Clinical trial NCT02732938
Conditions: Metastatic Pancreatic Ductal Adenocarcinoma
Keywords: CCR2i, nab-paclitaxel, Abraxane, gemcitabine, pancreas
Sponsor: Pfizer
Start date: 2016-05-04; Completion date: 2017-10-10
Enrollment: 22 participants; Allocation: ; Intervention model: 

Brief summary:
The purpose of this Phase 1b/2 study is to evaluate the safety and tolerability of PF-04136309 in combination with nab-paclitaxel and gemcitabine, characterize the dose-limiting toxicities (DLTs) and overall safety profile of escalated doses of PF-04136309 and the associated schedule, determine the maximum tolerated dose (MTD), and to assess the enhancement of efficacy of PF-04136309 in combination with nab-paclitaxel and gemcitabine versus nab-paclitaxel + gemcitabine + placebo in terms of Progression Free Survival.

Detailed description:
The study has 2 parts:

Phase 1b (dose-finding cohorts) will be open label as patients will receive ascending doses of PF-04136309 in combination with nab-paclitaxel + gemcitabine. The observation period for dose-limiting toxicities (DLTs) will be from Day 1 to Day 28. Pharmacokinetic (PK) and pharmacodynamic (PD) properties of PF-04136309 will also be assessed. The criteria for dose escalation will be based on a modified toxicity probability interval (mTPI) method. After evaluating the safety and other results (eg, PK) from patients enrolled in the dose escalation cohorts, a dose level will be selected to be further evaluated as the Recommended Phase 2 Dose (RP2D). A minimum of 6 patients, up to 12 patients, will be treated at this dose level to establish it as the RP2D. To further evaluate safety and pharmacodynamics, the number of patients enrolled during this part of the study (Phase 1b) may be N up to 20. The study will stop if all PF-04136309 doses explored appear to be overly toxic.

Phase 2 randomized double blinded placebo control. Approximately 92 patients will be randomized 1:1 to receive the RP2D of PF-04136309 in combination with nab-paclitaxel + gemcitabine (ARM A; n=46) versus nab-paclitaxel + gemcitabine + placebo (ARM B; n=46). The primary objective will be the enhancement of efficacy in terms of PFS.

Patients will be treated as long as they are clinically benefiting from investigational product without unacceptable toxicity, objective disease progression, or withdrawal of consent.

Arms: arm 1: PF-04136309 oral dosing

Nab-paclitaxel IV dosing Gemcitabine IV dosing
Interventions: intervention 1: PF-04136309 intervention 2: Nab-paclitaxel intervention 3: Gemcitabine
Intervention descriptions: intervention 1: PF-04136309 oral dosing intervention 2: Nab-paclitaxel IV dosing intervention 3: Gemcitabine IV dosing

Protocol documents:
Prot_000.pdf: 
PF-04136309
A9421018
Final Protocol Amendment 2, 30 September 2016   
Page 1
PHASE 1B/2 STUDY OF PF-04136309 IN COMBINATION WITH GEMCITABINE
AND NAB-PACLITAXEL IN PATIENTS WITH PREVIOUSLY UNTREATED 
METASTATIC PANCREATIC DUCTAL ADENOCARCINOMA
Compound:
PF-04136309
Compound Name:
Not Applicable (NA)
United States (US) Investigational New 
Drug (IND) Number:
128040
European Clinical Trials Database 
(EudraCT) Number:
2015-003767-11 
Protocol Number:
A9421018
Phase:
1b/2
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Document History
Document
Version Date
Summary of Changes and Rationale
Original protocol
09 November 2015
Not applicable (N/A)
Amendment 1
25 November 2015

Added the EORTC QLQ-CIPN20 
questionnaire to be collected on 
Cycle 1 Day 1 (baseline), Day 1 for all 
subsequent cycles, End of Treatment 
(EOT) and at the Follow-up visits.  

