Clinical trial NCT02764151
Conditions: Oligodendroglioma Astrocytoma Malignant Glioma
Keywords: GBM malignant glioma glioma anaplastic glioma astrocytoma IDO IDO1 PF-06840003
Sponsor: Pfizer
Start date: 2016-09-09; Completion date: 2018-12-26
Enrollment: 17 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study will evaluate the safety and tolerability of increasing doses of PF-06840003 in patients with malignant gliomas.

Detailed description:

Arms: arm 1: Daily Oral PF-06840003
Interventions: intervention 1: PF-06840003
Intervention descriptions: intervention 1: Daily Oral PF-06840003

Protocol documents:
Prot_000.pdf: 
PF-06840003
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A PHASE 1 DOSE ESCALATION STUDY EVALUATING THE SAFETY AND 
TOLERABILITY OF PF-06840003 IN PATIENTS WITH MALIGNANT GLIOMAS
Compound:
PF-06840003
Compound Name:
Not applicable
United States (US) Investigational New 
Drug (IND) Number:
European Clinical Trials Database 
(EudraCT) Number:
Not applicable
Protocol Number:
C0591001
Phase:
Phase 1
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Document History
Document
Version Date
Summary of Changes and Rationale
Amendment 1
19 December 2016
The reasons for Amendment 1 include:
•
Revision to timepoint when Disease Control 
Rate will be evaluated from Week 26 to 
Week 25. – Section 2.
Rationale – Based on an imaging frequency of 
every 8 weeks, Week 25 is the appropriate 
assessment timepoint.
•
 
 
Rationale – Administrative correction to 
ensure consistency across sections of the 
protocol.
•
Inclusion of the potential for evaluation of 
twice daily (BID) dosing – Schedule of 
Activities and Sections 3 and 5.4.
Rationale – Based on emerging PK data from 
this study, twice a day dosing may be 
evaluated as part of the dose escalation if the 
exposure from once per day dosing does not 
allow for sufficient target coverage. 
•
Clarification on overall sample size for Part 1 
of the study. – Sections 3.1 and 9.3.
Rationale – With the inclusion of the 
possibility to explore BID dosing, more than 
6 cohorts may be included in the study.  
Therefore, the total sample size may be more 
than approximately 72 for Part 1.
•
Inclusion of inpatient evaluation for PK 
collection on Cycle 1 Day 1 and Cycle 1 
Day 15 for patients enrolled in cohorts where 
doses of 500 mg QD or 500 mg BID or higher 
will be evaluated – Schedule of Activities and 
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Section 7.2.
Rationale – In order to adequately collect 
urine for the 24 hour pharmacokinetic 
assessment, patients will need to be kept as 
inpatients for sample collection.

F-18-FLT-PET imaging is to be collected in 
all patients dosed at 500 mg QD or 
500 mg BID or higher at sites where the 
assessment can be performed. – Schedule of 
Activities and Section 7.4.1.
Rationale – Language added to clarify the 
assessment is not optional for sites who can 
complete the imaging.

Blood samples for PF-06840003 
pharmacokinetic evaluation and triplicate 
ECGs are to be obtained on Day 15 of 
Cycle 3 and beyond. – Schedule of Activities.
Rationale – Administrative clarification.

Urine PK is to be collected in patients 
enrolled in cohorts where 500 mg QD or 
500 mg BID or higher will be evaluated. –
Schedule of Activities.
Rationale – As the urine collection requires 
inpatient evaluation, this will be limited to 
patients enrolled at doses where the most 
meaningful data will be collected.

Correction to definition of patients to be 
enrolled in Part 1 of the study – Section 4.1.
Rationale - Administrative corrections to 
ensure consistency throughout the entry 
criteria.

Estimated creatinine clearance is to be 
calculated using Cockcroft-Gault, a 24-hour 
urine collection is not required. – Section 4.1.
Rationale – Clarification added to ensure 
consistency in evaluation of this criteria based 


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on feedback received from the FDA during 
the initial Investigational New Drug (IND) 
application review from the ‘Study May 
Proceed’ letter for IND 129245 of April 25, 
2016 (CDER reference ID:3921862).

Revisions to the inclusion criteria to allow for 
patients with Grade 3 disease following a 
third or fourth recurrence or progression to be 
included – Section 4.1.
Rationale – Inclusion of later stage patients 
will still allow the study to meets its 
objectives while also allowing more potential 
patients to be eligible.

Revisions to exclusion criteria relating to 
prior VEGF treatment – Section 4.2.
Rationale – Criteria revised to allow more 
patients to be considered as prior VEGF is not 
considered to be a safety concern for patients.

Removal of time requirement for stereotactic 
biopsy – Section 4.2.
Rationale – Timing for biopsy removed to 
allow for possible performance of a screening 
biopsy as part of the study procedures.

Details on rater qualification included –
Section 4.5.
Rationale - Additional details on certifications 
required prior to administration of certain 
assessments added.

Inclusion of reference to 25 mg strength for 
tablets in case a intermediate dose requiring 
use of the 25 mg tablets is required. –
Section 5.3.1.
Rationale – Included to allow for potential 
inclusion of 25 mg tablets should evaluation 
of an intermediate dose be required.

Fasting for dosing defined as no food for two 


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hours before or two hours after dosing –
Section 5.4.
Rationale – Administrative clarification.

Clarification on how the C-SSRS is to be 
administered included – Section 7.7.
Rationale: Correction on how the assessment 
will be administered has been included.

Study assessments added in the Appendices –
Appendix 3, 4, 5 and 6.
Rationale – Administrative clarification.

Administrative corrections and edits included 
– Schedule of Activities and Sections 2.1, 3.1, 
4.2, 5.1, 7.2.3, 7.3.2, 7.3.5, 7.6.2 and 
Appendix 1.
Rationale - Administrative changes.
Original 
protocol
02 March 2016
Not applicable (N/A)
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities, institutional review boards/ethics committees 
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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................10
LIST OF FIGURES .................................................................................................................10
APPENDICES .........................................................................................................................11
PROTOCOL SUMMARY.......................................................................................................12
SCHEDULE OF ACTIVITIES................................................................................................17
1. INTRODUCTION ...............................................................................................................25
1.1. Mechanism of Action/Indication.............................................................................25
1.2. Background and Rationale ......................................................................................25
1.3. Malignant Gliomas..................................................................................................25
1.3.1. Rationale for Evaluation in Malignant Gliomas.........................................26
1.4. PF-06840003 in Malignant Gliomas.......................................................................26
1.4.1. IDO1 in Malignant Gliomas.......................................................................26
1.4.2. Mechanisms ................................................................................................28
1.4.3. Perspectives ................................................................................................28
1.5. Nonclinical Pharmacology and Safety....................................................................29
1.5.1. Nonclinical Pharmacokinetics ....................................................................29
1.5.2. Nonclinical Safety ......................................................................................30
1.6. Starting Dose Rationale...........................................................................................32
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................32
2.1. Objectives................................................................................................................32
2.2. Endpoints.................................................................................................................33
3. STUDY DESIGN.................................................................................................................35
3.1. Study Overview.......................................................................................................35
3.1.1. Criteria for Dose Escalation........................................................................36
3.2. DLT Definition........................................................................................................38
3.3. MTD Definition.......................................................................................................39
3.4. Late Onset Toxicity and Toxicities Observed in the Expansion Phase...................39
3.5. Recommended Phase 2 Dose (RP2D) Definition ...................................................40
4. PATIENT SELECTION......................................................................................................40
4.1. Inclusion Criteria.....................................................................................................40
4.2. Exclusion Criteria....................................................................................................42


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4.3. Lifestyle Guidelines ................................................................................................44
4.4. Sponsor’s Qualified Medical Personnel..................................................................45
4.5. Rater Qualifications.................................................................................................45
5. STUDY TREATMENTS.....................................................................................................45
5.1. Allocation to Treatment ..........................................................................................46
5.2. Patient Compliance .................................................................................................46
5.3. Investigational Product Supplies.............................................................................46
5.3.1. Dosage Form(s) and Packaging..................................................................46
5.3.2. Preparation and Dispensing........................................................................46
5.4. Administration.........................................................................................................47
5.4.1. Recommended Dose Modifications............................................................47
5.4.2. Dosing Interruptions...................................................................................48
5.4.3. Dose Delays................................................................................................48
5.4.4. Dose Reductions.........................................................................................49
5.5. Investigational Product Storage ..............................................................................50
5.6. Investigational Product Accountability...................................................................51
5.6.1. Destruction of Investigational Product Supplies ........................................51
6. STUDY PROCEDURES .....................................................................................................53
6.1. Screening.................................................................................................................53
6.2. Study Period ............................................................................................................53
6.3. Follow-up Visit .......................................................................................................53
6.4. Patient Withdrawal..................................................................................................53
7. ASSESSMENTS..................................................................................................................54
7.1. Safety Assessment...................................................................................................54
7.1.1. Pregnancy Testing ......................................................................................54
7.1.2. Adverse Events...........................................................................................55
7.1.3. Laboratory Safety Assessment ...................................................................55
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7.1.4. Vital Signs and Physical Examination........................................................56
7.1.5. (12-Lead) Electrocardiogram......................................................................57
7.3. Biomarker and Pharmacodynamic Assessments.....................................................59
7.3.1. Target Engagement – Assessment of Kynurenine, Tryptophan and 
Metabolites.......................................................................................................59
7.3.3. Cytokines and Chemokines ........................................................................60
7.3.4. T Cell Receptor (TCR) Sequencing............................................................60
7.3.5. Tumor Biopsies...........................................................................................61
7.4. Tumor Response Assessments ................................................................................61
7.4.1. F-18-FLT PET ............................................................................................64
8. ADVERSE EVENT REPORTING......................................................................................67
8.1. Adverse Events........................................................................................................67
8.2. Reporting Period .....................................................................................................67
8.3. Definition of an Adverse Event...............................................................................67
8.4. Medication Errors....................................................................................................68
8.5. Abnormal Test Findings..........................................................................................69
8.6. Serious Adverse Events...........................................................................................69
8.6.1. Protocol-Specified Serious Adverse Events ...............................................70
8.6.2. Potential Cases of Drug-Induced Liver Injury............................................70
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8.7. Hospitalization ........................................................................................................71
8.8. Severity Assessment................................................................................................72
8.9. Causality Assessment..............................................................................................73
8.10. Exposure During Pregnancy..................................................................................73
8.11. Occupational Exposure .........................................................................................74
8.12. Withdrawal Due to Adverse Events (See also the Section on Patient 
Withdrawal)...............................................................................................................74
8.13. Eliciting Adverse Event Information ....................................................................75
8.14. Reporting Requirements........................................................................................75
8.14.1. Serious Adverse Event Reporting Requirements .....................................75
8.14.2. Non-Serious Adverse Event Reporting Requirements .............................75
8.14.3. Sponsor’s Reporting Requirements to Regulatory Authorities ................76
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................76
9.1. Analysis Sets ...........................................................................................................76
9.2. Statistical Methods and Properties ..........................................................................77
9.2.1. Statistical Methods for Dose Escalation/De-Escalation .............................77
9.3. Sample Size Determination.....................................................................................77
9.4. Efficacy Analysis ....................................................................................................78
9.5. Analysis of Pharmacokinetics and Pharmacodynamics..........................................78
9.5.1. Analysis of Pharmacokinetics.....................................................................78
9.5.1.1. Single-Dose and Steady-State PF-06840002 and PF-
06840001 Pharmacokinetic Analysis ................................................78
9.5.2. Analysis of Pharmacodynamics..................................................................79
9.5.2.1. Analysis of Biomarker Endpoints .............................................79
9.5.3. Population Pharmacokinetic Analysis or 
Pharmacokinetic/Pharmacodynamic (PK/PD) Modeling ................................79
9.6. Safety Analysis........................................................................................................79
9.6.1. Analysis of the Primary Endpoint...............................................................79
9.6.2. Analysis of Secondary Safety Endpoints....................................................79
9.6.3. Electrocardiogram.......................................................................................80
9.8. Data Safety Monitoring Committee ........................................................................81
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10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................81
11. DATA HANDLING AND RECORD KEEPING .............................................................82
11.1. Case Report Forms/Electronic Data Record .........................................................82
11.2. Record Retention...................................................................................................82
12. ETHICS..............................................................................................................................83
12.1. Institutional Review Board /Ethics Committee.....................................................83
12.2. Ethical Conduct of the Study ................................................................................83
12.3. Patient Information and Consent...........................................................................83
12.4. Patient Recruitment...............................................................................................84
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................84
13. DEFINITION OF END OF TRIAL...................................................................................84
14. SPONSOR DISCONTINUATION CRITERIA ................................................................84
15. PUBLICATION OF STUDY RESULTS..........................................................................85
15.1. Communication of Results by Pfizer ....................................................................85
15.2. Publications by Investigators ................................................................................85
16. REFERENCES ..................................................................................................................87
LIST OF TABLES
Table 1.
Dose Escalation Potential Dose Levels ................................................................37
Table 2.
Decision Rules......................................................................................................38
Table 3.
Dose Modifications for Investigational Product-Related Toxicity.......................50
Table 4.
Laboratory Assessments .......................................................................................56
Table 5.
Pharmacodynamic Summary................................................................................59
Table 6.
Overall Response Criteria.....................................................................................63
LIST OF FIGURES
Figure 1.
IDO1 mRNA and protein expression levels correlated with overall patient 
survival (Wainwright et al, 2012).........................................................................27
Figure 2.
Overall Study Design............................................................................................36


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APPENDICES
Appendix 1. Abbreviations......................................................................................................90
Appendix 2. Karnofsky Performance Scoring (Karnofsky et al, 1948)...................................93
Appendix 3. Columbia-Suicide Severity Rating Scale (CSSRS) – Baseline...........................94
Appendix 4. Columbia-Suicide Severity Rating Scale (C-SSRS) – Since Last Visit ...........100
Appendix 5. Patient Health Questionnaire (PHQ-8)..............................................................104
Appendix 6. Neurologic Assessment in Neuro-Oncology (NANO) Scale............................105


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PROTOCOL SUMMARY
Background and Rationale:
Indoleamine 2, 3-dioxygenase (IDO1) is a heme-containing dioxygenase that catalyzes the 
oxidation of tryptophan to N-formyl kynurenine in the first and rate-limiting step of 
tryptophan catabolism. N-formyl kynurenine is subsequently converted to kynurenine and 
other cytotoxic metabolites via the kynurenine pathway.  IDO1 acts to inhibit T-cell function 
both through depletion of tryptophan and production of kynurenine (Munn & Mellor, 2013; 
van Baren & Ven den Eynde, 2015).15,24  IDO1 expression is often higher in the tumor 
microenvironment, typically in response to inflammatory stimuli such as interferon gamma
(IFN-) (Mellor & Munn, 2004).12  The enzymatic activity of IDO1 is associated with 
suppression of T-cell responses (Uyttenhove et al, 2003)23 and is correlated with poor 
prognosis in several cancer indications (Okamoto et al, 2005; Brandacher et al, 2006).18,5  As 
such, IDO1 is a target of interest for cancer immunotherapy.
IDO1 is expressed in 96% of malignant glioma (Mitsuka et al, 2013).13 In a study reported 
by Mitsuka, IDO immunohistochemistry (IHC) expression has been assessed in 75 surgical 
specimens. Stronger expression in malignant gliomas was found compared with low-grade 
gliomas. In 6 cases of secondary glioblastoma, IDO expression was stronger than in the 
initial low-grade glioma. IDO was expressed more strongly in both primary and secondary 
glioblastoma tissue than low-grade glioma and could affect clinical outcome. Grade IV 
patients with strong IDO expression had significantly worse overall survival rates (P = .04) 
than patients with weak IDO expression. 
The higher IDO expression in both primary and secondary glioblastoma tissue compared to 
low-grade glioma has been confirmed by other authors who reported that this may affect 
clinical outcome. (Wainwright et al, 2012).25
IDO1 messenger ribonucleic acid (mRNA) and protein expression levels correlate with 
overall patient survival. IDO1 is involved in malignant glioma immunosuppression. IDO1 
plays a key role in resistance to immune therapy. The selective nature of IDO1 expression in 
malignant glioma provides a high potential for targeting specificity.
Study Objectives and Endpoints:
Objectives
Primary Objective – Part 1

To evaluate the safety and tolerability of increasing dose levels of daily oral 
PF-6840003 in patients with malignant gliomas.

To characterize the dose limiting toxicities (DLTs) of escalated doses of 
PF-06840003.


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•
To determine the maximum tolerated dose (MTD) or recommended phase 2 dose 
(RP2D).
Primary Objective – Part 2
•
To further evaluate the safety and tolerability of PF-06840003 at the RP2D.
•
To evaluate the efficacy of PF-06840003 in patients with glioblastoma.
Secondary Objectives – Parts 1 and 2
•
To evaluate the overall safety profile.
•
To characterize the single and multiple dose plasma pharmacokinetics (PK) of active 
enantiomer PF-06840002, and inactive enantiomer PF-06840001 after administration 
of the racemic mixture, PF-06840003.
•
To document any anti-tumor activity (Part 1 only).
•
To evaluate dose and concentration response relationship for target engagement and
pharmacodynamic (PD) biomarkers and to then correlate with PK, safety and efficacy 
to select dose with full or optimal target engagement.
•
To assess the cerebrospinal fluid (CSF) PK exposure of active enantiomer 
PF-06840002, and inactive enantiomer PF-06840001 after administration of the 
racemic mixture, PF-06840003.
 
 
 
 
 
 
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Endpoints
Primary Endpoint – Part 1
•
Incidence and grade of treatment-emergent adverse events (TEAE) including DLTs as 
graded by National Cancer Institute Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03.
Primary Endpoints – Part 2
•
Adverse Events (AE) as characterized by type, frequency, severity, timing, 
seriousness, and relationship to study therapy.
•
Disease control rate (DCR) at 9 and 25 weeks by magnetic resonance imaging (MRI)
using Macdonald criteria (Macdonald et al, 1990).9
Secondary Endpoints
•
Laboratory abnormalities as characterized by type, frequency, severity [as graded by 
National Cancer Institute (NCI) CTCAE v.4.03] and timing;
•
Vital Signs; 
•
PK parameters in the blood of PF-06840002 and PF-06840001 Single Dose (SD) –
Cmax, Tmax, AUClast, AUCτ, CL/F, and Vz/F and t1/2, AUCinf as data permit.  Multiple 
Dose (MD) (assuming steady state is achieved) – Css,max, Tss,max, AUCss,τ, t1/2, Css,min, 
Css,av, CL/F, Vss/F, Rac (AUCss,τ /AUCsd,τ) and Rss (AUCss,τ /AUCsd,inf) as data permit;
•
Objective tumor response based on Macdonald criteria;
•
Disease Control Rate (DCR) at 9 and 25 weeks by MRI based on Response 
Assessment for Neuro-Oncology (RANO) criteria;
•
On-target activity of PF-06840003 by measurement of kynurenine, tryptophan and 
kyn/trp (ratio) levels in peripheral blood;
•
Steady-state trough level ratio between CSF and plasma samples for PF-06840002 
and PF-06840001.
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Study Design
This is a Phase 1, open-label, multi-center, multiple-dose, safety, PK and PD study of single 
agent PF-06840003.  This study contains two parts, dose escalation (Part 1) followed by dose 
expansion (Part 2).  In Part 1, sequential cohorts of patients with recurrent malignant gliomas 
[Glioblastoma Multiforme (GBM) and/or World Health Organization (WHO) grade III 
anaplastic gliomas] will receive escalating doses of PF-06840003.  Part 2 will evaluate safety 
as well as explore preliminary antitumor activity of the dose selected from Part 1 in 
additional patients with GBM.
The actual number of patients enrolled in the study will depend on the tolerability of 
PF-06840003 and the number of dose levels required to identify the MTD or Recommended 
Phase 2 Dose (RP2D) if the MTD is not reached.  The target sample size for each cohort in 
Part 1 is 2-4 patients, but, the actual number of patients treated at each dose will vary from 
2 to 12. It is estimated that the maximum sample size will be approximately 72 patients in 
Part 1 of the study, although this may be higher if more than 6 dose levels are required to be 
evaluated.  Up to approximately 20 to 25 patients are anticipated to be enrolled in Part 2 of 
the study.
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Study Treatment
PF-06840003 will be administered daily as an oral dose in 28 day cycles with a starting dose 
of 125 mg once daily (QD).  The pre-specified nominal doses for use in the dose escalation 
are 125 mg/day, 250 mg/day and 500 mg/day of PF-06840003.  If the MTD or the RP2D are
not reached within the pre-planned nominal dose range, and the PK and PD data show that 
the target coverage is not optimal, the sponsor, in conjunction with the investigators, after 
careful consideration of all available safety, laboratory and PK information may expand the 
nominal dose range to a higher dosage, up to a maximum dosage of 1000 mg per day.  Based 
on emerging clinical and PK data, twice a day (BID) dosing may be explored.  For example, 
if the exposure over 24 hours does not allow for sufficient target coverage it may be 
determined that BID dosing is needed.  In such a case, BID dosing will be initiated at the QD 
dose level where no DLTs are observed (ie, starting dose of BID dosing will be 250 mg BID 
after safety and tolerability profile of 250 mg QD is confirmed). Once a BID dosing regimen 
is initiated for further escalation towards the maximum tolerated dose (MTD), the escalation 
with a QD regimen will be suspended.  Intermediate doses may also be used if required.
In Part 1 of the study, dose escalation and de-escalation will follow a modified Toxicity 
Probability Interval (mTPI) method, targeting a DLT rate of 27.5% and an acceptable DLT 
interval 22.5 to 32.5%.  
The dose escalation portion of the study is completed when at least 6 to 12 evaluable patients 
have been treated at the highest dose associated with DLT rate 32.5%.


