cells to support T-cell-mediated antitumor immunity. 
1.3. 
Clinical Experience 
1.3.1. 
PLX3397 Clinical Pharmacokinetics 
Exposure to PLX3397 has been evaluated in 8 clinical studies. PLX3397 was 
administered as single agent in 5 studies and in combination with paclitaxel, 
temozolomide, or vemurafenib in 3 studies. The PK of PLX3397 at dose levels between 
200 mg/day and 1200 mg/day was evaluated in the dose-escalation and extension study, 
PLX108-01, using once daily (QD) or twice daily (BID) dosing in the fasting state. The 
time to peak plasma concentration (Tmax) is approximately 2 hours, and the mean 
accumulation ratio compared to Day 1 values is approximately 2-fold. In general, there is 
dose-proportional exposure. In the PLX108-05 acute myeloid leukemia dose-escalation 
study at dose levels between 800 mg/day and 5000 mg/day, saturation of exposure was 
observed at 3000 mg/day. 


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The steady state exposure of 900 mg/day (QD) cohort in PLX108-03 Hodgkin’s 
lymphoma study and of 1000 mg/day (BID) cohorts in all the other single agent studies 
(PLX108-04 glioblastoma, PLX108-05 AML, PLX108-06 prostate cancer) were similar 
to the exposure of the respective dose groups in PLX108-01 Solid tumors study. 
The mean PLX3397 plasma concentrations for the 800 mg/day (BID) cohorts at 2, 4, and 
6 hours in the combination studies with paclitaxel (PLX108-07), temozolomide 
(PLX108-08), and vemurafanib (PLX108-09) were comparable to those seen in PLX3397 
single agent studies. 
Subjects administered a single dose of 600 mg of PLX3397 with a high-fat, high-calorie 
meal displayed an approximately 2-fold increase in peak plasma concentration (Cmax) and 
area under the plasma concentration–time curve (AUC) compared with subjects 
administered PLX3397 in the fasted state (PLX108-11). When PLX3397 was 
administered in the presence of esomeprazole, overall exposure was reduced 
approximately 30%. 
1.3.2. 
PLX3397 Clinical Safety 
As of 30 June 2014, data are available on 345 subjects who have been enrolled in the 
PLX3397 clinical program across 8 clinical studies:  PLX108-01, PLX108-03, 
PLX108-04, PLX108-05, PLX108-06, PLX108-07, PLX108-08, and PLX108-09. Of the 
345 subjects, 181 subjects with solid tumors received PLX3397 as a single agent (which 
included advanced, incurable, solid tumors; relapsed or refractory Hodgkin’s lymphoma; 
recurrent glioblastoma multiforme; or progressive castration resistant prostate cancer 
with high circulating tumor cell counts). Ninety subjects received PLX3397 as a single 
agent for relapsed or refractory AML. Seventy-four subjects received PLX3397 in 
combination with other therapies. Most of these studies are ongoing. 
The most frequently reported treatment-emergent adverse events (>20% of subjects) 
among all treated subjects included fatigue, nausea, decreased appetite, diarrhea, anemia, 
vomiting, and increases in aspartate aminotransferase (AST). Hair color changes 
(depigmentation) and constipation also commonly occurred in solid tumor subjects 
receiving single agent PLX3397. With the exception of febrile neutropenia (which 
occurred at a high rate in the AML study), less than 10% of these common adverse events 
(AEs) were considered as Grade 3 or higher. 
Treatment-related serious adverse events (SAEs) reported more than once included 
neutropenia (including febrile neutropenia), anemia, pneumonia, increased AST or ALT, 
increased international normalized ratio (INR), dehydration, hyponatremia, and maculo-
papular rash. 
During the Dose-escalation Phase of this study, preliminary analyses show the following:  
one cohort was studied at 600 mg total daily dose of PLX3397 in combination with 
pembrolizumab. Two liver-related DLTs were observed, both in subjects with liver 
metastases. One subject entered the study with Grade 2 AST that worsened to Grade 3 at 
C1D8; the subject stopped PLX3397 and terminated the study due to rapid disease 
progression. The second subject entered the study with normal transaminases, 
experienced Grade 3 elevation at C2D8 that resolved; after a short rechallenge with 


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PLX3397, the subject had disease progression and terminated the study. Amendment 1 
was instituted that excluded liver metastases and excluded Grade 2 transaminase 
elevations at screening. The next cohort was enrolled at 400 mg total daily dose of 
PLX3397 in combination with pembrolizumab and 3 subjects completed the 42-day DLT 
window without any DLTs. Re-escalation to 600 mg total daily dose of PLX3397 in 
combination with pembrolizumab in 11 evaluable subjects with and without liver 
metastasis and with normal transaminases at study entry resulted in no DLTs. Cohorts of 
800 mg total daily dose of PLX3397, either continuous or intermittent, in combination 
with pembrolizumab in subjects without liver metastasis showed 4 liver-related DLTs out 
of 9 evaluable subjects. Thus the recommended phase 2 dose (RP2D) of PLX3397 in 
combination with pembrolizumab was determined to be 600 mg/day (as a split dose, 
200 mg in the morning and 400 mg in the evening) based on the incidence of observed 
toxicities (i.e., ≥2 patients with DLT at the 800 mg total daily dose level) and overall 
tolerability. 
1.3.3. 
Pembrolizumab in Clinical Trials 
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody 
(mAb) with high specificity of binding to the programmed cell death 1 (PD-1) receptor, 
thus inhibiting its interaction with programmed cell death ligand 1 (PD-L1) and 
programmed cell death ligand 2 (PD-L2). Based on preclinical in vitro data, 
pembrolizumab has high affinity and potent receptor blocking activity for PD-1. 
Pembrolizumab has an acceptable preclinical safety profile and is in clinical development 
as an intravenous (IV) immunotherapy for advanced malignancies. Keytruda™ 
(pembrolizumab) is indicated for the treatment of patients across a number of indications. 
For more details on specific indications refer to the Investigator Brochure. 
1.4. 
Study Rationale 
Many patients who do not respond to conventional anticancer therapies lack intratumoral 
and invasive margin infiltration by T-cells, most likely due to a tumor microenvironment 
that inhibits the activity of antitumor T-cells. Prominent in this tumor microenvironment 
are immune suppressive macrophages that serve as an “invisibility cloak,” precluding 
activation of antitumor T-cells. 
In an animal model, specific depletion of immune suppressive macrophages with 
PLX3397, a small molecule inhibitor of the CSF1R inhibitor, resulted in increased 
intratumoral accumulation and function of antigen-specific CD8+ T-cells (Mok 2014). 
Additionally, analysis of over 100 melanoma biopsies of patients receiving 
pembrolizumab, an anti-PD-1 antibody, allowed understanding of the critical role of 
intratumoral CD8+ T-cells in mediating the antitumor responses achieved with this 
therapy (Tumeh 2014). 
Based on these data, Plexxikon proposes to conduct a Phase 1/2a trial combining the 
CSF1R inhibitor PLX3397 with the anti-PD-1 antibody pembrolizumab. The rationale is 
that combined administration of these agents will inhibit the immunosuppressive 
macrophages that mask cancer cells and activate T-cell responses to them. 


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In subjects with melanoma and other solid tumors who have relapsed from or are 
refractory to treatment, it is hoped that this process will result in tumor regression, 
improved survival, and measurably improved quality of life. The primary objective of the 
study is determination of safety; analyses of clinical activity will focus on the anticipated 
effects of depletion of intratumoral immune suppressive macrophages, which is believed 
will result in improved number and functionality of intratumoral CD8+ T-cells. 
1.5. 
Benefits and Risks for Study Subjects 
PLX3397 in combination with pembrolizumab may provide an alternative therapy for 
subjects with metastatic melanoma/solid tumors. 
Risks of treatment with PLX3397 include bone marrow suppression and elevations of 
liver transaminases and bilirubin. 
In uncontrolled clinical studies of single-agent PLX3397 and in combination with other 
anticancer agents, bone marrow suppression with leukopenia (neutropenia and/or 
lymphopenia), anemia and thrombocytopenia, either alone or with pancytopenia, has 
been observed. Therefore, subjects will be monitored closely for clinically significant 
reduction of neutrophils, serum hemoglobin, or platelet counts, and should this condition 
arise, standard of care supportive measures will be initiated, including broad spectrum 
antibiotics, as appropriate. 
In addition, elevations of liver transaminases and bilirubin have also been observed in 
studies with PLX3397. Protocol-defined dose reductions and discontinuations of 
PLX3397, increased frequency of laboratory monitoring, and reporting of findings will 
be performed, as appropriate. Rechallenge with PLX3397 will not be attempted without 
prior discussion with the Plexxikon Medical Monitor. 
For additional descriptions of risks and benefits, see the Plexxikon PLX3397 
Investigator’s Brochure, Section 6, Summary of Data and Guidance for the Investigator. 
Risks of treatment with pembrolizumab include immune-mediated conditions, 
specifically, pneumonitis, colitis, hypophysitis, and nephritis, hyperthyroidism, 
hypothyroidism; renal failure; other immune-mediated adverse reactions; and 
embryofetal toxicity. See the Keytruda Package Insert and the Pembrolizumab 
Investigator’s Brochure. 
Despite the potential benefits of combination treatment of PLX3397 and pembrolizumab 
described above, the combination could further heighten the risks of immune-mediated 
disease. 
2. 
STUDY OBJECTIVES AND HYPOTHESIS 
2.1. 
Study Objectives 
2.1.1. 
Primary Objectives 
• To establish the recommended phase 2 dose (RP2D) and schedule of 
PLX3397 for the combination of PLX3397 and pembrolizumab. 


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• To determine the safety and tolerability of the combination the CSR-1R 
inhibitor PLX3397 and the anti-PD-1 antibody pembrolizumab. 
2.1.2. 
Secondary Objectives 
• To define the AE profile of the combination of PLX3397 and pembrolizumab 
and to determine the relationship of AEs to study treatment. 
• To evaluate the objective response rate (ORR) by Response Evaluation 
Criteria in Solid Tumors, version 1.1 (RECISTv1.1) guidelines 
(Appendix 17.4), relative to the assumed historical control rate for 
pembrolizumab, for each of the tumor types in subjects treated with the RP2D 
of PLX3397 for the combination of PLX3397 and pembrolizumab (Expansion 
Phase). Subjects with each of the tumor types will also be analyzed by 
RECISTv1.1 for progression-free survival (PFS) 
2.1.3. 
Exploratory Objectives for Dose-escalation and Expansion Phases 
• To evaluate biomarkers of drug effects on liver. 
• To evaluate biomarkers of treatment effects, including but not limited to 
myeloid-derived suppressor cell function. 
• To evaluate ORR by immune-related RECIST (irRECIST), relative to the 
assumed historical control rate for pembrolizumab in subjects treated with the 
RP2D for the combination of PLX3397 and pembrolizumab (Expansion 
Phase). 
• To determine effects of the combination of PLX3397 and pembrolizumab on 
multiple biomarkers of disease or treatment, through analysis of available 
paired tumor biopsy samples using methods that include but are not limited to 
Nanostring and IHC of intratumoral CD68+ macrophages and CD8+ T-cells. 
Mandatory baseline (up to -2 days) and 28-day (± 3 days) post-treatment 
biopsies will be collected in the Expansion Phase, unless deemed medically 
unsafe by the Investigator. Biopsies will be optional in the Dose-escalation 
Phase. 
2.2. 
Study Hypothesis 
The null hypothesis (applicable to the secondary objective, determination of ORR) is that 
the combination treatment of PLX3397 and pembrolizumab in subjects with advanced 
melanoma and other solid tumors who have relapsed from or are refractory to treatment, 
results in no difference in tumor regression than historical data observed with single-
agent pembrolizumab. 




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The second part comprises an Expansion Phase, which uses a truncated sequential 
probability ratio test for single-arm binary response studies. Subjects with any 1 of 
the tumor types (Table 2) will receive pembrolizumab 200 mg IV every 3 weeks in 
combination with oral PLX3397 administered twice daily as a split dose at the RP2D of 
PLX3397. Dosing will continue until a subject experiences disease progression as 
determined by irRECIST, unacceptable toxicity, or meets any other discontinuation 
criterion. 
Throughout the study, dose decrements of 200 mg/day of PLX3397 are permitted for 
management of toxicity (Table 3). 
3.1.1.1. 
Dose-escalation Phase 
During the Dose-escalation Phase, up to 42 subjects with advanced solid tumors (any type) 
will be enrolled sequentially in up to 7 cohorts of 3 to 6 subjects using a standard 3+3 
design. Each cohort represents a different dose or regimen. Subjects will receive 
pembrolizumab 200 mg IV in combination with oral PLX3397, in combination with a 
starting dose of PLX3397 at 600 mg/day, with sequential escalations to 800 and 
1000 mg/day. (If the 600 mg/day dose of PLX3397 is not well tolerated, de-escalation to 
400 mg/day will be allowed.) If 400 mg/day is tolerated (i.e., no DLTs in 3 subjects or 
≤1 DLT in 6 subjects), then re-escalation to 600 mg/day may be considered within the 
hepatic laboratory test limits in inclusion #10. Further dose escalation will be considered 
depending upon safety and tolerability of each cohort. PLX3397 is administered twice daily 
as a split dose. (See Section 3.2.1, which provides the rationale for PLX3397 dosing). 
If a DLT is observed during the 42-day DLT window in 1 subject in a given cohort, at 
least 6 subjects will be treated at that dose. If DLT is observed in 2 or more of 6 subjects 
at a dose level, then this dose level will have exceeded the 33% DLT rate, and the next 
lower dose level will be tested to have a total of at least 6 subjects with ≤1 DLT and be 
defined as the MTD. Dose escalation will only be permitted if adequate safety and 
tolerability have been demonstrated at the previous lower dose for 42 days. If PLX3397 
1000 mg/day, orally administered twice daily as a split dose, in combination with 
pembrolizumab 200 mg IV, every 3 weeks, is not the MTD, no further dose escalation 
will be conducted, and this dose level will be the defined MAD after observation of at 
least 6 subjects during the DLT window. After completion of the Dose-escalation Phase, 
all safety and tolerability data will be reviewed and the RP2D (i.e., MTD/MAD) will be 
determined. 
Subjects who complete the Dose-escalation Phase may continue in the study and receive 
treatment at the dose determined for their cohort, assuming that dose is considered 
pharmacodynamically active. Also, these subjects can be titrated up to the RP2D, at the 
discretion of the Investigator. 


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Table 1. 
Treatments During the Dose-escalation Phase of Study PLX108-14 
Dose Cohorta 
Number of Subjects 
Starting Dose of 
PLX3397b 
Pembrolizumab 
[int]  
(if needed)d 
3 (+ 3) 
400, 600 or 800 
mg/day orally 
200 mg IV every 3 weeks 
[-1] (if needed) 
3 (+ 3) 
400 mg/day orallyc 
200 mg IV every 3 weeks  
1 
3 (+ 3) 
600 mg/day orally 
200 mg IV every 3 weeks 
2 
3 (+ 3) 
800 mg/day orally 
200 mg IV every 3 weeks 
3 
3 (+ 3) 
1000/day orally 
200 mg IV every 3 weeks 
IV = intravenous 
a 
Cohort numbering is an example and may vary depending on the dose levels and regimens that are 
studied. 
b 
Throughout the study, dose decrements of 200 mg/day of PLX3397 are permitted for management 
of toxicity. 
c 
If the dose of 600 mg/day is not well tolerated, a dose cohort starting at 400 mg/day may be employed. 
d 
Intermittent regimen:  PLX3397will begin 7 days after pembrolizumab administration and continue 
for 14 days until the next pembrolizumab dose throughout the course of the study. A run-in of up to 
2 weeks with PLX3397 is optional. PLX3397 dose will be determined by the Cohort 1–3 dose if 
DLT are observed (see Section 3.1.7.2 and Figure 1).  
 
3.1.1.2. 
Expansion Phase 
During the Expansion Phase, additional subjects with advanced solid tumors of any 1 of 
the tumor types summarized in Table 2 will be enrolled into the study and receive the 
RP2D of PLX3397 (administered twice daily as a split dose) in combination with 
pembrolizumab 200 mg IV every 3 weeks. Dosing will continue until a subject experiences 
disease progression as determined by irRECIST, unacceptable toxicity, or meets any other 
discontinuation criterion such as meeting criteria for complete response (CR). Enrollment 
into each tumor type may occur simultaneously or in a staggered fashion. 


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Table 2. 
Tumor Types Investigated in the Expansion Phase of PLX108-14 
Tumor Types 
Maximum Total Sample Sizeb 
Advanced melanoma:  anti-PD-1/PD-L1 naïve and CSF1R naïve 
23 
Advanced melanoma:  prior anti-PD-1/PD-L1 therapy but never 
responded 
33 
Advanced melanoma:  prior anti-PD-1/PD-L1 therapy and responded 
but later progressed as defined by irRECIST while on therapy 
33 
NSCLC (non-squamous; EGFR and ALK wild-type showing primary 
progression with anti-PD1/anti-PDL1 therapy) 
33 
Ovarian 
33 
TNBC 
38 
SCCHN Showing primary progression with anti-PD1/anti-PDL1 
therapy 
33 
Clear cell renal cell carcinoma (CCRCC) 
48 
PDA 
33 
Gastric 
39 
Glioblastoma multiforme (GBM) 
33 
GIST 
33 
High grade soft tissues sarcomaa 
38 
Cholangiocarcinoma 
33 
Total  
483 
irRECIST = immune-related Response Evaluation Criteria in Solid Tumors (see irRECIST Tip Sheet 
provided in the Study Reference Manual); NSCLC = non-small cell lung cancer;  
PDA = pancreatic ductal adenocarcinoma; SCCHN = squamous cell carcinoma of the head and neck; 
GIST=gastrointestinal stromal tumor; TNBC = triple-negative breast cancer; 
a 
High grade soft tissue sarcoma includes undifferentiated pleomorphic sarcoma and liposarcoma. 
b 
Subjects must be naïve to anti-PD1/PDL1 inhibitors unless otherwise noted. 
 
3.1.1.3. 
Dose Decrements 
Throughout the study, dose decrements of 200 mg/day of PLX3397 are permitted for 
management of toxicity (see Table 1 and Table 3). 
3.1.2. 
Study Sites 
The Dose-escalation Phase will be conducted at up to 5 study sites in the US. Additional 
sites may be added for the Expansion Phase. 
3.1.3. 
Study Population 
Adult subjects (≥18 years of age) with histologically confirmed Stage III or Stage IV 
metastatic melanoma or solid tumors are eligible. Subjects enrolled in the Dose-
escalation Phase could have any type of solid tumor and could have previously received 
an anti-PD-1 or anti-PD-L1 antibody or could be naïve to both these therapies. 
Subjects enrolled in the Expansion Phase should have one of the tumor types and 
pretreatment requirements specified in Table 2. 


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3.1.4. 
Study Endpoints 
3.1.4.1. 
Primary Endpoint 
• To establish the recommended RP2D and schedule of the combination of 
pembrolizumab and PLX3397, i.e., the MTD or MAD, for future trials. The 
MTD is defined as the dose level below the one at which more than 1 of 
6 subjects experience DLT in Cycle 1 (1 cycle = 42 days). The planned MAD 
is defined as PLX3397 administered orally at 1000 mg/day as a split dose 
(Table 1). 
3.1.4.2. 
Secondary Endpoints 
• To evaluate the safety and tolerability of the combination of pembrolizumab 
and PLX3397, based on the incidence of AEs, as graded by the National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events, 
(CTCAE). 
• To evaluate ORR by RECISTv1.1 guidelines (Appendix 17.4), relative to the 
assumed historical control rate for pembrolizumab, for each of the tumor types 
in subjects treated with the RP2D of PLX3397 for the combination of 
PLX3397 and pembrolizumab (Expansion Phase). Subjects with each of the 
tumor types will also be analyzed by RECISTv1.1 for PFS. 
3.1.4.3. 
Exploratory Endpoints 
• To evaluate ORR by irRECIST guidelines (see the irRECIST Tip Sheet, 
provided in the Study Reference Manual), relative to the assumed historical 
control rate for pembrolizumab, for each of the tumor types in subjects treated 
with the RP2D for the combination of PLX3397 and pembrolizumab. Subjects 
with each of the tumor types will also be analyzed by irRECIST for PFS. 
• To evaluate ORR and PFS by RECISTv1.1 guidelines (Appendix 17.4) 
descriptively by cohort for subjects in the Dose-escalation Phase. 
• To determine effects of the combination of PLX3397 and pembrolizumab on 
multiple biomarkers of disease or treatment, through analysis of available 
paired tumor biopsy samples using methods that include but are not limited to 
Nanostring and IHC of intratumoral CD68+ macrophages and CD8+ T-cells. 
Paired biopsies are optional in Dose-escalation and mandatory in the 
Expansion Phase, unless deemed medically unsafe by the Investigator. 
3.1.5. 
Duration of the Study 
It is estimated that it will take approximately 12 months to complete the Dose-escalation 
Phase and up to 2 years to enroll subjects in and subsequently complete the Expansion 
Phase.  


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3.1.6. 
Duration of Subject Participation 
Subjects who complete a maximum number of 16 cycles (approximately 24 months; 
1 cycle = 42 days) on study treatment and demonstrate clinical benefit with manageable 
toxicity will stop both Study Drugs. 
3.1.7. 
Modifications and Rules During the Dose-escalation Phase (i.e., the 42-day 
DLT Observation Period) 
DLTs are defined in Section 3.1.7.1. Dose-escalation rules, based on the principles 
underlying the standard 3+3 design, are provided in Section 3.1.7.2. The definition of the 
MTD is provided in Section 3.1.7.3. 
3.1.7.1. 
Dose-Limiting Toxicities 
A DLT is defined as any AE that is temporally related to Study Drug administration and 
is not due to the subject’s underlying malignancy and for which there is no clear evidence 
for an alternative etiology, and that meets one of the following NCI CTCAE criteria 
during the first 42 days of Study Drug administration (the “DLT observation period”): 
• Hematologic Toxicities 
− Grade 4 anemia 
− Grade 3 or 4 neutropenia lasting ≥7 days 
− Grade ≥3 neutropenia with fever 
− Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia with clinically 
significant bleeding 
• Other Toxicities 
− Any other Grade ≥3 toxicity despite adequate supportive care except for 
the following: 
o Grade 3 nausea, vomiting, or diarrhea that resolves to Grade ≤1 within 
7 days, with or without appropriate supportive therapy 
o Grade ≥3 rash that resolves to Grade ≤2 within 7 days 
o Grade 3 fatigue that resolves to ≤Grade 2 within 14 days 
o Grade ≥3 laboratory abnormalities that, in the judgment of the 
Investigator are not clinically significant 
− As judged by Investigator and Medical Monitor, a high rate of missed 
doses if related to an AE. Study Drug interruption longer than 14 days (or 
permanent discontinuation) for a persistent drug-related AE will be 
considered a DLT, irrespective of severity. 
Use of hematopoietic growth factors during the DLT period requires approval by the 
Medical Monitor. 