Added Section 7.1.5 European 
Organization for Research and 
Treatment of Cancer Quality of Life 
Questionnaire-Chemotherapy-Induced 
Peripheral Neuropathy 20 (EORTC 
QLQ-CIPN20).

Added Secondary Objective to 
evaluate to evaluate the improvement 
of peripheral neurotoxicity induced by 
nab-paclitaxel by the addition of 
PF-04136309 to the combination 
therapy of nab-paclitaxel plus
gemcitabine.

Added Secondary Endpoint to 
evaluate Peripheral neurological 
adverse events as characterized by 
frequency, severity (as graded by NCI 
CTCAE v.4.03 and by self-assessment 
according to the EORTC QLQ-
CIPN20 questionnaire), and timing.

Clarified Study Overview for Phase 1b 
– Section 3.1.

Clarified dose finding and stopping 
rules – Study Design Section, and 
Section 3.2 Study Design and 
Stopping Rules (Phase 1b).

Added Section 3.4 – Late Onset 
Toxicity and Toxicities.
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Version Date
Summary of Changes and Rationale

Corrected typo in Section 9.1.3 –
Analysis Set numbering [4. Per 
protocol analysis set…]

Corrected Section 9.2.2 – Statistical 
Methods for Dose Escalation/De-
Escalation (Phase 1b) [Target size for 
each cohort will be n=2 to 
4 patients….]

Corrected Section 3.3 – Dose Limiting 
Toxicities. Subjects are planned to be 
enrolled in cohorts of 2 to 4 subjects.

Section 9.6.3 renamed as 
section 9.6.2.1.

Section 9.6.2.2 added: Analysis of 
Peripheral Neurological Adverse 
Events and of the EORTC QLQ-
CIPN20 Questionnaire.

Added a footnote for clarification 
purposes for TABLE 11.

Section 5.1.2 corrected randomization 
ratio to 1:1.
Amendment 2
30 September 2016

Incorporated Protocol Administrative 
Clarification Letters (PACL):

PACL  #1 12Jan2016:  

Updated Table 1 Footnote 27 
(formally footnote 25), Table 2 
deleted footnote 7, and 
Section 7.5 with an additional 
banked blood biospecimen 
added at C3D1.  Collection 
should be at Screening and 
pre-dose C3D1.
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Version Date
Summary of Changes and Rationale

PACL #2 27Jan2016:  

Clarification in Table 1 and 
Section 7.1.4 - Weight is 
collected when the Physical 
Examination is performed: 
Screening, each Cycle on
Days 1, 8, and 15, and at the
EOT and Follow-up Visits.  

Background and Rationale 
(Protocol Summary) and 
Section 1.2.1 Study Rationale -
This clarification provides 
background and rationale for 
how CCR2 in primary sensory 
neurons contributes to 
paclitaxel-induced peripheral 
neuropathy.

Section 7.1.3.1 Hematology 
and Blood Chemistry and 
Table 6 (formally Table 9) -
This clarification is being 
provided to remove the 
reference to Day 0 collection 
in footnote c, as well as delete 
the urine drug collection at 
screening.  Both items were 
errors and should be removed 
from the protocol.

This clarification was provided 
to remove incorrect footnote 
text for Banked Biospecimens
in Table 1 and replace with the 
correct consistent text for 
Banked Biospecimens. 
Collection of the banked
biospecimens at Screening and 
C3D1 pre-dose.
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Version Date
Summary of Changes and Rationale

The following clarification was 
made to remove any reference 
to the term “legally acceptable 
representative” in the protocol
Section 8.13 Eliciting Adverse 
Event Information, and Section 
12.3 Patient Information and 
Consent.  

Correction in Section 9.3 
Sample Size Determination -
This clarification is provided 
to correct a typographical 
error. New Text: Phase 2: 
Ninety-two (92).

PACL #3 11Feb2016:

Clarification to remove the 
"(X)” mark for triplicate 
12-lead ECG activity 
(assessment) at the Follow-up 
Visit.