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SCHEDULE OF ACTIVITIES
The schedule of activities table provides an overview of the protocol visits and procedures.  Refer to the ASSESSMENTS section of 
the protocol for detailed information on each assessment required for compliance with the protocol.   
The investigator may schedule visits (unplanned visits) in addition to those listed on the schedule of activities, in order to conduct 
evaluations or assessments required to protect the well-being of the patient.
Protocol Activity
Screening
(28 days 
prior to 
registration)
CYCLE 1*
(28 day duration)
CYCLE 2
(28 day duration)
CYCLE ≥3
(Each with a 
28 day duration)
End of 
Treatment
Follow-
up20
Study Day
Day 1
Day 4
Day 8
Day 15
Day 22
Day 1
Day 15
Day 1
Day 15
Visit Window (days)**
(1)
(1)
(1)
(1)
(2)
(2)
(2)
Informed consent1
X
Tumor history
X
Medical history
X
Complete physical 
examination
X
X2
X
Abbreviated physical 
examination
X
X
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
Vital signs3
X
X
X
X
X
X
X
X
X
X
X
X
Performance status4
X
X
X
X
X
X
Contraception check
X
X
X
X
X
Laboratory
Unique screening labs5
X
Hematology6
X
X
X
X
X
X
X
X
X
X
X
X
Blood Chemistry7
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation8
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis9
X
X
X
X
X
X
X
X
X
Pregnancy test10
X
X
X
X
X
Single 12 Lead ECG
X
Triplicate(12 lead) ECG
Refer to Schedule of Electrocardiogram, Pharmacokinetic and Pharmacodynamic Assessments


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Protocol Activity
Screening
(≤28 days 
prior to 
registration)
CYCLE 1*
(28 day duration)
CYCLE 2
(28 day duration)
CYCLE ≥3
(Each with a 
28 day duration)
End of 
Treatment
Follow-
up20
Study Day
Day 1
Day 4
Day 8
Day 15
Day 22
Day 1
Day 15
Day 1
Day 15
Visit Window (days)**
(±1)
(±1)
(±1)
(±1)
(±2)
(±2)
(±2)
ECHO or MUGA
X
X
X
X
X
Registration and 
Treatment 
Registration11
X
Study treatment12
→
→
→
→
→
→
→
→
→
Inpatient Evaluation for PK 
collection13
X
X
PF-06840003 Dispensing
X
X
X
PF-06840003 
Accountability
X
X
X
Tumor assessments
Tumor assessments, 
including MRI14
X
X (every 
8 weeks)
X
F-18-FLT-PET15
X
X15
X15
Other clinical assessments
 
 
 
 
 
 
Adverse events19
X
X
X
X
X
X
X
X
X
X
X
Other samplings
Banked biospecimen
X
Tumor biopsy
Refer to Schedule of Electrocardiogram, Pharmacokinetic and Pharmacodynamic Assessments
Pharmacokinetics
Pharmacodynamics
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* A cycle is 28 days in duration
** Visit windows are calculated off the first day of each cycle.
Abbreviations: = continuous daily dosing; AEs = adverse events; CT = computed tomography; ECG = electrocardiogram; ECHO = echocardiogram; MRI =
magnetic resonance imaging; MUGA = multi-gated acquisition scan
1.
Informed Consent: Must be obtained prior to undergoing any study specific procedures.  May be obtained more than 28 days prior to registration.
2.
Complete Physical Examination: No need to repeat on Cycle 1 Day 1 (C1D1) if screening assessment is performed within 7 days of dosing.
3.
Vital signs: Includes temperature (oral, tympanic, temporal or axillary) and blood pressure (BP) to be recorded in seated position.
4.
Performance Status: Use Karnofsky performance status scale – (Appendix 2)
5.
Unique Screening Laboratory Tests: Hepatitis B surface antigen, hepatitis B core antibody, hepatitis C antibody and human immunodeficiency virus 
(HIV) as well as follicle stimulating hormone (FSH) for post-menopausal women who are amenorrheic for at least 12 consecutive months only.  Samples 
will be analyzed locally.
6.
Hematology: No need to repeat on Cycle 1 Day 1 if screening assessment is performed within 7 days prior to that date.  Complete blood count (CBC) to 
include hemoglobin, platelets, white blood cells (WBC), absolute neutrophils, lymphocytes, monocytes, eosinophils and basophils.  Assessments performed 
at all subsequent dosing visits should be performed within 48 hours prior to dosing.  Samples will be analyzed locally.
7.
Blood Chemistry: No need to repeat on Cycle 1 Day 1 if screening assessment is performed within 7 days prior to that date.  Should include sodium, 
potassium, chloride, BUN (or urea), uric acid, creatinine, glucose, calcium, magnesium, phosphorus, albumin, aspartate aminotransferase (AST/SGOT), 
alanine aminotransferase (ALT/SGPT), alkaline phosphatase and total bilirubin. Assessments performed at all subsequent dosing visits should be performed 
within 48 hours prior to dosing.  Samples will be analyzed locally.
8.
Coagulation: No need to repeat on Cycle 1 Day 1 if baseline assessment is performed within 7 days prior to that date.  Should include prothrombin Time 
(PT) or International Normalized Ratio (INR) and Partial Thromboplastin Time (PTT).  Samples will be analyzed locally.
9.
Urinalysis: No need to repeat on Cycle 1 Day 1 if baseline assessment is performed within 7 days prior to that date.  Dipstick is acceptable.  Microscopic 
analyses if dipstick abnormal.  Samples will be analyzed locally.
10. Pregnancy Test: For female patients of childbearing potential, a serum or urine pregnancy test, with sensitivity of at least 25 mIU/mL and assayed in a 
certified laboratory, will be performed on two occasions prior to starting study treatment – once at the start of screening and once on C1D1 immediately 
before investigational product administration.  Pregnancy tests will also be routinely repeated at every cycle during the active treatment period, at the end of 
study treatment and additional whenever one menstrual cycle is missed or when potential pregnancy is otherwise suspected.  Additional pregnancy tests may 
also be undertaken if requested by institutional review board (IRB) or if required by local regulations.
11. Registration: Patient number and dose level allocation provided by Pfizer Inc.  Registration should occur before any other Day 1 activities are performed 
and preferably no more than 3 business days before Day 1.
12. Study Treatment: Daily oral dosing with PF-06840003 will be initiated on Cycle 1 Day 1 and should continue until end of treatment.  Patients assigned to a 
BID dosing regimen should be instructed to take PF-06840003 every 12 hours (1 hour).  On days when patients have clinic visits where PK assessments are 
to be obtained, PF-06840003 should be held (NOT taken) prior to the study visit.  The PF-06840003 can be taken after the study procedures required for that 
visit have been performed. 


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13. Inpatient Evaluation for PK Assessment: For cohorts where 500 mg QD or 500 mg BID or higher will be evaluated, patients will be required to undergo 
inpatient evaluation for at least 24 hours following receipt of the Cycle 1 Day 1 and Cycle 1 Day 15 dose.  The evaluation will be used for collection of 
samples for evaluation of the PF-06840003 pharmacokinetics.
14. Tumor Assessments: Tumor assessments will include all known or suspected disease sites.  Imaging should include brain MRI with contrast. Tumor
assessments will be made using the Macdonald criteria.  On study MRIs are to be collected every 8 weeks (±5 days). Where possible, responses should be 
confirmed with two assessments at least 4 weeks apart.  Tumor assessment should be repeated at the end of treatment visit if more than 4 weeks have passed 
since the last evaluation. Efficacy evaluations using the Macdonald criteria involve post-contract MRI findings, non-contrast T1 and T2 fluid attenuated 
inversion recovery (FLAIR) images, use of corticosteroid dose, and neurological examination.  Disease progression will be confirmed with two consecutive 
timepoints at least 8 weeks apart in the absence of substantial neurological decline if progression is suspected within 6 months of treatment initiation.
15. F-18-flurothymidine (FLT) PET: For locations who are able to perform the assessment, l F-18-FLT-PET imaging will be performed in all patients 
assigned to receive doses of 500 mg/day or higher.  Assessment will be performed at screening after all eligibility criteria have been confirmed and at 
Weeks 9 and 25. Should be performed if the patient discontinues the study prior to Week 9 or between Weeks 9 and Week 25 if more than 4 weeks have 
passed since the last evaluation.  
  
 
 
 
19. Adverse Event (AE) Assessments: Adverse events should be documented and recorded at each visit using the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.  Patients must be followed for AEs for 28 days after the last study treatment 
administration or until all drug-related toxicities have resolved, whichever is later; or earlier than 28 days should the patient commence another anticancer 
therapy in the meantime.  For serious adverse events (SAEs), the active reporting period to Pfizer or its designated representative begins from the time that 
the patient provides informed consent, which is obtained prior to the patient’s participation in the study, ie, prior to undergoing any study-related procedure 
and/or receiving investigational product, through and including 28 calendar days after the last administration of the investigational product.  SAEs occurring 
to a patient after the active reporting period has ended should be reported to the sponsor if the investigator becomes aware of them; at a minimum, all SAEs 
that the investigator believes have at least a reasonable possibility of being related to investigational product are to be reported to the sponsor.
20. Follow-up: At least 28 days, and no more than 35 days, after discontinuation of treatment, patients will return to undergo the assessments included in the 
table above which includes a review of concomitant medications and assessment for resolution of any treatment-related toxicity.  Patients continuing to 
experience toxicity at this point following discontinuation of treatment will continue to be followed at least every 4 weeks until resolution or determination, 
in the clinical judgment of the investigator, that no further improvement is expected.
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SCHEDULE OF ELECTROCARDIOGRAM, PHARMACOKINETIC AND PHARMACODYNAMIC ASSESSMENTS –
FOR COHORTS WHERE INPATIENT EVALUATION IS NOT REQUIRED
Protocol Activity
Screening
(≤28 days)
Treatment Period
Cycle 1 Only
Cycle 2
Cycle 3 and 
beyond
End of 
Treatment
Study Day
Day 1
Day 
2
Day 
4
Day 
8
Day 15
Day 
16
Day 
1
Day 
15
Day 1
Day 15
Hours Pre-
/Post-Dose*
Pre-
dose
1
2
4
6
8
24
Pre-
dose
Pre-
dose
Pre-
dose
1
2
4
6
8
24
Pre-
dose
Pre-
dose
Pre-
dose
Pre-dose
Triplicate (12 Lead) 
ECGs1
X
X
X
X
X
X
X
X
X
X
X
X2
X
X
Blood samples for 
PF-06840003 PK
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Cerebrospinal fluid 
samples for 
PF-06840003 PK and 
PD3
X
X
Kyn and trp
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Cytokine/chemokines
X
X
X
X
X
X
X
X
X
X
 
TCR sequencing in 
peripheral blood
X
X
X
Tumor biopsies4
X
X5
* All efforts will be made to obtain the PK samples at the exact nominal time relative to dosing.  However, samples obtained within 10% of the nominal time 
from dosing are acceptable.
Abbreviations: → = continuous sample collection; ECG = electrocardiogram; kyn = kynurenine; PK = pharmacokinetics; TCR = T cell repertoire; 
trp = tryptophan
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1.
Triplicate 12-Lead ECGs: Triplicate 12-lead ECG: At each timepoint, 3 consecutive 12-lead ECGs will be performed approximately 2 minutes apart.  
When coinciding with blood sample draws for pharmacokinetics (PK), ECG assessment should be performed prior to blood sample collection, such that the 
blood sample is collected at the nominal time.  If the mean QTcF is prolonged (>500 msec), the ECGs should be re-evaluated by a qualified person at the 
institution for confirmation.  Additional triplicate ECGs may be performed as clinically indicated.
2.
Triplicate ECGs are to be collected pre-dose on Day 1 and Day 15 of each subsequent cycle.
3.
Cerebrospinal fluid sample for PF-06840003 PK and PD: Cerebrospinal fluid will be collected at screening and prior to dosing on Cycle 1 Day 15
(1 days)  in at least 4 patients in Part 1 and at least 6 patients in Part 2 from select sites.  Collection will be optional based on investigator assessment of the 
safety of the patient.  The screening sample should preferably be collected after all other screening assessments have been completed.  Samples may also be 
used for evaluation of pharmacodynamic markers.
4.
Tumor biopsies: If feasible, optional fresh tumor biopsies will be collected at screening and C2D1 (predose) 2 days for measurement of 
kynurenine/tryptophan (and metabolites), assessment of tumor-infiltrating lymphocytes, RNA-profiling and TCR sequencing. The screening biopsy should 
preferably be collected after all other screening assessments have been completed.  The screening and C2D1 biopsies should preferably be taken from the 
same site.  Biopsies collected within 30 days of registration will be acceptable.


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SCHEDULE OF ELECTROCARDIOGRAM, PHARMACOKINETIC AND PHARMACODYNAMIC ASSESSMENTS –
FOR INPATIENT EVALUATION COHORTS
Protocol Activity
Screen
(≤28 
days)
Treatment Period
Cycle 1 Only
Cycle 2
Cycle 3 and 
beyond
End of 
Treatment
Study Day
Day 1
Day 
2
Day 
4
Day 
8
Day 15
Day 
16
Day 
1
Day 
15
Day 
1
Day 
15
Hours Pre-/Post-
Dose*
Pre-
dose
1
2
4
8
12
16
20
24
Pre-
dose
Pre-
dose
Pre-
dose
1
2
4
8
12
16
20
24
Pre-
dose
Pre-
dose
Pre-
dose
Pre-
dose
Triplicate (12 Lead) 
ECGs1
X
X
X
X
X
X
X
X
X
X
X
X2
X
X
Blood samples for 
PF-06840003 PK
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine samples for 
PF-06840003 PK3
X
→
→
→
→
→
→
→
→
→
Cerebrospinal fluid 
samples for 
PF-06840003 PK and 
PD4
X
X
Kyn and trp
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Cytokine/chemokines
X
X
X
X
X
X
X
X
X
X
 
TCR sequencing in 
peripheral blood
X
X
X
Tumor biopsies5
X
X5
*All efforts will be made to obtain the PK samples at the exact nominal time relative to dosing.  However, samples obtained within 10% of the nominal time 
from dosing are acceptable.
Abbreviations: → = continuous sample collection; ECG = electrocardiogram; kyn = kynurenine; PK = pharmacokinetics; TCR = T cell repertoire; 
trp = tryptophan
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1.
Triplicate 12-Lead ECGs: Triplicate 12-lead ECG: At each timepoint, 3 consecutive 12-lead ECGs will be performed approximately 2 minutes apart.  When 
coinciding with blood sample draws for pharmacokinetics (PK), ECG assessment should be performed prior to blood sample collection, such that the blood 
sample is collected at the nominal time.  If the mean QTcF is prolonged (>500 msec), the ECGs should be re-evaluated by a qualified person at the 
institution for confirmation.  Additional triplicate ECGs may be performed as clinically indicated.
2.
Triplicate ECGs are to be collected pre-dose on Day 1 and Day 15 of each subsequent cycle.
3.
Urine sample for PF-06840003 PK: Urine will be collected on Cycle 1 Day 1 and for 24 hours after PF-06840003 dosing on Cycle 1 Day 15 over the 
following intervals: 0 to 4 hours, 4 to 12 hours, and 12 to 24 hours post-dose.
4.
Cerebrospinal fluid sample for PF-06840003 PK and PD: Cerebrospinal fluid will be collected at screening and prior to dosing on Cycle 1 Day 15 (1 days)  
in at least 4 patients in Part 1 and at least 6 patients in Part 2 from select sites.  Collection will be optional based on investigator assessment of the safety of 
the patient.  The screening sample should preferable be collected after all other screening assessments have been completed. Samples may also be used for 
evaluation of pharmacodynamic markers.
5.
Tumor biopsies: If feasible, optional fresh tumor biopsies will be collected at screening and C2D1 (predose) 2 days for measurement of 
kynurenine/tryptophan (and metabolites), assessment of tumor-infiltrating lymphocytes, RNA-profiling and TCR sequencing. The screening biopsy should 
preferably be collected after all other screening assessments have been completed.  The screening and C2D1 biopsies should preferably be taken from the 
same site.  Biopsies collected within 30 days of registration will be acceptable.


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1. INTRODUCTION
1.1. Mechanism of Action/Indication
PF-06840003 is an Indoleamine 2,3-Dioxygenase (IDO1) inhibitor that is currently being 
investigated in patients with malignant gliomas. 
1.2. Background and Rationale
Indoleamine 2, 3-dioxygenase (IDO1) is a heme-containing dioxygenase that catalyzes the 
oxidation of tryptophan to N-formyl kynurenine in the first and rate-limiting step of 
tryptophan catabolism. N-formyl kynurenine is subsequently converted to kynurenine and 
other cytotoxic metabolites via the kynurenine pathway.  IDO1 acts to inhibit T-cell function 
both through depletion of tryptophan and production of kynurenine (Munn & Mellor, 2013; 
van Baren & Ven den Eynde, 2015).15,24  IDO1 expression is often higher in the tumor 
microenvironment, typically in response to inflammatory stimuli such as interferon gamma
(IFN-) (Mellor & Munn, 2004).12  The enzymatic activity of IDO1 is associated with 
suppression of T-cell responses (Uyttenhove et al, 2003)23 and is correlated with poor 
prognosis in several cancer indications (Okamoto et al, 2005; Brandacher et al, 2006).18,5  As 
such, IDO1 is a target of interest for cancer immunotherapy.
1.3. Malignant Gliomas
In 2010 an estimated 23,000 primary brain and central nervous system neoplasms were 
diagnosed in the United States, representing approximately 1.5% of all primary malignant 
cancers (Altekruse et al, 2010).2  The most common of these in the adult population are 
malignant intra-parenchymal tumors that arise from glial cells and are termed malignant 
gliomas.  Malignant gliomas are classified as: Grade III (anaplastic astrocytoma, anaplastic 
oligodendroglioma, anaplastic oligoastrocytoma, anaplastic ependymoma and Grade IV 
(glioblastoma).  Of these tumors, Glioblastoma (GBM) (World Health Organization WHO 
Grade IV), and Anaplastic Astrocytoma (AA) (WHO Grade III), have the highest incidence, 
accounting for an estimated 13,000 cases annually in the United States.  
Despite representing only 1.5% of all primary malignant cancers, these tumors are 
responsible for approximately 2.8% of all cancer deaths, indicating both the severity of the 
disease and that GBMs are responsible for the highest number of “average years of life lost” 
(approximately 20 years) of all cancers (Burnet et al, 2005).6  The median survival for 
patients with primary GBM from first diagnosis who receive best current treatment options is 
approximately 15 months, with only 5% to 10% of patients surviving longer than 2 years 
(Furnari et al, 2007).9  Standard therapy for primary GBM and AA consists of surgical 
resection with adjuvant chemoradiation followed by post-radiation temozolomide 
maintenance therapy and systemic steroids to reduce edema in brain tissue.  At recurrence a 
second surgical resection is possible in some patients (approximately 30 – 40%), where they 
may also receive an intra-operative carmustine-impregnated polymer wafer implantation in 
the resection site and possible additional systemic therapies.  Patients with recurrent disease 
who are not candidates for a surgical resection may receive additional temozolomide 
maintenance therapy and bevacizumab (Avastin) (Cohen et al, 2009).7


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There are very few treatments that have demonstrated clear therapeutic benefit and received 
regulatory approval for patients diagnosed with GBM or Grade 3 glioma.  This may be due to 
a number of factors, including the highly anaplastic and infiltrative nature of these tumors, 
reflected in their uncontrolled growth characterized by robust angiogenesis and resistance to 
apoptosis.  In addition, GBM and AA have shown pronounced genetic heterogeneity and 
instability, which may confer multiple resistance phenotypes and consequent generally poor 
chemosensitivity (Mellinghoff et al, 2005; Beroukhim et al, 2007).11,4  There are different 
subtypes of Grade 3 gliomas including anaplastic astrocytoma, anaplastic oligodendroglioma, 
anaplastic oligoastrocytoma and anaplastic ependymoma.  There are several forms of GBM: 
pure GBM, GBM with oligodendroglial features, MOA4, small cell GBM; Grade 3 
astrocytomas display the same heterogeneity: anaplastic astrocytomas, oligoastrocytomas, 
oligodendrogliomas. Their prognosis and outcomes may be different if they share the same 
very poor prognosis.
Therefore, treatment of GBM or AA remains a crucial unmet medical need.
1.3.1. Rationale for Evaluation in Malignant Gliomas
There is a very high degree of unmet medical need for improved treatment for recurrent 
GBM and Grade 3 glioma patients.  Upon recurrence, management depends on age, 
performance status, histology, initial therapy response, time from original diagnosis and 
whether the occurrence is local or diffuse. In the case of diffuse or multiple tumor 
recurrences, palliative care is the preferred choice. In patients with localized disease, 
combination of surgery (20 to 25% of patients), biospecimens-based therapies and radiation 
(standard re-irradiation or highly conformal) is used with poor results. A response to 
chemotherapy is unlikely after 2 consecutive agents have failed to produce a response 
(Stewart, 2002).22
Bevacizumab has shown an overall response rate (ORR) of ~20 to 25% and a median 
response duration of 3.9 to 4.2 months, in two pivotal Phase 2 trials of recurrent high grade 
glioma patients following prior surgery, radiotherapy, and temozolomide treatment (Cohen et 
al, 2009).7  Grade 3-5 adverse events related to bevacizumab included bleeding/hemorrhage, 
hypertension, proteinuria, thromboembolic events, wound-healing complications and 
gastrointestinal perforation. An agent with a >20% ORR, durable response and with 
manageable toxicity in a patient population expressing a specific target for the molecule 
would be highly relevant within the recurrent GBM clinical landscape.
1.4. PF-06840003 in Malignant Gliomas
1.4.1. IDO1 in Malignant Gliomas
IDO1 is expressed in 96% of malignant glioma (Mitsuka et al, 2013).13 In a study reported 
by Mitsuka, IDO immunohistochemistry (IHC) expression has been assessed in 75 surgical 
specimens. Stronger expression in malignant gliomas was found compared with low-grade 
gliomas. In 6 cases of secondary glioblastoma, IDO expression was stronger than in the 
initial low-grade glioma. IDO was expressed more strongly in both primary and secondary 
glioblastoma tissue than low-grade glioma and could affect clinical outcome. Grade IV 


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patients with strong IDO expression had significantly worse overall survival rates (P = .04) 
than patients with weak IDO expression. 
The higher IDO expression in both primary and secondary glioblastoma tissue compared to 
low-grade glioma has been confirmed by other authors who reported that this may affect 
clinical outcome. (Wainwright et al, 2012).25
Figure 1.
IDO1 mRNA and protein expression levels correlated with overall patient 
survival (Wainwright et al, 2012)
The overall survival of patients with upregulated-, intermediate- and down regulated- expression in glioma 
specimens was 24.9 2.76, 34 ± 2.71 and 44.3 6.21 months, respectively. Moreover, glioma upregulated for 
IDO was significantly correlated to an earlier average time of death (post-diagnosis), when compared to 
patients with intermediate (p<0.05)- and down regulated (p<0.005)- expressing glioma. Further analysis 
correlated the absolute expression level of IDO with survival, age of diagnosis and Karnofsky score, among 
grade(s) II, III and IV astrocytoma. Upregulated IDO expression in glioma predicted a poor prognosis in 
patients and this expression level tends to predominate in high grade glioma.
The immunosuppressive impact of IDO1-mediated tryptophan (Trp) catabolism is well 
known, as well as active transport of Trp and the IDO1-downstream Trp catabolite, 
kynurenine (Kyn), across the blood brain barrier. The depletion of Trp and/or accumulation 
of Kyn has been shown to induce T cell deactivation, apoptosis and/or the induction of 
immunosuppressive programming via the expression of FoxP3 in malignant gliomas (Zhai et 
al, 2015).27
When comparing individuals without tumors to GBM patients prior to surgical resection, or 
at the 48 hour (48 h) and 10 week (10w+) postoperative time points, Trp levels in blood 
were significantly decreased (p < 0.0002). Similarly, Kyn levels were decreased in the 
pre- and 48 h postoperative GBM patients (p <0.0001). Patients with a high Kyn/Trp ratio 
(9.5) at 10 week postoperative had a mean overall survival (OS) of 23.6 a standard error 
of 6.8 months, compared to an OS of 38.7 4.9 months for patients with lower Kyn/Trp 
values. Kyn/Trp index may be a relevant clinical benchmark, providing prognostic value for 
GBM patients who are enrolled in immunotherapeutic regimens (Zhai et al, 2015).27


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1.4.2. Mechanisms
The lack of response to treatment, immune therapy or chemotherapy in GBM patients may be 
attributed to the immunosuppressed microenvironment that is characteristic of invasive 
glioma. 
GBMs are actively infiltrated by regulatory T-cells (Tregs) and some authors reported a 
strong correlation between glioma-induced immunosuppression and Tregs. (Ooi et al, 
2014).19 IDO in brain tumors increases the recruitment of T Regs and negatively impacts 
survival by promoting tumor invasion, migration, and growth, leading to a poor prognosis in 
high-grade glioma patients (Wainwright et al, 2014).26 Induction of Treg activity has been 
correlated with glioma development in both murine models and patients. Tregs may 
contribute critically to the evasion of immunosurveillance by malignant gliomas: gliomas 
induce secretion of immunosuppressive factors such as HIF-and PGE2, which are 
responsible for Treg recruitment and preferential proliferation and survival within the tumor 
microenvironment. Increased percentages of Tregs in glioma patients may induce 
immunosuppressive factors such as IL-10, TGF-, and various other cytokines. 
IDO, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and programmed death-ligand 
1 (PD-L1) are dominant molecular participants in the suppression of GBM immunity through 
complementary mechanisms including: IDO-mediated accumulation of Tregs 
(CD4+CD25+FoxP3+) in the tumor microenvironment; interaction of CTLA-4 expressed on 
tumor infiltrating T-cells with CD80 expressing dendritic cells; and the interaction of PD-L1 
expressed by tumor cells and/or macrophages with PD-1 expressed by T-cells.
Individual inhibition of each pathway has been shown to increase survival in the context of 
experimental GBM. IDO-deficient tumors provide a selectively competitive survival 
advantage against IDO-competent tumors. 
Therapeutic inhibition of IDO, CTLA-4, and PD-L1 in a mouse model of glioma maximally 
decreases tumor-infiltrating Tregs, coincident with a significant increase in T-cell–mediated 
long-term survival. 100% of mice bearing intracranial tumors are long-term survivors 
following triple combination therapy. Expression and/or frequency of T cell expressed 
CD44, CTLA-4, PD-1, and IFN-depended on timing after immunotherapeutic 
administration.  Individual inhibition of each pathway has been shown to increase survival in 
the context of experimental GBM and therapeutic inhibition of IDO, CTLA-4, and PD-L1 in 
mouse models of glioma maximally decreases tumor-infiltrating Tregs, coincident with a 
significant long-term survival (Wainwright et al, 2014).26
Unlike its competitors, PF-06840003 crosses the blood brain barrier (BBB).
1.4.3. Perspectives
IDO1 messenger ribonucleic acid (mRNA) and protein expression levels correlate with 
overall patient survival. IDO1 is involved in malignant glioma immunosuppression. IDO1 
plays a key role in resistance to immune therapy. The selective nature of IDO1 expression in 
malignant glioma provides a high potential for targeting specificity.