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3.1.7.2. 
Rules for Dose Escalation 
The study is designed to reduce the chance of escalating the dose when the probability of 
DLT is high and to increase the chance of escalating the dose when the probability of 
DLT is low. The rules for dose escalation, based on the standard 3+3 design, are provided 
below: 
• If none (0) of the initial 3 subjects in a cohort experiences a DLT, then a new 
cohort of 3 subjects will be treated at the next higher dose level. 
• If 1 of 3 subjects in a cohort experiences a DLT, then up to 3 additional 
subjects will be treated at the same dose. Escalation will continue if no more 
than 1 of 6 subjects experiences a DLT. 
• If 2 or more subjects in a cohort experience a DLT, then the MTD will have 
been exceeded, and no further dose escalation will occur. The previous dose 
level will be considered the MTD or an intermediate dose level may be 
introduced. 
• If only 3 subjects were treated at a dose level under consideration as the MTD, 
then up to 3 additional subjects will be accrued. If no more than 1 of 
6 subjects treated at the dose level under consideration as the MTD 
experiences a DLT, then that dose level will be confirmed as the MTD. If 2 or 
more subjects in that cohort experience a DLT, then the previous or an 
intermediate dose level will be studied in the same fashion. 
• If PLX3397 1000 mg (given orally twice daily as a split dose) and 
pembrolizumab 200 mg given IV every 3 weeks is not the MTD, no further 
dose escalation will be conducted and this dose level will be defined as the 
MAD and hence the RP2D after observation of at least 6 subjects during the 
DLT window. 
An intermediate dose level may comprise alternative dosing regimens such as 
intermittent dosing (e.g., 1 week off and 2 weeks on for PLX3397 doses during the 
3-week pembrolizumab dosing interval; see Appendix 17.7) and optionally with the same 
dose level with a run in period of PLX3397 for 2 weeks prior to starting pembrolizumab 
(see Appendix 17.8). See Figure 1 for graphical representation of alternate dosing 
regimens. Another alternative regimen may be 5 days on and 2 days off. For all regimens, 
the cumulative 3-week PLX3397 exposure may not exceed the dose level where 2 or 
more subjects experienced a DLT. For example, if 800 mg/day continuous dosing of 
PLX3397 results in 2 or more subjects experiencing a DLT, then an intermediate dose 
level of 1 week off and 2 weeks on 800 mg/day PLX3397 may be studied. The 
intermediate dose level or regimen will be determined by the Sponsor and Investigators 
based on the totality of available safety, pharmacodynamics and pharmacokinetic data. 
If the Sponsor and Investigators determine that, in the absence of DLTs, enrollment of 
additional subjects is required to better determine PK or safety, enrollment of an 
additional 3 or more subjects may be undertaken at one or more of the dose levels already 
studied, including intermediate doses. 


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3.1.7.3. 
Maximum Tolerated Dose 
The MTD is defined as the dose level below the one at which more than 1 of 6 subjects 
experience DLT in Cycle 1. 
3.1.8. 
Dosing Interruptions During Both Phases of the Study 
Dosing interruptions are permitted in the case of medical/surgical events or logistical 
reasons not related to study therapy (e.g., elective surgery, unrelated medical events, 
subject vacation, and/or holidays). Subjects should be placed back on study therapy 
within 3 weeks of the scheduled interruption, unless otherwise discussed with the 
Sponsor. The reason for interruption should be documented in the subject's study record. 
3.1.9. 
Guidelines for Management of Potential Toxicities Associated with 
PLX3397 and Pembrolizumab 
Guidelines for management of potential PLX3397-associated toxicities are summarized 
in Section 3.1.9.1 and for pembrolizumab-associated toxicities in Section 3.1.9.2. All 
guidelines presented below apply to both phases of the study (Dose-escalation and 
Expansion). However, if during the Dose-escalation Phase any toxicity qualifies as a 
DLT (see Section 3.1.7.1); the guidelines for determining the MTD should be followed 
(see Section 3.1.7.3). 
In those instances in which a possible drug-related toxicity requires dose modification, 
and it is unclear which agent is more likely be responsible, both compounds should be 
interrupted and the dose modification guideline for each should be followed. 
3.1.9.1. 
Potential PLX3397 Toxicities and Guidelines for Management 
Reductions or interruptions of the dose for toxicity may take place at any time during the 
study according to the guidelines in Table 3 and Table 4. Dose reduction/interruption 
guidelines for hematologic and nonhematologic treatment-related TEAEs are based on 
severity. Dose interruptions can be implemented at the discretion of the treating 
Investigator to manage intolerable or clinically significant toxicity. If a dose interruption 
is required, study assessments should be performed as scheduled, irrespective of the study 
drug delay, with the exception of PK assessments, which should be deferred until 
treatment is resumed. Interruptions due to toxicity lasting >3 weeks require treatment 
discontinuation unless the medical monitor approves continuation. 
Table 3 provides guidelines for the management of PLX3397-related toxicities. Dose 
reductions for management of toxicity should occur in decrements indicated in Table 3, 
depending on the toxicity grade shown in the table. These parameters are only a guide 
and are not intended to supersede the clinical judgment of the treating physician. Table 4 
provides guidelines for the management of PLX3397-related liver toxicities. 
All adjustments should be made in consultation with the Medical Monitor. 


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Table 3. 
PLX3397-related Toxicities and Guidelines for Management, Excluding 
Hepatic Toxicities 
Toxicity Grade (CTCAE) or 
Toxicity Description 
PLX3397 Dose Changes During 
Current Treatment Perioda 
Dose Adjustments for 
Resumption of Treatmenta 
Hematologic Toxicities 
Grade 3 or Grade 4 neutropenia 
1st Appearance 
Interrupt until ANC recovers to 
≥1 × 109/L. 
If recovered to ANC ≥1 × 109/L in 
≤7 days, resume at same dose.  
If ANC does not recover to 
≥1 × 109/L after 7 days, reduce 
dose by 200 mg. 
2nd Appearance 
Interrupt until ANC recovers to 
≥1 × 109/L. 
If recovered to ANC ≥1 × 109/L in 
≤7 days, reduce dose by 200 mg.  
If ANC does not recover to 
≥1 × 109/L after 7 days, reduce 
dose by an additional 200 mg. 
3rd Appearance 
Interrupt until ANC recovers to 
≥1 × 109/L. 
If recovered to ANC ≥1 × 109/L in 
≤7 days, reduce dose by 200 mg.  
If ANC does not recover to 
≥1 ×109/L after 7 days, discontinue 
permanently. 
4th Appearance 
Discontinue Permanently 
NA 
Grade 3 or Grade 4 febrile neutropenia 
1st Appearance 
Interrupt until ANC and fever 
recover. 
Once resolved to ANC ≥1 ×109/L 
and  
T ≤38°C, reduce dose by 200 mg 
per day. 
2nd Appearance 
Interrupt until ANC and fever 
recover. 
Once resolved to ANC ≥1 × 109/L 
and  
T ≤38°C, reduce dose by an 
additional 200 mg.  
3rd Appearance 
Discontinue permanently. 
NA 
Grade 4 thrombocytopenia 
1st Appearance 
Interrupt until PLT ≥75 ×109/L 
Reintroduce at same dose 
2nd Appearance 
Interrupt until PLT ≥75 ×109/L 
If PLT does not recover to 
≥75 ×109/L after 7 days, reduce 
dose by 200 mg. 
3rd Appearance 
Interrupt until PLT ≥75 ×109/L 
Reduce dose by an additional 
200 mg. 
4th Appearance 
Discontinue permanently. 
NA 
Other Related Toxicities (≥Grade 3), with the exceptions of liver-enzyme abnormalities (for which, 
see Tables 4 and 5  below).  
Other Related Grade 3 (start symptomatic treatment when possible) 
1st Appearance 
Interrupt until resolved  
(Grade 0–1). 
If recover <5 days, resume at same 
dose. Reduce by 200 mg if 
symptoms persist for ≥5 days 
despite supportive management. 
2nd Appearance 
Interrupt until resolved  
(Grade 0–1). 
Reduce by an additional 200 mg. 


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Toxicity Grade (CTCAE) or 
Toxicity Description 
PLX3397 Dose Changes During 
Current Treatment Perioda 
Dose Adjustments for 
Resumption of Treatmenta 
3rd Appearance 
Discontinue permanently. 
NA 
Other Related Grade 4 (start symptomatic treatment when possible) 
1st Appearance 
Interrupt until resolved 
(Grade 0–1). 
Reduce by 200 mg. 
2nd Appearance 
Discontinue permanently. 
NA 
Related Grade 3 Rash (start symptomatic treatment when possible) 
1st Appearance 
Interrupt until resolved 
(Grade 0–1). 
As agreed upon by the 
investigator and medical monitor:  
Rechallenge at 200 mg/day; if 
safely tolerated after 1 cycle 
(6 weeks), dose can be re-
escalated by 200mg increments to 
the RP2D as agreed upon by the 
investigator and medical monitor 
2nd Appearance 
Discontinue permanently. 
NA 
Prolonged QTcF 
QTcF >500 msec on at least 2 
separate ECGs (i.e., Grade 3). 
Hold PLX3397 until recovery to 
QTcF ≤500 msec. 
Upon recovery to QTcF ≤500 msec 
(Grade ≤2), restart at a reduced 
dose (minimum reduction 
decrement of 200 mg). Monitor 
ECG and electrolytes, including 
potassium, magnesium, and 
calcium, after dose modification of 
PLX3397 for QTcF prolongation. 
QTcF interval remains 
>500 msec and increased 
>60 msec from pretreatment 
values after controlling cardiac 
risk factors for QT prolongation 
(e.g., electrolyte abnormalities, 
congestive heart failure, and 
bradyarrhythmias). 
Permanently discontinue 
PLX3397. 
NA 
ANC = absolute neutrophil count; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
ECG = electrocardiogram; INR = international normalized ratio; NA = not applicable; PLT = platelet(s); 
QTcF = QT interval corrected using Fridericia’s formula; T = temperature = ULN = upper limit of normal 
a 
Throughout the study, dose decrements of 200 mg/day of PLX3397 are permitted for management of 
toxicity. 
 
Dose interruptions for toxicities that last up to 1 week but not shown on Table 3 can be 
implemented at the discretion of the treating physician to manage intolerable or clinically 
significant toxicity. No dose reduction is required when resuming treatment. 
Liver enzyme abnormalities, including increased transaminase values, have occurred with 
PLX3397 and should be managed as described in Table 4 and Table 5. 


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


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Table 5. 
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. 
Detailed history focusing on medications and 
substances used: alcohol, change in medication 
dosages, new medications added, attention to use of 
acetaminophen, OTC medication use, and 
recreational drug use. Check for change in diet or 
use of dietary supplements, with particular attention 
to dose and duration of any herbal product. 
Suspect medications will be discontinued or 
substituted for if possible. 
Detailed medical history and physical examination 
seeking new abnormalities. 
Evaluate abnormalities found. 
Full serological evaluation for hepatitis A, B, C, and 
E (IgG and IgM). Check for autoimmune hepatitis 
with serological laboratory studies. 
If viral hepatitis or autoimmune hepatitis suggested, 
have patient evaluated by hepatologist. 
Liver ultrasound performed to evaluate liver and 
biliary tree. 
Evaluate any abnormalities found. 
Check history for exposure to chemical agents. 
Remove chemical exposure and have patient seen 
by hepatologist. 
Obtain hepatology consult if liver function 
continues to rise beyond 14 days. 
Contact Medical Monitor. 
We request that cases be discussed with the Medical Monitor as defined in the protocol whenever 
investigational product is being held for liver function test abnormality. 
Ig = Immunoglobulin; INR = international normalized ratio; OTC = over-the-counter. 
 
For suspected cases of cholestatic liver injury (e.g., aminotransferase increase concurrent 
with hyperbilirubinemia, or liver biopsy suggesting cholestasis and/or ductopenia), 
patients will be followed to assess long-term outcome. Additional diagnostic and follow-
up procedures might be implemented as appropriate to fully assess the event.  
Generally, rechallenge of subjects with significant AST/ALT elevations (>5 × ULN, 
Grade 3) should not be attempted. Rechallenge can be considered if the subject has 
shown important benefit from the drug and other options are not available and the AST, 
ALT, or bilirubin elevations of Grade 2 or higher are deemed not related to 
pembrolizumab; relationship to pembrolizumab will be determined as related if 
1) evidence of immune hepatitis if a liver biopsy is performed OR 2) if the Investigator 
otherwise assesses the AST/ALT elevations as related to pembrolizumab. Rechallenge 
must be discussed with the medical monitor prior to re-starting. The subject should be 
made aware of the potential risk and consent to the rechallenge, and the Institutional 
Review Board (IRB) informed. The rechallenge should start at 200 mg/day PLX3397 
and, if safely tolerated after 1 cycle (6 weeks), can be re-escalated by 200mg increments 
to the RP2D as agreed upon by the investigator and medical monitor. 


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If there is Grade 2 or higher ALT or AST elevation (i.e., >3 × ULN) at any time during 
treatment, the subject should be followed closely, which includes: 
• Obtain liver effect biomarkers:  mir122, cytokeratin (18 full-length and 
caspase-cleaved), HMGB1 (native and acetylated). Frequency of collection as 
determined by the Investigator and Medical Monitor and should include a 
sample at 5to 8 days after PLX3397 dose hold or discontinuation. 
• Repeating liver enzyme and serum bilirubin tests 2 or 3 times weekly. 
Frequency of retesting can decrease to once a week or less if abnormalities 
stabilize or the trial drug has been discontinued and the subject is 
asymptomatic. 
• Medical Monitor should be notified within 48 hours. 
And may include the following: 
• Obtaining a more detailed history of symptoms and prior or concurrent 
diseases. 
• Obtaining a history of concomitant drug use (including nonprescription 
medications and herbal and dietary supplement preparations), alcohol use, 
recreational drug use, and special diets. 
• Ruling out acute viral hepatitis types A, B, C, D, and E; autoimmune or 
alcoholic hepatitis; non-alcoholic steatohepatitis; hypoxic/ischemic 
hepatopathy; and biliary tract disease. 
• Obtaining a history of exposure to environmental chemical agents. 
• Obtaining additional tests to evaluate liver function, as appropriate (e.g., INR, 
direct bilirubin). 
• Consideration of gastroenterology or hepatology consultations. 
3.1.9.2. 
Potential Pembrolizumab Toxicities and Dose Modifications 
(Escalation/Titration/Other) 
AEs (both nonserious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology. These immune-related AEs (irAEs) may occur 
shortly after the first dose or several months after the last dose of pembrolizumab 
treatment and may affect more than one body system simultaneously. Therefore, early 
recognition and initiation of treatment is critical to reduce complications. Based on 
existing clinical study data, most irAEs were reversible and could be managed with 
interruptions of pembrolizumab, administration of corticosteroids and/or other supportive 
care. For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude 
other causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin 
biopsy may be included as part of the evaluation. Based on the severity of irAEs, 
withhold or permanently discontinue pembrolizumab and administer corticosteroids. 
Dose modification and toxicity management guidelines for irAEs associated with 
pembrolizumab are provided in Table 6. See Section 3.1.9.2.1 for supportive care 
guidelines, including use of corticosteroids. 


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Table 6. 
Dose Modification Guidelines for Adverse Events Related to Pembrolizumab 
Immune-related 
AEs 
Toxicity Grade or Conditions 
(CTCAEv4.0) 
Action Taken to 
Pembrolizumab 
irAE Management with 
Corticosteroid and/or Other 
Therapies  
Monitor and Follow-up Instructions 
Pneumonitis  
Grade 2 
Withhold  
Administer corticosteroids (initial 
dose of 1–2 mg/kg prednisone or 
equivalent) followed by taper 
Monitor participants for signs and symptoms of 
pneumonitis. 
Evaluate participants with suspected pneumonitis 
with radiographic imaging and initiate 
corticosteroid treatment. 
Add prophylactic antibiotics for opportunistic 
infections. 
Grade 3 or 4, or recurrent Grade 
2 
Permanently discontinue 
Diarrhea/Colitis  
Grade 2 or 3 
Withhold 
Administer corticosteroids (initial 
dose of 1–2 mg/kg prednisone or 
equivalent) followed by taper 
Monitor participants for signs and symptoms of 
enterocolitis (i.e., diarrhea, abdominal pain, blood 
or mucus in stool with or without fever) and of 
bowel perforation (i.e., peritoneal signs and 
ileus). 
Participants with ≥Grade 2 diarrhea suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis.  
Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear fluids. 
If sufficient oral fluid intake is not feasible, fluid 
and electrolytes should be substituted via IV 
infusion. 
Grade 4 
Permanently discontinue 
AST/ALT 
elevation or 
Increased 
bilirubin 
Grade 2 
Withhold 
Administer corticosteroids (initial 
dose of 0.5–1 mg/kg prednisone or 
equivalent) followed by taper 
Monitor with liver function tests (consider weekly 
or more frequently until liver enzyme value 
returned to baseline or is stable. 
Grade 3 or 4  
Permanently discontinue Administer corticosteroids (initial 
dose of 1–2 mg/kg prednisone or 
equivalent) followed by taper 
Type 1 diabetes 
mellitus (T1DM) 
or Hyperglycemia 
Newly onset T1DM or  
Grade 3 or 4 hyperglycemia 
associated with evidence of 
β-cell failure 
Withhold1 
Initiate insulin replacement therapy 
for participants with T1DM 
Administer anti-hyperglycemic in 
participants with hyperglycemia 
Monitor participants for hyperglycemia or other 
signs and symptoms of diabetes. 


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Immune-related 
AEs 
Toxicity Grade or Conditions 
(CTCAEv4.0) 
Action Taken to 
Pembrolizumab 
irAE Management with 
Corticosteroid and/or Other 
Therapies  
Monitor and Follow-up Instructions 
Hypophysitis 
Grade 2 
Withhold 
Administer corticosteroids and 
initiate hormonal replacements as 
clinically indicated.  
Monitor for signs and symptoms of hypophysitis 
(including hypopituitarism and adrenal 
insufficiency). 
Grade 3 or 4  
Withhold or permanently 
discontinue2 
Hyperthyroidism  Grade 2 
Continue  
Treat with non-selective beta-
blockers (e.g., propranolol) or 
thionamides as appropriate  
Monitor for signs and symptoms of thyroid 
disorders. 
Grade 3 or 4  
Withhold or permanently 
discontinue2 
Hypothyroidism 
Grade 2–4 
Continue  
Initiate thyroid replacement 
hormones (e.g., levothyroxine or 
liothyroinine) per standard of care 
Monitor for signs and symptoms of thyroid 
disorders. 
Nephritis and 
Renal dysfunction 
Grade 2 
Withhold  
Administer corticosteroids 
(prednisone  
1–2 mg/kg or equivalent) followed 
by taper. 
Monitor changes of renal function. 
Grade 3 or 4  
Permanently discontinue 
Myocarditis 
Grade 1 or 2 
Withhold 
Based on severity of AE administer 
corticosteroids 
Ensure adequate evaluation to confirm etiology 
and/or exclude other causes. 
Grade 3 or 4 
Permanently discontinue 
All other immune-
related AEs 
Intolerable/ persistent Grade 2 
Withhold 
Based on type and severity of AE 
administer corticosteroids  
Ensure adequate evaluation to confirm etiology 
and/or exclude other causes. 
Grade 3 
Withhold or discontinue 
based on the type of 
event. Events that require 
discontinuation include 
and are not limited to:  
Gullain-Barre Syndrome, 
encephalitis 
Grade 4 or recurrent Grade 3  
Permanently discontinue 
General Instructions: 
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks. 
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and corticosteroid has been tapered. 
Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot be reduced to ≤10 mg prednisone or 
equivalent per day within 12 weeks.  
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment should be initiated if 
irAEs cannot be controlled by corticosteroids. 


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1 For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed when AE resolves 
to Grade ≤2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM). 
2 Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.  


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3.1.9.2.1. 
Rescue Medications & Supportive Care for Reactions Associated with 
Administration of Pembrolizumab 
Participants should receive appropriate supportive care measures as deemed necessary by 
the treating investigator. Suggested supportive care measures for the management of AEs 
with potential immunologic etiology are outlined along with the dose modification 
guidelines in Table 6. Where appropriate, these guidelines include the use of oral or IV 
treatment with corticosteroids, as well as additional anti-inflammatory agents if 
symptoms do not improve with administration of corticosteroids. Note that several 
courses of steroid tapering may be necessary as symptoms may worsen when the steroid 
dose is decreased. For each disorder, attempts should be made to rule out other causes 
such as metastatic disease or bacterial or viral infection, which might require additional 
supportive care. The treatment guidelines are intended to be applied when the 
investigator determines the events to be related to pembrolizumab.  
Note:  If after the evaluation of the event, it is determined not to be related to 
pembrolizumab, the investigator does not need to follow the treatment guidance. Refer to 
Table 6 for guidelines regarding dose modification and supportive care.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, 
or skin photography as part of evaluation of the event.  
Table 7. 
Treatment Guidelines for Infusion Reactions Associated with 
Pembrolizumab 
NCI CTCAE Grade 
Treatmenta 
Premedication at 
Subsequent Dosing 
Grade 1 
 
 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the Investigator. 
None. 
Grade 2 
 
 
Requires infusion 
interruption but responds 
promptly to symptomatic 
treatment 
(e.g., antihistamines, 
NSAIDS, narcotics, IV 
fluids); prophylactic 
medications indicated for 
≤24 hours 
Stop infusion and monitor symptoms. 
Additional appropriate medical therapy may 
include but is not limited to: 
• 
IV fluids 
• 
Antihistamines 
• 
NSAIDS 
• 
Acetaminophen 
• 
Narcotics 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the Investigator. 
If symptoms resolve within one hour of stopping 
drug infusion, the infusion may be restarted at 50% 
of the original infusion rate (e.g., from 100 mL/hr 
to 50 mL/hr). Otherwise dosing will be held until 
symptoms resolve and the subject should be 
premedicated for the next scheduled dose. 
Subjects who develop Grade 2 toxicity despite 
Subject may be 
premedicated 
1.5 hours 
(± 30 minutes) prior 
to infusion of 
pembrolizumab 
with: 
Diphenhydramine 
50 mg PO (or 
equivalent dose of 
antihistamine). 
Acetaminophen 
500–1000 mg PO 
(or equivalent dose 
of antipyretic). 


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NCI CTCAE Grade 
Treatmenta 
Premedication at 
Subsequent Dosing 
adequate premedication should be permanently 
discontinued from further trial treatment 
administration. 
Grades 3 or 4 
 
 
Grade 3: 
Prolonged (i.e., not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption 
of infusion); recurrence of 
symptoms following 
initial improvement; 
hospitalization indicated 
for other clinical sequelae 
(e.g., renal impairment, 
pulmonary infiltrates) 
Grade 4: 
Life-threatening; pressor 
or ventilatory support 
indicated 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
• 
IV fluids 
• 
Antihistamines 
• 
NSAIDS 
• 
Acetaminophen 
• 
Narcotics 
• 
Oxygen 
• 
Pressors 
• 
Corticosteroids 
• 
Epinephrine 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the Investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued from 
further trial treatment administration. 
No subsequent 
dosing. 
IV = intravenous; NSAID = nonsteroidal anti-inflammatory drug; PO = oral 
a 
Appropriate resuscitation equipment should be available in the room and a physician readily 
available during the period of drug administration. 
 