Clarification in Schedule of 
Activities Table 1, Section 
1.2.2, and Section 7.1.5: 
EORTC QLQ-C30 in
combination with QLQ-
CIPN20: Questionnaires will 
be completed prior to any 
study or medical procedure on 
Cycle 1 Day 1 (-2 day 
window), Day 1 of all 
subsequent cycles, and at the 
End of Treatment visit.  One 
final questionnaire will be 
completed 4 weeks after 
discontinuation of IP during 
the Follow-up Visit.

PACL #4 01Mar2016:

This administrative 
clarification is provided to 
remove the “3” under 
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Version Date
Summary of Changes and Rationale
subsequent cycles. Schedule of 
Activities (SOA) Table 2 has 
been corrected to properly 
reflect the RNA Profiling 
(whole blood) is collected on 
pre-dose Day 1, 2, 8, and 15 of 
Cycle 1, Day 1 (pre-dose) of 
Cycles 2, 4, 7 and at End of 
Treatment.  The collection 
noted for Cycle 3 has been 
removed and the table now 
aligns with Table 2 –
Footnote #4.

PACL #5 20May2016:

Remove the secreted protein 
acidic and rich in cysteine 
(SPARC) blood sample 
collection from the protocol. 
Rationale: no longer required.

This administrative change and 
rationale is provided to clear 
up the inconsistency between 
the guidance in Table 4.
Section 3.7.1: PF-04136309 
does not have to be interrupted 
in case of hematologic toxicity 
or peripheral neurotoxicity 
with the exception for grade 4 
hematological toxicity (see 
Table 4: Recommended Dose 
Modifications for Neutropenia 
and/or Thrombocytopenia).  
PF-04136309 should be 
interrupted in case of > 
Grade 2 non-hematologic or 
non-peripheral neurological 
toxicity, potentially due to 
PF-04136309.
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Version Date
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
Remove all fasting requirement 
prior to PF-04136309 oral 
administration. Section 5.4.1.
Rationale: There is no food effect 
on PF-04136309 based on the food 
effect study (A9421019).

Provision added for allowable 
treatment window for 
PF-04136309 as a result of the 
food effect study (A9421019) PK 
data.  See section 5.4.1 and SOA 
Table 1 – Footnote 16.

Provision added for the Cycle 1 
Day 1 12-hour post-dose
collection to be “optional’ for the 
target engagement ex-vivo 
inhibition of CCL2-induced, ERK 
phosphorylation by PF-04136309. 
See Table 2, Footnote 2.
Rationale: Not a mandatory 
sample collection and 12-hour post 
dose is an extremely difficult time 
point for the patients on Day 1 of 
chemo.

Removed duplicate Tables, 6, 7, 
and 8 from Section 5.4.6.  Please 
refer to the information in 
Tables 3, 4, and 5. Rationale: 
Clarification.

Updated Reference List – added 
9 new references (#20-28).

Statistical Updates and 
Clarifications provided in the 
following sections for Phase 2:

Section 5.1.2 - Phase 2 
Randomized.
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Version Date
Summary of Changes and Rationale

Table 6 – Change: added Total 
bile acids, Acetaminophen drug 
and/or protein adduct levels added 
for repeat potential Hy’s law 
cases.  Rationale: Additional tests 
were added in order to accurately 
conduct Hy’s Law assessments.

Section 9.1.3 – Analysis Sets.

Section 9.4.2 – Analysis of 
Objective Overall response (ORR: 
CR or PR).

Section 9.4.3 – Analysis of 
Duration of Objective Response 
(DR).

Section 9.5.1 – Analysis of 
PF-04136309 Pharmacokinetics.

Section 9.6.2.2 – Analyses of 
Peripheral Neurological Adverse 
Events, EORTC QLQ-C30 and 
QLQ – CIPN20 Questionnaires.