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1.5. Nonclinical Pharmacology and Safety
The nonclinical pharmacokinetics (PK) and metabolism program was designed to 
characterize the in vivo and in vitro absorption, distribution, and metabolism properties and 
the pharmacokinetic/pharmacodynamic (PK/PD) relationship of PF-06840003 to support the 
nonclinical safety evaluation. The single dose PK of PF-06840002 (active) and 
PF-06840001 (inactive) following intravenous (IV) and/or oral gavage administration of 
PF-06840003 was assessed in rats and monkeys as well as in the toxicology species (mice 
and dogs).  Toxicokinetic (TK) data were obtained using a validated liquid 
chromatography-mass spectrometry (LC-MS)/MS assay following repeated dose 
administration.  In vitro studies were also conducted to assess plasma protein binding as well 
as blood partitioning of PF-06840002 (active) and PF-06840001 (inactive) in mouse, dog and 
human matrices.  In vitro metabolism was assessed across species as well as the potential for 
drug-drug interactions using liver enzymes and hepatic and liver transporters.  Finally, 
studies were performed in vivo in tumor- and non-tumor-bearing mice to assess the PK/PD 
and efficacy relationship of PF-06840003 either as a monotherapy or in combination with 
PD-L1 blockade. Together, these studies helped to inform the human dose prediction.
General toxicity was evaluated by oral administration in exploratory single-dose and 
repeat-dose studies in mice and dogs, and pivotal 1-month studies in mice and dogs.  The oral 
route of administration was selected for these studies since it is the intended route of clinical 
administration.  Mice and dogs were selected as the nonclinical species based on the ability 
of PF-06840003 and its active enantiomer PF-06840002 to inhibit mouse, dog and human 
IDO1 enzymatic activity in an enzymatic mass spectrometry (MS) assay.  In addition, both 
mice and dogs showed adequate systemic exposure following oral administration.  
Exploratory genetic toxicology studies included an in vitro micronucleus and a microbial 
reverse mutation assays.
1.5.1. Nonclinical Pharmacokinetics
The PK parameters of the active enantiomer PF-06840002 were characterized after single 
oral and/or IV administration of the racemic mixture, PF-06840003 in CD-1 mice, Wistar 
Han rats, beagle dogs, and cynomolgus monkeys.  After IV dosing of PF-06840003, 
PF-06840002 (active) exhibited a low plasma clearance (CLp) in the mouse and rat, and 
moderate CLp in the dog with a low volume of distribution (Vss) in these species, resulting in 
a short apparent terminal half-life (t½).  PF-06840002 (active) was rapidly absorbed in all 
evaluated preclinical species after oral administration of PF-06840003 with an oral 
bioavailability (%F) in the mouse, rat, and dog of 59, 94, and 19%, respectively.
Systemic exposure [maximum observed concentration (Cmax) and area under the 
concentration-time curve from time zero to 24 hours (AUC24)] of PF-06840002 (active) 
increased with increasing dose of PF-06840003 and there were no sex-related differences in 
exposure in the pivotal toxicology studies in mouse and dogs. In vitro studies suggest that 
PF-06840003 is not likely to be a substrate of P-glycoprotein (P-gp) efflux in humans. 


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The fraction unbound (fu) of PF-06840002 (active) to plasma proteins in mouse, rat, dog, and 
human ranged from 0.25 to 0.48, and demonstrated relatively equal distribution into plasma 
relative to red blood cells.  PF-06840002 (active) was detected in the brain and the 
cerebrospinal fluid (CSF) after oral dosing to rats, suggesting that PF-06840002 (active) 
could cross central nervous system (CNS) barriers.  
Renal excretion of PF-06840002 (active) following dosing of PF-06840003 in rats and dogs 
and biliary excretion in rats was limited.  In vitro studies with PF-06840003 to assess the
biliary excretion of PF-06840002 (active) in humans using sandwich-cultured human 
hepatocytes suggested minimal biliary excretion in humans.
PF-06840003 was primarily metabolized by oxidation and hydrolysis in human hepatocytes.  
The in vitro metabolic profile observed in humans was similar to that observed in the 
preclinical species evaluated.  Phenotyping studies with PF-06840002 (active) indicated that 
cytochrome P450 (CYP)-mediated metabolism accounted for approximately 61% of the 
metabolic fate of this molecule and CYP1A2 was the primary enzyme responsible for 
oxidation.  PF-06840002 (active) also demonstrated chiral inversion in buffer at pH 7.4 and 
in plasma to its inactive enantiomer (PF-06840001). 
The mean IC50 values for inhibition of CYPs 1A2, 2B6, 2C8, 2C9, 2D6, and 3A4/5 were 
>100 M, while the IC50 value for CYP2C19 was 78 M.  In addition, PF-06840003 did not 
demonstrate metabolism-dependent or time-dependent inhibition of any of the CYP enzymes 
investigated.  Similarly, treatment of human hepatocytes with PF-06840003 did not cause 
induction of CYP1A2 mRNA however there was induction of CYP3A4 and CYP2B6 
mRNA.  The concentrations of PF-06840003 to inhibit 50% of substrates of P-gp or breast 
cancer resistance protein (BCRP) were >300 M (69600 ng/mL) and 65.4 M 
(15200 ng/mL), respectively. Since the dose of PF-06840003 in human will be determined in 
combination with other agents, drug-drug interaction (DDI) assessments will be made once 
the clinically effective dose has been ascertained. 
In vitro studies in human blood and in vivo PK/PD TGI studies in BALB/c mice suggested 
that the unbound concentration of PF-06840002 (active) required to achieve maximum tumor 
growth inhibition (TGI) and PD-modulation was approximately 5.00 to 5.69 M (1160 to 
1320 ng/mL) and can be considered to be the pharmacologically active concentration 
required to achieve 90% inhibition of IDO1.  In humans, PF-06840002 (active) is projected 
to have a CLp, of 0.64 ml/min/kg, Vss of 1.03 L/kg, and a t½ of approximately 18.7 hours.  
The bioavailability of PF-06840002 (active) after an oral dose of PF-06840003 was projected 
to be 64%.  Using the predicted human PK parameters and a conservative estimate of 
5.69 µM (1320 ng/mL) to achieve 90 % inhibition of IDO1, the pharmacologically active 
dose of PF-06840003 is projected to be 200 mg twice a day (BID) and 500 mg once daily 
(QD).  
1.5.2. Nonclinical Safety
PF-06840003 was assessed in a series of nonclinical studies with the oral route of exposure 
since this is the intended route of clinical administration.  Good Laboratory Practice (GLP) 
1-month repeat-dose studies were conducted in mice and dogs.  


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In the 1-month mouse study, the primary target organs were the CNS, liver, spleen, and 
adrenals.  Four animals (2 main study, 2 toxicokinetic) receiving 2000 (1000 BID) 
mg/kg/day were euthanized prior to dosing on Day 2 due to PF-06840003 related adverse 
clinical signs, including decreased activity, partially closed eyes, recumbency, unable to rise, 
twitching, tremors and convulsions.  No PF-06840003 related microscopic findings were 
observed in these animals, and therefore a cause for the morbidity was not determined.  
Dosing was discontinued after the second daily dose on Day 1 for this group of animals and 
resumed at 1200 (600 BID) mg/kg/day on Day 4.  PF-06840003-related, non-adverse 
findings included microscopic findings in the liver (minimal to mild centrilobular 
hypertrophy associated with higher liver weight, and minimal increases in extra medullary
hematopoiesis), spleen (increases in severity [mild and moderate] of extra medullary
hematopoiesis associated with higher splenic weight), adrenals (increases in severity [mild] 
of vacuolated cells in the X zone in female mice only), increased adrenal weight (male mice 
only), higher cholesterol (female mice only), and higher globulin values with lower 
associated albumin/globulin ratios (female mice only).  Additional PF 06840003-related, 
non-adverse findings included intermittent observation of discolored urine without associated 
microscopic changes, and higher body weight and food consumption.  All changes showed 
reversibility at the end of the 1-month recovery phase.
In the 1-month dog study, the primary target organs or systems were the liver, thyroid, and 
the cardiovascular, hematopoietic, and coagulation systems.  PF-06840003 related, adverse 
microscopic findings were noted in the liver (minimal to mild hepatocellular degeneration 
with accompanying increases in hepatic enzymes [1.4 19x baseline] and/or serum and urine 
bilirubin [2-4x baseline]); adverse effects on body weight and food consumption with 
associated adverse clinical signs were also noted.  Additional non-adverse liver effects 
included decreased glycogen content of hepatocytes considered secondary to decreased food 
consumption, higher liver weights without microscopic correlates, and deposition of 
pigmented material (hemosiderin) in Kupffer cells related to the primary finding of mild 
hepatocellular degeneration and associated hemorrhage.  PF-06840003-related, non-adverse 
effects were observed in the thyroid (minimal follicular cell hypertrophy) and thymus 
(minimal decrease in lymphoid cellularity, lower thymus weight).  The changes noted in the 
thymus were observed in a single high dose (600 [300 BID] mg/kg/day) male dog showing 
adverse clinical signs and were considered secondary to stress.  PF-06840003-related, 
non-adverse effects were also observed in clinical pathology parameters (decreased red cell 
mass parameters and albumin, increased prothrombin time, activated partial thromboplastin 
time and fibrinogen).  Additional PF-06840003-related, non-adverse changes included 
emesis, abnormal urine color and lower urine pH.  All changes showed reversibility at the 
end of the 1-month recovery phase, except for the deposition of hemosiderin in Kupffer cells 
and the change in prothrombin time.  Reversibility of the effects on prothrombin time could 
not be evaluated as recovery animals did not demonstrate these changes during the dosing 
phase, but would be expected to recover based on the normalization of activated partial 
thromboplastin time during recovery.


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1.6. Starting Dose Rationale
The selection of the starting dose for this first-in-patient (FIP) study is based on the 
preclinical toxicology results in accordance with the International Conference on 
Harmonization (ICH) S9 Guidance entitled “Nonclinical Evaluation for Anticancer 
Pharmaceuticals”, as well as predicted pharmacologically active dose in humans.  Results 
from preclinical toxicity studies indicate that mouse is the most sensitive species, and STD10 
in mouse was determined to be 1200 mg/kg. Based on S9 guidance, the STD10 of 
1200 mg/kg in mouse results in Maximum Recommended Starting Dose (MRSD) of 
approximately 580 mg in human (assuming body weight of 60 kg), which is greater than the 
projected human pharmacological active dose ranging from 125 to 500 mg derived from 
IDO1 inhibition.  Therefore, the recommended starting dose for this FIP study is 125 mg 
given as oral administration once daily (QD), and this dose represents approximately 1/47th
of mouse STD10 (based on human equivalent dose normalized to body surface area).  In 
addition, given the projected human PK parameters, the projected human AUC for 
PF-06840003 at the proposed starting dose of 125 mg is expected to be approximately 1/18th
of the observed mouse AUC at STD10.
Complete information for this compound may be found in the single reference safety
document (SRSD), which for this study is the investigator’s brochure.  
2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Objectives
Primary Objective – Part 1

To evaluate the safety and tolerability of increasing dose levels of daily oral 
PF-6840003 in patients with malignant gliomas.

To characterize the dose limiting toxicities (DLTs) of escalated doses of 
PF-06840003.

To determine the maximum tolerated dose (MTD) or recommended phase 2 dose 
(RP2D).
Primary Objective – Part 2

To further evaluate the safety and tolerability of PF-06840003 at the RP2D.

To evaluate the efficacy of PF-06840003 in patients with glioblastoma.


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Secondary Objectives – Parts 1 and 2
•
To evaluate the overall safety profile.
•
To characterize the single and multiple dose plasma PK of active enantiomer
PF-06840002, and inactive enantiomer PF-06840001 after administration of the 
racemic mixture, PF-06840003.
•
To document any anti-tumor activity (Part 1 only).
•
To evaluate dose and concentration response relationship for target engagement and 
PD biomarkers and to then correlate with PK, safety and efficacy to select dose with
full or optimal target engagement.
•
To assess the CSF PK exposure of active enantiomer PF-06840002, and inactive 
enantiomer PF-06840001 after administration of the racemic mixture, PF-06840003.
 
 
 
 
2.2. Endpoints
Primary Endpoint – Part 1
•
Incidence and grade of treatment-emergent adverse events (TEAE) including DLTs as 
graded by National Cancer Institute Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03.
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Primary Endpoints – Part 2
•
Adverse Events (AE) as characterized by type, frequency, severity, timing, 
seriousness, and relationship to study therapy.
•
Disease control rate (DCR) at 9 and 25 weeks by MRI using Macdonald criteria 
(Macdonald et al, 1990).10
Secondary Endpoints
•
Laboratory abnormalities as characterized by type, frequency, severity (as graded by 
NCI CTCAE v.4.03) and timing;
•
Vital Signs; 
•
PK parameters in the blood of PF-06840002 and PF-06840001 Single Dose (SD) –
Cmax, Tmax, AUClast, AUCτ, CL/F, and Vz/F and t1/2, AUCinf as data permit.  Multiple 
Dose (MD) (assuming steady state is achieved) – Css,max, Tss,max, AUCss,τ, t1/2, Css,min, 
Css,av, CL/F, Vss/F, Rac (AUCss,τ /AUCsd,τ) and Rss (AUCss,τ /AUCsd,inf) as data permit;
•
Objective tumor response based on Macdonald criteria.
•
Disease Control Rate at 9 and 25 weeks by MRI based on Response Assessment for 
Neuro-Oncology (RANO) criteria.
•
On-target activity of PF-06840003 by measurement of kynurenine, tryptophan and 
kyn/trp (ratio) levels in peripheral blood.
•
Steady-state trough level ratio between CSF and plasma samples for PF-06840002 
and PF-06840001.
 
 
 
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3. STUDY DESIGN
3.1. Study Overview
This is a Phase 1, open-label, multi-center, multiple-dose, safety, PK and PD study of single 
agent PF-06840003.  This study contains two parts, dose escalation (Part 1) followed by dose 
expansion (Part 2).  In Part 1, sequential cohorts of patients with recurrent malignant gliomas
(GBM and/or WHO grade III anaplastic gliomas) will receive escalating doses of 
PF-06840003.  Part 2 will evaluate safety as well as explore preliminary antitumor activity of 
the dose selected from Part 1 in additional patients with GBM.
The actual number of patients enrolled in the study will depend on the tolerability of 
PF-06840003 and the number of dose levels required to identify the MTD or Recommended 
Phase 2 Dose (RP2D) if the MTD is not reached.  The target sample size for each cohort in 
Part 1 is 2-4 patients, but, the actual number of patients treated at each dose will vary from 
2 to 12. It is estimated that the maximum sample size will be approximately 72 patients in 
Part 1 of the study, although this may be higher if more than 6 dose levels are required to be 
evaluated.  Up to approximately 20 to 25 patients are anticipated to be enrolled in Part 2 of 
the study.  
PF-06840003 will be administered daily as an oral dose in 28 day cycles with a starting dose 
of 125 mg once daily (QD). The pre-specified nominal doses for use in the dose escalation 
are 125 mg/day, 250 mg/day and 500 mg/day of PF-06840003.  If the MTD or RP2D are not 
reached within the pre-planned nominal dose range, and the PK and PD data show that the 
target coverage is not optimal, the sponsor, in conjunction with the investigators, after careful 
consideration of all available safety, laboratory and PK information may expand the nominal 
dose range to a higher dosage, up to a maximum dosage of 1000 mg per day.  Based on 
emerging clinical and PK data, twice a day (BID) dosing may be explored.  For example, if 
the exposure over 24 hours does not allow for sufficient target coverage it may be determined 
that BID dosing is needed.  In such a case, BID dosing will be initiated at the QD dose level 
where no DLTs are observed (ie, starting dose of BID dosing will be 250 mg BID after safety 
and tolerability profile of 250 mg QD is confirmed).  Once a BID dosing regimen is initiated 
for further escalation towards the MTD, the escalation with a QD regimen will be suspended.  
Intermediate doses may also be used if required.
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The overall study design is depicted in Figure 2.  Treatment will continue until either disease 
progression, patient refusal, or unacceptable toxicity occurs, whichever is earliest, unless the 
investigator and medical monitor agree to treatment beyond disease progression based on 
individual benefit/risk assessments.
Figure 2.
Overall Study Design
The proposed doses, schedule(s) and PK time points may be reconsidered and amended 
during the study based on the emerging safety and PK data.  Intermediate doses may be 
evaluated.
3.1.1. Criteria for Dose Escalation
In Part 1 of the study, dose escalation and de-escalation will follow a modified Toxicity 
Probability Interval (mTPI) method, targeting a DLT rate of 27.5% and an acceptable DLT 
interval 22.5 to 32.5%.  The dose levels to be evaluated in Part 1 of the study are listed in the 
following table:


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Table 1.
Dose Escalation Potential Dose Levels
Potential Dose Level
PF-06840003 (mg QD)*
PF-06840003 (mg BID)
Starting Dose
125
N/A
2
250
N/A
3
500
250
4
750
500
5
1000
750
6
To be determined
1000
7
Escalation to continue to the 
MTD or desired 
pharmacological activity
Escalation to continue to MTD 
or desired pharmacological 
activity
* While a more frequent dosing regimen is initiated for further escalation towards the MTD, the escalation with 
a QD regimen will be suspended.
The mTPI method relies upon a statistical probability algorithm, calculated using all patients 
treated in the current dose level to determine one of the following dose-finding decisions: the 
subsequent dose should be escalated, maintained at the current dose, or de-escalated in the 
next cohort of 2 to 4 patients, or the trial should be terminated.
As an example, if the total number of patients treated at the current dose level is 4, the 
following dosing rules are applied:

0 DLT -> escalate

1 DLT -> remain at the same dose 

2 DLTs -> de-escalate

3-4 DLTs -> de-escalate and consider current dose as intolerable
The general approach to dose-finding, using the mTPI method, involves the following:

The target cohort size is 2 to 4, depending on the number of potential patients 
identified at participating sites;

The next cohort can be enrolled when all patients at the current dose cohort have been 
evaluated for 28 days of the first treatment cycle, or experience a dose-limiting 
toxicity (DLT), whichever comes first;

If a patient withdraws from the study before receiving 80% of the planned first-
cycle dose for reasons other than investigational product-related toxicity, another 
patient will be enrolled to replace that patient at the current dose combination;

In the situation in which the safety of the starting dose does not allow for escalation to 
the next dose level, a lower dose will be considered.


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The dose escalation portion of the study is completed when at least 6 to 12 evaluable patients 
have been treated at the highest dose associated with DLT rate 32.5%.
Table 2.
Decision Rules
Number 
of 
Patients 
having 
DLT
Number of Patients Treated at a Dose Level
n=2
n=3
n=4
n=5
n=6
n=7
n=8
n=9
n=10
n=11
n=12
0
E
E
E
E
E
E
E
E
E
E
E
1
S
S
S
E
E
E
E
E
E
E
E
2
U
D
S
S
S
S
S
S
S
E
E
3
U
U
D
D
S
S
S
S
S
S
4
U
U
U
U
D
D
D
S
S
5
U
U
U
U
U
D
D
D
6
U
U
U
U
U
U
U
7
U
U
U
U
U
U
Actions to be taken:
D = De-escalate the dose; E: Escalate the dose; S: Stay at the dose.
U = Unacceptable toxicity.
3.2. DLT Definition
Severity of AEs will be graded according to CTCAE version 4.03. For the purpose of dose 
escalation, any of the following adverse events occurring in the first cycle of treatment 
(28 days) will be classified as DLTs, unless there is a clear alternative explanation 
(eg, related to underlying disease/progression, change in concurrent medication or co-morbid 
event):
Hematologic:

Grade 4 neutropenia lasting 5 days;

Febrile neutropenia [defined as absolute neutrophils count (ANC) <1,000/mm3 with a 
single temperature of >38.3°C (101°F) or a sustained temperature of 38°C (100.4°F) 
for more than one hour];

Grade 3 neutropenia with infection;

Grade 3 thrombocytopenia with bleeding;


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
Grade 4 thrombocytopenia.
Non-hematologic:

Any toxicity attributable to PF-06840003 that results in administration of less than 
80% of the planned doses during Cycle 1.

Grade 4 non hematologic AE.

Grade 3 AE lasting >7 days despite optimal supportive care.

Grade 3 CNS AE regardless of duration.  CNS AEs are those events listed within the 
nervous system disorders category in the NCI CTCAE version 4.03.

Grade 3 QTc prolongation (QTc >500 msec) will be considered a DLT only if 
persisting after correction of any reversible causes.

Concurrent aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 
>3 x upper limit of normal (ULN) and total bilirubin >2 x ULN.  
The following AEs will not be considered as DLTs:

Isolated Grade 3 or 4 laboratory abnormalities that are not associated with clinical 
sequelae or are corrected to Grade 1 with supplementation/appropriate management 
within 72 hours of their onset.
3.3. MTD Definition
The estimated MTD is the dose level associated with approximately 27.5% of DLT-evaluable 
patients experiencing a DLT.  The target interval for the DLT rate is (22.5%, 32.5%)  Due to 
the discreetness of the dose levels and in the interest of the safety of the patients, the 
estimated MTD is the highest tested dose level with DLT rate ≤32.5% (see Table 2).
3.4. Late Onset Toxicity and Toxicities Observed in the Expansion Phase
Adverse events that meet the same grading criteria as the DLT criteria listed above occurring 
after the DLT observation period will lead Pfizer to immediately schedule a meeting with the 
investigators to review the details of the potential late onset toxicity and determine if the 
enrollment has to be held for this dose level or if a dose reduction should be implemented for 
all ongoing patients.  Late onset toxicities meeting the definition of a DLT will be used in the 
evaluation of the MTD.
In addition, adverse events that meet the same grading criteria as the DLT criteria listed 
above occurring in the expansion phase (Part 2) will prompt Pfizer to immediately schedule a 
meeting with the investigators to review the details of the toxicity and determine the 
necessary action to be implemented for all patients.  