Dosing interruptions are permitted in the case of medical/surgical events or logistical 
reasons not related to study therapy (e.g., elective surgery, unrelated medical events, 
patient vacation, and/or holidays). Subjects should be placed back on study therapy 
within 3 weeks of the scheduled interruption, unless otherwise discussed with the 
Sponsor. The reason for interruption should be documented in the subject's study record. 
3.1.10. Radiologic Disease Progression:  Assessment and Treatment During Dose-
escalation and Expansion Phases 
3.1.10.1. Assessment of Radiologic Disease Progression 
Immunotherapeutic agents such as pembrolizumab may produce antitumor effects by 
potentiating endogenous cancer-specific immune responses. The response patterns seen 
with such as approach may extend beyond the typical time course of responses seen with 
cytotoxic agents, and can manifest as a clinical response after an initial increase in tumor 
burden or even the appearance of new lesions. 
irRECIST guidelines (see the irRECIST Tip Sheet, provided in the Study Reference 
Manual) will be applied by the site as the primary measure for assessment of tumor 
response and as a basis for protocol guidelines related to disease status (e.g., 
discontinuation of study therapy). These guidelines will also be applied by the site to 


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account for the unique tumor response seen with treatment of the combination of 
pembrolizumab and PLX3397. 
In determining whether or not the tumor burden has increased or decreased, Investigators 
should consider all target lesions as well as non-target lesions. All scans will be archived. 
Please refer to Study Reference Manual. 
Imaging during the follow-up period is to be repeated as clinically indicated for subjects 
who discontinue trial treatment for reasons other than disease progression until the 
subject experiences confirmed disease progression or starts a new anti-neoplastic therapy. 
3.1.10.2. Procedure and Treatment After Initial Evidence of Radiologic Disease 
Progression 
If radiologic imaging shows PD, tumor assessment should be repeated ≥4 weeks later to 
confirm PD with the option of continuing treatment per below while awaiting radiologic 
confirmation of progression. If repeat imaging shows a reduction in the tumor burden 
compared with the initial scan demonstrating PD, treatment may be continued per the 
treatment calendar. If repeat imaging confirms PD, subjects will be discontinued from the 
study. 
When feasible, subjects should not be discontinued until PD is confirmed; however, the 
decision to continue study treatment after the first evidence of disease progression is at 
the Investigator’s discretion based on the clinical status of the subject (Table 8). Subjects 
may receive study treatment while awaiting confirmation of PD if they are clinically 
stable as defined by the following criteria: 
• Absence of signs and symptoms (including worsening of laboratory values) 
indicating disease progression 
• No decline in Eastern Cooperative Oncology Group (ECOG) performance 
status 
• Absence of rapid progression of disease 
• Absence of progressive tumor at critical anatomical sites (e.g., cord 
compression) requiring urgent alternative medical intervention 
Subjects who are deemed clinically unstable are not required to have repeat imaging for 
confirmation. 
The Sponsor will receive radiologic images for possible retrospective analysis of subject 
eligibility and treatment response, to be performed by a central vendor, if an efficacy 
endpoint is met. 
If a subject with confirmed radiologic progression is clinically stable or clinically 
improved and there is no further increase in the tumor dimensions at the confirmatory 
scan, an exception may be considered to continue treatment after consultation with the 
Sponsor. For clinically stable subjects to continue study treatment, the confirmatory scan 
should show no further increase in the target lesions, no unequivocal increase in non-
target lesions, and no additional new lesions develop (non-worsening PD) (Table 8). 


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Table 8. 
Imaging and Treatment After First Radiologic Evidence of Disease 
Progression 
 
Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
1st radiologic 
evidence of PD 
by RECISTv1.1 
Repeat imaging at 
≥4 weeks at site 
to confirm PD. 
May continue study 
treatment at the 
local site’s 
Investigator 
discretion while 
awaiting 
confirmatory 
imaging by site by 
irRECIST. 
Repeat imaging 
at ≥4 weeks to 
confirm PD per 
physician 
discretion only 
Discontinue 
treatment. 
Repeat tumor 
imaging 
confirms PD by 
irRECIST at the 
local site 
No additional 
imaging required. 
Discontinue 
treatment 
(exception is 
possible upon 
consultation with 
Sponsor) 
No additional 
imaging required. 
NA 
Repeat imaging 
shows SD, PR, 
or CR by 
irRECIST at the 
local site 
Continue 
regularly 
scheduled 
imaging 
assessment every 
9 weeks. 
Continue study 
treatment at site’s 
Investigator 
discretion. 
Continue 
regularly 
scheduled 
imaging 
assessments 
every 9 weeks. 
May restart study 
treatment if 
condition has 
improved and/or 
clinically stable per 
Investigator’s 
discretion. Next 
tumor image should 
occur according to 
the every 9 week 
(± 7 days) imaging 
schedule 
CR = complete response; PD = progressive disease or disease progression; PR = partial response;  
SD = stable disease 
 
3.2. 
Selection of Doses 
3.2.1. 
PLX3397 
The dose-escalation plan, summarized in Table 1, was selected on the basis of data from 
Study PLX108-01, an ongoing phase 1, open-label, 2-part study of single-agent PLX3397 
in subjects with advanced, incurable, solid tumors (Dose-escalation Phase) and in 
subjects with selected tumors (Expansion Phase). The initial Dose-escalation Phase of the 
trial studied total daily oral doses from 200 mg through 1200 mg. Two subjects receiving 
1200 mg/day, administered as a split dose, experienced DLT toxicities:  anemia, 
neutropenia, and syncope in 1 subject and elevated AST in the other. Thus, a RP2D of 
1000 mg/day as a split dose was administered in the Extension Phase of this single-agent 
study. An interim analysis from the extension cohort with the longest duration of 
treatment (median duration of 219 days, n = 17 subjects) showed that approximately half 
of the subjects required a dose reduction to at least 800 mg/day as a split dose within the 
first 2 cycles (Plexxikon, data on file). Biomarker data have suggested that doses at or 


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below 400 mg/day are less likely to have pharmacodynamic activity. Thus, in 
consideration of data from single-agent PLX3397, 600 mg/day as a split dose is selected 
as the initial dose with an allowance for de-escalation to 400 mg/day as a split dose for 
this combination study. 
Note that per Section 3.1.7.2, allowance is made for alternative dosing regimens such as 
intermittent dosing (e.g., 1 week off and 2 weeks on for PLX3397 during the 3-week 
pembrolizumab dosing interval; see Figure 1 Cohort [int] as an example and 
Appendix 17.7); and/or for repeating a dose level with a run-in period of PLX3397 for 
2 weeks prior to starting pembrolizumab (see Appendix 17.8. Intermittent PLX3397 
dosing may allow pembrolizumab to function alone for one week before initiation of 
PLX3397 dosing. PLX3397 could then target emergent immune suppressive 
macrophages in the tumor microenvironment that results from pembrolizumab activity 
(Tumeh 2014). The intermittent PLX3397 dosing may also provide increased safety and 
tolerability by avoiding simultaneous peak exposures of pembrolizumab and PLX3397. 
The alternative regimen of a run-in period of PLX3397 for 2 weeks is supported by 
empirical observations of reduced liver transaminase elevations with a combination of 
targeted therapy (vemurafenib) and anti-PDL1 (Hamid 2015). 
3.2.2. 
Rationale for Pembrolizumab Dose Selection 
The dose of pembrolizumab planned to be studied in this trial is 200 mg every 3 weeks 
(Q3W). The dose recently approved in the United States and several other countries for 
treatment of melanoma subjects is 2 mg/kg Q3W. Information on the rationale for 
selecting 200 mg Q3W is summarized below. 
In KEYNOTE-001, an open-label Phase 1 study conducted to evaluate the safety, 
tolerability, pharmacokinetics (PK) and pharmacodynamics (PD), and anti-tumor activity 
of pembrolizumab when administered as monotherapy. The dose escalation portion of 
this trial evaluated three dose levels, 1 mg/kg, 3 mg/kg and 10 mg/kg, administered every 
2 weeks (Q2W) and dose expansion cohorts evaluated 2 mg/kg Q3W and 10 mg/kg Q3W 
in subjects with advanced solid tumors. All dose levels were well tolerated and no dose-
limiting toxicities were observed. This first-in-human study of pembrolizumab showed 
evidence of target engagement and objective evidence of tumor size reduction at all dose 
levels. No maximum tolerated dose (MTD) has been identified. In addition, two 
randomized cohort evaluations of melanoma subjects receiving pembrolizumab at a dose 
of 2 mg/kg versus 10 mg/kg Q3W have been completed, and one randomized cohort 
evaluating 10 mg/kg Q3W versus 10 mg/kg Q2W has also been completed. The clinical 
efficacy and safety data demonstrate a lack of important differences in efficacy or safety 
profile across doses. 
An integrated body of evidence suggests that 200 mg every 3 weeks (Q3W) is expected 
to provide similar response to 2 mg/kg Q3W, 10 mg/kg Q3W and 10 mg/kg Q2W. 
Previously, a flat pembrolizumab exposure-response relationship for efficacy and safety 
has been found in subjects with melanoma in the range of doses between 2 mg/kg and 
10 mg/kg. Exposures for 200 mg Q3W are expected to lie within this range and will be 
close to those obtained with 2 mg/kg Q3W dose. 


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A population pharmacokinetic (PK) model, which characterized the influence of body 
weight and other subject covariates on exposure, has been developed. The PK profile of 
pembrolizumab is consistent with that of other humanized monoclonal antibodies, which 
typically have a low clearance and a limited volume of distribution. The distribution of 
exposures from the 200 mg fixed dose are predicted to considerably overlap those 
obtained with the 2 mg/kg dose and importantly will maintain individual subject 
exposures within the exposure range established in melanoma as associated with maximal 
clinical response. Pharmacokinetic properties of pembrolizumab, and specifically the 
weight-dependency in clearance and volume of distribution are consistent with no 
meaningful advantage to weight-based dosing relative to fixed dosing. 
In translating to other tumor indications, similarly flat exposure-response relationships 
for efficacy and safety as observed in subjects with melanoma can be expected, as the 
anti-tumor effect of pembrolizumab is driven through immune system activation rather 
than through a direct interaction with tumor cells, rendering it independent of the specific 
tumor type. In addition, available PK results in subjects with melanoma, NSCLC, and 
other tumor types support a lack of meaningful difference in pharmacokinetic exposures 
obtained at tested doses among tumor types. Thus the 200 mg Q3W fixed-dose regimen 
is considered an appropriate fixed dose for other tumor indications as well. 
A fixed-dose regimen will simplify the dosing regimen to be more convenient for 
physicians and to reduce potential for dosing errors. A fixed-dosing scheme will also 
reduce complexity in the logistical chain at treatment facilities and reduce wastage. The 
existing data suggest 200 mg Q3W as the appropriate dose for pembrolizumab. 
3.2.3. 
Missed or Vomited Doses 
Subjects who miss a dose of PLX3397 should be instructed NOT to make up that dose. 
Doses that are vomited should not be replaced. 
4. 
STUDY POPULATION 
4.1. 
Enrollment 
Investigators will maintain a confidential screening log of all potential study candidates 
that includes limited information of the subjects (initials, age, sex) date and outcome of 
screening process (e.g., enrolled in the study, reason for ineligibility, refused to 
participate). 
Investigators will be expected to maintain an Enrollment Log of all subjects enrolled in 
the study indicating their assigned study number. 
Investigators will maintain a confidential subject identification code list. This 
confidential list of names of all subjects allocated to study numbers on enrolling in the 
study, allows the Investigator to reveal the identity of any subject when necessary. 
All subjects must personally sign and date (unless incapable of doing so; see 
Section 14.2) the ICF provided by the site before pre-screening or screening procedures 
are performed. For additional information on Informed Consent, see Section 14.2. 


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4.1.1. 
Inclusion Criteria 
A subject must satisfy all of the following criteria to be considered for inclusion in the 
study: 
1. Be willing and able to provide written informed consent for the trial. 
2. Male or female ≥18 years old. 
3. Subjects with histologically or cytologically-confirmed diagnosis of cancer 
that is recurrent, metastatic, or persistent, who have relapsed from or are 
refractory to treatment and who also meet the following corresponding 
requirements for the cohort or phase of the study into which they will enroll: 
• Dose-escalation Phase:  Subjects with advanced solid tumors (any tumor 
type) considered to have no standard-of-care treatment for their 
malignancy with a curative intent, either as initial therapy or after 
progressing to prior therapies; subjects who have been treated previously 
with a CSF1R inhibitor or an anti-PD1/PDL1 inhibitor may enroll. 
• Expansion Phase:  Subjects with 1 of the tumor types described in Table 2, 
who have relapsed from or are refractory to standard treatment. Subjects 
with:   
i. NSCLC (non-squamous; EGFR and ALK wild-type) and SCCHN 
cancer must show primary progression (i.e., no PR or CR) with 
anti-PD1/anti-PDL1 therapy 
ii. Melanoma subgroups are as follows:  (a) anti-PD-1/PD-L1 naïve 
and CSF1R naïve; (b) at least 4 months of prior anti-PD-1 PD-L1 
therapy but never responded (i.e., no PR or CR); (c) prior 
anti-PD-1/PD-L1 therapy and responded but later progressed as 
defined by irRECIST while on therapy 
iii. Ovarian includes primary peritoneal and fallopian tube cancers; 
(carcinosarcomas and low grade serous tumors are excluded) 
iv. Unresectable RCC with component of clear-cell histology and/or 
component of sarcomatoid histology 
v. World Health Organization Grade IV supratentorial malignant 
glioma (glioblastoma or gliosarcoma) following complete or 
partial surgical resection and radiation plus temozolomide 
vi. GIST cohort must have locally advanced or metastatic disease and 
have progressed on or have been intolerant to imatinib therapy. 
vii. All tumor types must be naïve to anti PD1/PDL1 inhibitors except 
as described in (i) and (ii). 


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4. Subjects with melanoma must have a histologically confirmed diagnosis of 
stage III or stage IV disease not amenable to local therapy. Melanoma 
subjects may have received any number of prior lines of therapy for 
metastatic disease and must have measurable disease per 
RECISTv1.1 (Appendix 17.4). Cutaneous lesions and other superficial 
lesions that are detectable only by physical examination are not considered 
measurable lesions for the purposes of this protocol, but may be considered 
as nontarget lesions. Tumor lesions situated in a previously irradiated area 
are considered measurable if progression has been demonstrated in such 
lesions. Subjects with melanoma who have received prior treatment with a 
MEK/BRAF inhibitor are acceptable candidates. 
5. Expansion cohorts:  Subjects must have relapsed or been refractory to 
standard treatment and have measurable disease per RECISTv1.1, using 
MRI or CT, with FDG-PET for GIST subjects only. They must have tumor 
accessible for sequential biopsy (core needle biopsy or excision required) 
and be willing to provide on-study tumor tissue biopsy. Repeat samples may 
be required if adequate tissue is not provided. When possible, newly 
obtained tissue should be collected from a non-target lesion. Subjects for 
whom newly obtained samples cannot be obtained (e.g. inaccessible or 
patient safety concern, glioblastoma tumor type) may submit an archived 
specimen only upon agreement from the Sponsor. 
6. ECOG performance status 0 or 1 (Appendix 17.3). 
7. Women of childbearing potential must have a negative serum pregnancy test 
within 72 hours prior to initiation of dosing. 
8. Women of childbearing potential should be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the 
course of the study through 120 days after the last dose of study medication. 
Effective forms of contraception include abstinence, hormonal contraceptive 
in conjunction with a barrier method, or a double-barrier method. Women of 
nonchildbearing potential may be included if they are either surgically 
sterile or have been postmenopausal for ≥1 year. 
9. Fertile men must agree to use an effective method of birth control starting 
with the first dose of study treatment through 120 days after the last dose of 
study treatment. 
10. Adequate organ function as demonstrated by the laboratory values shown 
below. These laboratory tests should be performed within 10 days prior to 
the first dose of study treatment.  


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System 
Laboratory Value 
Hematological 
Absolute neutrophil count (ANC) 
≥1.5 × 109/L 
Platelets 
≥100 × 109/L 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L  
Renal 
Creatinine OR 
Measured or calculateda creatinine 
clearance (crcl) 
(GFR can also be used in place of 
creatinine or crcl) 
≤1.5 × ULN OR 
≥60 mL/min for subject with 
creatinine levels >1.5 × institutional ULN 
Hepatic 
Total bilirubin 
≤1.25 × ULN (Gilbert’s Syndrome allowed) 
AST and ALT 
≤1.5 × ULN  
Coagulation 
INR or PT 
 
 
aPTT 
≤1.5 × ULN unless subject is receiving anticoagulant 
therapy as long as PT or PTT is within therapeutic 
range of intended use of anticoagulants 
≤1.5 × ULN unless subject is receiving anticoagulant 
therapy as long as PT or PTT is within therapeutic 
range of intended use of anticoagulants 
aPTT = activated partial thromboplastin time; ALT = alanine aminotransferase;  
ANC = absolute neutrophil count; AST = aspartate aminotransferase;  
INR = international normalized ratio; PT = Prothrombin time;  
ULN = upper limit of normal 
a 
Creatinine clearance should be calculated per institutional standard. 
 
4.1.2. 
Exclusion Criteria 
A subject who meets any of the following criteria will be disqualified from entering the 
study: 
1. Disease that is suitable for local therapy administered with curative intent. 
2. Diagnosis of immunodeficiency or is receiving systemic steroid therapy or 
any other form of immunosuppressive therapy within 7 days prior to the first 
dose of study treatment. The use of physiologic doses of corticosteroids may 
be approved after consultation with the Sponsor. 
3. Is currently participating and receiving study therapy or has participated in a 
study of an investigational agent and received study therapy or used an 
investigational device within 28 days prior to the first dose of study 
treatment. 
4. Has had monoclonal antibody treatment for cancer within 28 days of first 
dose of study treatment or has not recovered from AEs due to agents 
administered more than 28 days earlier (i.e., AEs should be ≤Grade 1 or 
≤the value collected at baseline). 
5. Has had chemotherapy, targeted small molecule therapy, or radiation 
therapy >30 Gray within 14 days prior to first dose of study treatment or 


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who has not recovered (i.e., AEs should be ≤Grade 1 or ≤the value collected 
at baseline) from AEs due to a previously administered intervention.  
 
Note:  Subjects with ≤Grade 2 neuropathy or ≤Grade 2 alopecia are an 
exception to this criterion and may qualify for the study. 
 
6. Has received transfusion of blood products (including platelets or red blood 
cells [RBC]) or administration of colony stimulating factors (including 
granulocyte colony-stimulating factor, granulocyte-macrophage colony-
stimulating factor, or recombinant erythropoietin) within 28 days prior to 
Day 1. 
7. Has a history of (non-infectious) pneumonitis that required steroids or 
current pneumonitis. 
8. Has a known additional malignancy that is progressing or requires active 
treatment. Exceptions include basal cell carcinoma of the skin, squamous 
cell carcinoma of the skin that has undergone potentially curative therapy, in 
situ cervical cancer and isolated elevation of prostate-specific antigen. 
Subjects with a completely treated prior malignancy with no evidence of 
disease for ≥2 years are eligible. 
9. For Dose-escalation Cohort [-1]:  Patients with liver metastases; inclusion of 
patients with liver metastases in subsequent cohorts will be based upon 
clinical safety data. 
10. For Expansion cohort subjects who have previously received an anti-PD-1, 
anti-PD-L1, or anti-PD-L2 agent or has previously participated in 
pembrolizumab clinical trials are excluded, except those tumor types listed 
under Inclusion Criteria #3. 
11. Has active autoimmune disease that has required systemic treatment in past 
2 years (i.e., with use of disease modifying agents, corticosteroids, or 
immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary 
insufficiency) is not considered a form of systemic treatment. 
12. Has an active infection requiring systemic therapy. 
13. Has known central nervous system metastases and/or carcinomatous 
meningitis. 
Note:  Subjects with previously treated brain metastases may participate if 
they meet the following criteria:  1) are stable (i.e., no evidence of 
progression per irRECIST (see the irRECIST Tip Sheet, provided in the 
Study Reference Manual) determined by imaging, using the identical 
imaging modality for each assessment, either MRI or CT scan) for at least 
35 days prior to the first dose of study treatment and if all neurologic 
symptoms returned to baseline; 2) have no evidence of new or enlarging 
brain metastases; and 3) have not been using steroids for at least 7 days prior 


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to first dose of study treatment. This exception does not include 
carcinomatous meningitis, which is excluded regardless of clinical stability. 
14. Uncontrolled intercurrent illness. 
15. Refractory nausea and vomiting, malabsorption, external biliary shunt, or 
significant small bowel resection that would preclude adequate absorption. 
16. QT interval corrected using Fridericia’s formula (QTc) ≥450 msec (males) 
or ≥470 msec (females) at Screening. 
17. Congenital long QT syndrome or patients taking concomitant medications 
known to prolong the QT interval. A list of drugs known to prolong the QT 
interval can be found in Appendix 17.1. 
18. Major surgery within 28 days prior to first dose of study treatment. 
Note:  If subject received major surgery, he or she must have recovered 
adequately from the toxicity and/or complications from the intervention 
prior to starting study treatment. 
19. History of active ethanol abuse. 
20. Has received a live vaccine administered within 30 days of planned 
treatment start or while participating in the trial. Seasonal flu vaccines that 
do not contain live virus are permitted. 
21. Has a history or current evidence of any condition, therapy, or laboratory 
abnormality that might confound the results of the trial, interfere with the 
subject’s participation for the full duration of the trial, or is not in the best 
interest of the subject to participate, in the opinion of the treating 
Investigator. 
22. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 
antibodies); has known active Hepatitis B (e.g., HBsAg reactive) or 
Hepatitis C (e.g., HCV RNA [qualitative] is detected). 
23. Any of the following within 48 weeks (~1 year) prior to first dose of study 
treatment:  myocardial infarction, uncontrolled angina, coronary/peripheral 
artery bypass graft, symptomatic congestive heart failure, cerebrovascular 
accident or transient ischemic attack. 
24. Imprisoned or under legal guardianship. 
25. Is pregnant or breastfeeding, or expecting to conceive or father children 
within the projected duration of the trial, starting with the screening visit 
through 120 days after the last dose of study treatment. 
26. Has known psychiatric or substance abuse disorders that would interfere 
with cooperation with the requirements of the trial. 
27. Has had prior exposure to PLX3397. 
28. Has had hypersensitivity (≥Grade 3) reaction to pembrolizumab and/or any 
of its excipients. 