All other changes are minor in 
nature added to this amendment to 
provide clarity and additional 
information.
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and institutional review boards (IRBs)/ethics committees 
(ECs).  
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ABBREVIATIONS
This is a list of abbreviations that may be used in the protocol.  
Abbreviation
Term
Ab
Antibody
AE
adverse event
AIDS
acquired immunodeficiency syndrome 
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ANCOVA
analysis of covariance
ANOVA
analysis of variance
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
AUC
area under the curve
BID
twice daily
BMA
bone marrow aspirate
BP
blood pressure
BSS
Baseline signs and symptoms
BUN
blood urea nitrogen
C
Cycle
C
Concentration
CA19.9
cancer antigen 19.9
CCL
chemokine ligand
CCL2
chemokine ligand-2 (JE-1, MCP-1)
CCR
chemokine receptor
CCR1
chemokine  (C-C motif) receptor 1
CCR2
chemokine  (C-C motif) receptor 2
CCR5
chemokine  (C-C motif) receptor 5
CDS
core data sheet
CHF
congestive heart failure
CI
confidence interval
CIPN
Chemotherapy induced peripheral neuropathy
CL
Clearance
Cmax
maximum observed concentration
CNB
core needle biopsy
CNS
central nervous system
CR
complete response
CRF
case report form
CRM
Continuous Reassessment Method
CSA
clinical study agreement
CSR
clinical study report
CT
computed tomography
CTA
clinical trial application
CTCAE
Common Terminology Criteria for Adverse Events
CV
coefficient of variation
CYP
cytochrome P450
D
Day
DAI
dosage and administration instructions
DEHP
di-(2-ethylhexyl)phthalate
DICOM
Digital Imaging and Communications in Medicine
DLT
dose-limiting toxicity
DMC
data monitoring committee
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Abbreviation
Term
DNA
deoxyribonucleic acid
DR
Duration of Response
EC
ethics committee
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EDP
exposure during pregnancy
EDTA
edetic acid (ethylenediaminetetraacetic acid)
eg
for example
EORTC QLQ-CIPN20
European Organization for Research and Treatment of Cancer Quality of 
Life Questionnaire-Chemotherapy-Induced Peripheral Neuropathy 20
EORTC QLQ-C30
European Organization for Research and Treatment of Cancer Quality of 
Life Questionnaire is a questionnaire developed to assess the quality of 
life of cancer patients (30 questions)
EOT
End of Treatment
ERK
extracellular signal regulated kinase
etc
‘and other things’ or ‘and so forth’
EudraCT
European Clinical Trials Database
5-FU
Fluorouracil
FDA
Food and Drug Administration (United States)
FDAAA
Food and Drug Administration Amendments Act (United States)
FFPE
formalin-fixed  paraffin-embedded 
FNA
fine-needle aspirate
FOLFIRINOX
chemotherapy regimen made up of the following four drugs: fluorouracil 
[5-FU], leucovorin, irinotecan, oxaliplatin
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GCSF
granulocyte-colony stimulating factor
HBV
hepatitis B virus
hCG
human chorionic gonadotropin
HCT
Hematocrit
HCV
hepatitis C virus
HDPE
high-density polyethylene
Hgb
Hemoglobin
HIV
human immunodeficiency virus
HR
heart rate
IB
investigator’s brochure
ICH
International Conference on Harmonisation
ID
Identification
ie
that is
IgA
immunoglobins A
IgG
immunoglobins G
IgM
immunoglobins M
IL
Interleukin
IM
inflammatory monocytes
IND
investigational new drug application
INR
international normalized ratio
IRB
institutional review board
IRC
internal review board
IUD
intrauterine device
IV
Intravenous
K2EDTA
dipotassium ethylene diamine tetraacetic acid
LFT
liver function test
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Abbreviation
Term
LPD
local product document
LSLV
last subject last visit
LVEF
left ventricular ejection fraction
mTPI
modified toxicity probability interval
MD
multiple dose
MDSC
myeloid-derived suppressor cells
MedDRA
Medical Dictionary for Regulatory Activities
MFD
maximum feasible dose
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
mTPI
modified toxicity probability interval method
N/A
not applicable
NCI 
National Cancer Institute 
OA
Osteoarthritis
OBD
optimal biological dose
ORR
objective response rate
OS
overall survival
pT
target probability
PCD
primary completion date
PD
progressive disease
PDAC
pancreatic ductal adenocarcinoma
PET
positron emission tomography
PFS
progression-free survival
PK
Pharmacokinetics
PK/PD
pharmacokinetics/pharmacodynamics
PLT
Platelet
PMAP
Population Modeling Analysis Plan
PMAR
Population Modeling and Analysis Report
PO
Oral
POM
proof of mechanism
PR
partial response
PS
performance status
PT
prothrombin time
PTT
partial thromboplastin time
QD
every day
QRS
Name for the combination of three of the graphical deflections seen on a 
typical electrocardiogram (EKG or ECG).
QT
time between the start of the Q wave and the end of the T wave
QTc
QT interval corrected
QTcF
QT interval corrected by Fridericia’s corrections
R
Ratio
RBC
red blood cell
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
ribonucleic acid
RP2D
recommended Phase 2 dose
RR
response rate
SAE
serious adverse event
SAP
statistical analysis plan
SD
single dose
SIB
suicidal ideation and behavior
SPC
Summary of Product Characteristics
SRSD
single reference safety document
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Abbreviation
Term
T
time
T1/2
terminal elimination half-life
T(cell)
thymic origin lymphocytes that have a central role in cell mediated 