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3.5. Recommended Phase 2 Dose (RP2D) Definition
The RP2D is the dose chosen for further study based on Phase 1 study results.  If the MTD 
proves to be clinically feasible for long-term administration in a reasonable number of 
patients, then this dose usually becomes the RP2D.  Further experience with the MTD may 
result in a RP2D dose lower than the MTD.
4. PATIENT SELECTION
This study can fulfill its objectives only if appropriate patients are enrolled.  The following 
eligibility criteria are designed to select patients for whom participation in the study is 
considered appropriate.  All relevant medical and non-medical conditions should be taken 
into consideration when deciding whether a particular patient is suitable for this protocol.
4.1. Inclusion Criteria
Patient eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before patients are included in the study.
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. Pathologically documented and definitively diagnosed recurrent WHO Grade IV GBM.
2. Pathologically documented and definitively diagnosed recurrent WHO Grade III 
anaplastic gliomas (including anaplastic astrocytoma, anaplastic oligodendroglioma,
anaplastic oglioastrocytoma and mixed gliomas) – Part 1 only.
3. Access to archived formalin fixed paraffin embedded material from the initial diagnosis 
or subsequent relapse of Grade IV GBM or Grade III anaplastic glioma that is of 
diagnostic quality and representative of their diagnosed malignancy available for 
submission to the sponsor.  If archival tissue is not available, the patient must consent to 
surgical intervention to acquire tumor tissue at screening.
4. For patients with Grade IV GBM, recurrent disease (confirmed by MRI and evaluable by 
Macdonald criteria) at the time of first or second recurrence or progression following 
prior definitive therapy(s) such as surgery with adjuvant radiation therapy and/or 
chemotherapy.  For patients with Grade III anaplastic glioma, recurrent disease 
(confirmed by MRI and evaluable by Macdonald criteria) at the time of at least a first 
recurrence but no more than a fourth recurrence or progression following prior definitive 
therapy(s).
5. Must have recovered to Grade 0 or 1 or pre-treatment baseline from clinically significant 
toxic effects of prior therapy (including but not limited to exceptions of alopecia, 
laboratory values listed per inclusion criteria, and lymphopenia which is common after 
therapy with temozolomide).


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6. Must have stable dosing of corticosteroid treatment for at least 7 days prior to registration 
and are neurologically stable.
7. Must have recovered from the acute effects of radiation therapy or surgery or systemic 
treatment prior to study entry. 
8. Age 18 years. 
9. Karnofsky performance score 70%.  
10. Have received no more than two prior lines of therapy.
11. Adequate Hematologic Function, including:
a.
Absolute Neutrophil Count (ANC) 1,500/mm3 or 1.5 x 109/L;
b. Platelets 100,000/mm3 or 100 x 109/L;
c.
Hemoglobin 9 g/dL.
d. Prothrombin time (PT) or partial thromboplastin time (PTT) <1.5 x upper limit of 
normal (ULN).
12. Adequate Renal Function, including:
a.
Estimated creatinine clearance 60 mL/min as calculated using the Cockcroft-Gault 
calculator.  A 24-hour urine collection is not required but should be used to confirm 
estimated creatinine clearance if a urine collection is obtained as part of standard of 
care.
13. Adequate Liver Function, including:
a.
Total serum bilirubin 1.0 x ULN unless the patient has documented Gilbert 
syndrome or extrahepatic source by increased indirect bilirubin function;
b. Aspartate and Alanine transaminase (AST and ALT) 1.5 x ULN (3 x ULN for 
patients on chronic anticonvulsive therapies known to increase transaminases)
c.
Alkaline phosphatase 1.5 x ULN; (3 x ULN for patients on chronic anticonvulsive 
therapies known to increase transaminases)
14. Serum or urine pregnancy test (for females of childbearing potential) negative at 
screening.
15. Male patients able to father children and female patients of childbearing potential and at 
risk for pregnancy must agree to use two highly effective methods of contraception
throughout the study and for at least 28 days after the last dose of assigned treatment.   


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Female patients who are not of childbearing potential (ie, meet at least one of the 
following criteria):

Have undergone a documented hysterectomy and/or bilateral oophorectomy;

Have medically confirmed ovarian failure; or

Achieved postmenopausal status, defined as follows: cessation of regular menses 
for at least 12 consecutive months with no alternative pathological or 
physiological cause and have a serum follicle-stimulating hormone (FSH) level 
within the laboratory’s reference range for postmenopausal women.
16. Evidence of a personally signed and dated informed consent document indicating that the 
patient has been informed of all pertinent aspects of the study.
17. Patients who are willing and able to comply with scheduled visits, treatment plans, 
laboratory tests and other procedures. 
4.2. Exclusion Criteria
Patients with any of the following characteristics/conditions will not be included in the study:
1. History of CNS bleeding as defined by stroke or intraocular bleed (including embolic 
stroke) within 6 months before registration. 
2. Evidence of acute intracranial / intratumoral hemorrhage, except for patients with stable 
Grade 1 hemorrhage.
3. Peripheral sensory neuropathy Grade 2.
4. Requires treatment with high dose systemic corticosteroids defined as dexamethasone (or 
equivalent) >2 mg/day or bioequivalent for at least 3 consecutive days within 2 weeks of 
registration.
5. Previous high-dose chemotherapy requiring stem cell rescue.
6. Previous anti-angiogenic or anti-vascular endothelial growth factor (VEGF) targeted 
agents (eg, bevacizumab, cediranib, aflibercept, vandetanib, XL-184, sunitinib, etc.)
within 12 months of registration.  In addition, patients who experienced significant 
bleeding during bevacizumab treatment will also be excluded.
7. Surgical resection within 4 weeks of registration.
8. Completion of radiation therapy within 12 weeks of registration unless there is a new area 
of enhancement consistent with recurrent tumor outside the radiation field or there is 
unequivocal histologic confirmation of tumor progression.


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9. Cytotoxic therapy within 4 weeks (except 6 weeks for nitrosoureas), investigational agent 
within 5 half-lives, antibody within 6 weeks or any other anti-tumor therapies within 4 
weeks (or 5 half-lives, whichever is shorter) of registration.  
10. History of suicidal ideation within 12 months of registration.  Patients who have a history 
of suicidal ideation within 12 months of registration can be included if a risk assessment 
by a qualified mental healthcare professional determines the patient is deemed acceptable 
for inclusion.
11. Life expectancy of less than 3 months in the opinion of the investigator. 
12. Prior treatment with a compound of the same mechanism.
13. Active and clinically significant bacterial, fungal, or viral infection, including hepatitis B 
(HBV), hepatitis C (HCV), known human immunodeficiency virus (HIV) or acquired 
immunodeficiency syndrome (AIDS)-related illness.
14. Any of the following in the previous 6 months: myocardial infarction, symptomatic 
congestive heart failure (New York Heart Association > class II), unstable angina, or 
uncontrolled hypertension (defined as systolic >160 mmHg or diastolic >100 mmHg).  
15. History of other malignancies, except: adequately treated non-melanoma skin cancer, 
curatively treated in-situ cancer, or other solid tumors curatively treated with no evidence 
of disease for 2 years.
16. Active inflammatory gastrointestinal disease, chronic diarrhea, known diverticular 
disease or previous gastric resection or lap-band.  Gastroesophageal reflux disease under 
treatment with proton pump inhibitors is allowed. 
17. Current use or anticipated need for food or drugs that are known strong CYP1A2 
inhibitors, including their administration within 10 days prior to the first PF-06840003
dose (such as, but not limited to: Strong CYP1A2 Inhibitors: fluvoxamine, ciprofloxacin, 
clinafloxacin, enoxacin, oltipraz, propranolol, rofecoxib, thiabendazole, and zafirlukast).
18. Current use or anticipated need for food or drugs that are known strong CYP1A2 
inducers, including their administration within 10 days prior to the first PF-06840003 
dose (ie, Strong CYP1A2 Inducers: tobacco (including cigarettes and products containing 
tobacco).
19. Patients with known malabsorption syndrome or other condition that may impair 
absorption of study medication.
20. Severe acute or chronic medical or psychiatric condition, including recent laboratory 
abnormality that may increase the risk associated with study participation or 
investigational product administration or may interfere with the interpretation of study 
results and, in the judgment of the investigator, would make the patient inappropriate for 
entry into this study.


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21. Patients who are investigational site staff members directly involved in the conduct of the 
study and their family members, site staff members otherwise supervised by the 
investigator, or patients who are Pfizer employees directly involved in the conduct of the 
study.
22. Pregnant female patients; breastfeeding female patients.
4.3. Lifestyle Guidelines
In this study, male patients who are able to father children and female patients who are of 
childbearing potential will receive PF-06840003, a compound for which the teratogenic risk 
is currently unknown.  Two (2) methods of highly effective contraception must be used 
throughout the study and continued for at least 28 days after the last dose.  The investigator
or his or her designee, in consultation with the patient, will confirm the patient has selected
two appropriate methods of contraception for the individual patient and his/her partner from 
the list of permitted contraception methods (see below) and will confirm the patient has been 
instructed in their consistent and correct use.  Patients need to affirm that they  meet the 
criteria for correct use of at least 2 of the selected methods of contraception.  The investigator
or his or her designee will discuss with the patient the need to use highly effective 
contraception consistently and correctly according to the schedule of activities and document 
such conversation in the patient’s chart.  In addition, the investigator or his or her designee 
will instruct the patient to call immediately if a selected contraception method is discontinued 
or if pregnancy is known or suspected in the patient or the patient’s partner.  
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include the following:
1. Established use of oral, inserted, injected, implanted or transdermal hormonal 
methods of contraception is allowed provided the patient plans to remain on the same 
treatment throughout the entire study and has been using that hormonal contraceptive 
for an adequate period of time to ensure effectiveness.
2. Correctly placed copper-containing intrauterine device (IUD).
3. Male condom or female condom used WITH a spermicide (ie, foam, gel, film, cream, 
or suppository).  For countries where spermicide is not available or condom plus 
spermicide is not accepted as highly effective contraception, this option is not 
appropriate.
4. Male sterilization with absence of sperm in the post vasectomy ejaculate.
5. Bilateral tubal ligation or bilateral salpingectomy or bilateral tubal occlusive 
procedure (provided that occlusion has been confirmed in accordance with the 
device’s label).


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6. Female partner who meets the criteria for non-childbearing potential, defined as:

Have undergone a documented hysterectomy and/or bilateral oophorectomy;

Have medically confirmed ovarian failure; or 

Achieved postmenopausal status, defined as follows: cessation of regular 
menses for at least 12 consecutive months with no alternative pathological or 
physiological cause; and have a serum follicle-stimulating hormone (FSH) 
level within the laboratory’s reference range for postmenopausal women.
4.4. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor’s appropriately qualified medical personnel for the 
study is documented in the study contact list located in the supporting study documentation.
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, patients are provided with a contact card.  The contact card contains, 
at a minimum, protocol and investigational compound identifiers, patient study numbers, 
contact information for the investigational site, and contact details for a contact center in the 
event that the investigational site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
patient’s participation in the study.  The contact number can also be used by investigational 
staff if they are seeking advice on medical questions or problems; however, it should be used 
only in the event that the established communication pathways between the investigational 
site and the study team are not available. It is therefore intended to augment, but not replace, 
the established communication pathways between the investigational site and the study team 
for advice on medical questions or problems that may arise during the study.  The contact 
number is not intended for use by the patient directly, and if a patient calls that number, he or 
she will be directed back to the investigational site.
4.5. Rater Qualifications
Site staff (eg, physicians, nurses, psychologists, social workers, coordinators and research 
assistants) must be trained on the administration of the C-SSRS form prior to completing the 
first assessment.  Completion of the necessary training will be documented in a training 
certificate.
Prior to implementation of the cognitive assessments in Part 2, site staff must also be trained 
on the administration of the COWA and HVLT-R.  Completion of the necessary training will 
be documented in a training certificate.
5. STUDY TREATMENTS
For the purposes of this study, and per International Conference on Harmonisation (ICH)
guidelines investigational product is defined as a pharmaceutical form of an active ingredient 
or placebo being tested or used as a reference in a clinical trial, including a product with a 
marketing authorization when used or assembled (formulated or packaged) in a way different 


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from the approved form, or when used for an unapproved indication, or when used to gain 
further information about an approved use (ICH E6 1.33).
5.1. Allocation to Treatment
Dose level allocation will be performed by the sponsor after patients have given their written 
informed consent and have completed the necessary screening assessments. Registration 
should occur before any other Day 1 activities are performed and preferably no more than 
3 business days before Day 1. The site staff will email a complete Patient Enrollment Form 
to the designated sponsor study team member.  The sponsor will assign a patient enrollment 
number and this email to the site.
No patient shall receive investigational product until the investigator or designee has received 
the following information in writing from the sponsor:

confirmation of the patient’s enrollment;

specification of the dose level for that patient and

permission to proceed with dosing the patient;
5.2. Patient Compliance
Patients will be required to return all unused study treatment at the beginning of each cycle.  
The number of tablets returned by the patient at the end of the cycle will be counted, 
documented, and recorded for drug accountability.  Treatment compliance (reported as a 
percent) will be defined as the number of tablets taken during the study divided by the 
expected number of tablets multiplied by 100%.  Tablets that are not returned will be 
considered to have been taken unless reported otherwise by the patient.  Drug diary records 
will be provided to the patients as an aid for the recording of study treatment compliance.  
Patients with a less than 75% compliance with the study requirements, for reasons other than 
toxicity, may be withdrawn from the study.
5.3. Investigational Product Supplies
5.3.1. Dosage Form(s) and Packaging
PF-06840003 will be provided as tablets for oral administration.  The 125 mg or 25 mg 
tablets will be supplied in high-density polyethylene (HDPE) bottles and labeled according to 
local regulatory requirements.
5.3.2. Preparation and Dispensing
The study treatment should be dispensed at each visit per the schedule of activities.  A 
qualified staff member will dispense the investigational product in the bottles provided, in 
quantities appropriate for the study visit schedule.  The patient should be instructed to 
maintain the product in the bottle provided throughout the course of dosing and return the 
bottle to the site at the next study visit where accountability is to be performed.


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See the Investigational Product manual for instructions on investigational product
dispensation for administration.  Investigational product should be dispensed by an 
appropriately qualified and experienced member of the study staff (eg, physician, nurse, 
physician’s assistant, practitioner, pharmacist, or medical assistant) as allowed by local, state, 
and institutional guidance.
5.4. Administration
On days when patients have clinic visits where PK assessments are to be obtained, 
PF-06840003 should not be taken prior to the study visit.  Daily oral dosing with 
PF-06840003 will be initiated on Cycle 1 Day 1 and should continue until end of treatment.  
The PF-06840003 can be taken after the study procedures required for that visit have been 
performed.  Patients will be instructed to swallow the investigational product whole, and to
not manipulate or chew the investigational product prior to swallowing.
PF-06840003 will be administered orally on an empty stomach (ie, no food or beverages 
other than water for two hours before or two hours after dosing) without adjustment for body 
size. Tablets should be administered with approximately 240 mL of ambient temperature 
water.  Patients should be instructed to take their medication at approximately the same time 
each day and to not take more than the prescribed dose at any time.  Patients who are 
assigned to a BID dosing regimen should be instructed to take their PF-06840003 every 
12 hours 1 hour.
If a patient assigned to take PF-06840003 one time per day misses a day of treatment, he/she
must be instructed not to “make it up” but to resume subsequent doses the next day as 
prescribed. 
If a patient assigned to take PF-06840003 two times per day misses a dose by more than 
4 hours of when they should have taken it, he/she must be instructed not to “make it up” but 
to resume subsequent doses at the next scheduled dosing time as prescribed.  
If a patient vomits any time after taking a dose, he/she must be instructed not to “make it up” 
but to resume subsequent doses the next day as prescribed.  If a patient inadvertently takes 
1 extra dose during a day, the patient should not take the next dose of PF-06840003.
5.4.1. Recommended Dose Modifications
Every effort should be made to administer investigational product on the planned dose and 
schedule.
In the event of significant toxicity, dosing may be delayed and/or reduced as described 
below.  In the event of multiple toxicities, dose modification should be based on the worst 
toxicity observed.  Patients are to be instructed to notify investigators at the first occurrence 
of any adverse symptom.


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Dose modifications may occur in one of three ways:

Within a cycle: dosing interruption until adequate recovery and dose reduction, if 
required, during a given treatment cycle; 

Between cycles: next cycle administration may be delayed due to persisting toxicity 
when a new cycle is due to start;

In the next cycle: dose reduction may be required in the current and/or subsequent 
cycle based on toxicity experienced in the current/previous cycle. 
5.4.2. Dosing Interruptions
Patients experiencing the following adverse events should have their treatment interrupted:

Grade 3 or 4 potentially treatment related toxicity;

Intolerable Grade 2 toxicity despite supportive care.
Appropriate follow up assessments should be done until adequate recovery occurs as 
assessed by the investigator.  Criteria required before treatment can resume are described in 
Section 5.4.3 Dose Delays.
Doses may be held as needed until toxicity resolution.  Depending on when the AE resolved, 
a treatment interruption may lead to the patient missing all subsequent planned doses within 
that same cycle or even to delay the initiation of the subsequent cycle. 
If the AE that led to the treatment interruption recovers within the same cycle, then re-dosing 
in that cycle is allowed.  Doses omitted for toxicity are not replaced within the same cycle.  
The need for a dose reduction at the time of treatment resumption should be based on the 
criteria defined in section Dose Reductions, unless expressly agreed otherwise following 
discussion between the investigator and the sponsor. 
In the event of a treatment interruption for reasons other than treatment-related toxicity
(eg, elective surgery) lasting >4 weeks, treatment resumption will be decided in consultation 
with the sponsor.
5.4.3. Dose Delays
Re-treatment following treatment interruption for treatment-related toxicity or at the start of 
any new cycle may not occur until all of the following parameters have been met:

ANC 1,000/mm3.

Platelet count 50,000/mm3.

Non-hematologic toxicities have returned to baseline or Grade 1 severity (or, at the 
investigator discretion, Grade 2 if not considered a safety risk for the patient).


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If a treatment delay results from worsening of hematologic or biochemical parameters, the 
frequency of relevant blood tests should be increased as clinically indicated.
If these conditions are met within 2 weeks of treatment interruption or cycle delay, 
PF-06840003 dosing may be resumed.  Refer to Section Dose Reductions for AEs requiring 
dose reduction at the time of treatment resumption. 
If these conditions are not met, treatment resumption must be delayed up to a maximum of 
2 weeks.  If these parameters have not been met after 2 weeks of dosing interruption, or 
2 weeks of new cycle delay, permanent discontinuation of treatment with PF-06840003
should be considered.  Treatment resumption for patients recovering from treatment-related 
toxicity after >2 weeks of treatment interruption or cycle delay may be considered only if the 
patient is deemed to be deriving obvious clinical benefit per the investigator’s best medical 
judgment and needs to be agreed between the investigator and the sponsor.
If a treatment interruption continues beyond Day 28 of the current cycle, then the day when 
treatment is restarted will be counted as Day 1 of the next cycle.  
5.4.4. Dose Reductions
Following dosing interruption or cycle delay due to toxicity, the PF-06840003 dose may need 
to be reduced when treatment is resumed.
No specific dose adjustments are recommended for Grade 1/2 treatment-related toxicity.  
However, investigators should always manage their patients according to their medical 
judgment based on the particular clinical circumstances.
Patients experiencing recurrent and intolerable Grade 2 toxicity may resume dosing at the 
next lower dose level once recovery to Grade 1 or baseline is achieved.
Dose reductions of PF-06840003 are not allowed for patients receiving the starting dose of 
125 mg.  Dose reduction of PF-06840003 by 1 and, if needed, 2 dose levels will be allowed 
depending on the type and severity of toxicity encountered.  However, dose reductions below 
125 mg daily are never allowed.  Patients requiring more than 2 dose reductions will be 
discontinued from the treatment and entered into the follow-up phase, unless otherwise 
agreed between the investigator and the sponsor.  All dose modifications/adjustments must 
be clearly documented in the patient’s source notes and case report form (CRF).  
Once a dose has been reduced for a given patient, all subsequent cycles should be 
administered at that dose level, unless further dose reduction is required.  Dose re-escalation 
is not allowed.
Patients experiencing a DLT may resume dosing at the next lower dose level (if applicable) 
once adequate recovery is achieved.  Dose reductions for patients experiencing a late onset 
toxicity or toxicity in the expansion phase will be discussed in consultation with the sponsor.


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Table 3.
Dose Modifications for Investigational Product-Related Toxicity
Toxicity
Grade 1
Grade 2
Grade 3
Grade 4
Non-hematologic 
Continue at the 
same dose level.
Continue at the same 
dose level. 
Withhold dose until 
toxicity is Grade 1, 
or has returned to 
baseline, then
resume treatment at 
the same dose level 
or reduce the dose 
by 1 level at the 
discretion of the 
investigator*.
Withhold dose 
until toxicity is 
Grade 1, or has 
returned to 
baseline within 
14 days, then 
reduce the dose by 
1 level and resume 
treatment, or 
discontinue at the 
discretion of the 
investigator*.
Hematologic
Continue at the 
same dose level.
Continue at the same 
dose level.
Withhold dose until 
toxicity is Grade 1, 
or has returned to 
baseline, then 
resume treatment at 
the same dose 
level**.
Withhold dose 
until toxicity is 
Grade 1, or has 
returned to 
baseline, then 
reduce the dose by 
1 level and resume 
treatment or 
discontinue at the 
discretion of the 
investigator**.
* Nausea, vomiting, or diarrhea must persist at Grade 3 or 4 despite maximal medical therapy to require dose 
modification.
** Cycle will not be extended to cover for the missing doses.
5.5. Investigational Product Storage
The investigator, or an approved representative, eg, pharmacist, will ensure that all 
investigational products, are stored in a secured area with controlled access under required 
storage conditions and in accordance with applicable regulatory requirements.
Investigational product should be stored in its original container and in accordance with the 
label.  
Storage conditions stated in the single reference safety document (SRSD) (eg, Investigator 
Brochure) will be superseded by the storage conditions stated in the labeling. 
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated and/or room temperature products).  This should be 
captured from the time of investigational product receipt throughout the study.  Even for 
continuous monitoring systems, a log or site procedure that ensures active daily evaluation 
for excursions should be documented.  The operation of the temperature monitoring device 
and storage unit (for example, refrigerator), as applicable, should be regularly inspected to 
ensure it is maintained in working order.  


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Any excursions from the product label storage conditions should be reported upon discovery. 
The site should actively pursue options for returning the product to the storage conditions as 
described in the labeling, as soon as possible.  Deviations from the storage requirements, 
including any actions taken, must be documented and reported to the sponsor.  
Once an excursion is identified, the investigational product must be quarantined and not used 
until the sponsor provides documentation of permission to use the investigational product. It 
will not be considered a protocol deviation if the sponsor approves the use of the 
investigational product after the temperature excursion. Use of the investigational product 
prior to sponsor approval will be considered a protocol deviation. 
Specific details regarding information the site should report for each excursion will be 
provided to the site. 
Site staff will instruct patients on the proper storage requirements for take home study 
treatment. 
5.6. Investigational Product Accountability
The investigative site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies. Patients will be required to return all 
unused study treatment at the beginning of each cycle.  
5.6.1. Destruction of Investigational Product Supplies 
The sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site). If destruction is authorized to take place at the study site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer, and all destruction must be adequately documented.
 