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4.2. 
Removal of Subjects From Therapy 
4.2.1. 
Reasons for Withdrawal/Early Discontinuation 
Subjects may be withdrawn from the study after signing informed consent for the 
following reasons: 
• Screen failure 
• AE 
• Withdrawal by subject 
• Physician’s Decision 
Subjects maybe discontinued from treatment during the treatment phase of the trial 
(i.e., during the Dose-escalation and/or Expansion Phase of the study), in cases of: 
• Unacceptable or intolerable AE 
• Lost to Follow-up 
• Withdrawal of consent by subject 
• Physician’s decision 
• Death 
• Lack of efficacy 
• Pregnancy 
• Progressive disease by irRECIST (see the irRECIST Tip Sheet, provided in 
the Study Reference Manual) 
• Study terminated by Sponsor 
• Other reasons 
4.2.2. 
Withdrawal Procedures 
If a subject withdraws from the study, the Investigator will complete and report the 
observations as thoroughly as possible up to the date of withdrawal including the date of 
last treatment and the reason for withdrawal. 
If the subject is withdrawn due to an AE, the Investigator will follow the subject until the 
AE has resolved or stabilized. 
All subjects who are withdrawn from the study should complete protocol-specified end-
of-treatment procedures (Section 6.5). 
4.2.3. 
Subject Replacement 
If treatment interruptions meet either of the following criteria for reasons other than a 
DLT, the subject can be replaced:  (1) for more than 10 days (11 days or more) during the 
42-day DLT observation period (within 6 weeks of C1D1) or (2) for more than 7 days 
(8 days or more) during the run-in period of 2 weeks of PLX3397. 


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If a subject discontinues treatment during the Expansion Phase of the study, that subject 
will not be replaced. 
4.2.4. 
Subject Rescreening Procedures 
Subjects can be rescreened if they were deemed a screen failure (i.e., met ≥1 exclusion 
criteria as specified in Section 4.1.2) due to ineligible laboratory values that recovered 
without medical intervention. However, screening procedures must be restarted within 
28 days from the screen failure (or the communication of the results to the site, in case of 
screen failures related to the tissue sample). 
The Principal Investigator will consult with the Sponsors or the contract research 
organization (CRO) before making the re-screen decision. 
Re-screened subjects will keep the same identification number they were assigned at first 
screening. 
4.2.5. 
Discontinuation of Study Treatment after Complete Response 
Discontinuation of both Study Drugs may be considered for subjects who have attained a 
confirmed CR and who have been treated for at least 24 weeks (4 cycles) with 
pembrolizumab and PLX3397 and had at least 2 treatments with pembrolizumab (and 
PLX3397) beyond the date when the initial CR was declared.  
5. 
TREATMENTS ADMINISTERED 
5.1. 
Investigational Products 
For combination treatment, there are 2 investigational products, pembrolizumab and 
PLX3397, described in the sections that follow. The Investigator must ensure that the 
investigational products described below will be used only in accordance with the 
protocol. 
5.1.1. 
Pembrolizumab 
Pembrolizumab was approved in the US on September 2014 as a single agent for the 
treatment of unresectable or metastatic melanoma and disease progression following 
ipilimumab, and if BRAF V600 mutative positive, a BRAF inhibitor. Pembrolizumab 
(Table 9) will be supplied by Plexxikon to the study sites. During both the 
Dose-escalation and Expansion Phases of the study, subjects will receive pembrolizumab 
200 mg IV over 30 minutes once every 3 weeks. Instructions for preparation and 
administration of pembrolizumab are provided in Section 5.4.1.1. 
5.1.2. 
PLX3397 
PLX3397 is formulated as an HCl salt capsule (200-mg strength of the active free base of 
PLX3397). PLX3397 HCl Salt will be referred to as PLX3397 throughout this document. 
During the Dose-escalation Phase of the study, up to 42 subjects in up to 7 cohorts will 
receive PLX3397 as summarized in Table 1. During the Expansion Phase, subjects with 


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1 of the tumor types (Table 2) will receive PLX3397 at the RP2D (Table 2). Instructions 
for preparation and administration of PLX3397 are provided in Section 5.4.1.2. 
5.2. 
Method of Assigning Subjects to Treatments 
Once all screening procedures have been completed and study eligibility has been 
confirmed, a subject will be considered enrolled in the study. Eligible subjects who enter 
the Dose-escalation Phase of the study will be assigned sequentially to 1 of the cohorts 
and receive treatment as described in Table 1 (a fourth cohort, 400 mg/day of PLX3397 is 
an option if subjects do not tolerate PLX3397 at 600 mg/day). After completion of the 
Dose-escalation Phase, subjects may continue to receive treatment with pembrolizumab 
200 mg IV every 3 weeks at the dose of PLX3397 determined for their cohort or may 
have the dose of PLX3397 changed to the RP2D, if warranted in the judgment of the 
Investigator. 
Eligible subjects who enter directly into the Expansion Phase of the study (i.e., did not 
participate in the Dose-escalation Phase) will have 1 of the tumor types described in 
Table 2 and will receive pembrolizumab 200 mg IV every 3 weeks in combination with 
the RP2D of PLX3397. 
5.3. 
Method of Assessing Treatment Compliance 
At the study visits indicated in the Schedule of Events (Appendix 17.6), unblinded 
PLX3397 will be dispensed to subjects. The appropriate study personnel will document 
and maintain records of PLX3397 dispensed to each subject and return of any amount of 
PLX3397 at each study visit. Subjects will complete a dosing Diary to record the number 
of capsules/date/time taken during each dosing cycle. At each clinic visit, subjects will be 
assessed for compliance with study treatment administration. 
Compliance with treatment with pembrolizumab is assured by having study personnel 
administer the drug IV at 200 mg over 30 minutes every 3 weeks at the time points 
indicated in the Schedule of Events (Appendix 17.6). 
Further details regarding treatment compliance can be found in the Plexxikon Study 
Reference Manual. 
5.4. 
Labeling and Packaging 
PLX3397 HCl capsules (200-mg strength of the active free base of PLX3397) are 
manufactured, packaged, and labeled according to Good Manufacturing Practices (GMP) 
and Good Clinical Practices (GCP). 
PLX3397 HCl capsules will be provided to the study sites by Plexxikon. 
Pembrolizumab (Table 9) will be provided to the study sites by Plexxikon. 
Table 9. 
Pembrolizumab Product Description 
Product Name and Potency 
Dosage Form 
MK-3475 50 mg 
Lyophilized Powder for Injection 
MK-3475 100 mg/4mL 
Solution for Injection 


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5.4.1. 
Preparation and Administration 
5.4.1.1. 
Pembrolizumab 
Pembrolizumab will be administered as a dose of 200 mg using a 30-minute IV infusion 
(treatment cycle intervals may be increased due to toxicity as described in Section 3.1.8). 
Sites should make every effort to target infusion timing to be as close to 30 minutes as 
possible. However, given the variability of infusion pumps from site to site, a window 
of -5 minutes and +10 minutes is permitted (i.e., infusion time is 30 [-5/+10] minutes). 
The Pharmacy Manual contains specific instructions for the preparation of the 
pembrolizumab infusion and administration of infusion solution. 
5.4.1.2. 
PLX3397 
No preparation is required for PLX3397. PLX3397 capsules will be administered orally 
twice daily as a split dose on an outpatient basis, except as indicated in the Schedule of 
Events (Appendix 17.6), when subjects will bring their morning dose to the clinic and 
receive it under the supervision of the study site staff. For patients who receive their 
medications through PEG tubes, e.g., those with tumors of the head and neck, PLX3397 
may be administered through the PEG tube. Study Drug preparation and method of 
delivery should remain the same for the duration of study. Preparation and administration 
of PLX3397 can be found in the Pharmacy Manual. 
Administration of PLX3397 will begin at C1D1 visit in the morning, at which time 
subjects will also receive their first 30-minute IV infusion of pembrolizumab 
200 mg/day. At that visit, subjects in Cohort 1 (600 mg/day) will receive 3 capsules of 
PLX3397 at 200 mg per capsule. Subjects will be instructed to take 1 capsule in the 
morning (i.e., 200 mg PLX3397) and 2 capsules (i.e., 400 mg of PLX3397) in the 
evening. Subjects in Cohort 2 (800 mg/day) will receive 4 capsules of PLX3397. They 
will be instructed to take 2 capsules in the morning (i.e., 400 mg PLX3397) and 
2 capsules in the evening (i.e., 400 mg PLX3397). Subjects at the 1000 mg/day PLX3397 
dose level will be instructed to take 2 capsules (i.e., 400 mg PLX3397) in the morning 
and 3 capsules (i.e., 600 mg PLX3397) in the evening. 
Alternative PLX3397 dose regimens may be employed to optimize safety in combination 
with pembrolizumab (see Section 3.1.7.2, Appendix 17.7, and Appendix 17.8). The 
intermediate dose level or regimen will be determined by the Sponsor and Investigators. 
PLX3397 should be taken with 240 mL (8 oz.) of water while in the fasting state (i.e., no 
food for 1 hour before and 2 hours after dose administration). However, during the 
fasting period, subjects will be permitted to eat a low-fat snack (e.g., crackers, toast, tea), 
if necessary. Doses will be taken at approximately the same times of the day, 
approximately 12 hours apart, with the exception of PK draw days, where the second 
dose of the day may be less than 12 hours from prior dose. 


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5.4.2. 
Storage and Stability 
PLX3397 HCl capsules will be stored at the clinical site, as indicated on the Study Drug 
label, i.e., room temperature (do not store above 25ºC/77ºF). Excursions are permitted 
from 15ºC to 30ºC (59ºF to 86ºF). 
Subjects will be requested to store the PLX3397 at the recommended storage conditions 
noted on the label, out of the reach of children or other cohabitants. 
Pembrolizumab vials must be stored under refrigeration at 2°C to 8°C (36°F to 46°F). 
See Section 16 of the Keytruda Package Insert. 
5.4.3. 
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 subject, and amount returned to Plexxikon, or a CRO designee, (or 
disposal of the drug, if approved by Plexxikon) will be maintained by the clinical site. 
Plexxikon 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. 
5.4.4. 
Product Complaints 
A product complaint is any dissatisfaction with a product that may be attributed to the 
identity, quality, durability, reliability, or safety of the product. Individuals who identify a 
potential product complaint situation should immediately report the event. Whenever 
possible, the associated product should be maintained in accordance with the label 
instructions pending further guidance from a Plexxikon quality representative. 
For Product Complaints, refer to the Study Pharmacy Manual for instructions and details. 
5.5. 
Concomitant Medications and Therapies 
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 CRF, including the reason for treatment, generic name of the 
drug, dosage, route, and date and time of administration. 
All concomitant medications received within 30 days before the first dose of trial 
treatment and 28 days after the last dose of trial treatment should be recorded 
Concomitant medications received greater than 30 days before the first dose of trial 
treatment may be recorded if deemed relevant to adverse events and/or clinically 
important medical history. Concomitant medications administered after 28 days after the 
last dose of trial treatment should be recorded for SAEs and ECI as specified in 
Section 11.2 and Section 11.6, respectively. 


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5.5.1. 
Concomitant Medications and Therapies Related to PLX3397 
Although PLX3397 does not appear to inhibit cytochrome P450 (CYP) drug-
metabolizing enzymes to an important extent, caution is warranted when administering 
PLX3397 to subjects taking drugs that are highly dependent on cytochrome P450 3A4 
(CYP3A4) for metabolism and have a narrow therapeutic index. It is not known whether 
systemic exposure to these medications will demonstrate an increase while subjects are 
receiving PLX3397. 
Of the 5 major CYP isoforms, 3A4 may be involved in Phase 1 metabolism of PLX3397, 
with possibly cytochrome P450 1A2 (CYP1A2) playing a minor role. Until information 
regarding exposure-toxicity and exposure-response relationships are available with 
PLX3397, concomitant CYP3A4 inhibitors and inducers should be administered with 
caution, in the event they alter the systemic exposure to PLX3397 (see Appendix 17.2 for 
a list of common CYP3A4 inhibitors and inducers). In general, strong inhibitors or 
inducers of CYP3A4 should be avoided unless clinically necessary. These include 
anticonvulsants, mycin antimicrobials, and antiretrovirals. 
Subjects are discouraged from taking proton pump inhibitors (PPIs) or other strong anti-
acids (e.g., H-2 antagonists), as these may interfere with the reliable identification of the 
MTD or R2PD for PLX3397 when used in combination with a fixed dose of 
pembrolizumab. 
5.5.2. 
Concomitant Medications/Vaccinations Related to Pembrolizumab 
(Allowed & Prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not 
allowed during the ongoing trial. If there is a clinical indication for any medication or 
vaccination specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required. The Investigator should discuss any questions regarding this 
with the Sponsor’s medical monitor. The final decision regarding any supportive therapy 
or vaccination rests with the Investigator and/or the subject's primary physician. 
However, the decision to continue the subject on trial therapy or vaccination schedule 
requires the mutual agreement of the Investigator, the Sponsor and the subject. 
5.5.2.1. 
Acceptable Concomitant Medications with Pembrolizumab 
All treatments that the Investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the Investigator in keeping with the community 
standards of medical care. All concomitant medication will be recorded on the case report 
form (CRF) including all prescription, over-the-counter (OTC), herbal supplements, and 
IV medications and fluids. If changes occur during the trial period, documentation of 
drug dosage, frequency, route, and date may also be included on the CRF. 
5.5.2.2. 
Prohibited Concomitant Medications with Pembrolizumab 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment periods (including retreatment for post-CR relapse) of this trial: 
• Antineoplastic systemic chemotherapy or biological therapy 


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• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Investigational agents other than pembrolizumab and PLX3397 
• Radiation therapy 
− Note:  Radiation therapy to a symptomatic solitary lesion or to the brain 
may be considered on an exceptional case-by-case basis after consultation 
with Sponsor. The subject must have clear measurable disease outside the 
radiated field. Administration of palliative RT will be considered clinical 
progression for the purposes of determining PFS. 
• Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial. Examples of live vaccines include, but are not limited to, 
the following:  measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, 
and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally 
killed virus vaccines and are allowed. However, intranasal influenza vaccines 
(e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed. 
• Systemic glucocorticoids for any purpose other than to modulate symptoms from 
an event of clinical interest of suspected immunologic etiology. The use of 
physiologic doses of corticosteroids may be approved after consultation with the 
Sponsor. 
Note:  Inhaled (nasal or pulmonary), ophthalmic, topical steroids and local steroid 
injection are allowed. 
Subjects who, in the assessment by the Investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the study. 
Subjects may receive other medications that the Investigator deems to be medically 
necessary. 
Also see Section 4.1.2, Exclusion Criteria, which describes other medications that are 
prohibited in this trial. There are no prohibited therapies during the Post-Treatment 
Follow-up period of the study (the Schedule of Events is provided in Appendix 17.6). 
6. 
STUDY PROCEDURES FOR THE DOSE-ESCALATION AND EXPANSION 
PHASES 
A Schedule of Events for the Dose-escalation and Expansion Phases is provided in 
Appendix 17.6, Appendix 17.7 (intermittent PLX3397 alternate dosing regimen), and 
Appendix 17.8 (run-in PLX3397 alternate dosing regimen). After written informed 
consent is obtained, a subject’s eligibility for the study and baseline disease status will be 
assessed. A subject must sign the consent form prior to starting any study-related 
procedures or assessments. 
The procedures below follow the Schedule of Events in Appendix 17.6, unless otherwise 
indicated. 


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6.1. 
Screening (Day -28 to Day -1) 
The following activities and/or assessments will be performed at/during Screening: 
• Informed consent, if not already obtained 
• Determination of eligibility. 
• Medical history. 
• Concomitant medication review. 
• Full physical examination, including height, weight, and vital signs 
(blood pressure, respiratory rate, pulse rate, and body temperature [°F]). 
• ECOG performance status. 
• AE assessment. 
• ECG. 
• Tumor imaging [CT, MRI, FDG-PET (for GIST subjects only)]. 
• Digital photography:  cutaneous lesions. 
• Tumor Tissue Collection (optional for Dose-escalation, required for Phase 2 
Expansion, unless deemed medically unsafe by the Investigator) 
• Blood sample collection for complete blood count (CBC) with differential; 
comprehensive serum chemistry; liver function tests; serum pregnancy test 
(women of childbearing potential only); HBV surface antigen test; HCV 
antibody test; coagulation studies (prothrombin time [PT]; activated partial 
thromboplastin time [aPTT], INR) (Appendix 17.5). 
• Urine sample collection for urinalysis with microscopic exam. 
6.2. 
Randomization 
Not applicable. This is an open-label study. 
6.3. 
Run-in Period 
A run-in dosing period with PLX3397 (see Appendix 17.8) may be implemented as an 
alternative dosing regimen. After screening, PLX3397 would be administered for 
2 weeks prior to C1D1 (i.e., first dose of pembrolizumab). 
6.4. 
Treatment Period 
Cycle 1 Day 1 is defined as the day of first pembrolizumab administration. For 
intermittent dosing with PLX3397 see Appendix 17.7 and Run-in, Appendix 17.8. 
6.4.1. 
Cycle 1 (-2 days for assessments on Day 1; ± 3 days for assessments other 
than Day 1) 
• Concomitant medication review:  Days 1, 8, 15, 22, 29, 36. 
• Directed physical examination:  Days 1, 8, 15, 22 or as clinically indicated. 


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• Assessment of Study Drug compliance:  Days 8, 15, 22, 29, 36. 
• ECOG performance status assessment:  Day 1. 
• Vital signs, including height (Day 1 only) and weight:  Days 1, 8, 15, 22, 29, 
36. 
• AE monitoring:  Days 1, 8, 15, 22, 29, 36. 
• Blood sample collection for complete blood count (CBC) with differential:   
Days 1, 8, 15, 22, 29, 36. 
• Blood sample collection for comprehensive serum chemistry panel:   
Days 1, 8, 15, 22, 29, 36. 
• Blood sample collection for liver function tests:   
Days 1, 8, 15, 22, 29, 36. 
• Blood sample collection for exploratory biomarkers of drug effects on liver:   
Days 1 (predose), 8, 15, 22, 29. 
• Blood sample collection for MDSC:   
Days 1 (predose), 15 
• Blood sample collection for thyroid function tests:  Day 1. 
• Urine sample collection for urinalysis with microscopic exam:  Days 1 and 22. 
• Pregnancy test (serum beta human chorionic gonadotropin [β-hCG]) for 
women of childbearing potential only:  must be performed ≤72 hours before 
dosing on Day 1. 
• Electrocardiogram (ECG):  Days 1 and 15. 
• Administration of IV pembrolizumab:  Days 1 and 22. 
• Administration of oral PLX3397:  Each day of Cycle 1 (i.e., Days 1 through 
42). (for Cohort [int], Days 8 through 21, then 29 through 42) 
• Blood sample collection for PK and anti-pembrolizumab antibodies:  see 
Table 10 for continuous dosing, Appendix 17.7 for intermittent dosing. 
• Tumor tissue collection:  Optional for Dose-escalation, required for Phase 2 
Expansion, unless deemed medically unsafe by the Investigator. Day 29 for 
continuous PLX3397 regimen (Day 22 for intermittent dosing). (For days 
other than Day 1, If PLX3397 study drug interruption occurs during the week 
prior to the on-treatment biopsy, the Medical Monitor should be contacted.) 
• Exploratory pharmacology blood sample collection:  predose on Days 1, 22 
and 29 
6.4.2. 
Cycle 2 (± 3 days) 
• Concomitant medication review:  Days 1, 8, 15, and 22. 
• Assessment of Study Drug compliance:  Days 1 and 22. 


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• Physical examination 
− Full physical examination, weight, and vital signs (blood pressure, 
respiratory rate, pulse rate, and body temperature [°F]):  Day 1. 
− At other visits, directed physical examination:  As clinically indicated. 
• ECOG performance status assessment:  Day 1. 
• Vital signs, including weight:  Days 1 and 22. 
• Tumor imaging [CT, MRI, FDG-PET (for GIST subjects only)]. 
• AE monitoring:  Days 1 and 22. 
• Blood sample collection for CBC with differential:  Day 1 and 22. 
• Urine sample collection for urinalysis with microscopic examination:  Day 1. 
• Blood sample collection for comprehensive serum chemistry panel:   
Days 1 and 22. 
• Blood sample collection for liver function tests:  Days 1, 8, 15 and 22. 
• Blood sample collection for thyroid function tests:  Day 1. 
• ECG:  Day 1 
• Administration of IV pembrolizumab:  Days 1 and 22. 
• Administration of oral PLX3397:  Each day of Cycle 2 (i.e., Days 1 through 
42). (Cohort [int], Days 8 through 21, then 29 through 42) 
• Blood sample collection for PK and anti-pembrolizumab antibodies:  Day 1 
(see Table 10). 
6.4.3. 
Cycle 3 (± 3 days) 
• Concomitant medication review:  Days 1 and 22. 
• Assessment of Study Drug compliance:  Days 1 and 22. 
• Physical examination 
− Full physical examination, weight, and vital signs (blood pressure, 
respiratory rate, pulse rate, and body temperature [°F]):  Day 1. 
− At other visits, directed physical examination:  As clinically indicated. 
• ECOG performance status assessment:  Day 1. 
• Vital signs, including weight:  Days 1 and 22. 
• AE monitoring:  Days 1 and 22. 
• Blood sample collection for CBC with differential:  Day 1 and Day 22. 
• Blood sample collection for thyroid function tests:  Day 1. 
• Urine sample collection for urinalysis with microscopic examination:  Day 1. 


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• Blood sample collection for comprehensive serum chemistry panel:  Day 1 
and Day 22. 
• Blood sample collection for liver function tests:  Day 1 and Day 22. 
• ECG:  Day 1. 
• Administration of IV pembrolizumab:  Days 1 and 22. 
• Administration of oral PLX3397:  Each day of Cycle 3 (i.e., Days 1 through 
42). (Cohort [int], Days 8 through 21, then 29 through 42) 
• Blood sample collection for PLX3397 PK:  Day 1 (see Table 10) 
6.4.4. 
Cycle 4 and Beyond (± 3 days) 
• Concomitant medication review:  Days 1 and 22. 
• Assessment of Study Drug compliance:  Days 1 and 22. 
• Physical examination 
− Full physical examination, weight, and vital signs (blood pressure, 
respiratory rate, pulse rate, and body temperature [°F]):  Day 1. 
− At other visits, directed physical examination:  As clinically indicated. 
• ECOG performance status assessment:  Day 1. 
• Vital signs, including height (Day 1 only) and weight:  Days 1 and 22. 
• Tumor imaging [CT, MRI, FDG-PET (for GIST subjects only)]. 
• AE monitoring:  Days 1 and 22. 
• Blood sample collection for CBC with differential:  Day 1 and Day 22. 
• Blood sample collection for thyroid function tests:  Day 1. 
• Urine sample collection for urinalysis with microscopic examination:  Day 1. 
• Blood sample collection for comprehensive serum chemistry panel:  Day 1 
and Day 22. 
• Blood sample collection for liver function tests:  Day 1 and Day 22. 
• ECG:  Day 1. 
• Administration of IV pembrolizumab:  Days 1 and 22. 
• Administration of oral PLX3397:  Each day of Cycle 4  
(i.e., Days 1 through 42). 
• Blood sampling for PK (beginning Cycle 8 PK every other cycle) and anti-
pembrolizumab antibodies (every other cycle):  Day 1 (see Table 10). 
6.5. 
End of Treatment (+3 days) 
The following procedures will be performed at time of the subject’s last dose: 


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• Concomitant medication review. 
• Assessment of Study Drug compliance. 
• Assessment of post-treatment discontinuation anticancer therapy status. 
• AE monitoring. 
• Full Physical Exam 
• ECOG performance status assessment. 
• Vital signs, including weight. 
• Blood sample collection for CBC with differential. 
• Urine sample collection for urinalysis with microscopic examination. 
• Blood sample collection for comprehensive serum chemistry panel. 
• Blood sample collection for liver function tests. 
• Blood sample collection for exploratory biomarkers of drug effects on liver. 
• ECG. 
• Tumor imaging, if not completed within the previous 7 days. 
• Digital photography of cutaneous lesions, if clinically indicated. 
• Tumor tissue collection - optional. (If PLX3397 study drug interruption 
occurs during the week prior to the on-treatment biopsy, the Medical Monitor 
should be contacted.) 
• Exploratory pharmacology blood sample collection. 
6.6. 
Follow-up 
6.6.1. 
Safety Follow-up (28 days ± 7 days) 
The safety follow-up visit will occur 28 days (± 7 days) after completion or 
discontinuation from study treatment. 
• Concomitant medication review. 
• Assessment of post-treatment discontinuation anticancer therapy status. 
• AE monitoring. 
• Vital signs, including weight. 
• Blood sample collection for CBC with differential. 
• Urine sample collection for urinalysis with microscopic examination. 
• Blood sample collection for comprehensive serum chemistry panel. 
• Blood sample collection for liver function tests. 
• Blood sample collection for thyroid function tests. 