immunity
TAM
tumor associated macrophages
TBIL
total bilirubin
TBR
tumor background ratio
TCR
T cell receptor
TE
target engagement
TGFβ
tumor growth factor beta
TILs
tumor infiltrating lymphocytes
Tmax
time to first  occurrence of Cmax
TTP
time to progression
ULN
upper limit of normal
UPM
unit probability mass
US
United States
USPI
United States Package Insert
UVB
ultraviolet B light
V
volume of distribution
vs
versus
Vss
steady state volume of distribution
WBC
white blood cell count
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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................18
APPENDICES .........................................................................................................................18
1. INTRODUCTION ...............................................................................................................38
1.1. Mechanism of Action/Indication.............................................................................38
1.2. Background and Rationale ......................................................................................38
1.2.1. Study Rationale...........................................................................................38
1.2.2. Dose Rationale............................................................................................39
1.2.3. Biomarker Rationale...................................................................................40
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................41
2.1. Objectives................................................................................................................41
2.1.1. Phase 1b Dose Finding Objectives .............................................................41
2.1.2. Phase 2 Randomized Double Blinded Placebo Controlled Study ..............42
2.2. Endpoints.................................................................................................................44
2.2.1. Phase 1b Dose Finding Endpoints..............................................................44
2.2.2. Phase 2 Randomized Double Blinded Placebo Controlled Study 
Endpoints .........................................................................................................45
3. STUDY DESIGN.................................................................................................................46
3.1. Study Overview.......................................................................................................46
3.2. Dose Finding and Stopping Rules (Phase 1b).........................................................47
3.3. Dose Limiting Toxicity (DLT)................................................................................48
3.4. Late Onset Toxicity and Toxicities .........................................................................49
3.5. Maximum Tolerated Dose/Recommended Phase 2 Dose.......................................49
3.6. Recommended Dose Modifications ........................................................................49
3.7. Dose Interruptions/Delays/Reductions....................................................................50
3.7.1. PF-04136309-Induced Dose Interruptions and Delays...............................50
3.7.2. Chemotherapy-Induced Dose Interruptions and Delays.............................50
3.7.3. Dose Reductions .........................................................................................51
4. PATIENT SELECTION......................................................................................................55
4.1. Inclusion Criteria.....................................................................................................56
4.2. Exclusion Criteria....................................................................................................57
4.3. Lifestyle Guidelines ................................................................................................59
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4.3.1. Contraception..............................................................................................59
4.4. Sponsor’s Qualified Medical Personnel..................................................................60
5. STUDY TREATMENTS.....................................................................................................61
5.1. Allocation to Treatment ..........................................................................................61
5.1.1. Phase 1b Dose-finding................................................................................61
5.1.2. Phase 2 Randomized...................................................................................61
5.2. Patient Compliance .................................................................................................62
5.2.1. PF-04136309 and Placebo..........................................................................62
5.2.2. Nab-paclitaxel and Gemcitabine.................................................................62
5.3. Investigational Product Supplies.............................................................................62
5.3.1. Dosage Form(s) and Packaging..................................................................63
5.3.2. Preparation and Dispensing........................................................................63