 
  
 
 
 
 
 
 
 
CCI
CCI


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5.7.1. Other Anti-tumor/Anti-cancer or Experimental Drugs
No additional anti-tumor treatment will be permitted while patients are receiving study 
treatment.  Additionally, the concurrent use of select vitamins or herbal supplements is not 
permitted.
5.7.2. Supportive Care
Palliative and supportive care for disease related symptoms may be administered at the 
investigator’s discretion and according to any available American Society of Clinical 
Oncology (ASCO) guidelines.  
5.7.3. Anti-inflammatory Therapy
Anti-inflammatory or narcotic analgesic may be offered as needed assuming there is no 
known or expected drug-drug interaction and assuming the drug is not included in the 
Concomitant Treatment(s) section. 
Due to the immunologic nature of PF-06840003 administration, cerebral edema could 
theoretically result as a consequence of PF-06840003 administration due to immune 
infiltration of the brain. Symptoms related to cerebral edema may include headache or 
neurologic deficit that is either new or worsened. Patients with any signs or symptoms of 
cerebral edema should be treated as clinically appropriate including initiation or increased 
systemic corticosteroid dosing, treatment with an osmotic diuretic or surgical decompression. 
Subsequent  PF-06840003 dosing should be immediately interrupted if significant clinical 
symptoms attributable to cerebral edema develop. Treatment with additional PF-06840003
doses may only be re-initiated if clinically significant symptoms attributable to cerebral 
edema have resolved to grade ≤1 or pre-treatment baseline. Patients who develop CTCAE 
4.0 grade 4 cerebral edema attributable to PF-06840003 administration should not receive 
further PF-06840003 doses and should discontinue study therapy.
5.7.4. Surgery
Caution is advised on theoretical grounds for any surgical procedures during the study.  The 
appropriate interval of time between surgery and PF-06840003 required to minimize the risk 
of impaired wound healing and bleeding has not been determined.  Stopping PF-06840003 is 
recommended at least 7 days prior to surgery.  Postoperatively, the decision to reinitiate 
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PF-06840003 treatment should be based on a clinical assessment of satisfactory wound 
healing and recovery from surgery.
6. STUDY PROCEDURES
6.1. Screening
For screening procedures see Schedule of Activities and ASSESSMENTS section.
6.2. Study Period
For treatment period procedures, see Schedule of Activities and ASSESSMENTS section.
6.3. Follow-up Visit
For follow-up procedures see Schedule of Activities and ASSESSMENTS section.
6.4. Patient Withdrawal
Patients may withdraw from treatment at any time at their own request, or they may be 
withdrawn at the discretion of the investigator or sponsor for safety or behavioral reasons, or 
the inability of the patient to comply with the protocol-required schedule of study visits or 
procedures at a given study site.  
Reasons for withdrawal of study treatment may include:

Objective disease progression according to the iRANO criteria.  Disease progression 
is to be confirmed with two consecutive timepoints at least 8 weeks apart in the 
absence of substantial neurological decline if progression is suspected within 6 
months of treatment initiation.

Global deterioration of health status requiring discontinuation;

Unacceptable toxicity;

Pregnancy;

Significant protocol violation;

Lost to follow-up;

Patient refused further treatment;

Study terminated by sponsor;

Investigator discretion;

Death.


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Reasons for withdrawal from study follow-up may include:

Completed study follow-up;

Study terminated by sponsor;

Lost to follow-up;

Refused further follow-up;

Death.
If a patient does not return for a scheduled visit, every effort should be made to contact the 
patient.  All attempts to contact the patient and information received during contact attempts 
must be documented in the patient’s medical record.  In any circumstance, every effort 
should be made to document patient outcome, if possible.  The investigator should inquire 
about the reason for withdrawal, request that the patient return all unused investigational 
product, request that the patient return for a final visit, if applicable, and follow-up with the 
patient regarding any unresolved AEs.
If the patient refuses further visits, no further study specific evaluations should be performed, 
and no additional data should be collected.  The sponsor may retain and continue to use any 
data collected before such withdrawal of consent.
7. ASSESSMENTS
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances, outside of the control of the investigator, that may make it unfeasible to 
perform the test. In these cases the investigator will take all steps necessary to ensure the 
safety and well-being of the patient. When a protocol-required test cannot be performed, the 
investigator will document the reason for this and any corrective and preventive actions that 
he or she has taken to ensure that normal processes are adhered to as soon as possible. The 
study team will be informed of these incidents in a timely fashion.
7.1. Safety Assessment
Safety assessments will include collection of AEs, serious adverse events (SAEs), vital signs 
and physical examination, electrocardiogram (ECG) [12-lead], laboratory assessments, 
including pregnancy tests and verification of concomitant treatments.
7.1.1. Pregnancy Testing
For female patients of childbearing potential, a serum or urine pregnancy test, with 
sensitivity of at least 25 mIU/mL and assayed in a certified laboratory, will be performed on 
2 occasions prior to starting study treatment – once at the start of screening and once at 
Cycle 1 Day 1 immediately before investigational product administration. Following a 
negative pregnancy result at screening, appropriate contraception must be commenced and a 


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further negative pregnancy result will then be required at the Cycle 1 Day 1 visit: within 
5 days after the first day of the menstrual period counting the first day as Day 1 > before the 
patient may receive the investigational product.  Pregnancy tests will also be routinely 
repeated at every cycle during the active treatment period, at the end of study treatment, and 
additionally whenever 1 menstrual cycle is missed or when potential pregnancy is otherwise 
suspected.  In the case of a positive human chorionic gonadotropin (hCG) test, the patient 
will be withdrawn from treatment and from the study.  Additional pregnancy tests may also 
be undertaken if requested by institutional review board (IRB)/ ethics committees (ECs) or if 
required by local regulations.
7.1.2. Adverse Events
Assessment of AEs will include the type, incidence, severity (graded by the NCI CTCAE 
version 4.03) timing, seriousness, and relatedness.  Patients must be followed for AEs for 
28 days after the last study treatment administration or until all drug-related toxicities have 
resolved, whichever is later; or earlier than 28 days should the patient commence another 
anti-cancer therapy in the meantime.
Adverse events that occur during the study, will be recorded on the AE CRF page.
7.1.3. Laboratory Safety Assessment
Haematology, blood chemistry, coagulation and urinalysis will be drawn at the time points 
described in the Schedule of Activities and analyzed at local laboratories.  Cycle 1 Day 1 
hematology, blood chemistry, coagulation and urinalysis assessments do not need to be 
repeated if the screening assessment is performed within 7 days prior to that date.  
Assessments collected on dosing days should be obtained within 48 hours prior to dosing.


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Table 4.
Laboratory Assessments
Hematology
Chemistry
Coagulation
Urinalysis
Pregnancy 
Test
Unique 
Screening 
Labs
Hemoglobin
ALT
PT or INR
Urine dipstick 
for urine protein: 
If positive collect 
24-hr and 
microscopic 
(Reflex Testing)
For female 
patients of 
childbearing 
potential,  
serum or urine 
(to be specified 
in the protocol)
Hepatitis B 
surface antigen
Platelets
AST
PTT
Hepatitis B 
core antibody
WBC
Alk Phos
Hepatitis C 
antibody
Absolute 
Neutrophils
Sodium
HIV
Absolute 
Lymphocytes
Potassium
FSH – for post-
menopausal
women
Absolute 
Monocytes
Magnesium
Urine dipstick 
for urine blood: 
If positive collect 
a microscopic 
(Reflex Testing)
Absolute 
Eosinophils
Chloride
Absolute 
Basophils
Total Calcium
Total 
Bilirubin***
BUN or Urea
Creatinine
Uric Acid
Glucose 
(non-fasted)
Albumin
Phosphorous or 
Phosphate
*** For potential Hy’s Law cases, in addition to repeating AST and ALT, laboratory tests should include 
albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, gamma-glutamyl transferase, prothrombin 
time (PT)/INR, and alkaline phosphatase.  
7.1.4. Vital Signs and Physical Examination
Patients will have a physical examination (PE) to include weight, vital signs, assessment of 
Karnofsky performance status and height; height will be measured at screening only.
A complete PE will be performed at Screening, Cycle 1 Day 1 and at the End of Treatment 
visit for each patient and will include an assessment of all body systems (including 
neurological examination, genitourinary examination is optional). The Cycle 1 Day 1 
assessment does not need to be repeated if the screening assessment is performed within 
7 days of dosing.  Findings of all physical examinations should be recorded in the source 
documents, and any change from baseline considered by the investigator to be clinically 
significant should be recorded as an AE in the CRF.


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Abbreviated PEs should be performed as appropriate per the Schedule of Activities, and on 
an as needed basis for assessment of AEs.  Abbreviated exams should include a neurological 
exam as well as be targeted to specific symptoms or complaints and be consistent with local 
standard of care. 
Vital signs will include measurements of blood pressure and temperature (oral, tympanic, 
temporal or axillary).  On dosing days, vital signs should be measured prior to administration 
of any of the study treatments.  Sitting blood pressure (BP) will be measured with the 
patient’s arm supported at the level of the heart and recorded to the nearest mmHg.  The 
same arm (preferably the dominant arm) should preferably be used throughout the trial.  A 
BP cuff, which has been properly sized and calibrated, should be used to measure BP.  The 
use of automated devices for measuring BP is acceptable. 
7.1.5. (12-Lead) Electrocardiogram
Electrocardiogram (ECG): Triplicate 12-lead (with a 10-second rhythm strip) tracing will be 
used for all ECGs, except the screening assessment.  It is preferable that the machine used 
has a capacity to calculate the standard intervals automatically.  At each time point (see the 
Schedule of Activities), 3 consecutive ECGs will be performed at approximately 2 minutes 
apart to determine the mean QTcF interval.  If the mean QTcF is prolonged (>500 msec, 
ie, CTCAE Grade 3), then the ECGs should be re-evaluated by a qualified person at the site 
for confirmation as soon as the finding is made, including verification that the machine 
reading is accurate.  If manual reading verifies a QTcF of >500 msec, immediate correction 
for reversible causes (including electrolyte abnormalities, hypoxia and concomitant 
medications for drugs with the potential to prolong the QTcF interval) should be performed.  
In addition, repeat ECGs should be immediately performed hourly for at least 3 hours until 
the QTcF interval falls below 500 msec.  If QTcF interval reverts to less than 500 msec, and 
in the judgment of the investigator(s) and sponsor is determined to be due to cause(s) other 
than investigational product, treatment may be continued with regular ECG monitoring.  If in 
that timeframe the QTcF intervals rise above 500 msec the investigational product will be 
held until the QTcF interval decreases to 500 msec.  Patients will then restart the 
investigational product at the next lowest dose level.  If the QTcF interval has still not 
decreased to <500 msec after 2-weeks, or if at any time a patient has a QTcF interval 
>515 msec or becomes symptomatic, the patient will be removed from the study.  Additional 
triplicate ECGs may be performed as clinically indicated. 
Prior to concluding that an episode of prolongation of the QTcF interval is due to 
investigational product, thorough consideration should be given to potential precipitating 
factors (eg, change in patient clinical condition, effect of concurrent medication, electrolyte 
disturbance) and possible evaluation by specialist.
If patient experiences a cardiac or neurologic AE (specifically syncope, dizziness, seizures, 
or stroke), an ECG (triplicate) should be obtained at the time of the event. 
When matched with PK sampling, the ECG must be carried out before each PK sample 
drawing such that the PK sample is collected at the nominal time (ie, the timing of the PK 
collections over rides the timing of the ECG collections). 


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7.3. Biomarker and Pharmacodynamic Assessments
One of the key elements of this study is the possibility to evaluate potential molecular targets 
that could be modified in vivo by PF-06840003 used in this study.  The biomarker studies 
will be used to help understand the in vivo mechanism of action of the agent(s) studied as 
well as potential mechanisms of resistance.  The studies may help in the future development 
of this drug as a single agent, or in combination with other compounds.
Table 5 summarizes representative assays to be used and the source of the samples.  Refer to 
the Schedule of Activities for details pertaining to specific days of sample collection and to 
the study manual for details of sample preparation.
Table 5.
Pharmacodynamic Summary
Assay
Source
Measurement of kynurenine, tryptophan, and 
metabolites by mass spectrometry
Peripheral blood, Tumor Tissue, CSF
 
 
Assessment of serum cytokines and 
chemokines
Peripheral Blood Serum
 
mRNA profiling (Part 2 only)
Tumor Tissue
TCR sequencing (Part 2 only)
Tumor Tissue
7.3.1. Target Engagement – Assessment of Kynurenine, Tryptophan and Metabolites
Blood samples (approximately 4 mL of whole blood) will be collected for the evaluation of 
pharmacodynamic markers; kyn, trp, and metabolites for patients as outlined in the Schedule 
of Activities.  Details regarding the collection, processing, storage and shipping of these 
samples will be provided in the study manual.
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The levels of kyn, trp, and metabolites in whole blood samples will be determined using a 
qualified analytical method in compliance with Pfizer standard operating procedures. 
An assay specific for the detection of kyn, trp, and metabolites will be developed.  This assay 
will provide proof of mechanism (target engagement) as IDO1 is a protein that catalyzes the 
first step in trp catabolism to N-formyl-kynurenine, and trp degradation by IDO1 yields a 
series of kynurenines.
 
 
 
 
 
 
 
 
7.3.3. Cytokines and Chemokines
Blood samples (approximately 4 mL) to provide approximately 1 mL serum for analysis of 
serum cytokine and chemokines will be collected at times specified in the SOA.
Instructions for sample collection, processing, storage and shipment will be provided in the 
laboratory manual.
Samples collected for this purpose will be retained in accordance with local regulations and if 
not used within this timeframe, will be destroyed.
7.3.4. T Cell Receptor (TCR) Sequencing
Whole blood samples (approximately 10 mL) for evaluation of T cell receptor usage, 
clonality, and frequency will be collected at the times specified in the SOA.
Instructions for sample collection, processing, storage and shipment will be provided in the 
laboratory manual.
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7.3.5. Tumor Biopsies
Patients enrolled into the trial must have access to their archival formalin-fixed paraffin 
embedded material containing tumor that is of diagnostic quality and representative of their 
diagnosed malignancy.  A fresh pre-treatment biopsy is acceptable if archival tumor is not 
available.  If required, the screening biopsy should preferably be obtained after all eligibility 
criteria have been verified.  Tissue blocks are preferred, but freshly-cut paraffin sections are 
acceptable and must comprise 10-15 paraffin sections, 4-microns in thickness, cut within 
1 week of submission, and placed individually on unstained, unbaked charged glass 
microscope slides.  
Additionally, fresh pre-treatment and on-treatment biopsies are optional. On-treatment 
biopsy samples are to be collected on Cycle 2 Day 1 and should preferably be taken from the 
same lesion and from a lesion that has not been previously irradiated.  Biopsies collected 
within 30 days of registration will be acceptable.
Biomarker evaluation will be performed on the biopsies.  Analyses will be conducted at an 
IHC reference lab and include IHC assessment of IDO1 in addition to lymphocyte markers 
such as CD4, CD8, CD3 and exploratory biomarkers. RNA profiling will be conducted to 
explore immune-modulatory (immune effector and tolerance-associated) and checkpoint, 
cytokine, chemokine transcripts, IO and non-IO gene signatures in Part 2 only. Additionally, 
evaluation of TCR usage, clonality, and frequency via TCR sequencing may be performed.
Instructions for sample collection, processing, storage and shipment will be provided in the 
study manual.  Samples may be retained in accordance with local regulations and if not used 
within this timeframe, will be destroyed.
7.4. Tumor Response Assessments
Tumor assessments will include all known or suspected disease sites. A standard contrast-
enhanced cranial MRI will be performed at screening/baseline and every 8 weeks (5 days).  
Non-contrast cranial MRI may only be used to document disease in those patients who are 
allergic to contrast.  Tumor assessments should be repeated at the end of treatment visit if 
more than 4 weeks have passed since the last evaluation.
The same imaging technique used to characterize each identified and reported lesion at 
screening will be employed in the following tumor assessments.
Anti-tumor activity will be assessed through radiological tumor assessments conducted at 
screening, during treatment as specified in the Schedule of Activity, whenever disease 
progression is suspected (eg, symptomatic deterioration), and at the time of withdrawal from 
treatment (if not done in the previous 4 weeks). All patients’ files and radiologic images 
must be available for source verification and for potential peer review.
Assessment of response will be made using the Macdonald criteria, RANO and iRANO.  
Disease progression will be confirmed with two consecutive timepoints at least 8 weeks apart 
in the absence of substantial neurological decline if progressive disease is suspected within 
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least 4 weeks apart.  Efficacy evaluations using the Macdonald criteria involve post-contrast 
MRI findings, non-contrast T1 and T2 fluid attenuated inversion recovery (FLAIR) images, 
use of corticosteroid dose, and neurological examination as defined below:
Complete Response (CR) – ALL of the following:

Complete disappearance of all enhancing measurable and non-measurable disease 
sustained for 4 weeks.

No new lesions.

Stable or improved non-enhancing (T2/FLAIR) lesions.

Off-steroids.

Neurological condition stable or improved.
Partial Response (PR) – ALL of the following:

Greater than or equal to 50% decrease compared to baseline in the sum of the 
perpendicular diameters of all measurable enhancing lesions sustained for at least 
4 weeks.

No progression of non-measurable disease.

No new lesions.

Stable or improved non-enhancing (T2/FLAIR) lesions on the same or lower dose of 
corticosteroids compared with baseline scan.

The corticosteroid dose at the time of the scan evaluation should be no greater than the 
dose at the time of the baseline scan.

Neurological condition stable or improved.
Progressive Disease (PD) – ANY of the following:

Greater than or equal to 25% increase in the sum of the products of perpendicular 
diameters of enhancing lesions compared to the smallest tumor measurement obtained 
either at baseline (if no decrease) or best response, on stable or increasing dose of 
corticosteroids*.

Significant increase in T2/FLAIR non-enhancing lesion on stable or increasing dose of 
corticosteroids compared with baseline scan or best response following initiation of 
therapy*, not due to co-morbid events (eg, radiation therapy, demyelination, ischemic 
injury, infection, seizures, post-operative changes, or other treatment effects).


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
Any new lesion.

Clinical deterioration not attributable to other causes apart from the tumor (eg, seizures, 
medication side effects, complications of therapy, cerebrovascular events, infection, etc.) 
or changes in corticosteroid dose.

Failure to return for evaluation due to death or deteriorating condition.

Clear progression of non-measurable disease.
*Stable doses of corticosteroids includes patients not on corticosteroids.
Stable Disease (SD):

Does not qualify for CR, PR, or PD.

Stable non-enhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids 
compared with baseline scan.  In the event that the corticosteroid dose has been 
increased, the last scan considered to show SD will be the scan obtained when the 
corticosteroid dose was equivalent to the baseline dose.

Stable clinically.
Table 6.
Overall Response Criteria
CR
PR
SD
PD1
T1-Gd
None
50%
<25%- <50%
25%*
T2/FLAIR
Stable or 
Stable or 
Stable or 
*
New Lesion
None
None
None
Present*
Corticosteroids
None
Stable or 
Stable or 
NA
Clinical Status
Stable or 
Stable or 
Stable or 
*
Requirement of response
All
All
All
Any*
1. Progression occurs when any of the criteria with * are present; NA: increase in 
corticosteroid dose alone will not be taken into account in determining progression in the 
absence of persistent clinical deterioration 
CR=complete response; PR=partial response; SD=stable disease; PD=progressive disease; 
=decrease; =increase


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7.4.1. F-18-FLT PET
For locations that are able to perform the tumor evaluation by F-18-FLT-PET, assessment
will be performed in all patients assigned to receive doses of 500 mg QD or 500 mg BID or 
higher.  Assessment will be performed at screening after all other eligibility criteria has been 
confirmed and again at Week 9 and Week 25 (Zhao et al, 2014; Corroyer-Dulmont et al, 
2013).28,8 F-18-FLT-PET should be performed at the end of treatment visit if the patient 
discontinues the study prior to Week 9 or between Weeks 9 and 25 if more than 4 weeks 
have passed since the last evaluation.
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
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8. ADVERSE EVENT REPORTING
8.1. Adverse Events
All observed or volunteered AEs regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
sections. 
For all AEs, the investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as an SAE
requiring immediate notification to Pfizer or its designated representative.  For all AEs, 
sufficient information should be obtained by the investigator to determine the causality of the 
AE.  The investigator is required to assess causality.  Follow-up by the investigator may be 
required until the event or its sequelae resolve or stabilize at a level acceptable to the 
investigator, and Pfizer concurs with that assessment.
As part of ongoing safety reviews conducted by the sponsor, any non-serious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE.  To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study.
8.2. Reporting Period
For SAEs, the active reporting period to Pfizer or its designated representative begins from 
the time that the patient provides informed consent, which is obtained prior to the patient’s 
participation in the study, ie, prior to undergoing any study-related procedure and/or 
receiving investigational product, through and including 28 calendar days after the last 
administration of the investigational product.  SAEs occurring to a patient after the active 
reporting period has ended should be reported to the sponsor if the investigator becomes 
aware of them; at a minimum, all SAEs that the investigator believes have at least a 
reasonable possibility of being related to investigational product are to be reported to the 
sponsor.
AEs (serious and non-serious) should be recorded on the CRF from the time the patient has 
taken at least 1 dose of investigational product through the patient’s last visit.

If a patient begins a new anticancer therapy, the AE reporting period for non-serious
AEs ends at the time the new treatment is started.  Death must be reported if it occurs 
during the SAE reporting period after the last dose of investigational product, 
irrespective of any intervening treatment.
8.3. Definition of an Adverse Event
An AE is any untoward medical occurrence in a clinical investigation patient administered a 
product or medical device; the event need not necessarily have a causal relationship with the 
treatment or usage.  Examples of AEs include but are not limited to:

Abnormal test findings;


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
Clinically significant symptoms and signs;

Changes in physical examination findings;

Hypersensitivity;

Drug abuse;

Drug dependency.
Additionally, they may include the signs or symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasations;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure;

Worsening of signs and symptoms of the malignancy under study should be reported 
as AEs in the appropriate section of the CRF.  Disease progression assessed by 
measurement of malignant lesions on radiographs or other methods should not be 
reported as AEs.
8.4. Medication Errors
Medication errors may result, in this study, from the administration or consumption of the 
wrong product, by the wrong patient, at the wrong time, or at the wrong dosage strength.  
Such medication errors occurring to a study participant are to be captured on the medication 
error CRF, which is a specific version of the AE page, and on the SAE form when 
appropriate.  In the event of medication dosing error, the sponsor should be notified
immediately.
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:

Medication errors involving patient exposure to the investigational product;


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
Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating patient.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is captured on the medication error version of the AE page 
and, if applicable, any associated AEs are captured on an AE CRF page.
8.5. Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be reported as 
an AE are as follows: 

Test result is associated with accompanying symptoms; and/or

Test result requires additional diagnostic testing or medical/surgical intervention;
and/or

Test result leads to a change in study dosing or discontinuation from the study, 
significant additional concomitant drug treatment, or other therapy; and/or

Test result is considered to be an AE by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
reporting as an AE.
8.6. Serious Adverse Events
A serious adverse event is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect;

Progression of the malignancy under study (including signs and symptoms of 
progression) should not be reported as an SAE unless the outcome is fatal within the 
safety reporting period. Hospitalization due to signs and symptoms of disease 
progression should not be reported as an SAE. If the malignancy has a fatal outcome 
during the study or within the safety reporting period, then the event leading to death 
must be recorded as an AE and as an SAE with CTCAE) grade 5 (see the section on 
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Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the patient or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.
8.6.1. Protocol-Specified Serious Adverse Events
There are no protocol-specified SAEs in this study.  All SAEs will be reported by the 
investigator as described in previous sections and will be handled as SAEs in the safety 
database (see the section on Serious Adverse Event Reporting Requirements).
8.6.2. Potential Cases of Drug-Induced Liver Injury 
Abnormal values in aspartate aminotransferase(AST) and/or alanine aminotransferase(ALT) 
levels concurrent with abnormal elevations in total bilirubin level that meet the criteria 
outlined below in the absence of other causes of liver injury are considered potential cases of 
drug-induced liver injury (potential Hy’s law cases) and should always be considered 
important medical events.  
The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the patient’s individual baseline values and underlying conditions. Patients who 
present with the following laboratory abnormalities should be evaluated further to 
definitively determine the etiology of the abnormal laboratory values:

Patients with AST or ALT and total bilirubin baseline values within the normal range 
who subsequently present with AST or ALT values 3 times the upper limit of 
normal (× ULN) concurrent with a total bilirubin value 2 × ULN with no evidence 
of hemolysis and an alkaline phosphatase value 2 × ULN or not available;

For patients with preexisting ALT OR AST OR total bilirubin values above the ULN, 
the following threshold values should be used in the definition mentioned above:

For patients with preexisting AST or ALT baseline values above the normal range,
AST or ALT value 2 times the baseline values and 3 × ULN, or 8 × ULN
(whichever is smaller);
Concurrent with

For patients with pre-existing values of total bilirubin above the normal range: Total 
bilirubin level increased from baseline by an amount of at least 1 × ULN or if the 
value reaches 3 × ULN (whichever is smaller).