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• Blood sample collection for pembrolizumab PK and anti-pembrolizumab 
antibodies:  see Table 10. 
6.6.2. 
SAE Follow-Up (± 7 days) 
SAE monitoring (12-week follow-up only if the patient has not started other 
chemotherapy, see Section 11.2) will occur every 12 weeks (± 7 days) via telephone 
or from available clinic notes, after completion or discontinuation from treatment. 
6.7. 
Follow-up 
6.7.1. 
Safety Follow-up (28 days ± 7 days) 
The safety follow-up visit will occur 28 days (± 3 days) after the subject’s last dose. 
• Concomitant medication review 
• Assessment of post-treatment discontinuation anticancer therapy status. 
• AE monitoring. 
• Directed physical exam as clinically indicated. Vital signs, including weight. 
• Blood sample collection for CBC with differential. 
• Blood sample collection for thyroid function tests. 
• Urine sample collection for urinalysis with microscopic examination. 
• Blood sample collection for comprehensive serum chemistry panel. 
• Blood sample collection for liver function tests. 
7. 
PROTOCOL DEVIATIONS 
The Sponsor must be notified of all intended or unintended deviations to the protocol 
(e.g., inclusion/exclusion criteria, dosing, missed study visits) on an expedited basis. 
The Investigator, or person designated by the Investigator, should document and explain 
any deviation from the approved protocol. 
If a subject who was deemed ineligible or received the incorrect dose or investigational 
treatment had at least 1 dose of investigational product, data should be collected for that 
subject for safety purposes. 
The Investigator should notify the IRB of significant deviations from the protocol in 
accordance with local procedures. 
8. 
EFFICACY ASSESSMENTS 
8.1. 
Primary Efficacy Variable:  Dose-escalation Phase 
There is no primary variable for clinical efficacy. 


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8.2. 
Secondary Efficacy Variable:  Expansion Phase 
The secondary efficacy variable is ORR as determined by RECISTv1.1 guidelines 
(Appendix 17.4) and applies to the Expansion Phase only of the study. Objective 
response rate will be assessed separately for each of the tumor types. 
Rationale for Determining ORR by RECISTv1.1 and by irRECIST 
In addition to RECISTv1.1 guidelines, (per Eisenhauer 2009; see Appendix 17.4), 
irRECIST guidelines will be used to account for the unique tumor response 
characteristics seen with treatment of the combination of pembrolizumab and PLX3397 
(see the irRECIST Tip Sheet, provided in the Study Reference Manual). 
Immunotherapeutic agents such as PLX3397 and pembrolizumab may produce antitumor 
effects by potentiating endogenous cancer-specific immune responses. The response 
patterns seen with such an approach may extend beyond the typical time course of 
responses seen with cytotoxic agents, and can manifest a clinical response after an initial 
increase in tumor burden or even the appearance of new lesions. Standard RECIST 
criteria may not provide a complete response assessment of immunotherapeutic agents 
such as pembrolizumab. Therefore, RECISTv1.1 will be used with the following 
adaptations: 
• If radiologic imaging shows initial PD, tumor assessment should be repeated 
≥4 weeks later in order to confirm PD with the option of continuing assigned 
study treatment while awaiting radiologic confirmation of progression. If 
repeat imaging shows a reduction in the tumor burden compared to the initial 
scan demonstrating PD, treatment may be continued/resumed. If repeat 
imaging confirms PD, subjects will be discontinued from study therapy. In 
determining whether or not the tumor burden has increased or decreased, 
Investigators should consider all target lesions as well as non-target lesions 
(please refer to the Site Imaging Manual). 
• In subjects who have initial radiological evidence of PD, it is at the discretion 
of the treating physician whether to continue a subject on study treatment until 
repeat imaging is obtained a minimum of 4 weeks later. This clinical 
judgment decision should be based on the subject’s overall clinical condition, 
including performance status, clinical symptoms, and laboratory data. 
Subjects may receive treatment while waiting for confirmation of PD if they 
are clinically stable as defined by the following criteria: 
− Absence of signs and symptoms indicating disease progression 
− No decline in ECOG performance status 
− Absence of rapid progression of disease 
− Absence of progressive tumor at critical anatomical sites (e.g., cord 
compression) requiring urgent alternative medical intervention 
• When feasible, subjects should not be discontinued until progression is 
confirmed. Subjects who are deemed clinically unstable are not required to 
have repeat imaging for confirmation of PD. 


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9. 
PHARMACOKINETIC/PHARMACODYNAMIC ASSESSMENTS 
9.1. 
Pharmacokinetic Variables 
The PK profile of plasma PLX3397 will be analyzed by measurement of area under the 
plasma concentration–time curve from time zero to 6 hours (AUC0-6), Cmax, and Tmax. 
Dose proportionality following study treatment will be explored by analyzing natural log-
transformed pharmacokinetic variables, AUC0-6, and Cmax, with a linear model including 
the natural log-transformed dose as a covariate. Dose linearity for AUC0-6, and Cmax will 
also be explored by a linear model. 
A formal PK statistical analysis plan will be created for this protocol, and a separate 
formal PK report will be written for inclusion in the final study report. 
A formal PK analysis of pembrolizumab levels will not be carried out in view of the lack 
of CYP-mediated drug-drug interaction for pembrolizumab. 
9.2. 
Pharmacodynamic Variables 
PK samples scheduled in Table 10 may be used for pharmacodynamic biomarkers as 
indicated in the Schedule of Events (Appendix 17.6 and Appendix 17.7) and will be 
analyzed for immunoregulatory effects of pembrolizumab and PLX3397, e.g., CD8 
immunohistochemistry. Preparation, handling and shipping of samples will be provided 
in the Laboratory Manual. 
9.3. 
Biomarker and Exploratory Variables 
Blood samples (plasma and serum) will be collected to measure biomarkers of drug 
effects on liver at the following time points:  Pre-Treatment, Day 8, Day 15, Day 22, 
Day 29, and 5 to 8 days after PLX3397 is withheld or discontinued and for subjects who 
experience Grade 2 or higher elevations in AST or ALT, preferably when elevations are 
still present. Preparation, handling and shipping of blood samples will be provided in the 
Laboratory Manual. 
Blood samples will be collected to assess MDSC at Cycle 1 Day 1 and Cycle 1 Day 15. 
Preparation, handling and shipping of blood samples will be provided in the Laboratory 
Manual. 
Pre- and post-treatment tissue (core needle or excisional biopsy required) will be archived 
for RNA analyses related to effects of pembrolizumab and PLX3397 on immune cells. 
For example, tissue will be analyzed for PD-L1, CD8, CD68, and NanoString. 
Preparation, handling and shipping of samples will be provided in the Lab Manual. 
Subjects for whom newly obtained samples cannot be obtained (e.g., inaccessible or 
patient safety concern) may submit an archived specimen only upon agreement from the 
Sponsor. 


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9.4. 
Timing of Assessments 
9.4.1. 
Routine Assessments 
Pharmacokinetic (PK) and Pharmacodynamic assessments to be performed during the 
study are summarized in Table 10 and the Schedule of Events, Appendix 17.6. For 
intermittent dosing see Appendix 17.7. For the PLX3397 run-in, a trough PK sample will 
be required at the end of the run-in period, i.e., C1D1. 


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Table 10. Pharmacokinetic and Pharmacodynamic Assessments in Study PLX108-14:  Dose-escalation and Expansion Phases 
 
Drug Treatment 
Post-treatment 
Combination Dosing Cycle  
C1D1 
C1D4–8 
C1D15 
C2D1 
C3D1 
C4D1 
C5D1 
C6D1 
C7D1 
C8D1 
EOT 
28 days 
Dose-escalation Phase:  PK Assessments 
Pembrolizumab 
Xa 
Xb 
Xc 
Xd 
 
Xd 
 
Xd 
 
Xd,e 
 
 
PLX3397f 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Expansion Phase:  PK Assessments 
Pembrolizumab 
Xa 
Xb 
Xc 
Xd 
 
 
 
 
 
 
 
 
PLX3397g 
 
 
X 
X 
 
 
 
 
 
 
 
 
Anti-drug Antibody Tests 
Anti-pembrolizumab antibody testh 
X 
 
 
X 
 
 
 
 
 
 
 
 
C = cycle (42 days); D = day; PK = pharmacokinetic; EOT = End of Treatment (date of last dose) 
Note (1):  Subjects will self-administer PLX3397 twice daily as a split dose at home. However, on days on which subjects are scheduled for clinic visits (see 
Appendix 17.6), subjects will bring their morning dose of PLX3397 to the clinic and receive it under the supervision of study site staff. If the patient has already 
taken their morning dose of PLX3397 prior to a PLX3397 trough PK day, do collect a PK sample even though it is not a trough sample. 
Note (2):  PK samples can be used for pharmacodynamics assays. 
Note (3):  PLX3397 trough PK sample will be drawn predose at -30 minutes (± 15 minutes). PLX3397 detailed PK sampling will be drawn post dose at 30 minutes 
(± 15 minutes), and 1, 2, 4, and 6 hours (± 30 minutes). 
Note (4):  For intermittent PLX3397 PK sampling see Appendix 17.7; for run in PLX3397 PK sampling see Appendix 17.8. 
a 
C1D1:  Collect samples predose within 24 hours of dosing of pembrolizumab and before dosing of PLX3397; post dose (within 30 minutes after end-of-infusion of 
pembrolizumab); and post dose 24 hours after end-of-infusion. 
b 
C1D4–8:  Collect a sample post dose between 72–168 hours after end-of-infusion. 
c 
C1D15:  Collect a sample post dose 336 hours after C1D1 end-of-infusion. 
d 
C2D1, C4D1, C6D1, C8D1 and then every 2 cycles (12 weeks) thereafter:  Collect samples predose within 24 hours before administration of pembrolizumab and 
before administration of PLX3397. 
e 
C8D1:  Collect samples post dose (within 30 minutes after end-of-infusion of pembrolizumab). 
f 
PLX3397 PK sampling time points (Dose-escalation Phase):  PLX3397 detailed PK sampling will be drawn on the first day of PLX3397 dosing (C1D1 for standard 
dosing Appendix 17.6; for intermittent PLX3397 PK sampling and dosing see Appendix 17.7). PLX3397 trough PK sample and detailed PK sampling will be drawn 
after the first 2 weeks of dosing (e.g., C1D15 for standard dosing). For subsequent cycles, PLX3397 trough PK samples will be drawn on the first day for that cycle 
(e.g., C2D1). 
g 
PLX3397 trough PK sample and detailed PK sampling will be drawn after two weeks of dosing (C1D15 for standard dosing). If PLX3397 study drug interruption 
occurs during the week prior to a scheduled PK blood sampling, the Medical Monitor should be contacted. For cycle 2, PLX3397 trough PK samples will be drawn 
on the first day for that cycle (i.e., C2D1). No PK samples will be collected from Cycle 3 and onward. However, PK blood samples may be requested if the subject 
undergoes a dose adjustment or experiences an SAE or ECI. Time since the last dose of PLX3397 should be noted. If a subject undergoes a dose adjustment, a trough 
sample and a 2 hour postdose sample (± 30 minutes) may be requested within approximately 2 weeks. 


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h 
C1D1, C2D1, C4D1, C6D1, C8D1 and D1 every 2 cycles (12 weeks) thereafter:  Collect samples for anti-pembrolizumab antibody test predose within 24 hours 
before infusion at the same time the pembrolizumab PK samples are collected. 


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9.4.2. 
Additional Pharmacokinetic Assessments 
Additional post-dose peak PK samples will be drawn within 30 minutes after the end of 
pembrolizumab infusion at Cycles 1 and 8. An additional single PK sample should be 
drawn at 24 hours (Day 2), between 72 and 168 hours (Day 4–8) and 336 hours (Day 15) 
after Cycle 1 dosing. 
10. SAFETY ASSESSMENTS 
10.1. General Procedures for Assessing and Recording Adverse Events 
All AEs will be recorded from the time the consent form is signed through 28 days 
following cessation of study treatment and at each examination. The reporting timeframe 
for AEs that meet any serious criteria (i.e., are SAEs) is described in Section 11.2 and for 
ECIs in Section 11.6. 
Medical conditions (including laboratory values/vital signs that are out of range) that 
were diagnosed or known to exist prior to the first dose will be recorded as part of 
medical history (including all events occurring during the screening period). All SAEs 
are to be reported according to the procedures in Section 11.2 SAE Reporting-Procedure 
for Investigators. Always report the diagnosis as the AE or SAE term. When a diagnosis 
is unavailable, report the primary sign or symptom as the AE or SAE term with additional 
details included in the narrative until the diagnosis becomes available. If the signs and 
symptoms are distinct and do not suggest a common diagnosis, report them as individual 
entries of AE or SAE. For events that are serious due to hospitalization, the reason for 
hospitalization must be reported as the SAE (diagnosis or symptom requiring 
hospitalization). A procedure is not an AE or SAE, but the reason for the procedure may 
be an AE or SAE. Pre-planned (prior to signing the ICF) procedure or treatment requiring 
hospitalization for pre-existing conditions that do not worsen in severity should not be 
reported as SAEs (see Section 10.1.1 for definitions, including Progression of Cancer). 
For deaths, the underlying or immediate cause of death should always be reported as an 
SAE unless due only to disease progression unrelated to Study Drug. Disease progression 
is a study endpoint and consequently, should not be reported as an AE/SAE 
(Section 10.1.1.2). In addition, any serious, untoward event that may occur subsequent to 
the reporting period that the Investigator assesses as related to Study Drug should also be 
reported and managed as an SAE. 
At each visit, the Investigator will determine whether any AEs have occurred by 
evaluating the subject. AEs may be directly observed, reported spontaneously by the 
subject or by questioning the subject at each study visit. Subjects should be questioned in 
a general way, without asking about the occurrence of any specific symptoms. The 
Investigator must assess all AEs to determine seriousness, severity, and causality, in 
accordance with the definitions in Section 10.1.1. The Investigator’s assessment must be 
clearly documented in the site’s source documentation with the Investigator’s signature. 
All laboratory values must be appraised by the Investigator as to clinical significance. All 
abnormal laboratory values considered clinically significant by the Investigator must be 


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recorded as an AE on the CRF, and if serious, report as an SAE following the procedures 
in Section 11.2. 
The Investigator should follow subjects with AEs until the event has resolved or the 
condition has stabilized. In case of unresolved AEs, including significant abnormal 
laboratory values at the end of study assessment, these events will be followed up until 
resolution or until they become clinically not relevant. 
10.1.1. Definitions 
10.1.1.1. Adverse Event 
Any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding, for example), symptom, or 
disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product (ICH E2A Guideline Clinical Safety Data 
Management:  Definitions and Standards for Expedited Reporting, Oct 1994). 
It is the responsibility of Investigators, based on their knowledge and experience, to 
determine, those circumstances or abnormal lab findings which should be considered 
AEs. 
10.1.1.2. Progression of Cancer 
Disease progression is a study endpoint and should not be reported as an AE/SAE unless 
it is considered to be drug-related by the Investigator. 
10.1.1.3. Serious Adverse Event 
Any untoward medical occurrence that at any dose: 
• Results in death 
• Is life-threatening 
• Requires inpatient hospitalization longer than 24 hours or prolongation of 
existing hospitalization. An emergency room visit without hospitalization is 
not considered a hospitalization. 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
• Is an important medical event 
Guidance for determining whether an event should be assessed as serious in nature: 
• The term life-threatening in the definition of serious refers to an event in 
which the subject was at risk of death at the time of the event; it does not refer 
to an event which hypothetically might have caused death if it were more 
severe (ICH E2A Guideline Clinical Safety Data Management:  Definitions 
and Standards for Expedited Reporting, Oct 1994). 


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• The term 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 1 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. 
Medical and scientific judgment should be exercised in deciding whether 
expedited reporting is appropriate for an important medical event. 
• A procedure (e.g., surgery, radiation) is not an AE or SAE, but the reason for 
the procedure may be an AE or SAE. 
• Preplanned (i.e., prior to signing the ICF) procedures or treatment requiring 
hospitalizations for pre-existing conditions that do not worsen in severity are 
not SAEs. 
10.1.2. Adverse Event Severity 
All AEs will be graded (1 to 5; see below) according to NCI CTCAE. For AEs not listed, 
the following guideline should be used: 
• Grade 1:  Mild AE, defined as, awareness of sign or symptom; however, these 
are easily tolerated and, does not interfere with activities of daily living 
(ADL). 
• Grade 2:  Moderate AE, defined as discomfort enough to cause interference 
with ADL. 
• Grade 3:  Severe AE, defined as limiting self-care ADL. 
• Grade 4:  Life-threatening consequences; urgent intervention indicated. 
• Grade 5:  Death. 
Severity vs. Seriousness:  Severity is used to describe the intensity of a specific event 
while the event itself, however, may be of relatively minor medical significance (such 
as severe headache). This is not the same as "seriousness," which is based on 
subject/event outcome at the time of the event. For example, the NCI CTCAE 
Grade 4 (life-threatening consequences; urgent intervention indicated) is assessed 
based on unique clinical descriptions of severity for each AE, and these criteria may 
be different from those used for the assessment of AE seriousness. An AE assessed as 
grade 4 based on the NCI CTCAE grades may or may not be assessed as serious 
based on the seriousness criteria. 
10.1.3. Causality Assessment 
The Investigator should assess causal relationship between an AE and each of the Study 
Drugs (pembrolizumab and PLX3977) on the basis or his/her clinical judgment and the 


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following definitions. The causality assessment should be made based on the available 
information and can be updated as new information becomes available. 
• 1 = Related: 
− The AE follows a reasonable temporal sequence from Study Drug 
administration, and cannot be reasonably explained by the subject’s 
clinical state or other factors (e.g., disease under study, concurrent 
diseases, and concomitant medications). 
− The AE follows a reasonable temporal sequence from Study Drug 
administration, and is a known reaction to the drug under study or its 
chemical group, or is predicted by known pharmacology. 
• 2 = Not Related: 
− The AE does not follow a reasonable sequence from study product 
administration, or can be reasonably explained by the subject’s clinical 
state or other factors (e.g., disease under study, concurrent diseases, and 
concomitant medications). 
10.1.4. Action Taken Regarding the Study Product 
• 1 = Dose Not Changed:  No change in Study Drug dosage was made. 
• 2 = Drug Withdrawn:  The study product was permanently stopped. 
• 3 = Dose Reduced:  The dosage of study product was reduced. 
• 4 = Drug Interrupted:  The study product was temporarily stopped. 
• 5 =Dose Increased:  The dosage of study product was increased. 
10.1.5. Adverse Event Outcome 
• 1 = Recovered/Resolved 
− The subject fully recovered from the AE with no residual effect observed. 
• 2 = Recovered/Resolved with Sequelae 
− The residual effects of the AE are still present and observable. 
− Include sequelae/residual effects. 
• 3 = Not Recovered/Not Resolved 
− The AE itself is still present and observable. 
• 4 = Fatal 
• 5 = Unknown 


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10.1.6. Other Action Taken for Event 
• 1 = None. 
− No treatment was required. 
• 2 = Medication required. 
− Prescription and/or OTC medication was required to treat the AE. 
• 3 = Hospitalization or prolongation of hospitalization required. 
− Hospitalization was required or prolonged due to the AE, whether or not 
medication was required. 
• 4 = Other. 
10.2. Serious Adverse Event Reporting–Procedure For Investigators 
Any SAE, or follow up to a SAE, including death due to any cause other than progression 
of the cancer under study (see Section 10.1.1.2) that occurs to any subject from the time 
the informed consent is signed through 90 days following cessation of treatment, or 
30 days following cessation of treatment if the subject initiates new anticancer therapy, 
whichever is earlier, whether or not related to the Sponsor's product, must be reported 
within 24 hours to the Sponsor. 
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. 
Medical 
Monitor:  
(Emergency 
Contacts) 
 
Plexxikon Inc.  
91 Bolivar Drive, Berkeley, CA 94710 
Telephone:  
 
Fax:  
 
E-mail:  
m 
SAE Reporting 
Contact 
The Investigator will ensure that the SAE 
reporting form is completed on the eCRF or 
E-mailed/eFaxed to the following address within 
24 hours of learning of the occurrence of any 
SAE. 
SynteractHCR Safety SAE Facsimile 
Fax:  760-268-6500 
Telephone:  
 
Email:  safetyfax@synteracthcr.com 
 


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10.2.1. Notifying Regulatory Authorities, Investigators, IRB/EC, and Competent 
Authorities 
Plexxikon and/or CRO will inform Investigators, IRBs or Ethics Committees, and 
regulatory authorities of any suspected unexpected serious adverse event reactions 
(SUSARs) occurring in other study centers or other Plexxikon studies of the 
investigational product, as appropriate per local reporting requirements. 
In the US, upon receipt of the Sponsor’s notification of SUSARs that occurred with the 
investigational product, unless delegated to the Sponsor, it is the Investigator’s 
responsibility to inform the IRB per Sponsor’s instruction. 
10.3. Contraception 
Pembrolizumab and PLX3397 may have adverse effects on a fetus in utero. Furthermore, 
it is not known if either drug has transient adverse effects on the composition of sperm. 
Therefore, nonpregnant, non-breast-feeding women may be enrolled only if they are 
willing to use 2 methods of birth control or are considered highly unlikely to conceive. 
Highly unlikely to conceive is defined as 1) surgically sterilized, or 2) postmenopausal 
(a woman who is ≥45 years of age and has not had menses for greater than ≥1 year will 
be considered postmenopausal), or 3) not heterosexually active for the duration of the 
study. For this trial, male subjects will be considered to be of non-reproductive potential 
if they have azoospermia (whether due to having had a vasectomy or due to an 
underlying medical condition). 
The two 2 birth control methods can be either 2 barrier methods or a barrier method plus 
a hormonal method to prevent pregnancy. Subjects should start using birth control from 
study Visit 1 throughout the study period up to 120 days after the last dose of study 
therapy. 
The following are considered adequate barrier methods of contraception:  diaphragm, 
condom (by the partner), copper intrauterine device, sponge, or spermicide as per local 
regulations or guidelines. Appropriate hormonal contraceptives will include any 
registered and marketed contraceptive agent that contains an estrogen and/or a 
progestational agent (including oral, subcutaneous, intrauterine, or intramuscular agents). 
Note:  hormonal contraceptives are contraindicated for triple-negative breast cancer. 
Subjects should be informed that taking the study medication may involve unknown risks 
to the fetus (unborn baby) if pregnancy were to occur during the study. In order to 
participate in the study they must adhere to the contraception requirement (described 
above) for the duration of the study and during the follow-up period defined in 
Section 11.4. If there is any question that a subject will not reliably comply with the 
requirements for contraception, that subject should not be entered into the study. 
10.4. Pregnancy and Lactation and Reporting Requirements to Plexxikon 
Although pregnancy and lactation are not considered AEs, it is the responsibility of 
Investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them), including the pregnancy of a male subject's female 
partner that occurs during the trial or within 120 days of completing the study. All 


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subjects and female partners of male subjects who become pregnant must be followed to 
the completion/termination of the pregnancy. Pregnancy outcomes of spontaneous 
abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal death, 
intrauterine death, miscarriage, and stillbirth must be reported as serious events 
(Important Medical Events). If the pregnancy continues to term, the outcome (health of 
infant) must also be reported. 
Such events must be reported within 24 hours to the Sponsor either by electronic media 
or paper. Sponsor Contact information can be found in the Study Reference Manual. 
10.5. Use in Nursing Women 
It is unknown whether pembrolizumab is excreted in human milk. Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, subjects who are breast-feeding are not eligible for enrollment. 
10.6. Events of Clinical Interest (ECI) 
Selected nonserious and SAEs are also known as ECI and must be recorded as such on 
the AE CRF/worksheets. For reporting, Plexxikon contact information can be found in 
the Investigator Trial File Binder (or equivalent). 
ECI for this trial include: 
1. An overdose of Sponsor's product, as defined in Section 10.11, which is not 
associated with clinical symptoms or abnormal laboratory results should be 
reported to Plexxikon or its designee within 24 hours either by electronic 
media or paper. 
2. An elevated AST or ALT lab value that is greater than or equal to 3 × ULN 
and an elevated total bilirubin lab value that ≥2 × ULN and, at the same 
time, an alkaline phosphatase (AP) lab value that <2 × ULN, as determined 
by way of protocol-specified laboratory testing or unscheduled laboratory 
testing should be reported to Plexxikon or its designee within 24 hours 
either by electronic media or paper. 
Note:  These criteria are based upon available regulatory guidance 
documents. The purpose of the criteria is to specify a threshold of abnormal 
hepatic tests that may require an additional evaluation for an underlying 
etiology. The trial site guidance for assessment and follow up of these 
criteria can be found in the Study Reference Manual. 
Subjects should be assessed for possible ECIs prior to each dose. 
10.7. Clinical Laboratory Evaluations 
Clinical laboratory evaluations will be performed at the study visits indicated in the 
Schedule of Events (Appendix 17.6). Collection, processing, labeling, handling, and 
shipment of samples will be outlined in the separate Laboratory Manual. Clinical 
laboratory evaluations will be performed as described in Appendix 17.5. 


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10.8. Vital Signs 
Assessments of vital signs include blood pressure, heart rate, respiratory rate, and 
temperature (oral, axillary or tympanic, °F), height (at protocol-specified visits only), 
weight,). The subject is to be in the same position each time vital signs are assessed (i.e., 
supine, etc.) over the course of the study. 
10.9. Electrocardiograms 
ECGs should be performed pre-dose. Subjects should rest in the supine or semi-
recumbent 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, RR interval, PR interval, QRS interval, 
QT interval, and QTcF interval. 
10.10. Physical Findings and ECOG Performance Status 
Physical findings will be assessed via a complete physical examination (at protocol-
specified visits). All other physical examinations will be disease-specific and symptom-
directed. Photography may be included as part of the physical examination for subjects 
who consent to the procedure. ECOG Performance Status (Appendix 17.3) will be 
assessed at protocol specified visits. 
10.11. Overdose and Reporting of Overdose to Plexxikon 
For purposes of this trial, an overdose of pembrolizumab will be defined as 
≥1000 mg (5 times the dose) of pembrolizumab. An overdose of PLX3397 for reporting 
as described in Section 11.6 will be defined as any dose exceeding the prescribed daily 
dose by ≥40%; smaller overdoses will be collected as described in the Study Reference 
Manual. 
No specific information is available on the treatment of overdose of pembrolizumab or 
PLX3397. In the event of overdose, study treatment (either pembrolizumab or PLX3397) 
should be temporarily discontinued and the subject should be observed closely for signs 
of toxicity. Appropriate supportive treatment should be provided if clinically indicated. 
If an AE is associated with (“results from”) the overdose of Sponsor’s product or vaccine, 
the AE is to be reported as an SAE even if no other seriousness criteria are met. 
If a dose of Sponsor’s product meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose 
will be reported as a nonserious ECI (Section 11.6), using the terminology “accidental or 
intentional overdose without adverse effect.” 


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11. STATISTICAL METHODS 
11.1. Analysis Sets 
For each of the 2 phases of the study (Dose-escalation Phase, Expansion Phase), there 
will be 3 analysis sets: 
• Safety Analysis Set:  Defined as all subjects who received at least 1 dose of 
study treatment (i.e., PLX3397 or pembrolizumab). This is the primary 
analysis set for safety. 
• Efficacy Analysis Set (EAS):  Defined as all subjects in the Safety Analysis 
Set who met all enrollment criteria and received at least 1 dose of study 
treatment (i.e., PLX3397 or pembrolizumab). The EAS is the primary analysis 
set for efficacy. 
In the Expansion Phase, efficacy will be described separately for each of the tumor type 
cohorts in Table 2. 
11.2. General Statistical Considerations 
Continuous variables will be summarized by the number of observations, mean, standard 
deviation, median, and minimum and maximum values. Categorical variables will be 
summarized using frequency counts and percentages. In general, the baseline value for a 
variable is the last non-missing value before study treatment. 
11.2.1. Dose-escalation Phase 
The Dose-escalation Phase of the study will employ a standard 3+3 design in order to 
determine the MTD/MAD for PLX3397 (which will be the RP2D for future trials) when 
administered with pembrolizumab 200 mg IV every 3 weeks. As shown in Table 1, up to 
4 dose levels of continuous PLX3397 dosing will be investigated. Alternative PLX3397 
dose regimens at one or more of these dose levels also may be explored (see 
Section 3.1.1). Subjects will be treated and analyzed in cohorts of 3 to 6, and the dose 
level will be escalated if the clinical toxicity is acceptable. 
11.2.2. Expansion Phase 
Once the RP2D is determined, the Expansion Phase will be initiated to investigate the use 
of PLX3397 in combination with pembrolizumab in separate disease cohorts based on 
tumor type/subtype (Table 2). A key objective of this phase is to obtain preliminary 
estimates of disease response in each cohort. A truncated sequential probability ratio test 
for single-arm binary response studies will be employed in each of these cohorts 
(DOD RAC 2005). This sequential monitoring procedure establishes continuous 
boundary conditions to stop enrollment for either success (efficacy) or futility at any time 
up to the total prescribed sample size; hence, monitoring of response outcomes may be 
applied continuously for early closing of a cohort for success or futility using the 
sequential monitoring boundaries. Subjects will be evaluated for response until they 
discontinue treatment or until 6 months after the last subject is enrolled in the cohort, 
whichever occurs first. The study team will make decisions regarding early closing of a 


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cohort for success or futility. Since response rates to single-agent pembrolizumab therapy 
vary by disease type, there will be different sample sizes, operating characteristics and 
stopping rules for each cohort. Table 11 lists each tumor type of interest, with associated 
null rate and assumed true response rate under the alternative hypothesis, and the total 
sample size planned for each cohort to evaluate success or futility. The last two columns 
in the table list by cohort the total sample size and the minimum number of responders 
needed to conclude success for that total sample size (i.e., reject the null response rate). 
Table 11. Sequential Monitoring Approach During Expansion Phase:  
Study PLX108-14 
Tumor Type 
Null Rate  
(%) 
Assumed True 
Response Rate 
(%) 
Number of Subjects 
When Monitoring to 
Start (Minimum) 
For Total Sample Size 
Total 
Number 
Minimum No. 
Responders for 
Success Criterion 
Melanoma (Tx-naïve) 
40 
70 
7 
23 
15 
Melanoma (1º progr.) 
5 
20 
10 
33 
6 
Melanoma (2º progr.) 
10 
30 
10 
33 
9 
NSCLC 
(non-squamous; 
EGFR and ALK wild-
type) 1º progr. with 
anti-PD1/anti-PDL1 
therapy 
5 
20 
10 
33 
6 
Ovarian 
10 
30 
10 
33 
9 
TNBC 
15 
35 
9 
38 
12 
SCCHN 
(1º progr. with anti-
PD1/anti-PDL1 
therapy) 
5 
20 
10 
33 
6 
Clear cell renal cell 
carcinoma (CCRCC) 
20 
40 
13 
48 
17 
PDA 
5 
20 
10 
33 
6 
Gastric 
30 
55 
9 
39 
20 
Glioblastoma 
multiforme (GBM) 
5 
20 
10 
33 
6 
GIST 
10 
30 
10 
33 
9 
High grade soft tissue 
sarcomaa 
15 
35 
9 
38 
12 
Cholangiocarcinoma 
10 
30 
10 
33 
9 
Totals 
- 
- 
137 
483 
- 
1º progr. = primary progressive; 2º progr. = secondary progressive; GIST = gastrointestinal stromal tumor; 
NSCLC = non-small-cell lung cancer; PDA = pancreatic ductal adenocarcinoma;  
SCCHN = squamous cell cancer of the head and neck; TNBC = triple-negative breast cancer; 
Tx = treatment 
 
 
a 
High grade soft tissue sarcoma includes undifferentiated pleomorphic sarcoma and liposarcoma. 
 


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Depending on the null response rate, target response rate, minimum (monitoring start 
point) and total sample sizes, alpha level (one-sided) and power, this sequential 
monitoring procedure sets up criteria for the number of responders required to indicate 
either efficacy or futility continuously, i.e., for any given number of subjects who enter 
the cohort. As an example, the stopping conditions for the scenario of null rate of 20%, 
target rate of 40%, minimum and total of 13 and 48 evaluable subjects (respectively), 
one-sided alpha of 0.05 and power of 80% is presented in Figure 2. This scenario shows 
that at least 17 responders are required for success in these indications with a total sample 
size of 48. 
For all tumor types/subtypes, one-sided alpha of 0.05 and 80% power were used for 
calculating boundary conditions. The stopping criteria for the numbers of responders for 
either efficacy or futility, for the other tumor subtypes will be displayed in the statistical 
analysis plan (SAP). 
Figure 2: Stopping Conditions for Null Response Rate of 20% versus Target Rate of 
40%:  Expansion Phase 
 
Note:  Scenario:  null rate of 20%, target rate of 40%, minimum and total of 13 and 48 evaluable subjects 
(respectively), one-sided alpha of 0.05 and power of 80%. 
 
11.2.3. Efficacy Analyses 
In general, efficacy in the Expansion Phase will be evaluated separately within each 
tumor-type cohort. Disease response will be evaluated using RECISTv1.1 criteria using 
the FAS. ORR is defined as the proportion of subjects who achieve a best disease 


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response of either CR or PR based on RECIST 1.1 criteria. Patients who discontinue 
study therapy due to clinical progression, radiographic progression or death without the 
required tumor assessments will be considered to be non-responders in the ORR 
calculation. The efficacy analysis will include all subjects with baseline tumor 
measurements who received at least one dose of study treatment. The primary analysis of 
ORR will be performed with the FAS in each tumor-type cohort in the Expansion Phase. 
The point estimate, confidence interval (CI), and adjusted p-values for testing whether the 
observed ORR is statistically greater than the specified null rate will be provided. Exact 
methods for binary, sequential data will be employed for the analysis (DOD RAC 2005). 
Details of the analysis will be included in a separate SAP. 
PFS is defined at the time from start of Study Drug to date of disease progression or 
death due to any cause. For PFS and any other time-to-event analyses, the Kaplan-Meier 
product limit method will be used to compute the estimate and 95% CI of the median and 
25th and 75th percentiles. The number of responders, the number with subsequent disease 
progression, and the number with censored values will be displayed as well. 
The proportion of irRECIST-based responses will be tabulated with 95% CIs. 
11.2.4. Power and Sample Size 
For the Dose-escalation Phase of the study, 3 to 6 subjects will be accrued per dose level 
or regimen in order to insure the safety and tolerability. The number of subjects is not 
based on statistical power considerations. 
The Expansion Phase of the study will enroll a minimum of 7 to 13 subjects in each 
tumor type cohort as the monitoring start point. The total sample size is shown in 
Table 11. A one-sided alpha of 0.05 and 80% power were required for each cohort. Once 
the prescribed minimum number of efficacy-evaluable subjects in a cohort have had at 
least one post-baseline response assessment, a sequential monitoring procedure will be 
used to evaluate for efficacy and futility simultaneously based on the number of subjects 
with a response according to the rules outlined in Figure 2 (for the case of a null vs. target 
rates of 20% and 40% as an example). For other null and target rates, the corresponding 
figure will be provided in the SAP. 
Depending on the enrollment rate, it is possible that more than the minimum number of 
subjects may be enrolled prior to the first evaluation of efficacy or futility. Enrollment is 
expected to be continuous and will not be held. Once the minimum number of subjects 
are evaluable for confirmed or unconfirmed response, subsequent rules for pausing 
enrollment and future evaluations will be based on the boundaries identified by the 
sequential monitoring procedure until the total sample size has been enrolled. 
The calculation is based on the binomialSPRT function in the gsDesign package and is 
carried out using R version 3.1.3 (R Core Team 2015). 
11.2.5. Subjects Who Continue From the Dose-escalation Phase 
Subjects who participated in the Dose-escalation Phase can continue at the dose 
determined for their cohort, assuming that dose is pharmacologically active, or can be 


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titrated up to the RP2D, at the discretion of the Investigator. These subjects will be 
analyzed descriptively. 
11.2.6. Study Population Data 
Subject disposition will be summarized by each dose cohort and for total in the Dose-
escalation Phase and by tumor type and for total in the Expansion Phase for the Efficacy 
Analysis Set. The total number of subjects for each defined analysis population will also 
be tabulated. 
The demographic and baseline characteristics will be summarized descriptively for the 
Safety Analysis Set. Study treatment exposure and study duration will be summarized 
using descriptive statistics for the Safety Analysis Set. 
All study data will be presented in by-subject data listings. 
11.3. Analyses 
11.3.1. Analysis of Primary Endpoint 
The primary endpoint, defined in Section 3.1.4.1, is restated below: 
• To establish the RP2D of PLX3397 in combination with pembrolizumab for 
future trials. The RP2D is defined as the MTD or MAD of PLX3397. The 
MTD is defined as the dose level below the one at which more than 1 of 
6 subjects experience DLT in Cycle 1 (1 cycle = 42 days). The planned MAD 
is defined as PLX3397 administered orally at 1000 mg/day as a split dose 
(Table 1). 
The 3+3 design allows for determination of the MTD/MAD, based on the incidence of 
DLT during Cycle 1. DLTs are defined in Section 3.1.7.1. The Rules for Dose-escalation 
are provided in Section 3.1.7.2. The MTD is defined in Section 3.1.7.3. The probabilities 
of dose based on true DLT risk in the 3+3 design are summarized in Table 12. 
Table 12. Probabilities of Dose Escalation Based on True DLT Risk in the 3+3 
Design:  Statistical Basis for Dose Escalation 
True Incidence of Dose-limiting Toxicity  
10% 
20% 
30% 
40% 
50% 
60% 
Probability of escalating the dose 
0.91 
0.71 
0.49 
0.31 
0.17 
0.08 
DLT = dose-limiting toxicity 
 
11.3.2. Analyses of Secondary Endpoints 
The secondary endpoints, defined in Section 3.1.4.2, are restated below: 
• To evaluate the safety and tolerability of the combination of pembrolizumab 
and PLX3397, based on the incidence of AES, as graded by the NCI CTCAE. 
• To evaluate ORR by RECISTv1.1 guidelines (Appendix 17.4), relative to the 
assumed historical control rate for pembrolizumab, for each of the tumor types 
(Table 2) in subjects treated with the RP2D of PLX3397 for the combination 


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of PLX3397 and pembrolizumab. Subjects with each of the tumor types will 
also be analyzed by RECISTv1.1 for PFS. See Section 11.2.3 and the SAP for 
details of these analyses. 
11.3.3. Analysis of Exploratory Endpoints 
The exploratory endpoints and methods for analyzing them, defined in Section 3.1.4.3, 
are restated below: 
• To evaluate ORR by irRECIST guidelines (see the irRECIST Tip Sheet, 
provided in the Study Reference Manual), relative to the assumed historical 
control rate for pembrolizumab, for each of the tumor types (Table 2 ) in 
subjects treated with the RP2D of PLX3397 for the combination of PLX3397 
and pembrolizumab (Expansion Phase). Subjects with each of the tumor types 
will also be analyzed by irRECIST for PFS. 
• To evaluate ORR and PFS by RECISTv1.1 guidelines (Appendix 17.4) 
descriptively by cohort for subjects in the Dose-escalation Phase. The PFS 
distributions for each tumor type will be estimated using the Kaplan-Meier 
method (Section 11.2.3). 
• To determine effects of the combination of PLX3397 and pembrolizumab on 
multiple biomarkers of disease or treatment, through analysis of available 
paired tumor biopsy samples using methods that include but are not limited to 
Nanostring and IHC of intratumoral CD68+ macrophages and CD8+ T-cells. 
Mandatory baseline (up to -2 days) and Day 29 (± 3 days) or Day 22 
(± 3 days) for intermittent, post-treatment biopsies will be collected in the 
Expansion Phase, unless deemed medically unsafe by the Investigator. 
Biopsies will be optional in Dose-escalation. 
11.3.3.1. Safety and Tolerability 
The safety and tolerability of the combination of pembrolizumab and PLX3397 will be 
determined by the incidence of AEs that occur throughout dosing of one or both study 
medications. Frequencies of toxicities will be summarized based on the NCI CTCAE, 
version 4.03. AEs that occur will be reported for and described in terms of incidence and 
severity. 
11.3.3.2. Evaluation of the Objective Response Rate in the Expansion Phase 
To obtain preliminary estimates of efficacy, the Expansion Phase will be conducted in 
several tumor types described in Table 2. For each tumor type, the objective is to estimate 
the ORR, defined as proportion of subjects who achieve a CR or PR among all subjects, 
relative to the assumed historical control ORR. Response to study treatment will be 
evaluated by RECISTv1.1 (Appendix 17.4). 
For each of the subject populations (defined by tumor type; see Table 2), a truncated 
sequential probability ratio test for single-arm binary response studies will be used. A 
one-sided alpha of 0.05 and 80% power will be used for all tumor types for calculating 


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boundary conditions. In addition, the monitoring start point, total sample size (range 23 to 
48), null rate, and target rate are stated for each tumor type in Table 11. 
11.3.4. Exploratory Pharmacology Studies of Drug Activity 
To confirm drug target activity, baseline (up to -2 days) and 28-day (± 3 days) biopsies 
will be performed on subjects recruited during the Expansion Phase, who will be treated 
at the RP2D. Immunohistochemistry (IHC) and pathologist scoring of percent positive 
T-cells and percent positive macrophage in tumor will be conducted to determine T-cell 
infiltration and macrophage depletion. Transformation of quantitative variable will be 
performed to achieve normality if possible. A paired t-test or Wilcoxon signed-rank test 
will be used to determine if there is a statistically significant change. 
11.3.5. Clinical Laboratory Evaluation Analyses 
Descriptive statistics will be provided for the clinical laboratory results by scheduled time 
of evaluation, as well as for the change from baseline. The baseline value is defined as 
the last non-missing value before the initial administration of study treatment. In addition, 
mean change from baseline will be summarized for the maximum and minimum post-
treatment values and the values at the End-of-Treatment visit. 
Abnormal clinical laboratory results will be graded according to NCI CTCAE, if 
applicable, and the grade will be presented in a by-subject data listing. A shift table, 
presenting by treatment group the 2-way frequency tabulation for baseline and the worst 
post-treatment value according to the NCI CTCAE grade, may be provided for clinical 
laboratory tests. Abnormal clinical laboratory test results deemed of clinical significance 
or of Grade 3 or 4 will be listed. 
11.3.6. Vital Sign Analyses 
Descriptive statistics will be provided for the vital signs measurements by scheduled time 
of evaluation, as well as for the change from baseline. The baseline value is defined as 
the last non-missing value before the initial administration of study treatment. In addition, 
mean change from baseline will be presented by treatment group for the maximum and 
minimum post-treatment values and the values at the End-of -Treatment visit. 
11.3.7. Electrocardiogram Analyses 
Descriptive statistics will be provided for the ECG measurements by scheduled time of 
evaluation, as well as for the change from baseline. The baseline value is defined as the 
last nonmissing value before the initial administration of study treatment. In addition, the 
number and percentage of subjects with ECG interval values meeting the criteria will be 
tabulated (e.g., QTc ≤450 ms, >450 to ≤480 ms, >480 ms to ≤500 ms, and >500 ms) and 
QTcF maximum changes from baseline (>30 and >60 ms) over all post-treatment 
evaluations will be summarized. ECG data will also be presented in the data listings. 
11.3.8. Physical Finding Analyses 
Physical examination data will be listed. 