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The patient should return to the investigational site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment.  The possibility of hepatic 
neoplasia (primary or secondary) should be considered. In addition to repeating 
measurements of AST and ALT, laboratory tests should include albumin, creatine kinase, 
total bilirubin, direct and indirect bilirubin, gamma-glutamyl transferase, prothrombin time
(PT)/international normalized ratio (INR), and alkaline phosphatase.  A detailed history, 
including relevant information, such as review of ethanol, acetaminophen, recreational drug,
and supplement consumption, family history, occupational exposure, sexual history, travel 
history, history of contact with a jaundiced person, surgery, blood transfusion, history of liver 
or allergic disease, and work exposure, should be collected. Further testing for acute 
hepatitis A, B, or C infection and liver imaging (eg, biliary tract) may be warranted. All 
cases confirmed on repeat testing as meeting the laboratory criteria defined above, with no 
other cause for LFT abnormalities identified at the time, should be considered potential Hy’s 
law cases irrespective of availability of all the results of the investigations performed to 
determine etiology of the abnormal LFTs. Such potential Hy’s law cases should be reported 
as SAEs.
8.7. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility or any prolongation of an existing admission. Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit). An emergency room visit does not necessarily constitute an 
hospitalization; however, the event leading to the emergency room visit should be assessed 
for medical importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same-day surgeries (as outpatient/same day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
AE is not in itself an SAE.  Examples include: 


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
Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of persistent pre-treatment laboratory abnormality);

Social admission (eg, patient has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual patient;

Admission exclusively for the administration of blood products.
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as AEs.  However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE.  For example, an acute appendicitis 
that begins during the AE reporting period should be reported as the AE, and the resulting 
appendectomy should be recorded as treatment of the AE.
8.8. Severity Assessment
GRADE
Clinical Description of Severity
0
No Change from normal or reference range (This grade is not included in the 
Version 4.03 CTCAE document but may be used in certain circumstances.)
1
MILD adverse event
2
MODERATE adverse event
3
SEVERE adverse event
4
LIFE-THREATENING consequences; urgent intervention indicated
5
DEATH RELATED TO adverse event
Note the distinction between the severity and the seriousness of an AE. A severe event is not 
necessarily an SAE. For example headache may be severe (interferes significantly with the 
patient’s usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs listed above.


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8.9. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and non-
serious); the investigator must record the causal relationship in the CRF, as appropriate, and 
report such an assessment in accordance with the SAE reporting requirements if applicable.  
An investigator’s causality assessment is the determination of whether there exists a 
reasonable possibility that the investigational product caused or contributed to an AE; 
generally the facts (evidence) or arguments to suggest a causal relationship should be 
provided.  If the investigator does not know whether or not the investigational product caused 
the event, then the event will be handled as “related to investigational product” for reporting 
purposes, as defined by the sponsor (see the section on Reporting Requirements).  If the 
investigator’s causality assessment is “unknown but not related to investigational product,”
this should be clearly documented on study records.  
In addition, if the investigator determines that an SAE is associated with study procedures, 
the investigator must record this causal relationship in the source documents and CRF, as 
appropriate, and report such an assessment in accordance with the SAE reporting 
requirements, if applicable.
8.10. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy occurs if:
1. A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product;
An example of environmental exposure would be a case involving direct contact with 
a Pfizer product in a pregnant women (eg, a nurse reports that she is pregnant and has 
been exposed to chemotherapeutic products).
2. A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy.
If a study patient or study patient’s partner becomes or is found to be pregnant during the 
study patient’s treatment with the investigational product, the investigator must submit this 
information to the Pfizer drug safety unit on an SAE report form and an EDP supplemental
form, regardless of whether an SAE has occurred.  In addition, the investigator must submit 
information regarding environmental exposure to a Pfizer product in a pregnant woman (eg, a 
patient reports that she is pregnant and has been exposed to a cytotoxic product by inhalation 
or spillage) using the EDP supplemental form.  This must be done irrespective of whether an 
AE has occurred and within 24 hours of awareness of the exposure.  The information 
submitted should include the anticipated date of delivery (see below for information related 
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Follow-up is conducted to obtain general information on the pregnancy and its outcome for
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer of the outcome as a follow-up 
to the initial EDP supplemental form. In the case of a live birth, the structural integrity of the 
neonate can be assessed at the time of birth.  In the event of a termination, the reason(s) for
the termination should be specified and, if clinically possible, the structural integrity of the 
terminated fetus should be assessed by gross visual inspection (unless preprocedure test 
findings are conclusive for a congenital anomaly and the findings are reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported as SAEs follows: 

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the investigational product.
Additional information regarding the EDP may be requested by the investigator.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays).  In the case of paternal exposure, the 
investigator will provide the study patient with the Pregnant Partner Release of Information 
Form to deliver to his partner.  The investigator must document in the source documents that 
the patient was given the Pregnant Partner Release of Information Form to provide to his 
partner.
8.11. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to the drug safety unit within 24 hours of the
investigator’s awareness, using the SAE report form, regardless of whether there is an 
associated AE/SAE. Since the information does not pertain to a patient enrolled in the study, 
the information is not reported on a CRF; however, a copy of the completed SAE report 
form is maintained in the investigator site file.
8.12. Withdrawal Due to Adverse Events (See also the Section on Patient Withdrawal)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted earlier, and recorded on the appropriate AE CRF 
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When a patient withdraws because of an SAE, the SAE must be reported in accordance with 
the reporting requirements defined below.
8.13. Eliciting Adverse Event Information
The investigator is to report all directly observed AEs and all AEs spontaneously reported by 
the study patient.  In addition, each study patient will be questioned about AEs.
8.14. Reporting Requirements
Each AE is to be assessed to determine if it meets the criteria for SAEs.  If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate.
8.14.1. Serious Adverse Event Reporting Requirements
If an SAE occurs, Pfizer is to be notified within 24 hours of investigator awareness of the 
event.  In particular, if the SAE is fatal or life-threatening, notification to Pfizer must be 
made immediately, irrespective of the extent of available AE information.  This time frame 
also applies to additional new information (follow-up) on previously forwarded SAE reports 
as well as to the initial and follow-up reporting of EDP, exposure via breastfeeding, and 
occupational exposure cases.  
In the rare event that the investigator does not become aware of the occurrence of an SAE 
immediately (eg, if an outpatient study patient initially seeks treatment elsewhere), the 
investigator is to report the event within 24 hours after learning of it and document the time 
of his or her first awareness of the AE.
For all SAEs, the investigator is obligated to pursue and provide information to Pfizer in 
accordance with the time frames for reporting specified above.  In addition, an investigator 
may be requested by Pfizer to obtain specific additional follow-up information in an 
expedited fashion.  This information collected for SAEs is more detailed than that captured 
on the AE CRF.  In general, this will include a description of the AE in sufficient detail to
allow for a complete medical assessment of the case and independent determination of 
possible causality.  Information on other possible causes of the event, such as concomitant 
medications, vaccines, and/or illnesses, must be provided.  In the case of a patient death, a 
summary of available autopsy findings must be submitted as soon as possible to Pfizer or its 
designated representative. 
8.14.2. Non-Serious Adverse Event Reporting Requirements
All AEs will be reported on the AE page(s) of the CRF.  It should be noted that the form for 
collection of SAE information is not the same as the AE CRF.  Where the same data are 
collected, the forms must be completed in a consistent manner.  For example, the same AE
term should be used on both forms.  AEs should be reported using concise medical 
terminology on the CRFs as well as on the form for collection of SAE information.


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8.14.3. Sponsor’s Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in a statistical analysis plan (SAP), which will be maintained by the 
sponsor.  This document may modify the plans outlined in the protocol; however, any major 
modifications of the primary endpoint definition and/or its analysis will also be reflected in a 
protocol amendment.
9.1. Analysis Sets
1. Safety analysis set.
The safety analysis set includes all enrolled patients who receive at least one dose of study 
treatment.
2. Full analysis set.
The full analysis set includes all enrolled patients.
3. Per-protocol analysis set (evaluable for MTD).
The per-protocol analysis set includes all enrolled patients who receive at least one dose of 
study treatment and who do not have major treatment deviations during the 28-day 
observation period. Patients with major treatment deviations in this cycle are not evaluable 
for the MTD assessment and will be replaced as needed to permit MTD estimation. Major 
treatment deviations include:

Administration of less than 50% of the planned dose of PF-06840003, provided that it
is not due to toxicity attributable to PF-06840003

Administration of more than 150% of the planned dose of PF-06840003
4. PK analysis sets
The PK parameter analysis population is defined as all enrolled patients treated who have 
sufficient information to estimate at least 1 of the PK parameters of interest.
The PK concentration population is defined as all enrolled patients who are treated and have 
at least 1 analyte concentration.
5. Biomarker analysis set(s)
The biomarker analysis set includes all enrolled patients with at least one of the 
PD/biomarker parameters evaluated at pre- and/or post-dose.


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9.2. Statistical Methods and Properties
9.2.1. Statistical Methods for Dose Escalation/De-Escalation
Part 1, the dose escalation phase of this study, employs an mTPI design to estimate the MTD.  
The mTPI design employs a simple beta binomial model with a conjugated prior beta 
(0.5, 0.5).  Decision rules are based on calculating the unit probability mass (UPM) of 
3 intervals corresponding to underdosing, proper dosing, and overdosing in terms of dose 
limiting toxicity.  A proper dosing interval is centered at the target toxicity rate (pT) of 
27.5% with 5% uncertainty (0.225 < pT <0.325).  The under dosing interval is (0, 0.225), and 
the overdosing interval is (0.325, 1).  The 3 dosing intervals are associated with 3 different 
dose escalation decisions.  The underdosing interval corresponds to a dose escalation I, 
overdosing corresponds to a dose de-escalation, and proper dosing corresponds to staying at 
the same current dose.  Given an interval and a probability distribution, the UPM of that 
interval is defined as the probability of the interval divided by the length of the interval.  The 
mTPI design calculates the UPMs for the 3 dosing intervals, and the one with the largest 
UPM implies the corresponding dose finding decision.  That decision provides the dose level 
to be used for future patients.  For example, if the underdosing interval has the largest UPM, 
decision E (to escalate) will be executed, and the next cohort of patients will be treated at the 
next higher dose level.  Under the mTPI design, a trial is terminated when either the lowest 
dose is above the MTD or a pre-specified maximum sample size is reached.  Doses with an 
incidence of DLT >33% (eg, 4 out of 10) will not be declared as MTD even though it is 
allowed by the mTPI method.
9.3. Sample Size Determination
Due to the dynamic nature of the Bayesian allocation procedure, the sample size using the 
mTPI approach cannot be determined in advance in the dose escalation phase of the study.  
The target sample size for each cohort is 2 to 4, the actual number of patients treated at each 
dose will vary from 2 to 12. It is estimated no more than approximately 72 DLT evaluable 
patients will be enrolled in the dose escalation stage in order to have a reliable and accurate 
estimate of the MTD, although this may be higher if more than 6 dose levels are required to 
be evaluated.  Up to approximately 20 to 25 patients are anticipated to be enrolled in Part 2 
of the study.
In Part 2, the expansion phase of the study, multiple efficacy endpoints will be investigated, 
namely: 1) disease control rate (DCR) at Week 9; 2) DCR at Week 25; 3) objective response 
rate (ORR) by MRI by or at Week 9; 4) ORR by F-18-FLT-PET scan by or at Week 9 (if 
collected). The sample size is driven by DCR at Week 9 and ORR by MRI. 
The expansion phase of the study will be a single arm study, the recommended dose from 
Part 1 will be used in this phase. With 20 patients, the study will have an approximately 
75% power to detect a 25% improvement in Disease Control Rate (DCR), aiming for a 
65% DCR, from the null hypothesis of 40% DCR.  The study will have an approximately 
78% power to detect a 15% improvement in ORR, aiming for a 20% ORR, from the null 
hypothesis of 5% ORR. These sample size calculations use an one-sample test for a single 
proportion with an one-sided alpha level of 0.05. The statistical power will be slightly higher 
than stated above if this phase of the study enrolls more than 20-25 patients. 


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As data accumulates, a Bayesian approach with a non-informative Jeffery’s prior beta 
(0.5,0.5) will be used to calculate the posterior probability of observing certain DCR and 
ORR. For example, if 2 responders were observed in the first 10 patients enrolled, the 
posterior probability of observing 20% ORR is about 53.3%; if 2 responders were observed 
in the first 12 patients enrolled, the posterior probability of observing 20% ORR is about 
41.5%; if only 1 responder was observed in the first 15 patients enrolled, the posterior 
probability of observing 20% ORR is about 8.7%. If a posterior probability is less than 
15% for both of the 2 efficacy endpoints, the study team may choose to stop the expansion 
phase for futility.  The safety data will also be reviewed in that decision-making process. 
9.4. Efficacy Analysis
There is no efficacy analysis in the dose escalation phase of the study (Part 1).
In the expansion phase (Part 2), anti-tumor activity is one of the two primary objectives.
Tumor assessment in the study will be based on the Macdonald criteria. DCR, ORR, duration 
of response (DOR), and Progression-Free Survival (PFS) will be calculated and presented.  
For binary variable (eg, ORR, DCR), descriptive statistics will be used; for time-to-event 
variables (eg, DOR, PFS), Kaplan-Meier analysis may be performed.  The detailed analyses 
will be described in the statistical analysis plan. 
9.5. Analysis of Pharmacokinetics and Pharmacodynamics 
9.5.1. Analysis of Pharmacokinetics
9.5.1.1. Single-Dose and Steady-State PF-06840002 and PF-06840001 Pharmacokinetic
Analysis
Plasma PK parameters including the maximum plasma concentration (Cmax), time to 
maximum plasma concentration (Tmax), and area under the plasma concentration versus time 
curve (AUClast, AUCτ) for PF-06840002 and PF-06840001 will be estimated using 
non-compartmental analysis.  If data permit or if considered appropriate, area under the 
plasma concentration versus time curve to infinity (AUCinf), terminal elimination half-life 
(t1/2), oral plasma clearance (CL/F), apparent volume of distribution (Vz/F), accumulation 
ratio (Rac) and linearity ratio (Rss) will be also estimated.  The single-dose and steady-state 
PK parameters will be summarized descriptively by dose, cycle and day.
Urine concentration data will be analyzed to estimate the fraction of drug excreted
unchanged in urine (Ae%) and renal clearance (CLr) for PF-6840002 and PF-06840001.  
CSF concentration data will be analyzed to estimate steady-state trough level ratio between 
CSF and plasma samples.
Drug concentrations will be summarized descriptively (n, mean, SD, coefficient of variation
[CV], median, minimum, maximum, geometric mean and its associated CV) by dose, cycle, 
day and nominal time.  Individual patient and median profiles of the concentration-time data 
will be plotted by dose, cycle and day (single dose and steady state) using nominal times.  
Individual and median profiles will be presented on both linear-linear and log-linear scales.


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9.5.2. Analysis of Pharmacodynamics.
9.5.2.1. Analysis of Biomarker Endpoints
For biomarker samples, summary statistics (eg, the mean and standard deviation, median, and 
minimum/maximum levels of continuous, and frequencies and percentages of categorical 
biomarker measures) will be determined at baseline and post-treatment.  For each pair of 
specimens, the percent change from baseline of these same parameters will also be 
calculated.
Data from biomarker assays may be analyzed using graphical methods and descriptive 
statistics such as linear regression, t-test, and analysis of variance (ANOVA).  The statistical 
approach will examine correlations of biomarker results with pharmacokinetic parameters 
and measures of anti-tumor efficacy.
9.5.3. Population Pharmacokinetic Analysis or Pharmacokinetic/Pharmacodynamic 
(PK/PD) Modeling
Pharmacokinetic and PD data from this study may be analyzed using modeling approaches 
and may also be pooled with data from other studies to investigate any association between
PF-06840002 exposure and biomarkers or significant safety endpoints.  The results of these 
analyses, if performed, may be reported separately.
9.6. Safety Analysis
Summaries and analyses of safety parameters will include all patients in the Safety Analysis 
Set.
9.6.1. Analysis of the Primary Endpoint
Dose-Limiting Toxicity (DLT) is the primary endpoint of the dose escalation component of 
the study.  The occurrence of DLTs observed in the dosing cohorts is used to estimate the 
MTD as described in the STUDY DESIGN section.  Adverse Events constituting DLTs will 
be listed per dose level. DLT summary table by dose level may be generated, if deemed 
necessary, for data interpretation or for estimating the MTD purposes
9.6.2. Analysis of Secondary Safety Endpoints
Adverse Events
Adverse Events will be graded by the investigator according to the CTCAE version 4.03 and 
coded using the Medical Dictionary for Regulatory Activities (MedDRA).  The focus of AE 
summaries will be on TEAEs, those with initial onset or increasing in severity after the first 
dose of study treatment.  The number and percentage of patients who experienced any AE, 
SAE, TEAE, and treatment related SAE will be summarized according to worst toxicity 
grades.  The summaries will present AEs both on the entire study period and by cycle. 


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Laboratory Test Abnormalities
The number and percentage of patients who experience laboratory test abnormalities will be 
summarized according to worst toxicity grade observed for each laboratory assay.  The 
analyses will summarize laboratory tests both on the entire study period and by cycle.  Shift 
tables will be provided to examine the distribution of laboratory toxicities.
For laboratory tests without CTCAE grade definitions, results will be categorized as normal, 
abnormal, or not done. 
Other safety endpoints, including physical examination, vital signs, ECHO/MUGA, and 
concomitant medications may be summarized by dose and visit, if deemed necessary. 
Detailed analyses will be described in the statistical analysis plan.
9.6.3. Electrocardiogram
The analysis of ECG results will be based on patients in the safety analysis set with baseline 
and on-treatment ECG data. Baseline is defined as the latest assessment prior to receipt of 
the first dose (ie, Cycle 1 Day 1). 
ECG measurements (an average of the triplicate measurements) will be used for the 
statistical analysis and all data presentations.  Any data obtained from ECGs repeated for 
safety reasons after the nominal time-points will not be averaged along with the preceding 
triplicates.  Interval measurements from repeated ECGs will be included in the outlier 
analysis (categorical analysis) as individual values obtained at unscheduled time points.
QT intervals will be corrected for heart rate (QTc) using standard correction factors (ie, 
Fridericia’s).  Data will be summarized and listed for QT, HR, response rate (RR), PR, QRS, 
QTcF, and dose.  Individual QT (all evaluated corrections) intervals will be listed by time 
and dose.  The most appropriate correction factor will be selected and used for the following 
analyses of central tendency and outliers and used for the study conclusions.  Descriptive 
statistics (n, mean, median, standard deviation, minimum, and maximum) will be used to 
summarize the absolute corrected QT interval and changes from baseline in corrected QT 
after treatment by dose and time point.  For each patient and by treatment, the maximum 
change from baseline will be calculated as well as the maximum post-baseline interval across 
time-points.  Categorical analysis will be conducted for the maximum change from baseline 
in corrected QT and the maximum post-baseline QT interval. 
Shift tables will be provided for baseline vs worst on treatment corrected QT using maximum 
CTCAE Grade.  Shift tables will also be provided for ECG abnormality at baseline vs. on 
treatment (yes, no, not done: (n, %)). Patients experiencing clinically-relevant morphological 
ECG changes will be summarized (including frequency and percentage).
The effect of drug concentrations on corrected QT change from baseline will be explored 
graphically. Additional concentration-corrected QT analyses may be performed. Data may 
be pooled with other study results and/or explored further with PK/PD models.


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9.8. Data Safety Monitoring Committee
An external Data Safety Monitoring Committee will not be established for the study. For the 
purpose of this protocol, Pfizer procedures for periodic safety review will be applied by an 
internal safety review team with medical and statistical capabilities to review individual and 
summary data collected in the safety and clinical databases. Procedures include:
•
Surveillance for serious adverse events (SAEs) according to regulatory guidelines;
•
Discussions between the investigators and the sponsor of AEs and laboratory tests 
alterations seen at each dose level in an on-going manner at regular teleconferences 
and/or meetings to determine the safety profile and risk/benefit ratio and decide if further 
enrollment is appropriate.
10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer or its agent will conduct periodic monitoring visits during study conduct to ensure that 
the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs are accurate.  The 
investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification.  This 
verification may also occur after study completion.
During study conduct and/or after study completion, the study site may be subject to review 
by the IRB/EC, and/or to quality assurance audits performed by Pfizer, or companies 
working with or on behalf of Pfizer, and/or to inspection by appropriate regulatory 
authorities.
The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study. Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the study site for the inspection and will allow Pfizer or its agent, 
whenever feasible, to be present during the inspection. The investigator will promptly 
provide copies of the inspection findings to Pfizer or its agent.  Before response submission 
to the regulatory authorities, the investigator will provide Pfizer or its agents with an 
opportunity to review and comment on responses to any such findings.
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.
CCI
CCI
CCI


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11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included patient.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true. Any corrections to entries made in the CRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry.
In most cases, the source documents are the hospital’s or the physician’s patient chart.  In 
these cases, data collected on the CRFs must match the data in those charts. 
In some cases, the CRF, or part of the CRF, may also serve as source documents.  In these 
cases, a document should be available at the investigative site as well as at Pfizer and clearly 
identify those data that will be recorded in the CRF, and for which the CRF will stand as the 
source document.
11.2. Record Retention
To enable evaluations and/or audits from regulatory authorities or Pfizer, the investigator 
agrees to keep records, including the identity of all participating patients (sufficient 
information to link records, eg, CRFs and hospital records), all original signed informed 
consent documents, copies of all CRFs, safety reporting forms, source documents, and 
detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, and telephone call reports).  The records should 
be retained by the investigator according to ICH guidelines, according to local regulations, or 
as specified in the clinical study agreement (CSA), whichever is longer.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer.  
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.  


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The investigator must obtain Pfizer’s written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board /Ethics Committee 
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, eg, 
recruitment advertisements, if applicable, from the IRB/EC.  All correspondence with the 
IRB/EC should be retained in the investigator file.  Copies of IRB/EC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the patients.  In 
that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as well as 
the general principles set forth in the International Ethical Guidelines for Biomedical 
Research Involving Human Subjects (Council for International Organizations of Medical 
Sciences 2002), Guidelines for GCP (ICH 1996), and the Declaration of Helsinki (World 
Medical Association 2008). 
In addition, the study will be conducted in accordance with the protocol, the ICH guideline 
on GCP, and applicable local regulatory requirements and laws.
12.3. Patient Information and Consent
All parties will ensure protection of patient personal data and will not include patient names 
or other identifiable data in any reports, publications, or other disclosures, except where 
required by law.
When study data are compiled for transfer to Pfizer and other authorized parties, patient
names, addresses, and other identifiable data will be replaced by a numerical code consisting 
of a numbering system provided by Pfizer in order to de-identify study patients. The study 
site will maintain a confidential list of patients who participated in the study, linking each 
patient’s numerical code to his or her actual identity. In case of data transfer, Pfizer will 
maintain high standards of confidentiality and protection of patients’ personal data consistent 
with applicable privacy laws.
The informed consent documents must be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements, including applicable privacy laws.
The informed consent documents used during the informed consent process must be 
reviewed and approved by the sponsor, approved by the IRB/EC before use, and available for 
inspection.


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The investigator must ensure that each study patient, is fully informed about the nature and 
objectives of the study and possible risks associated with participation. 
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each patient before any study-specific activity is performed. The investigator 
will retain the original of each patient’s signed consent document.
12.4. Patient Recruitment
Advertisements approved by IRBs/Ecs and investigator databases may be used as recruitment 
procedures.  
Pfizer will have an opportunity to review and approve the content of any study recruitment 
materials directed to potential study patients before such materials are used.
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
competent authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, Pfizer should be informed immediately.  
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study patients against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
13. DEFINITION OF END OF TRIAL
End of trial in all participating countries is defined as the last subject last visit (LSLV).
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, or investigational product safety problems, or at the 
discretion of Pfizer.  In addition, Pfizer retains the right to discontinue development of PF-
06840003 at any time.
If a study is prematurely terminated or discontinued, Pfizer will promptly notify the 
investigator.  After notification, the investigator must contact all participating patients and 
the hospital pharmacy (if applicable) within a time period set by Pfizer.  As directed by 
Pfizer, all study materials must be collected and all CRFs completed to the greatest extent 
possible.


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15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations. 
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies conducted in patients that evaluate the safety and/or efficacy of a Pfizer 
product, regardless of the geographical location in which the study is conducted.  US Basic 
Results are submitted for posting within 1 year of the primary completion date for studies in 
adult populations or within 6 months of the primary completion date for studies in pediatric 
populations.
Primary completion date is defined as the date that the final patient was examined or received 
an intervention for the purposes of final collection of data for the primary outcome, whether 
the clinical study concluded according to the pre-specified protocol or was terminated.
EudraCT
Pfizer posts European Union (EU) Basic Results on EudraCT for all Pfizer-sponsored 
interventional studies that are in scope of EU requirements.  EU Basic Results are submitted 
for posting within 1 year of the primary completion date for studies in adult populations or 
within 6 months of the primary completion date for studies in pediatric populations.
www.pfizer.com
Pfizer posts Public Disclosure Synopses (clinical study report synopses in which any data 
that could be used to identify individual patients has been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the US Basic Results document is 
posted to www.clinicaltrials.gov.
15.2. Publications by Investigators
Pfizer supports the exercise of academic freedom and has no objection to publication by 
principal investigator of the results of the study based on information collected or generated 
by principal investigator, whether or not the results are favorable to the Pfizer product.  
However, to ensure against inadvertent disclosure of confidential information or unprotected 
inventions, the investigator will provide Pfizer an opportunity to review any proposed 
publication or other type of disclosure of the results of the study (collectively, “Publication”) 
before it is submitted or otherwise disclosed.


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The investigator will provide any publication to Pfizer at least 30 days before they are 
submitted for publication or otherwise disclosed. If any patent action is required to protect 
intellectual property rights, the investigator agrees to delay the disclosure for a period not to 
exceed an additional 60 days.
The investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study- or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results.
If the study is part of a multicenter study, the investigator agrees that the first publication is 
to be a joint publication covering all study sites, and that any subsequent publications by the  
principal investigator will reference that primary publication. However, if a joint manuscript 
has not been submitted for publication within 12 months of completion or termination of the 
study at all participating sites, the investigator is free to publish separately, subject to the 
other requirements of this section.
For all publications relating to the study, Institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II – “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the CSA between Pfizer and the 
institution.  In this section entitled Publications by Investigators, the defined terms shall have 
the meanings given to them in the CSA.
If there is any conflict between the CSA and any Attachments to it, the terms of the CSA 
control.  If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study patients, and the CSA will control as to all other 
issues.


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16. REFERENCES
1.
“Metabolism and Transport, Drug Interaction Database”, Department of Pharmaceutics, 
University of Washington. www.druginteractioninfo.org . Accessed May 2009.
2.
Altekruse SF, Kosary CL, Krapcho M, et al (eds). SEER Cancer Statistics Review, 
1975-2007, National Cancer Institute. Bethesda, MD, 
http://seer.cancer.gov/csr/1975_2007/, based on November 2009 SEER data 
submission, posted to the SEER web site, 2010.
3.
Benedict RHB, et al. Hopkins Verbal Learning Test–Revised: Normative data and 
analysis of inter-form and test-retest reliability. The Clinical Neuropsychologist. 
1998;12:43–55.
4.
Beroukhim R, Getz G, Nghiemphu L, et al. Assessing the significance of chromosomal 
aberrations in cancer: methodology and application to glioma. Proc Natl Acad Sci U S 
A. 2007 Dec 11;104(50):20007-12.
5.
Brandacher G, Perathoner A, Ladurner R, et al. Prognostic value of indoleamine 2,3-
dioxygenase expression in colorectal cancer: effect on tumor-infiltrating T cells. Clin 
Cancer Res 2006; 12(4):1144-51.
6.
Burnet NG, Jefferies SJ, Benson RJ, et al. Years of life lost (YLL) from cancer is an 
important measure of population burden—and should be considered when allocating 
research funds. Br J Cancer. 20005 Jan 31;92(2)241:5.
7.
Cohen MH, Shen YL, Keegan P, et al. FDA drug approval summary: bevacizumab 
(Avastin) as treatment of recurrent glioblastoma multiforme. Oncologist. 2009 
Nov;14(11):1131-8.
8.
Corroyer-Dulmont A, Peres EA, Petit E, et al. Noninvasive assessment of hypoxia with 
3-[18F]-fluoro-1-(2-nitro-1-imidaxolyl)-2-propanol ([18F]-FMISO): a PET study in two 
experimental models of human glioma. Biol Chem. 2013 Apr;394(4):529-39.
9.
Furnari FB, Fenton T, Bachoo RM, et al. Malignant astrocytic glioma: genetics, 
biology, and paths to treatment. Genes Dev. 2007 Nov 1;21(21):2683-710.
10.
Macdonald DR, Cascino TL, Schold SC, et. al. Response criteria for Phase II studies of 
supratentorial malignant glioma. J. Clin. Oncol. 1990;8 (7): 1277-80.
11.
Mellinghoff IK, Wang MY, Vivanco I, et al. Molecular determinants of the response of 
glioblastomas to EGFR kinase inhibitors. N Engl J Med. 2005 Nov 10;353(19):2012-24.
12.
Mellor AL, Munn DH. IDO expression by dendritic cells: tolerance and tryptophan 
catabolism. Nat Rev Immunol 2004; 4(10):762-74.


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13.
Mitsuka K, Kawataki T, Satoh E, et al. Expression of indoleamine 2,3-dioxygenase and 
correlation with pathological malignancy in gliomas. Neurosurgery. 2013 
Jun;72(6):1031-8.
14.
Mellor AL, Munn DH. IDO expression by dendritic cells: tolerance and tryptophan 
catabolism. Nat Rev Immunol. 2004 Oct;4(20):762-74. Review.
15.
Munn DH, Mellor AL. Indoleamine 2,3 dioxygenase and metabolic control of immune 
responses. Trends Immunol 2013; 34(3):137-43.
16.
Nayak L, DeAngelis L, Wen P. et al. The Neurologic Assessment in Neuro-Oncology 
(NANO) Scale: A Tool to Assess Neurologic Function for Integreation in the 
Radiologic Assessment in Neuro-Oncology (RANO) Criteria.  Neurology April 8, 2014 
vol. 82 no. 10 Supplement S22.005
17.
Okada H, Weller M, Huang R, et al.  Immunotherapy response assessment in nuero-
oncology: a report of the RANO working group.  Lancet Oncol. 2015 Nov;16(15):e534-
42.
18.
Okamoto A, Nikaido T, Ochiai K, et al. Indoleamine 2,3-dioxygenase serves as a 
marker of poor prognosis in gene expression profiles of serous ovarian cancer cells. 
Clin Cancer Res 2005; 11(16):6030-9.
19.
Ooi YC, Tran P, Ung N, et al. The role of regulatory T-cells in glioma immunology. 
Clin Neurol Neurosurg. 2014 Apr:119:125-32.
20.
Reitan RM. Trail Making Test: Manual for administration and scoring. Tucson, AZ: 
Reitan Neuropsychology Laboratory; 1958. 1992.
21.
Ruff RM, et al. Benton Controlled Oral Word Association Test: reliability and updated 
norms. Arch Clin Neuropsychol. 1996;11:329–338.
22.
Stewart LA. Chemotherapy in adult high-grade glioma: a systematic review and 
metaanalysis of individual patient data from 12 randomised trials 2002 Lancet 359: 
1011-1018.
23.
Uyttenhove C, Pilotte L, Theate I, et al. Evidence for a tumoral immune resistance 
mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat Med 
2003; 9(10):1269-74.
24.
Van Baren N, Van den Eynde BJ. Tumoral immune resistance mediated by enzymes 
that degrade tryptophan. Cancer Immunol Res 2015; 3(9):978-85.
25.
Wainwright DA, Balyasnikova IV, Chang AL, et al. IDO expression in brain tumors 
increases the recruitment of regulatory T cells and negatively impacts survival. Clin 
Cancer Res. 2012 Nov 15;18(22):6110-21.


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26.
Wainwright DA, Chang AL, Dey M, et al. Durable therapeutic efficacy utilizing 
combinatorial blockade against IDO, CTLA-4, and PD-L1 in mice with brain tumors. 
Clin Cancer Res. 2014 Oct 15;20(20):5290-301.
27.
Zhai L, Lauing KL, Chang AL, et al. The role of IDO in brain tumor immunotherapy. J 
Neurooncol. 2015 Jul ;123(3) :395-403.
28.
Zhao F, Cui Y, Li M, et al. Prognostic value of 3’-deoxy-3’-18F-fluorothymidine 
([(18)F] FLT PET) in patients with recurrent malignant gliomas. Nucl Med Biol. 2014 
Sep;41(8):710-5.


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Appendix 1. Abbreviations
Abbreviation
Term
AA
Anaplastic astrocytoma
AE
Adverse Event
AIDS
Acquired immune deficiency
ALT
Alanine aminotransferase
ANC
Absolute Neutrophil Count
ASCO
American Society of Clinical Oncology
AST
Aspartate aminotransferase
AUC
Area under the curve
BBB
Blood brain barrier
BCRP
Breast cancer resistance protein
BID
Twice a day
BP
Blood pressure
C1D1
Cycle 1 Day 1
CD
Cluster of differentiation
CLp
Plasma clearance
Cmax
Maximum observed
CNS
Central nervous system
CR
Complete response
CRF
Case Report Form
CSA
Clinical supply agreement
CSF
Cerebrospinal fluid
CT
Computerized tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP
Cytochrome
DCR
Disease control rate
DDI
Drug-drug interaction
DLT
Dose limiting toxicity
DNA
Deoxyribonucleic acid
EC
Ethics committee
ECG
Electrocardiogram
EDP
Exposure during pregnancy
FIP
First in patient
FLAIR
Fluid-attenuated inversion recovery
FSH
Follicle stimulating hormone
GBM
Glioblastoma Multiforme
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
h
hour
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HBV
Hepatitis B Virus
HCV
Hepatitis C Virus
HDPE
High-density polyethylene
HIV
Human Immunodeficiency Virus
ID
Identification
ICH
International Conference on Harmonisation
IDO1
Indoleamine 2,3-Dioxygenase
IHC
Immunohistochemistry
IND
Investigational new drug
IRB
Institutional review board
IUD
Interuterine device
IV
Intravenous
kg
kilogram
LFT
Liver function test
LSLV
Last subject last visit
MAO
Monoamine oxidase inhibitor
MDRD
Modified Diet in Renal Disease
mg
milogram
mL
milliliter
MRI
Magnetic resonance imaging
MRSD
Maximum Recommended Starting Dose
mRNA
Messenger ribonucleic acid
MTD
Maximum tolerated dose
mTPI
Modified toxicity probability interval
N/A
Not applicable
NCI
National Cancer Institute
ORR
Overall response rate
OS
Overall survival
PD
Progressive disease
PE
Physical examination
PET
Positron emission tomography
PR
Partial response
PT
Prothrombin time
PTT
Partial thromboplastin time
QD
Once daily
RNA
Ribonucleic acid
RP2D
Recommended Phase 2 Dose
SAE
Serious adverse event
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SD
Stable disease
SNRI
Serotonin-norepinephrine reuptake inhibitor
SOA
Schedule of activities
SRSD
Single reference safety document
SSRI
Selective serotonin reuptake inhibitor
t1/2
Terminal half-life
TCR
T-cell repertoire
TEAE
Treatment emergent adverse event
TK
Toxicokinetic
Trp
Tryptophan
ULN
Upper limit of normal
UPM
Unit probability mass
US
United States 
VEG-F
Vascular endothelial growth factor
Vss
Volume of distribution
WHO
World Health Organization
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Appendix 2. Karnofsky Performance Scoring (Karnofsky et al, 1948)

100 - Normal; no complaints; no evidence of disease.

90 - Able to carry on normal activity; minor signs or symptoms of disease.

80 - Normal activity with effort; some signs or symptoms of disease.

70 - Cares for self; unable to carry on normal activity or to do active work.

60 - Requires occasional assistance, but is able to care for most of their personal needs.

50 - Requires considerable assistance and frequent medical care.

40 - Disabled; requires special care and assistance.

30 - Severely disabled; hospital admission is indicated although death not imminent.

20 - Very sick; hospital admission necessary; active supportive treatment necessary.

10 - Moribund; fatal processes progressing rapidly.

0 – Dead.


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Appendix 3. Columbia-Suicide Severity Rating Scale (CSSRS) – Baseline


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Appendix 4. Columbia-Suicide Severity Rating Scale (C-SSRS) – Since Last Visit


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Appendix 5. Patient Health Questionnaire (PHQ-8)


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Appendix 6. Neurologic Assessment in Neuro-Oncology (NANO) Scale


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SAP_001.pdf: 
C0591001 Statistical Analysis Plan
Page 1
Protocol C0591001
A PHASE 1 DOSE ESCALATION STUDY EVALUATING THE SAFETY AND 
TOLERABILITY OF PF-06840003 IN PATIENTS WITH MALIGNANT GLIOMAS
Statistical Analysis Plan 
(SAP)
Version:
Amendment 1
Author:
 (Clinical Statistician, Cambridge, MA)
Date:
28-FEB-2017
PPD


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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................3
LIST OF FIGURES ...................................................................................................................3
APPENDICES ...........................................................................................................................3
1. AMENDMENTS FROM PREVIOUS VERSION(S) ...........................................................4
2. INTRODUCTION .................................................................................................................4
2.1. Study Design .............................................................................................................4
2.2. Study Objectives .......................................................................................................5
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING..................................6
4. HYPOTHESES, SAMPLE SIZE AND DECISION RULES................................................6
4.1. Statistical Hypotheses ...............................................................................................6
4.2. Statistical Decision Rules..........................................................................................6
4.3. Sample Size Determination.......................................................................................8
5. ANALYSIS SETS .................................................................................................................9
5.1. Safety Analysis Set....................................................................................................9
5.2. Full Analysis Set .......................................................................................................9
5.3. Per-Protocol Analysis Set..........................................................................................9
5.4. PK analysis sets.........................................................................................................9
5.5. Biomarker analysis set(s) ..........................................................................................9
5.6. Treatment Misallocations..........................................................................................9
5.7. Protocol Deviations.................................................................................................10
6. ENDPOINTS AND COVARIATES ...................................................................................10
6.1. Primary Endpoint – Part 1.......................................................................................10
6.2. Primary Endpoint – Part 2.......................................................................................10
6.3. Secondary Endpoint ................................................................................................10
6.5. Covariates................................................................................................................11
7. HANDLING OF MISSING VALUES ................................................................................12
7.1. Missing Values For Safety, Immune Responses, Pharmacodynamics, 
Immunogenicity, 
.............................................12
7.2. Immune Responses Lower Limit Of Quantitation..................................................12
7.3. Pharmacokinetic Concentrations And Parameters ..................................................12
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES ..........................13
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8.1. Statistical Methodology...........................................................................................13
8.2. Statistical Analyses .................................................................................................13
8.2.1. Subject Disposition.....................................................................................14
8.2.2. Subject Demographics and Baseline Characteristics..................................14
8.2.3. Study Treatment Exposure and Dose Intensity ..........................................14
8.2.4. Safety Analysis ...........................................................................................14
8.2.4.1. Analysis of Primary Safety Endpoint........................................14
8.2.4.2. Analysis of Secondary Safety Endpoint....................................15
8.2.5. Efficacy Analysis........................................................................................16
8.2.5.1. Primary Efficacy Analysis ........................................................16
8.2.5.2. Secondary Efficacy Analysis.....................................................17
8.2.7. Analysis of Biomarker Endpoints...............................................................20
8.2.8. Population Pharmacokinetic Analysis or 
Pharmacokinetic/Pharmacodynamic (PK/PD) Modeling ................................20
LIST OF TABLES
Table 1.
Decision Rules....................................................Error! Bookmark not defined.7
LIST OF FIGURES
Figure 1.
Overall Study Design..............................................................................................4
APPENDICES
Appendix 1. Appendices..........................................................................................................22
Appendix 1.1. Summarizing Relative Dose (RD) and Relative Dose Intensity (RDI)............22
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1. AMENDMENTS FROM PREVIOUS VERSION(S) 
Amendment 1
Section 2.1 and 
4.3
Wording for sample size was updated to be 
consistent with the protocol amendment. 
Section 8.2.4.2
Shift table for ECG abnormality was deemed 
unnecessary in this study and was removed. 
Section 8.2.4.2
A brief paragraph about ECHO/MUGA data was 
added. 
Section 8.2.9.1
Further details about neurologic and cognitive 
assessment data (HVLT-R, TMT, COWA, 
NANO) were added. 
Other editorial updates to be consistent with the 
protocol amendment. 
2. INTRODUCTION
This document presents the statistical analysis plan (SAP) for study C0591001. The SAP is 
based on the protocol amendment 1 for C0591001 dated December 19, 2016.
Note: in this document any text taken directly from the protocol is italicized.
2.1. Study Design
This is a Phase 1, open-label, multi-center, multiple-dose, safety, PK and PD study of single 
agent PF-06840003.  This study contains two parts, dose escalation (Part 1) followed by 
dose expansion (Part 2).  In Part 1, sequential cohorts of patients with recurrent malignant 
gliomas (GBM and/or WHO grade III gliomas) will receive escalating doses of 
PF-06840003.  Part 2 will evaluate safety as well as explore preliminary antitumor activity 
of the dose selected from Part 1 in additional patients with GBM.
The actual number of patients enrolled in the study will depend on the tolerability of 
PF-06840003 and the number of dose levels required to identify the MTD or Recommended 
Phase 2 Dose (RP2D) if the MTD is not reached.  The target sample size for each cohort in 
Part 1 is 2-4 patients, but, the actual number of patients treated at each dose will vary from 2 
to 12. It is estimated that the maximum sample size will be approximately 72 patients in Part 
1 of the study, although this may be higher if more than 6 dose levels are required to be 
evaluated.  Up to approximately 20 to 25 patients are anticipated to be enrolled in Part 2 of 
the study.  
The overall study design is depicted in Figure 1.


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Figure 1.
Overall Study Design
2.2. Study Objectives
Primary Objective – Part 1

To evaluate the safety and tolerability of increasing dose levels of daily oral 
PF-6840003 in patients with malignant gliomas.

To characterize the dose limiting toxicities (DLTs) of escalated doses of 
PF-06840003.

To determine the maximum tolerated dose (MTD) or recommended phase 2 dose 
(RP2D). 
Primary Objective – Part 2

To further evaluate the safety and tolerability of PF-06840003 at the RP2D.

To evaluate the efficacy of PF-06840003 in patients with glioblastoma.
Secondary Objectives Parts 1 and 2

To evaluate the overall safety profile.

To characterize the single and multiple dose plasma PK of active enantiomer 
PF-06840002, and inactive enantiomer PF-06840001 after administration of the 
racemic mixture, PF-06840003.


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•
To document any anti-tumor activity (Part 1 only).
•
To evaluate dose and concentration response relationship for target engagement and 
PD biomarkers and to then correlate with PK, safety and efficacy to select dose with
full or optimal target engagement.
•
To assess the CSF PK exposure of active enantiomer PF-06840002, and inactive 
enantiomer PF-06840001 after administration of the racemic mixture, PF-06840003.
 
 
 
 
 
 
 
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING
There is no formal interim analysis planned in this study. This is an open label study, the 
Pfizer study team will review safety, immunogenicity, pharmacodynamics, 
 
and other data throughout the study.
4. HYPOTHESES, SAMPLE SIZE AND DECISION RULES
4.1. Statistical Hypotheses
There are no statistical hypotheses in this study. 
4.2. Statistical Decision Rules
In Part 1 of the study, dose escalation and de-escalation will follow a modified Toxicity 
Probability Interval (mTPI) method, targeting a DLT rate of 27.5% and an acceptable DLT 
interval 22.5 to 32.5%.  The mTPI method relies upon a statistical probability algorithm, 
calculated using all patients treated in the current dose level to determine one of the 
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following dose-finding decisions: the subsequent dose should be escalated, maintained at the 
current dose, or de-escalated in the next cohort of 2 to 4 patients, or the trial should be 
terminated.
As an example, if the total number of patients treated at the current dose level is 4, the 
following dosing rules are applied:

0 DLT -> escalate;

1 DLT -> remain at the same dose;

2 DLTs -> de-escalate;

3-4 DLTs -> de-escalate and consider current dose as intolerable.
The general approach to dose-finding, using the mTPI method, involves the following:

The target cohort size is 2 to 4, depending on the number of potential patients 
identified at participating sites;

The next cohort can be enrolled when all patients at the current dose cohort have 
been evaluated for 28 days of the first treatment cycle, or experience a dose-limiting 
toxicity (DLT), whichever comes first;

If a patient withdraws from the study before receiving ≥80% of the planned first-cycle 
dose for reasons other than investigational product-related toxicity, another patient 
will be enrolled to replace that patient at the current dose combination;

In the situation in which the safety of the starting dose does not allow for escalation 
to the next dose level, a lower dose will be considered.
The dose escalation portion of the study is completed when at least 6 to 12 evaluable patients 
have been treated at the highest dose associated with DLT rate 32.5%.