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11.4. Interim Analyses 
During the Expansion Phase, the number of responders will be monitored continuously in 
each tumor-type cohort, once a minimum number of subjects have been enrolled in that 
cohort. Enrollment may be stopped within a cohort for futility or efficacy based on the 
stopping criteria described in Section 11.2.2. 
11.5. Data Monitoring Committee (DMC) 
Generally, a DMC will not be used for this study. This is an open-label, Phase I/II study, 
and the Sponsor Medical Monitor (MM) and individual Investigators will have access to 
the safety data on a regular basis during the study and conduct regularly scheduled 
teleconferences to discuss the available safety data. These teleconferences will serve as a 
mechanism for determination of unanticipated problems involving risks to subjects or 
others; an additional mechanism is the reporting of SAEs to the IRB and/or health 
authorities (Section 11.2). 
11.5.1. Dose-escalation Phase 
The Sponsor MM and Investigators will discuss data on all subjects on an approximately 
biweekly basis and also meet at the end of each treatment cohort to discuss and evaluate 
all of the available safety data. At dose escalation teleconferences, the clinical course 
(safety information including both DLTs and all CTCAE Grade 2 or higher toxicity data 
during the first cycle of treatment, and if applicable, PK data) for each subject in the 
current dose cohort will be described in detail. Updated safety data on other ongoing 
subjects, including data in later cycles, will be discussed as well. 
Dose escalation decisions will be based on a clinical synthesis of all relevant available 
data and not solely on DLT information. The Sponsor MM and the Investigators must 
reach a consensus on whether to declare MTD, escalate the dose, de-escalate the dose 
and/or study an additional cohort of subjects at the current or an intermittent regimen. 
11.5.2. Expansion Phase 
Due to the exploratory nature of this phase I/II study an independent DMC will not be 
constituted for the Expansion Phase of this study. Instead, a review of the safety data will 
be performed at periodic interim data safety reviews by the Sponsor MM and the 
Investigators in a data review meeting with the first review meeting occurring when 
about 30 subjects in the Expansion Phase have received at least about 1 cycle of study 
treatment. There will also be regularly scheduled teleconferences between the Sponsor 
MM and participating Investigators to review ongoing data for active subjects. 
It is envisioned that the team may make the following recommendations at each of the 
interim data safety reviews: 
• No safety or efficacy issues, ethical to continue the trial as planned 
• Serious safety concerns requiring modification of dosing regimens or 
guidelines (e.g., one-third occurrence of DLT as described in Section 3.1.7.2 
and Section 3.1.9.1) or precluding further study treatment, regardless of 
efficacy 


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In addition, the best overall response for each subject will be derived from the overall 
lesion response assessments recorded in the eCRF to calculate the probability of success 
or futility estimate for the respective tumor type per the truncated sequential monitoring 
approach (Section 11.2.2 and Figure 2). The first such interim will occur for a particular 
tumor type once the minimum number of subjects has been treated within the cohort 
according to the statistical plan. For each cohort, this will be after 7 to 10 subjects have 
been treated (Table 11). Thereafter, additional interim data safety reviews will occur after 
additional groups of 7 to10 subjects have been treated. The tumor type cohort or study is 
terminated due to lack of significant activity 
12. DATA INTEGRITY AND QUALITY ASSURANCE 
The Investigator/investigational site will permit study-related monitoring, audits, 
IRB/IEC review and regulatory inspections by providing direct access to source 
data/documents. Direct access includes permission to examine, analyze, verify, and 
reproduce any records and reports that are important to the evaluation of a clinical study. 
12.1. Monitoring and Inspections 
The Plexxikon monitor or appropriately qualified designee and regulatory authority 
inspectors are responsible for contacting and visiting the Investigator for the purpose of 
inspecting the facilities and, upon request, inspecting the various records of the study 
(e.g., CRFs, source data, and other pertinent documents). 
The monitor is responsible for visiting site(s) at regular intervals throughout the study to 
verify adherence to the protocol; completeness, accuracy, and consistency of the data; 
and adherence to ICH GCP and local regulations on the conduct of clinical research. The 
monitor is responsible for reviewing the CRFs against source documents for 
completeness and accuracy. The monitor should have access to subject medical records 
and other study-related records needed to verify the entries on the CRFs. The monitor 
will also ensure study essential documents are up to date and filed appropriately. 
The monitor will communicate deviations from the protocol, SOPs, GCP and applicable 
regulations to the Investigator and will ensure that appropriate action designed to prevent 
recurrence of the detected deviations is taken and documented. 
The Investigator agrees to cooperate with the monitor to ensure that any problems 
detected in the course of these monitoring visits are addressed and documented. 
In accordance with ICH GCP and the Sponsor’s audit plans, this study may be selected 
for audit by representatives from Sponsor. Inspection of site facilities (e.g., pharmacy, 
drug storage areas, laboratories) and review of study related records will occur in order to 
evaluate the study conduct and compliance with the protocol, ICH GCP, and applicable 
regulatory requirements. 


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12.2. Data Collection 
eCRF completion should be kept current to enable the monitor to review the subject’s 
status throughout the course of the study. eCRF will be completed, reviewed and e-signed 
by the Investigator. 
The Investigator will e-sign according to the study data flow. These signatures will 
indicate that the Investigator inspected or reviewed the data on the CRF, the data queries, 
and the site notifications, and agrees with the content. 
Any data recorded on the eCRF will be collected and included in the database according 
to Clinical Data Interchange Standards Consortium standards and subjected to the same 
procedures as other data. 
12.3. Data Management 
Each subject will be identified in the database by a unique subject identifier as defined by 
the Sponsor. 
To ensure the quality of clinical data across all subjects and sites, a Clinical Data 
Management review will be performed on subject data according to specifications in the 
Data Management Plan. Data will be vetted both electronically and manually. For 
electronic CRFs (eCRFs), the data will be electronically vetted by programmed data rules 
within the application. Queries generated by rules and raised by reviewers will be 
generated within the EDC application. During this review, subject data will be checked 
for consistency, omissions, and any apparent discrepancies. 
SAEs in the clinical database will be reconciled with the safety database. 
All AEs will be coded using MedDRA. 
12.4. Study Documentation and Storage 
The Investigator will maintain a Delegation Log of appropriately qualified persons to 
whom he/she has delegated study duties. All persons authorized to make entries and/or 
corrections on CRFs will be included on the Signature List. 
Source documents are original documents, data, and records from which the subject’s 
CRF data are obtained. These include but are not limited to hospital records, clinical and 
office charts, laboratory and pharmacy records, diaries, microfiches, X-rays, and 
correspondence. 
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 include: 
• Subject files containing completed CRFs, informed consents, 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 


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commencing a clinical study, and all correspondence to and from the IEC/IRB 
and the Sponsor. 
• Records related to the Investigational Product(s) including acknowledgment 
of receipt at 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. 
12.5. Record Keeping 
Records of subjects, source documents, monitoring visit logs, data correction forms, 
CRFs, inventory of study product, regulatory documents (e.g., protocol and amendments, 
IRB/EC correspondence and approvals, approved and signed ICFs, Investigator’s 
Agreement, clinical supplies receipts, distribution and return records), and other Sponsor 
correspondence pertaining to the study must be kept in appropriate study files at the site. 
Source documents include all recordings and observations or notations of clinical 
activities and all reports and records necessary for the evaluation and reconstruction of 
the clinical study. These records will be retained in a secure file for the period required 
by the institution or site policy. Prior to transfer or destruction of these records, the 
Sponsor must be notified in writing and be given the opportunity to further store such 
records. 
13. COMPLIANCE STATEMENT, ETHICS AND REGULATORY 
COMPLIANCE 
This study will be conducted in compliance with the protocol, the ethical principles that 
have their origin in the Declaration of Helsinki, the International Conference on 
Harmonization (ICH) consolidated Guideline E6 for Good Clinical Practice 
(CPMP/ICH/135/95), and the following applicable regulatory requirement: 
• FDA GCP Regulations:  Code of Federal Regulations Title 21, parts 11, 50, 
54, 56, and 312 as appropriate 
13.1. Subject Confidentiality 
The Investigators and the Sponsor will preserve the confidentiality of all subjects taking 
part in the study, in accordance with GCP and local regulations. 
The Investigator must ensure that the subject’s anonymity is maintained. On the 
CRFs/eCRFs or other documents submitted to Plexxikon, subjects should be identified by 
a unique subject identifier as designated by the Sponsor. Documents that are not for 
submission to Plexxikon or appropriately qualified designee (e.g., signed Informed 
Consent Forms [ICFs]) should be kept in strict confidence by the Investigator. 
In compliance with Federal regulations/ICH GCP Guidelines, it is required that the 
Investigator and institution permit authorized representatives of the company, of the 
regulatory agency(s), and the IEC or IRB direct access to review the subject’s original 
medical records for verification of study-related procedures and data. The Investigator is 


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obligated to inform the subject that his/her study-related records will be reviewed by the 
above named representatives without violating the confidentiality of the subject. 
13.2. Informed Consent Procedure 
Before a subject’s participation in the study, it is the Investigator’s responsibility to 
obtain freely given consent, in writing, from the subject or legally acceptable 
representative after adequate explanation of the aims, methods, anticipated benefits, and 
potential hazards of the study and before any protocol-specific screening procedures or 
any Study Drugs are administered. A legally acceptable representative is an individual or 
other body authorized under applicable law to consent, on behalf of a prospective subject, 
to the subject’s participation in the clinical study. The written ICF should be prepared in 
the local language(s) of the potential subject population. 
In obtaining and documenting informed consent, the Investigator should comply with the 
applicable regulatory requirements, and should adhere to GCP and to the ethical 
principles that have their origin in the Declaration of Helsinki. The consent form and any 
revision(s) should be approved by the IRB prior to being provided to potential subjects. 
The subject’s written informed consent should be obtained prior to his/her participation in 
the study, and should be documented in the subject’s medical records, as required 
by Code of Federal Regulations Title 21, Part 312.62. The ICF should be signed and 
personally dated by the subject or a legally acceptable representative, and by the person 
who conducted the informed consent discussion (not necessarily the Investigator). The 
original signed ICF should be retained in accordance with institutional policy, and a copy 
of the signed consent form should be provided to the subject or legal representative. The 
date and time (if applicable) that informed consent was given should be recorded on the 
CRF. 
If the subject or legally acceptable representative cannot read, then according to ICH 
GCP Guideline, Section 4.8.9, an impartial witness should be present during the entire 
informed consent discussion. This witness should sign the ICF after the subject or the 
legally acceptable representative has orally consented to the subject’s participation and, if 
possible, signed the ICF. By signing the ICF, the witness attests that the information in 
the ICF and any other written information was adequately explained to and apparently 
understood by the subject or the legally acceptable representative and that informed 
consent was freely given by the subject or the legally acceptable representative. 
Suggested model text for the ICF for the study and any applicable subparts (genomic, 
pharmacokinetic, etc.) and assent forms for pediatric subjects (if applicable) are provided 
in the Sponsor ICF template for the Investigator to prepare the documents to be used at 
his or her site. Updates to applicable forms will be communicated via letter from the 
Clinical Study Manager. An additional consent is required for the Health Insurance 
Portability and Accountability Act. 
13.3. Regulatory Compliance 
The study protocol, subject information and consent form, the Investigator’s Brochure, 
any subject Diary card or written instructions to be given to the subject, available safety 
information, subject recruitment procedures (e.g., advertisements), information about 


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payments and compensation available to the subjects and documentation evidencing the 
Investigator’s qualifications should be submitted to the IRB for ethical review and 
approval according to local regulations, prior to the study start. The written approval 
should identify all documents reviewed by name and version. 
Changes in the conduct of the study or planned analysis will be documented in a protocol 
amendment and/or the Statistical Analysis Plan. 
The Investigator must submit and, where necessary, obtain approval from the IRB and/ or 
Sponsor for all subsequent protocol amendments and changes to the informed consent 
document or changes of the investigational site, facilities or personnel. The Investigator 
should notify the IRB of deviations from the protocol or SAEs occurring at the site and 
other AE reports received from Plexxikon or its designee, in accordance with local 
procedures. 
As required by local regulations, the Sponsor’s local Regulatory Affairs group will insure 
all legal aspects are covered, and approval of the appropriate regulatory bodies obtained, 
prior to study initiation, and that implementation of changes to the initial protocol and 
other relevant study documents happen only after the appropriate notification of or 
approval by the relevant regulatory bodies. 
14. PUBLICATION POLICY 
A study site may not publish results of a study until after a coordinated multicenter 
publication has been submitted for publication or until one year after the study has ended, 
whichever occurs first. Therefore, the study site will have the opportunity to publish the 
results of the study, provided that Plexxikon has had the opportunity to review and 
comment on the study site’s proposed publication prior to its being submitted for 
publication with the prior advice of Plexxikon Legal Affairs (intellectual property 
council) and with proper regard to the protection of subjects’ identities. 
15. STUDY ADMINISTRATIVE INFORMATION 
15.1. Protocol Amendments 
Any amendments to the study protocol that seem to be appropriate as the study 
progresses will be communicated to the Investigator by the Sponsor. All protocol 
amendments will undergo the same review and approval process as the original protocol. 
A protocol amendment may be implemented after it has been approved by the IRB/EC, 
unless immediate implementation of the change is necessary for subject safety. In this 
case, the situation must be documented and reported to the IRB/EC within five working 
days. The Sponsor will assure the timely submission of amendments to regulatory 
authorities. 


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16. REFERENCES 
Coffelt SB, Hughes R, Lewis CE. Tumor-associated macrophages:  effectors of 
angiogenesis and tumor progression. Biochim Biophys Acta. 2009;1796(1):11–18. 
Department of Defense (DOD) Reliability Analysis Center (RAC). Understanding 
sequential testing. Selected Topics in Assurance Related Technologies. 2005;12(2):1–8. 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford .R et al. New 
response evaluation criteria in solid tumours:  Revised RECIST guideline (version 1.1). 
Eur J Cancer. 2009;45(2):228–247. 
Hamid O, Patel M, Hodi S, Amaria R, Boasberg P, Sullivan R, Wallin J, He X, Cha E, 
Richie N, Ballinger M, Hwu P. Preliminary clinical safety, tolerability and activity of 
atezolizumab (anti-PDL1) combined with vemurafenib in BRAFV600 metastatic 
melanoma. Society of Melanoma Research 2015 Congress, 2015:  778. 
Lin EY, Nguyen AV, Russell RG, Pollard JW. Colony-stimulating factor 1 promotes 
progression of mammary tumors to malignancy. J Exp Med. 2001;193(6):727–739. 
Merck & Co., Inc. Keytruda Package Insert. Available at:  
http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf. Revised 
January 2015. Accessed February 2015. 
Mok S, Koya RC, Tsui C, Xu J, Robert L, Wu L, et al. Inhibition of CSF-1 receptor 
improves the antitumor efficacy of adoptive cell transfer immunotherapy. Cancer Res. 
2014;74 (1):153–161. 
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(6):649–655. 
R Core Team. R:  a language and environment for statistical computing (version 3.1.3; 
2015-03-09). Vienna, Austria:  R Foundation for Statistical Computing, 2014. 
http://cran.r-project.org/. Revised 2015. 
Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, et al. PD-1 
blockade induces responses by inhibiting adaptive immune resistance. Nature. 
2014;515(7528):568–571. 
Zhu Y, Knolhoff BL, Meyer MA, Nywening TM, West BL, Luo J, et al. CSF1/CSF1R 
blockade reprograms tumor-infiltrating macrophages and improves response to T-cell 
checkpoint immunotherapy in pancreatic cancer models. Cancer Res.  
2014;74(18):5057–5069. 


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17. APPENDICES 
 


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17.1. Drugs Clearly Associated with the Risk of Torsades de Pointes and QT 
Prolongation 
Anti-arrhythmics 
- Amiodarone 
- Disopyramide 
- Dofetilide 
- Dronedarone 
- Flecainide 
- Ibutilide 
- Procainamide (oral off US market) 
- Quinidine 
- Sotalol 
- Ritonavir 
- Indinavir 
- Nelfinavir 
 
Anti-retrovirals 
- Ritonavir 
- Indinavir 
- Nelfinavir 
 
Antimicrobials 
- Azithromycin 
- Ciprofloxacin 
- Clarithromycin 
- Erythromycin 
- Grepafloxacin (off market worldwide) 
- Levofloxacin 
- Moxifloxacin 
- Sparfloxacin (removed from US market) 
- Pentamidine 
- Fluconazole 
 
Anti-psychotics 
- Haloperidol 
- Mesoridazine (removed from US market) 
- Pimozide 
- Thioridazine 
- Chlorpromazine 
- Droperidol 
- Sulpiride (on non-US market) 
Anti-cancer 
- Arsenic trioxide 
- Vandetanib 
 
Anti-depressants, SSRIs 
- Citalopram 
- Escitalopram 
 
Antihistamines 
- Astemizole (removed from US market) 
- Terfenadine (removed from US market) 
 
Anti-malarials 
- Chloroquine 
- Halofantrine 
 
Antilipemic 
- Probucol (removed from US market) 
- Ondansetron 
 
Opiates 
- Levomethadyl acetate (removed from US market) 
- Methadone 
 
Anesthetics, general 
- Propofol 
- Sevoflurane 
 
Others 
- Cisapride (removed from US market) 
- Cocaine 
- Anagrelide 
- Bepridil (removed from US market) 
- Domperidone (on non US market) 
 


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17.2. CYP3A4 Inhibitors and Inducers 
Common CYP3A4 Inhibitors 
The following lists describe medications and foods which are common inhibitors of 
CYP3A4. This list should not be considered all-inclusive. Consult individual drug labels 
for specific information on a compound’s propensity to inhibit CYP3A4. 
Protease Inhibitors 
Others 
indinavir 
nelfinavir 
ritonavir 
clarithromycin 
erythromycin 
gemfibrozil 
itraconazole 
ketoconazole 
nefazodone 
verapamil 
telithromycin 
fluconazole 
chloramphenicol 
aprepitant 
trimethoprim 
thiazolidinedione 
montelukast 
quercetin 
Food/Juice 
grapefruit juice 
 
Common CYP3A4 Inducers 
The following lists describe medications which are common inducers of CYP3A4. This 
list should not be considered all-inclusive. Consult individual drug labels for specific 
information on a compound’s propensity to induce CYP3A4. 
HIV Antivirals 
Others 
efavirenz 
nevirapine 
etravirine 
barbiturates 
carbamazepine 
glucocorticoids 
modafinil 
phenobarbital 
phenytoin 
rifampin 
St. John's Wort 
rifabutin 
oxcarbazepine 
cyproterone 
 


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17.3. Eastern Cooperative Oncology Group Performance Status 
 
ECOG PERFORMANCE STATUSa 
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 
a 
As published in Oken 1982. 
 
The ECOG Performance Status is in the public domain and is therefore available for public use. To 
duplicate the scale, please cite the reference above and credit the Eastern Cooperative Oncology Group, 
Robert Comis M.D., Group Chair. 
 
All contents copyright © 1998–2000 Eastern Cooperative Oncology Group. 
All rights reserved. 
Revised:  July 27, 2006 
 


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17.4. Response Evaluation Criteria for Solid Tumors, version 1.1 
Below are the RECISTv1.1 criteria as developed by Eisenhauer, et al. 2009. 
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 1 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. 
• 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. 


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


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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 
1 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 CR 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 CR. Because tumor markers are disease 
specific, instructions for their measurement should be incorporated into protocols on a 
disease specific basis. Specific guidelines for both CA-125 response (in recurrent ovarian 
cancer) and PSA response (in recurrent prostate cancer), have been published. In 
addition, the Gynecologic Cancer Intergroup has developed CA-125 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. 


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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 1 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 1 measurable lesion is present at baseline all lesions up to a maximum 
of 5 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 1 or 2 organ sites involved a maximum 
of 2 (1 site) and 4 lesions (2 sites), respectively, will be recorded. Other lesions in that 
organ will be recorded as non-measurable lesions (even if size is greater than 10 mm by 
CT scan). 
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter), be representative of all involved organs, but in addition should be those that 
lend themselves to reproducible repeated measurements. It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be 
selected. 
Lymph nodes merit special mention since they are normal anatomical structures which 
may be visible by imaging even if not involved by tumor. Pathological nodes which are 
defined as measurable and may be identified as target lesions must meet the criterion of a 
short axis of ≥15 mm by CT scan. Only the short axis of these nodes will contribute to 
the baseline sum. The short axis of the node is the diameter normally used by radiologists 
to judge if a node is involved by solid tumor. Nodal size is normally reported as two 
dimensions in the plane in which the image is obtained (for CT scan this is almost always 
the axial plane; for MRI the plane of acquisition may be axial, sagittal or coronal). The 
smaller of these measures is the short axis. For example, an abdominal node which is 
reported as being 20 mm × 30 mm has a short axis of 20 mm and qualifies as a 
malignant, measurable node. In this example, 20 mm should be recorded as the node 
measurement. All other pathological nodes (those with short axis ≥10 mm but <15 mm) 
should be considered non-target lesions. Nodes that have a short axis <10 mm are 
considered non-pathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum diameters. If lymph 
nodes are to be included in the sum, then as noted above, only the short axis is added into 


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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 CRF (e.g., ‘multiple enlarged 
pelvic lymph nodes’ or ‘multiple liver metastases’). 
Response criteria 
This section provides the definitions of the criteria used to determine objective tumor 
response for target lesions. 
Evaluation of target lesions 
• Complete Response (CR):  Disappearance of all target lesions. Any 
pathological lymph nodes (whether target or non-target) must have reduction 
in short axis to <10 mm. 
• Partial Response (PR):  At least a 30% decrease in the sum of diameters of 
target lesions, taking as reference the baseline sum diameters. 
• Progressive Disease (PD):  At least a 20% increase in the sum of diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study). In addition to the relative 
increase of 20%, the sum must also demonstrate an absolute increase of at 
least 5 mm. (Note:  the appearance of 1 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 
CR criteria are met, since a normal lymph node is defined as having a short axis of 
<10 mm. CRFs 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 


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report them as being ‘too small to measure’. When this occurs it is important that a value 
be recorded on the CRF: 
• 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 below the measurable limit (BML) should be ticked 
(Note:  It is less likely that this rule will be used for lymph nodes since they 
usually have a definable size when normal and are frequently surrounded by 
fat such as in the retroperitoneum; however, if a lymph node is believed to be 
present and is faintly seen but too small to measure, a default value of 5 mm 
should be assigned in this circumstance as well and BML should also be 
ticked). 
This default value is derived from the 5 mm CT slice thickness (but should not be 
changed with varying CT slice thickness). The measurement of these lesions is 
potentially non-reproducible, therefore providing this default value will prevent false 
responses or progressions based upon measurement error. 
To reiterate, however, if the radiologist is able to provide an actual measure, that 
should be recorded, even if it is below 5 mm and in that case BML should not be 
ticked. (BML is equivalent to a less than sign <) 
Lesions that split or coalesce on treatment:  When non-nodal lesions ‘fragment’, the 
longest diameters of the fragmented portions should be added together to calculate the 
target lesion sum. Similarly, as lesions coalesce, a plane between them may be 
maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion. If the lesions have truly coalesced such that they are no longer 
separable, the vector of the longest diameter in this instance should be the maximal 
longest diameter for the ‘coalesced lesion’. 
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 1 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 1 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: 


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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 1 or more non-
target lesions is usually not sufficient to qualify for unequivocal progression status. The 
designation of overall progression solely on the basis of change in non-target disease in 
the face of SD or PR of target disease will therefore be extremely rare. 
When the patient has only non-measurable disease:  this circumstance arises in some 
phase III trials when it is not a criterion of study entry to have measurable disease. The 
same general concepts apply here as noted above, however, in this instance there is no 
measurable disease assessment to factor into the interpretation of an increase in non-
measurable disease burden. Because worsening in non-target disease cannot be easily 
quantified (by definition:  if all lesions are truly non-measurable) a useful test that can be 
applied when assessing patients for unequivocal progression is to consider if the increase 
in overall disease burden based on the change in non-measurable disease is comparable in 
magnitude to the increase that would be required to declare PD for measurable disease:  
i.e., an increase in tumor burden representing an additional 73% increase in ‘volume’ 
(which is equivalent to a 20% increase diameter in a measurable lesion). Examples 
include an increase in a pleural effusion from ‘trace’ to ‘large’, an increase in 
lymphangitic disease from localized to widespread, or may be described in protocols as 
‘sufficient to require a change in therapy’. If ‘unequivocal progression’ is seen, the 
subject 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 subject’s baseline lesions show PR or 
CR. 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 subject who has visceral disease at baseline and while on study has a brain CT 
or MRI ordered which reveals metastases. The subject’s brain metastases are considered 
to be evidence of PD even if he/she did not have brain imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of the 
initial scan. 