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Table 1.
Decision Rules
4.3. Sample Size Determination
Due to the dynamic nature of the Bayesian allocation procedure, the sample size using the 
mTPI approach cannot be determined in advance in the dose escalation phase of the study.  
The target sample size for each cohort is 2 to 4, the actual number of patients treated at each 
dose will vary from 2 to 12. It is estimated that the maximum sample size will be 
approximately 72 patients in Part 1 of the study, although this may be higher if more than 
6 dose levels are required to be evaluated. Up to approximately 20 to 25 patients are 
anticipated to be enrolled in Part 2 of the study.
In Part 2, the expansion phase of the study, multiple efficacy endpoints will be investigated, 
namely: 1) disease control rate (DCR) at Week 9; 2) DCR at Week 25; 3) objective response 
rate (ORR) by MRI by or at Week 9; 4) ORR by F-18-FLT-PET scan by or at Week 9 (if 
collected). The sample size is driven by DCR at Week 9 and ORR by MRI. 
The expansion phase of the study will be a single arm study, the recommended dose from 
Part 1 will be used in this phase. With 20 patients, the study will have an approximately 
75% power to detect a 25% improvement in Disease Control Rate (DCR), aiming for a 
65% DCR, from the null hypothesis of 40% DCR.  The study will have an approximately 
78% power to detect a 15% improvement in ORR, aiming for a 20% ORR, from the null 
hypothesis of 5% ORR. These sample size calculations use a one-sample test for a single 
Number of 
Patients 
having 
DLT
Number of Patients Treated at a Dose Level
n=2
n=3
n=4
n=5
n=6
n=7
n=8
n=9
n=10
n=11
n=12
0
E
E
E
E
E
E
E
E
E
E
E
1
S
S
S
E
E
E
E
E
E
E
E
2
U
D
S
S
S
S
S
S
S
E
E
3
U
U
D
D
S
S
S
S
S
S
4
U
U
U
U
D
D
D
S
S
5
U
U
U
U
U
D
D
D
6
U
U
U
U
U
U
U
7
U
U
U
U
U
U
Actions to be taken:
D = De-escalate the dose; E: Escalate the dose; S: Stay at the dose.
U = Unacceptable toxicity.


C0591001 Statistical Analysis Plan
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proportion with a one-sided alpha level of 0.05. The statistical power will be slightly higher 
than stated above if this phase of the study enrolls more than 20-25 patients. 
5. ANALYSIS SETS
5.1. Safety Analysis Set
The safety analysis set includes all enrolled patients who receive at least one dose of study 
treatment.
5.2. Full Analysis Set
The full analysis set includes all enrolled patients. All efficacy endpoints will be analysed 
with this population. 
5.3. Per-Protocol Analysis Set
The per-protocol analysis set includes all enrolled patients who receive at least one dose of 
study treatment and who do not have major treatment deviations during the 28-day 
observation period.  Patients with major treatment deviations in this cycle are not evaluable 
for the MTD assessment and will be replaced as needed to permit MTD estimation.  Major 
treatment deviations include:

Administration of less than 50% of the planned dose of PF-06840003, provided that it 
is not due to toxicity attributable to PF-06840003;

Administration of more than 150% of the planned dose of  PF-06840003.
5.4. PK analysis sets
The PK parameter analysis population is defined as all enrolled patients treated who have 
sufficient information to estimate at least 1 of the PK parameters of interest.
The PK concentration population is defined as all enrolled patients who are treated and have 
at least 1 analyte concentration.
5.5. Biomarker analysis set(s)
The biomarker analysis set includes all enrolled patients with at least one of the 
PD/biomarker parameters evaluated at pre- and/or post-dose.
5.6. Treatment Misallocations 
For patients with errors in treatment allocation the following approach will be followed:  
If a patient was:

Enrolled but not treated, then they will be reported under their enrolled treatment 
group for demographic analyses only. These patients will be excluded from the 
immunogenicity, efficacy and safety analyses as the actual treatment is missing;


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
Enrolled but took incorrect treatment, then they will be reported under their enrolled 
treatment group for efficacy analyses, excluded from analyses based on PP, but will 
be reported under the treatment they actually received for all safety, PK, immune 
responses, and immunogenicity analyses.
5.7. Protocol Deviations
Protocol deviations will be determined on an ongoing basis per medical data review. Any 
major protocol deviation will prevent the patient from being included in the per-protocol 
population. 
A full list of major protocol deviations will be compiled prior to database closure. Once the 
final list of major protocol deviations is determined the per-protocol population flag will be 
updated. 
6. ENDPOINTS AND COVARIATES
6.1. Primary Endpoint – Part 1

Incidence and grade of treatment-emergent adverse events (TEAE) including Dose 
Limiting Toxicity (DLTs) as graded by National Cancer Institute Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03. The specific 
definition of DLT is provided in the study protocol. 
6.2. Primary Endpoint – Part 2

Adverse Events (AE) as characterized by type, frequency, severity, timing, 
seriousness, and relationship to study therapy.

Disease control rate (DCR) at 9 and 25 weeks by MRI using Macdonald criteria 
(Macdonald et al, 1990). DCR is defined as the proportion of patients achieving CR, 
PR, or SD as assessed by MacDonald criteria. 
6.3. Secondary Endpoint

Laboratory abnormalities as characterized by type, frequency, severity (as graded by 
NCI CTCAE v.4.03) and timing;

Vital Signs; 

PK parameters in the blood of PF-06840002 and PF-06840001 Single Dose (SD) –
Cmax, Tmax, AUClast, AUC, CL/F, and Vz/F and t1/2, AUCinf as data permit.  Multiple 
Dose (MD) (assuming steady state is achieved) – Css,max, Tss,max, AUCss,, t1/2, Css,min, 
Css,av, CL/F, Vz/F, Rac (AUCss,/AUCsd,) and Rss (AUCss,/AUCsd,inf) as data permit;

Objective tumor response based on Macdonald criteria. Objective tumor response is 
defined as the proportion of patients achieving CR or PR as assessed by Macdonald 
criteria. 


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•
Disease Control Rate at 9 and 25 weeks by MRI based on Response Assessment for 
Neuro-Oncology (RANO) criteria.
•
On-target activity of PF-06840003 by measurement of kynurenine, tryptophan and 
kyn/trp (ratio) levels in peripheral blood.
•
Steady-state trough level ratio between CSF and plasma samples for PF-06840002 
and PF-06840001.
 
 
 
 
 
 
 
 
 
 
 
 
6.5. Covariates
Not applicable. 
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7. HANDLING OF MISSING VALUES
7.1. Missing Values For Safety, Immune Responses, Pharmacodynamics, 
Immunogenicity,
All the safety, immune responses, pharmacokinetic, pharmacodynamics, immunogenicity
analyses and summaries will be based on data as observed and no explicit imputation will be 
applied.
7.2. Immune Responses Lower Limit Of Quantitation
Titers below the assay detection limit will be assigned a value of one-half that limit  
7.3. Pharmacokinetic Concentrations And Parameters
Drug concentrations below the limit of quantification
In all data presentations (except listings), drug concentrations below the limit of 
quantification (BLQ) will be set to zero. In the listings BLQ values will be reported as 
“<LLQ”, where LLQ will be replaced with the value for the lower limit of quantification.
Deviations, missing concentrations and anomalous values
Subjects who experience events that may affect their PK (eg, incomplete dosing) may be 
excluded from the PK analysis.
In summary tables and plots of mean profiles of PK, statistics will be calculated having set 
concentrations to missing if 1 of the following cases is true:
1. A concentration has been collected as ND (ie, not done) or NS (ie, no sample);
2. A deviation in sampling time is of sufficient concern or a concentration has been 
flagged anomalous by the PK analyst.
Note that summary statistics will not be presented at a particular time point if more than 
50% of the data are missing.
An anomalous concentration value is one that, after verification of bioanalytical validity, is 
grossly inconsistent with other concentration data from the same individual or from other
subjects. For example, a BLQ concentration that is between quantifiable values from the 
same dose is considered as anomalous. Anomalous concentration values may be excluded 
from PK analysis at the discretion of the PK analyst.
Pharmacokinetic parameters
Actual PK sampling times will be used in the derivation of PK parameters. In the event that 
the actual sampling time is not available, the nominal time may be used if there is no 
evidence that the actual sampling time deviates substantially from the nominal time.
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If a PK parameter cannot be derived from a subject’s concentration data, the parameter will 
be coded as NC (ie, not calculated). 
In summary tables, statistics will be calculated by setting NC values to missing; and statistics 
will not be presented for a particular treatment if more than 50% of the data are NC.  For 
statistical analyses (ie, analysis of variance, if applicable), PK parameters coded as NC will 
also be set to missing.
If an individual subject has a known biased estimate of a PK parameter (due, for example, to 
an unexpected event such as vomiting before all the drug is absorbed in the body), this will 
be footnoted in summary tables and will not be included in the calculation of summary 
statistics or statistical analyses.
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES
In general, all continuous endpoints will be summarized descriptively by dose level. If data 
are categorical then the standard contingency tables with counts and percent by dose level 
will be displayed.
8.1. Statistical Methodology 
Part 1, the dose escalation phase of this study, employs an mTPI design to estimate the MTD.  
The mTPI design employs a simple beta binomial model with prior a conjugated prior beta 
(0.5, 0.5).  Decision rules are based on calculating the unit probability mass (UPM) of 
3 intervals corresponding to underdosing, proper dosing, and overdosing in terms of dose 
limiting toxicity.  A proper dosing interval is centered at the target toxicity rate (pT) of 
27.5% with 5% uncertainty (0.225 < pT <0.325).  The under dosing interval is (0, 0.225), 
and the overdosing interval is (0.325, 1).  The 3 dosing intervals are associated with 
3 different dose escalation decisions.  The underdosing interval corresponds to a dose 
escalation, overdosing corresponds to a dose de-escalation, and proper dosing corresponds 
to staying at the same current dose.  Given an interval and a probability distribution, the 
UPM of that interval is defined as the probability of the interval divided by the length of the 
interval.  The mTPI design calculates the UPMs for the 3 dosing intervals, and the one with 
the largest UPM implies the corresponding dose finding decision.  That decision provides the 
dose level to be used for future patients.  For example, if the underdosing interval has the
largest UPM, decision E (to escalate) will be executed, and the next cohort of patients will be 
treated at the next higher dose level.  Under the mTPI design, a trial is terminated when 
either the lowest dose is above the MTD or a pre-specified maximum sample size is reached.  
Doses with an incidence of DLT >33% (eg, 4 out of 10) will not be declared as MTD even 
though it is allowed by the mTPI method.
8.2. Statistical Analyses 
There are 2 parts in the study. Generally analysis output is to be generated for Part 1 and 
Part 2 separately, unless where it specifies a combined analysis is to be conducted. 


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8.2.1. Subject Disposition
Subject disposition will be summarized by dose level and will include the number of patients
enrolled, treated, treated and completed the study, treated but did not complete the study and 
reason for early discontinuation from the study. Subject disposition summary will be 
generated using the full analysis set. 
8.2.2. Subject Demographics and Baseline Characteristics
Demographic, ECOG performance status (Karnofsky Performance Score, as detailed in 
Appendix 2 of the study protocol), childbearing potential and other baseline characteristics
 and number 
of prior therapies) will be summarized by dose level using the full analysis set. 
8.2.3. Study Treatment Exposure and Dose Intensity
Duration of treatment (number of days and number of cycles) will be summarized by dose 
level. Relative Dose Intensity (ratio of actually administered dose to scheduled/planned dose 
per unit time) will be summarized for each dose level and by cycle. Relative Dose will be 
summarized for each dose level across all cycles. Detailed algorithms for these calculations 
are provided in the appendix. (Appendix 1.1).
The number of patients with missed dose may be summarized by dose level.  
Patient level study treatment administration data will be listed in chronological order by dose 
level. 
These analyses will be performed with the safety analysis set. 
8.2.4. Safety Analysis
Safety analysis will be based on the safety analysis set. 
8.2.4.1. Analysis of Primary Safety Endpoint
In Part 1 of the study, dose limiting toxicity (DLT) is a primary endpoint. Adverse events 
constituting DLTs are detailed in the study protocol. Adverse events constituting DLTs will 
be listed by dose level. A binary variable will be created at the patient level to indicate 
whether or not a patient has experienced any of the adverse events that are considered DLT.
If required, a summary table will be created by dose to present number and percentage of 
patients experiencing DLT. 
Treatment-emergent adverse events (TEAE) are defined as those events that occur after the 
first dosing or any pre-existing adverse event that worsened after the first dosing. The lag 
time required for defining TEAE will be based on Pfizer Standard. TEAE will be listed by 
dose level where system organ class and preferred term as well as other collected variables 
about the AE will be displayed. If necessary, a summary table for TEAE by system organ 
class and preferred term for each dose level will be generated. Similarly serious adverse 
events (SAE), and treatment related SAEs will be listed. Summary tables may be generated 
if necessary. 
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In Part 2, TEAE, treatment related TEAE, SAE, and treatment related SAEs will be listed 
and summarized.  TEAE will also be summarized by CTC AE (version 4.03) grade and by 
system organ class and preferred term.  
8.2.4.2. Analysis of Secondary Safety Endpoint
These safety endpoints will be analyzed according to the Pfizer Data Standard.  
Laboratory Tests Abnormalities
Laboratory tests will be listed by dose level and cycle and day. Upon reviewing the lab data 
listing, if study team deems necessary, summary tables and tables presenting the change and 
percent change from baseline may be generated by dose level and cycle and day. Shift tables
may be provided to examine the distribution of laboratory toxicities. Shift tables will be 
created for each laboratory test for baseline relative to each post-baseline measurement by 
maximum CTCAE grade, cycle, and dose. The most recent measurement prior to dosing is 
considered as baseline. 
On-target activity of PF-06840003 by measurement of kynurenine, tryptophan and kyn/trp 
(ratio) levels in peripheral blood will be listed by dose and cycle and day.
Vitals signs
Vital signs, (ie, body temperature and blood pressure), will be listed by dose level and cycle
and day. Upon reviewing the vital signs data listing, if study team deems necessary, 
summary tables and tables presenting change and percent change from baseline may be 
generated by dose level and cycle and day. The most recent measurement prior to dosing is 
considered as baseline.
ECG
The analysis of ECG results will be based on patients in the safety analysis set with baseline 
and on-treatment ECG data.  Baseline is defined as the latest assessment prior to receipt of 
the first dose (ie, Cycle 1 Day 1), ie, the average of the latest pre-dose triplicate ECG on 
Cycle 1 Day 1. If the Cycle 1 Day 1 timepoint is not available, the screening assessment will 
be used as the baseline.
ECG measurements (an average of the triplicate measurements) will be used for the 
statistical analysis and all data presentations.  Any data obtained from ECGs repeated for 
safety reasons after the nominal time-points will not be averaged along with the preceding 
triplicates.  Interval measurements from repeated ECGs will be included in the outlier 
analysis (categorical analysis) as individual values obtained at unscheduled time points.
QT intervals will be corrected for heart rate (QTc) using standard correction factors (ie, 
Fridericia’s).  Data will be summarized and listed for QT, HR, response rate (RR), PR, QRS, 
QTcF, and dose.  Individual QT (all evaluated corrections) intervals will be listed by time 
and dose.  The most appropriate correction factor will be selected and used for the following 
analyses of central tendency and outliers and used for the study conclusions.  Descriptive 


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statistics (n, mean, median, standard deviation, minimum, and maximum) will be used to 
summarize the absolute corrected QT interval and changes from baseline in corrected QT 
after treatment by dose and time point.  For each patient and by treatment, the maximum 
change from baseline will be calculated as well as the maximum post-baseline interval 
across time-points.  Categorical analysis will be conducted for the maximum change from 
baseline in corrected QT and the maximum post-baseline QT interval. 
Shift tables will be provided for baseline vs worst on treatment corrected QT using maximum 
CTCAE Grade.  Patients experiencing clinically-relevant morphological ECG changes will 
be summarized (including frequency and percentage).
The effect of drug concentrations on corrected QT change from baseline will be explored 
graphically.  Additional concentration-corrected QT analyses may be performed.  Data may 
be pooled with other study results and/or explored further with PK/PD models.
Physical Examination
Physical examination results will be listed by dose level and cycle. Upon reviewing the 
subject level data listing, if study team deems necessary, summary table may be generated by 
dose level and cycle. 
ECHO/MUGA
LVEF (left ventricle ejection fraction) results from the cardiac function evaluation by ECHO 
or MUGA will be listed by dose level and cycle in a subject data listing. Upon reviewing the 
subject data listing, if study team deems necessary, summary table of LVEF over time and/or 
change from baseline in LVEF may be generated by dose level and cycle.
8.2.5. Efficacy Analysis
Efficacy will be investigated in both Part 1 and Part 2 of the study. 
8.2.5.1. Primary Efficacy Analysis
Tumor assessments including MRI will be performed every 8 weeks (with an allowable 
window per study protocol) after the first dose. Disease control rate (DCR), defined as the 
proportion of patients achieving CR, PR, or SD as assessed by Macdonald criteria, will be 
summarized and listed by dose level and week. A cycle is 4 weeks long. Number of weeks 
will be derived based on cycle numbers. This will be performed for Part 1 and Part 2 
separately. If deemed necessary and data permits, a combined analysis may be performed 
where Part 2 and the same dose level in Part 1 as that in Part 2 will be combined. These 
analyses will be based on investigator provided overall disease assessment.
As data accumulates, a Bayesian approach with a non-informative Jeffery’s prior beta 
(0.5, 0.5) will be used to calculate the posterior probability of observing certain DCR (eg,
40%, 50%, 60% etc.). The purpose of it is to monitor data on an ongoing basis and to 
provide more analytical data for the study team. No official analysis output needs to be 
generated for this. This is only applicable to Part 2. 


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8.2.5.2. Secondary Efficacy Analysis
ORR with Macdonald Criteria
Objective tumor response (ORR), defined as the proportion of patients achieving CR or PR 
as assessed by Macdonald criteria, will be summarized and listed by dose level week. This 
will be performed for Part 1 and Part 2 separately. If deemed necessary and data permits, a 
combined analysis may be performed where Part 2 and the same dose level in Part 1 as that 
in Part 2 will be combined.
As data accumulates, a Bayesian approach with a non-informative Jeffery’s prior beta 
(0.5, 0.5) will be used to calculate the posterior probability of observing certain ORR (eg,
5%, 10%, 15%, or 20% etc.). The purpose of it is to monitor data on an ongoing basis and to 
provide more analytical data for the study team. No official analysis output needs to be 
generated for this. This is only applicable to Part 2. 
For example, if 2 responders were observed in the first 10 patients enrolled, the posterior 
probability of observing 20% ORR is about 53.3%; if 2 responders were observed in the first 
12 patients enrolled, the posterior probability of observing 20% ORR is about 41.5%; if only 
1 responder was observed in the first 15 patients enrolled, the posterior probability of 
observing 20% ORR is about 8.7%. If a posterior probability is less than 15% for both of the 
2 efficacy endpoints, the study team may choose to stop the expansion phase for futility.  The 
safety data will also be reviewed in that decision-making process.
DCR with RANO Criteria
Overall DCR based on Response Assessment for Neuro-Oncology (RANO) criteria will be 
summarized by week. The analysis will be based on investigator provided overall response 
in the Response Assessment in Neuro-Oncology. This will be performed for Part 1 and 
Part 2 separately. If deemed necessary and data permits, a combined analysis may be 
performed where Part 2 and the same dose level in Part 1 as that in Part 2 will be combined.
 
 On the basis of RANO, 
the key component of iRANO is specific additional guidance for the determination of PD 
among neuro-oncology patients undergoing immunotherapy.  Specifically, iRANO advocates 
the confirmation of radiographic progression in appropriate patients defined by clinical status 
and time from initiation of immunotherapy. Other details related to the PD confirmation will 
be documented in the Programming Plan. 
PFS
Progress-free survival (PFS) is defined as the time from date of enrollment to first PD or 
death due to any cause in the absence of documented PD. PFS will be analyzed in an 
exploratory manner. Kaplan-Meier analysis may be performed. If it is performed, the median 
PFS and 2-sided 95% confidence interval will be reported by dose level. Kaplan-Meier plot 
may also be generated by dose level. 
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This will be performed for Part 1 and Part 2 separately. If deemed necessary and data 
permits, a combined analysis may be performed where Part 2 and the same dose level in Part 
1 as that in Part 2 will be combined.
Tumor measurement and assessment data
Tumor measurement data (target lesions, new measurable lesions, non-target lesions, and 
new non-measurable lesions), as collected, will be listed at patient level by dose and cycle. 
Tumor assessment data for both Macdonald criteria and RANO criteria will be listed at 
patient level by dose and cycle. 
Summary table for this data may be generated, if deemed necessary. 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
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8.2.7. Analysis of Biomarker Endpoints
For biomarker samples, summary statistics (eg, the mean and standard deviation, median, 
and minimum/maximum levels of continuous, and frequencies and percentages of categorical 
biomarker measures) will be determined at baseline and post-treatment.  For each pair of 
specimens, the percent change from baseline of these same parameters will also be 
calculated.
Data from biomarker assays may be analyzed using graphical methods and descriptive 
statistics such as linear regression, t-test, and analysis of variance (ANOVA).  The statistical 
approach will examine correlations of biomarker results with pharmacokinetic parameters 
and measures of anti-tumor efficacy.
8.2.8. Population Pharmacokinetic Analysis or Pharmacokinetic/Pharmacodynamic 
(PK/PD) Modeling
Pharmacokinetic and PD data from this study may be analyzed using modeling approaches 
and may also be pooled with data from other studies to investigate any association between 
PF-06840002 exposure and biomarkers or significant safety endpoints.  The results of these 
analyses, if performed, may be reported separately.
 
 
 
 
 
 
 
 
 
 
 
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Appendix 1. Appendices
Appendix 1.1. Summarizing Relative Dose (RD) and Relative Dose Intensity (RDI)
Conventions:

The Intended Dose Intensity is the same for all cycles: the daily dose is fixed at the 
start of treatment rather than start of a cycle and the intended treatment duration is the 
same for the entire dosing period; 

Actual Dose Intensity is calculated based on actual cycle length in all but last cycle 
where it is fixed at the intended length (eg, 3 weeks for a 2/1 dosing schedule).
Table 1.
Treatment / 
Summary 
Calculation of RD
Example
Overall 
                                                           
100
*
Dose
Total
Intended
Dose
Total
Actual
RD 
%
Actual Total Dose = sum of Total daily dose 
across all cycles (as recorded on CRF)
Intended Total Dose =  (Planned Daily 
Dose) * (Actual Dose Duration in days)
Actual Dose Duration (days) = (date of last 
dose – date of first dose +1)

IDO is to be dosed at 125 mg 
QD.  

1st IDO: January 1, last IDO: 
December 31 (same year)

Actual dosing: 125 mg for 250 
days and 100 mg for 115 days 
Actual Total Dose = 125*250 + 
100*115=42,750 mg
Actual Dose Duration (days) = 365
Intended Total Dose = 125*365=45,625
mg
RD=(42,750 / 45,625)*100%=93.7%


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Table 2.
Treatment / 
Summary 
Type (#)
Calculation of RDI
Example
By Cycle 
                                
100
*
Intensity
Dose
Intended
Intensity
Dose
Actual
RDI 
%
Actual Dose Intensity (per week) = (Actual Total 
Dose per cycle) / (Actual number of weeks in cycle)
Actual Number of Weeks in Cycle = (Start date of 
next cycle – Start date of current cycle) / 7.  
Intended Dose Intensity (per week) = (Intended 
Total Dose per cycle) / (Intended number of weeks 
in cycle)

IDO is to be dosed at 
125 mg QD for a cycle 
of 28 days (4 weeks)
Intended Dose Intensity = 
(125*7*4) / 4 = 875 mg/wk
Cycle 1:
Actual Dose Intensity = 
(125*7*4) / 4 = 875 mg/wk
RDI = (875/875) * 100% = 100%
Cycle 2 (only took 3-week worth 
of dose overall a 4-week 
duration):
Actual Dose Intensity = 
(125*7*3) / 4 = 656.25 mg/wk
RDI = (656.25/875) * 100% = 
75%