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Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the study 
treatment until the end of treatment taking into account any requirement for confirmation. 
On occasion a response may not be documented until after the end of therapy so 
protocols should be clear if post-treatment assessments are to be considered in 
determination of best overall response. Protocols must specify how any new therapy 
introduced before progression will affect best response designation. The subject’s best 
overall response assignment will depend on the findings of both target and non-target 
disease and will also take into consideration the appearance of new lesions. Furthermore, 
depending on the nature of the study and the protocol requirements, it may also require 
confirmatory measurement. Specifically, in non-randomized trials where response is the 
primary endpoint, confirmation of PR or CR is needed to deem either 1 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 13 provides a summary of the overall response status calculation at each time point 
for subjects who have measurable disease at baseline. 
When subjects have non-measurable (therefore non-target) disease only, Table 14 is to be 
used. 
Missing assessments and not-evaluable designation 
When no imaging/measurement is done at all at a particular time point, the subject is not 
evaluable at that time point. If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered not evaluable at that time point, unless a 
convincing argument can be made that the contribution of the individual missing lesion(s) 
would not change the assigned time point response. This would be most likely to happen 
in the case of PD. 
For example, if a subject had a baseline sum of 50 mm with 3 measured lesions and at 
follow-up only 2 lesions were assessed, but those gave a sum of 80 mm, the subject will 
have achieved PD status, regardless of the contribution of the missing lesion. 
If 1 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 subject is not evaluable. Similarly, 
if 1 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 subject is known. 


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Table 13. Time Point Response:  Patients with Target (+/- 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; NE = inevaluable; PR = partial response; PD = progressive disease;  
SD = stable disease 
 
Table 14. Time Point Response:  Patients with Non-target Disease Only 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/Non-PD 
No 
Non-CR/non-PDa 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
CR = complete response; NE = not evaluable; PR = partial response; PD = progressive disease;  
SD = stable disease 
a 
Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly 
used as endpoint for assessment of efficacy in some trials so to assign this category when no lesions 
can be measured is not advised. 
 


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Table 15. Best Overall Response When Confirmation of CR and PR is 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; NE = not evaluable; PR = partial response; PD = progressive disease;  
SD = stable disease 
a 
If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease 
meeting PR criteria relative to baseline, makes the disease PD at that point (since disease must have 
reappeared after CR). Best response would depend on whether minimum duration for SD was met. 
However, sometimes ‘CR’ may be claimed when subsequent scans suggest small lesions were likely 
still present and in fact the patient had PR, not CR at the first time point. Under these circumstances, 
the original CR should be changed to PR and the best response is PR. 
 
Special notes on response assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to 
‘normal’ size (<10 mm), they may still have a measurement reported on scans. This 
measurement should be recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the nodes. As noted earlier, 
this means that subjects with CR may not have a total sum of ‘zero’ on the 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 
subject with time point responses of PR-NE-PR as a confirmed response. 
Subjects 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 


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objective response status of such subjects is to be determined by evaluation of target and 
non-target disease as shown in Table 13, Table 14, and Table 15. 
Conditions that define “early progression, early death, and inability to evaluate” 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 CR depends upon this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) before assigning a 
status of CR. 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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17.5. Clinical Laboratory Evaluations 
Blood samples will be obtained for analyses of the following parameters: 
Comprehensive Serum Chemistry Panel 
• Sodium 
• Phosphorus 
• Albumin 
• Potassium 
• Glucosea 
• Uric acid 
• Chloride 
• Blood urea nitrogen 
(BUN) 
• Lactate 
dehydrogenase 
• CO2 
• Creatinine 
• Magnesium 
• Calcium 
• Total protein 
 
a 
Fasting is recommended but not required. 
 
Thyroid Function Panel 
• T3 or FT3 (choose one for any individual subject) 
• FT4, TSH 
 
Liver Function Tests 
• AP 
• Total bilirubin 
• AST 
• Direct bilirubin 
• Alanine aminotransferase (ALT) 
 
• Gamma-Glutamyl Transferase (GGT) 
 
Biomarkers of Drug Effects on Liver 
• miR122 
• HMGB1 (native and acetylated) 
• Cytokeratin (18 full-length and 
caspase-cleaved) 
 
Hematology 
• RBC count 
• Hemoglobin 
• White blood cell (WBC) count with differential  
• Hematocrit 
• Platelet count 
 
 
Hepatitis Panel 
• HBV surface antigen test and HCV antibody test 
 
Coagulation Studies 
• Prothrombin time (PT), aPTT, and INR 
 


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Serum Pregnancy Test (β-hCG):  women of child-bearing potential 
 
Urinalysis (dipstick and microscopic analysis) 
Urine samples will be obtained for analysis of the following parameters: 
• pH 
• Ketones/acetone 
• Protein/albumin 
• Hemoglobin/blood 
• Glucose/sugar 
• RBC, WBC, epithelial cells, bacteria, casts, 
crystals 


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17.6. Schedule of Events for Protocol PLX108-14:  Dose-escalation and Expansion Phases 
Trial Period Screening 
Treatment 
Post-Treatment 
Follow-up 
Cycle 
 
1 
2 
3 and 
Beyond 
End of 
Treatment 
Safety  
Follow-up 
SAE  
Follow-upa 
Day -28 to -1 
1c 
8 
15 22 29 36 
1 
8 
15 
22 
1 
22 
At Time 
of DC 
28 Days 
Post-DC 
Every 12 
Weeksb 
Scheduling Window Days 
±3 
-2 ±3 ±3 ±3 ±3 ±3 
±3 
±3 
±3 
±3 
±3 
±3 
+3 
±7 
±7 
Eligibility Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medication Review 
X 
X 
X 
X 
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Study Drug Compliance 
 
 
X 
X 
X X X 
X 
 
 
X 
X 
X 
X 
 
 
Post-treatment DC anticancer therapy status 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Clinical Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Full Physical Examination (including height, 
only at Screening) 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
 
Directed Physical Examination 
 
X 
X 
X 
X 
As clinically indicated 
ECOG Performance Status 
X 
X 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs (including weight) 
X 
X 
X 
X 
X X X 
X 
 
 
X 
X 
X 
X 
X 
 
AE Monitoring 
X 
X 
X 
X 
X X X 
X 
X 
X 
X 
X 
X 
X 
Xj 
 
Laboratory Procedures/Assessmentsi 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with Differential 
X 
X 
X 
X 
X X X 
X 
 
 
X 
X 
X 
X 
X 
 
HBV, HCV testing 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation Studies (PT, aPTT, and INR) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis (with microscopic exam) 
X 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
X 
X 
 
Comprehensive Serum Chemistry Panel 
X 
X 
X 
X 
X X X 
X 
 
 
X 
X 
X 
X 
X 
 
Liver Function Tests 
X 
X 
X 
X 
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Exploratory Biomarkers (Liver effect 
biomarkers)c,d 
 
X 
X 
X 
X X 
 
 
 
 
 
 
 
X 
 
 
MDSCc 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 


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Trial Period Screening 
Treatment 
Post-Treatment 
Follow-up 
Cycle 
 
1 
2 
3 and 
Beyond 
End of 
Treatment 
Safety  
Follow-up 
SAE  
Follow-upa 
Day -28 to -1 
1c 
8 
15 22 29 36 
1 
8 
15 
22 
1 
22 
At Time 
of DC 
28 Days 
Post-DC 
Every 12 
Weeksb 
Scheduling Window Days 
±3 
-2 ±3 ±3 ±3 ±3 ±3 
±3 
±3 
±3 
±3 
±3 
±3 
+3 
±7 
±7 
CA-125k 
X 
X 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
 
Thyroid Function Panele 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
Pregnancy Test (serum β-hCG) f 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
 
Drug Dispensation, Administration, and 
Associated Analyses 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pembrolizumab Administration 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
 
 
 
PLX3397 Administration 
Subjects will self-administer PLX3397 at home as 2 split doses, administered ~12 hours apart. 
On days where PLX3397 PK samples are collected, subjects will bring their morning dose of PLX3397 to the clinic and 
receive it under the supervision of study site staff. 
Pharmacokinetics 
Please refer to Table 10 
Anti-pembrolizumab Antibodies (ADA) 
Efficacy Measurements 
 
 
 
 
 
Tumor Imagingg 
X 
Every 9 weeks ± 7 days 
X 
 
 
Digital Photography:  Cutaneous Lesions 
X 
As clinically indicated 
Pharmacodynamic Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor Tissue Collection (i.e., Biopsies)h 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Exploratory Pharmacology Blood Sample 
Collection  
 
X 
 
 
X X 
 
 
 
 
 
 
 
X 
 
 
ADA = anti-drug antibody; aPTT = activated partial thromboplastin time; β-hCG = beta human chorionic gonadotropin; DC = date of last dose; ECG = electrocardiogram; 
ECOG = Eastern Cooperative Oncology Group; FDG-PET= [18F]-fluorodeoxyglucose (FDG) positron emission tomography-computer tomography (PET/CT);  
HBV = hepatitis B virus; HCV; hepatitis C virus; INR = international normalized ratio; irRECIST = immune-related Response Evaluation Criteria in Solid Tumors;  
PT = prothrombin time; SAE = serious adverse event 
a 
SAE follow-up will include disease status:  scheduled visit on 12-and 24-week follow-up; phone call or visit every 12 weeks thereafter. 
b 
Post 24-week follow-up via telephone:  Serious Adverse Event (SAE) monitoring only. 
c 
Treatment period, Cycle 1:  Samples for laboratory evaluation should be collected prior to dosing with pembrolizumab and PLX3397. 
d 
Liver effect biomarkers at scheduled visits, also if ALT or AST are Grade 2 or higher and 5–8 days after PLX3397 dose hold or interruption. 


Protocol PLX108-14 
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Page 118 of 123 
e 
Thyroid Function Test to be performed every 6 weeks. If TSH is not within normal limits at baseline, the subject may still be eligible if total T3 or free T3 and free T4 
are within normal limits. If TSH, T3 and T4 are all abnormal, the thyroid function tests should be repeated Q3 weeks to be sure there is no change that meets 
autoimmune thyroiditis. 
f 
For women of childbearing potential only:  To be performed within 72 hours prior to Cycle 1 Day 1. Monthly pregnancy testing should be conducted as per local 
regulations where applicable. 
g 
Per irRECIST used in this protocol, if imaging shows progressive disease, the imaging assessment should be repeated at a minimum of 4 weeks later in order to 
confirm progressive disease (see the irRECIST Tip Sheet, provided in the Study Reference Manual). FDG-PET should be assessed at screening and C2D22 for GIST 
subjects only. 
Tumor Imaging Screening and End of Treatment (EOT) visit window ± 7 days. 
h 
Paired biopsies are optional in Dose-escalation, and required in the Expansion Phase (Baseline, Day 29) but optional for Expansion Phase at EOT, unless deemed 
medically unsafe by the Investigator. If PLX3397 study drug interruption occurs during the week prior to the on-treatment biopsy, the Medical Monitor should be 
contacted. 
i 
Screening labs required for Inclusion Criteria #10:  these laboratory tests should be performed within 10 days of C1D1. 
j 
SAEs are collected through 90 days following cessation of treatment, or 30 days following cessation of treatment if the subject initiates new anticancer therapy, 
whichever is earlier, whether or not related to the Sponsor's product, must be reported within 24 hours to the Sponsor. 
k 
CA-125 results to be collected per institutional standard of care for ovarian tumor type:  e.g., two pre-treatment samples, first sample within 3 months of starting 
therapy and second sample within 1 week of C1D1; subsequent samples on the first day of each cycle starting with Cycle 2 Day 1 and at the End-of-Study Visit. 
 


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17.7. Schedule of Events for Protocol PLX108-14:  Dose-escalation and Expansion Phase:  Cohort Intermittent PLX3397 
Administration 
Trial Period Screening 
Treatment 
Post-Treatment 
Follow-up 
Cycle 
 
1 
2 
3 and Beyond 
End of 
Treatment 
Safety  
Follow-up 
SAE 
Follow-upa 
Day 
-28 to -1 
1c 
8 
15 
22 
29 
36 
1 
8 
15 22 29 
1 
8 
22 
29 
At Time 
of DC 
28 Days 
Post-DC 
Every 12 
Weeksb 
Scheduling Window Days 
±3 
-2 
±3 ±3 
±3 
±3 
±3 
±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 
±3 
+3 
±7 
±7 
Eligibility Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medication Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
 
Study Drug Compliance 
 
 
X 
X 
X 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
X 
 
 
Post-treatment DC anticancer therapy 
status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Clinical Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Full Physical Examination (including 
height, only at Screening) 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
Directed Physical Examination 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
As clinically indicated 
ECOG Performance Status 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs (including weight) 
X 
X 
X 
X 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
AE Monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
Xl 
 
Laboratory Procedures/ 
Assessmentsk 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with Differential 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
 
HBV, HCV testing 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation Studies (PT, aPTT, and 
INR) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis (with microscopic exam) 
X 
X 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
X 
 
Comprehensive Serum Chemistry 
Panel 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
 


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Trial Period Screening 
Treatment 
Post-Treatment 
Follow-up 
Cycle 
 
1 
2 
3 and Beyond 
End of 
Treatment 
Safety  
Follow-up 
SAE 
Follow-upa 
Day 
-28 to -1 
1c 
8 
15 
22 
29 
36 
1 
8 
15 22 29 
1 
8 
22 
29 
At Time 
of DC 
28 Days 
Post-DC 
Every 12 
Weeksb 
Scheduling Window Days 
±3 
-2 
±3 ±3 
±3 
±3 
±3 
±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 
±3 
+3 
±7 
±7 
Liver Function Tests 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
 
X 
 
X 
 
X 
X 
 
Exploratory Biomarkers (Liver effect 
biomarkers)c,d 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
MDSCc 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CA-125m 
X 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
Thyroid Function Panele 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
Pregnancy Test (serum β-hCG) f 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
X 
 
X 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
Drug Dispensation, Administration, 
and Associated Analyses 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pembrolizumab Administration 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
PLX3397 Administration 
 
 
X 
X 
 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
Beginning 7 days (Day 8) after pembrolizumab infusion, subjects will self-administer PLX3397 at home as 2 split doses, 
administered ~12 hours apart until the day before the next pembrolizumab administration (Day 22). 
On days where PLX3397 PK samples are collected, subjects will bring their morning dose of PLX3397 to the clinic and receive 
it under the supervision of study site staff. 
PLX3397 PK Assessments 
 
X 
 
 
X 
 
Xi 
X 
 
 
 
 
X 
 
 
 
 
 
 
Anti-pembrolizumab Antibodies 
(ADA) and pembrolizumab 
pharmacokinetics 
Please refer to Table 10 
Efficacy Measurements 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor Imagingg 
X 
Every 9 weeks ± 7 days 
X 
 
 
Digital Photography:  Cutaneous 
Lesions 
X 
As clinically indicated 
Pharmacodynamic Assessmentsh 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor Tissue Collection (i.e., 
Biopsies)j 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol PLX108-14 
Amendment 6, 14 Dec 2017 
Proprietary | Confidential 
Page 121 of 123 
Trial Period Screening 
Treatment 
Post-Treatment 
Follow-up 
Cycle 
 
1 
2 
3 and Beyond 
End of 
Treatment 
Safety  
Follow-up 
SAE 
Follow-upa 
Day 
-28 to -1 
1c 
8 
15 
22 
29 
36 
1 
8 
15 22 29 
1 
8 
22 
29 
At Time 
of DC 
28 Days 
Post-DC 
Every 12 
Weeksb 
Scheduling Window Days 
±3 
-2 
±3 ±3 
±3 
±3 
±3 
±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 
±3 
+3 
±7 
±7 
Exploratory Pharmacology Blood 
Sample Collection  
X 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
ADA = anti-drug antibody; aPTT = activated partial thromboplastin time; β-hCG = beta human chorionic gonadotropin; DC = date of last dose; ECG = electrocardiogram; 
ECOG = Eastern Cooperative Oncology Group; HBV = hepatitis B virus; HCV; hepatitis C virus; INR = international normalized ratio; 
 irRECIST = immune-related Response Evaluation Criteria in Solid Tumors; PT = prothrombin time; SAE = serious adverse event 
a 
SAE follow-up will include disease status:  Scheduled visit on 12-and 24-week follow-up; phone call or visit every 12 weeks thereafter. 
b 
Post 24-week follow-up via telephone:  Serious Adverse Event (SAE) monitoring only. 
c 
Treatment period, Cycle 1:  Samples for laboratory evaluation should be collected prior to dosing with pembrolizumab. 
d 
Liver effect biomarkers at scheduled visits, also if ALT or AST are Grade 2 or higher and 5–8 days after PLX3397 dose hold or interruption. 
e 
Thyroid Function Test to be performed every 6 weeks. If TSH is not within normal limits at baseline, the subject may still be eligible if total T3 or free T3 and free T4 
are within normal limits. If TSH, T3 and T4 are all abnormal, the thyroid function tests should be repeated Q3 weeks to be sure there is no change that meets 
autoimmune thyroiditis. 
f 
For women of childbearing potential only:  To be performed within 72 hours prior to Cycle 1 Day 1. Monthly pregnancy testing should be conducted as per local 
regulations where applicable. 
g 
Per irRECIST used in this protocol, if imaging shows progressive disease, the imaging assessment should be repeated at a minimum of 4 weeks later in order to 
confirm progressive disease (see the irRECIST Tip Sheet, provided in the Study Reference Manual).  
Tumor Imaging Screening and End of Treatment (EOT) visit window ± 7 days. 
h 
If entering the study with a PLX3397 run-in, baseline biopsy and exploratory biomarker collection will be taken at Screening before starting PLX3397. 
i 
C1D36 requires PLX3397 predose trough PK sample drawn at -30 minutes (± 15 minutes) and detailed PK sampling drawn post dose at 30 minutes (± 15 minutes), 
1, 2, 4, and 6 hours (± 30 minutes). All other visits are for trough levels, i.e., approximately 30 min before the morning dose or 12 hours after the PLX3397 evening 
dose taken the day before the clinic visit. 
j 
Paired biopsies are optional in Dose-escalation and required in the Phase 2 Expansion, unless deemed medically unsafe by the Investigator. If PLX3397 study drug 
interruption occurs during the week prior to the on-treatment biopsy, the Medical Monitor should be contacted. 
k 
Screening labs required for Inclusion Criteria #10:  these laboratory tests should be performed within 10 days of C1D1. 
l 
SAEs are collected through 90 days following cessation of treatment, or 30 days following cessation of treatment if the subject initiates new anticancer therapy, 
whichever is earlier, whether or not related to the Sponsor's product, must be reported within 24 hours to the Sponsor. 
m 
CA-125 results to be collected per institutional standard of care for ovarian tumor type:  e.g., two pre-treatment samples, first sample within 3 months of starting 
therapy and second sample within 1 week of C1D1; subsequent samples on the first day of each cycle starting with Cycle 2 Day 1 and at the End-of-Study Visit. 


Protocol PLX108-14 
Amendment 6, 14 Dec 2017 
Proprietary | Confidential 
Page 122 of 123 
17.8. Schedule of Events for Protocol PLX108-14:  Run-in with PLX3397 Before Combination with Pembrolizumab (C1D1) 
Trial Period Screening 
Run-in 
Treatment 
Day (relative to C1D1) 
-42 to -15 
-14 
-7 
C1D1d 
Scheduling Window Days 
±3 
-2 
±3 
-2 
Eligibility Criteria 
X 
X 
 
 
Informed Consent 
X 
 
 
 
Medical History 
X 
 
 
 
Concomitant Medication Review 
X 
X 
X 
X 
Study Drug Compliance 
 
 
X 
X 
Clinical Procedures 
 
 
 
 
Full Physical Examination 
X 
 
 
 
Directed Physical Examination 
 
X 
X 
X 
ECOG Performance Status 
X 
X 
 
 
Height 
X 
 
 
 
Vital Signs (including weight) 
X 
X 
X 
X 
AE Monitoring 
X 
X 
X 
X 
Laboratory Procedures/Assessmentsh 
 
 
 
 
CBC with Differentiala 
X 
X 
X 
X 
HBV, HCV testing 
X 
 
 
 
Coagulation Studies (PT, aPTT, and INR)a 
X 
 
 
 
Urinalysis (with microscopic exam) 
X 
X 
 
X 
Comprehensive Serum Chemistry Panela 
X 
X 
X 
X 
Liver Function Testsa 
X 
X 
X 
X 
Exploratory Biomarkers (Liver effect, MDSC)a 
 
X 
X 
X 
Pregnancy Test (serum β-hCG)b 
X 
X 
 
X 
ECG 
X 
X 
 
X 
PLX3397 Administrationc 
 
X 
X 
 
PLX3397 Pharmacokineticse 
 
 
 
X 


Protocol PLX108-14 
Amendment 6, 14 Dec 2017 
Proprietary | Confidential 
Page 123 of 123 
Trial Period Screening 
Run-in 
Treatment 
Day (relative to C1D1) 
-42 to -15 
-14 
-7 
C1D1d 
Scheduling Window Days 
±3 
-2 
±3 
-2 
Efficacy Measurements 
 
 
 
 
Thyroid Function Panelf 
 
 
 
X 
Tumor Imaging 
X 
 
 
 
Digital Photography:  Cutaneous Lesions 
X 
 
 
 
Pharmacodynamic Assessments 
 
 
 
 
Tumor Tissue Collection (i.e., Biopsiesg) 
X 
 
 
 
Exploratory Pharmacology Blood Sample Collection 
X 
 
 
 
aPTT = activated partial thromboplastin time; β-hCG = beta human chorionic gonadotropin; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; 
HBV = hepatitis B virus; HCV; hepatitis C virus; INR = international normalized ratio 
a 
Treatment period:  Samples for laboratory evaluation should be collected prior to dosing with PLX3397. 
b 
For women of childbearing potential only:  To be performed within 72 hours prior to first dose of PLX3397. Monthly pregnancy testing should be conducted as per 
local regulations where applicable. 
c  
Subjects will self-administer PLX3397 at home from Days -14 to -1as 2 split doses, administered ~12 hours apart each day. However, on days when clinical visits are 
scheduled, subjects will bring their morning dose of PLX3397 to the clinic and receive it under the supervision of study site staff. 
d 
C1D1 defined as day of first pembrolizumab dose. 
e 
PLX3397 trough PK sample. 
f 
Thyroid Function Test to be performed every 6 weeks. If TSH is not within normal limits at baseline, the subject may still be eligible if total T3 or free T3 and free T4 
are within normal limits. 
g 
Paired biopsies are optional in Dose-escalation and required in the Phase 2 Expansion, unless deemed medically unsafe by the Investigator. If PLX3397 study drug 
interruption occurs during the week prior to the on-treatment biopsy, the Medical Monitor should be contacted. 
h 
Screening labs required for Inclusion Criteria #10:  these laboratory tests should be performed within 10 days of C1D1.