5.3.2.1. PF-04136309 and Placebo.........................................................63
5.3.2.2. Nab-paclitaxel ...........................................................................63
5.3.2.3. Gemcitabine ..............................................................................64
5.4. Administration.........................................................................................................64
5.4.1. PF-04136309...............................................................................................64
5.4.2. Nab-paclitaxel.............................................................................................65
5.4.3. Gemcitabine................................................................................................65
5.4.4. Recommended Dose Modifications............................................................66
5.4.5. Dosing Interruptions/Delays/Reductions....................................................66
5.4.5.1. PF-04136309-Induced Dose Interruptions and Delays .............66
5.4.5.2. Chemotherapy-Induced Dose Interruptions and Delays ...........66
5.4.6. Dose Reductions .........................................................................................68
5.5. Investigational Product Storage ..............................................................................69
5.6. Investigational Product Accountability...................................................................70
5.7. Destruction of Investigational Product Supplies.....................................................70
5.8. Concomitant Treatment(s).......................................................................................70
5.8.1. Other Anti-tumor/Anti-cancer or Experimental Drugs...............................71
5.8.2. Supportive Care ..........................................................................................71
5.8.3. Hematopoietic Growth Factors...................................................................71
5.8.4. Anti-Diarrheal, Anti Emetic Therapy.........................................................71
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5.8.5. Anti-inflammatory Therapy........................................................................71
5.8.6. Corticosteroids............................................................................................71
5.8.7. Surgery........................................................................................................72
6. STUDY PROCEDURES .....................................................................................................72
6.1. Screening.................................................................................................................72
6.2. Study Period. ...........................................................................................................72
6.3. End of Treatment.....................................................................................................72
6.4. Follow-up Visit .......................................................................................................73
6.5. Patient Withdrawal..................................................................................................73
6.6. Survival Follow-up..................................................................................................74
7. ASSESSMENTS..................................................................................................................74
7.1. Safety Assessment...................................................................................................74
7.1.1. Pregnancy Testing ......................................................................................75
7.1.2. Adverse Events...........................................................................................75
7.1.3. Laboratory Safety Assessment ...................................................................75
7.1.3.1. Hematology and Blood Chemistry............................................75
7.1.4. Vital Signs and Physical Examination........................................................77
7.1.5. European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire C30 (QLQ-C30) in combination with the 
Chemotherapy-Induced Peripheral Neuropathy-20 Questionnaire 
(EORTC QLQ-CIPN20)..................................................................................77
7.1.6. Triplicate (12-Lead) Electrocardiogram.....................................................77
7.2. Pharmacokinetics Assessments...............................................................................78
7.2.1. Blood for PF-04136309 Pharmacokinetic Analysis ...................................78
7.3. Biomarker and Pharmacodynamic Assessments.....................................................80
7.4. Tumor Response Assessments ................................................................................81
7.5. Banked Biospecimens .............................................................................................82
7.5.1. Additional Research....................................................................................83
7.6. Assessment of Suicidal Ideation and Behavior.......................................................83
7.7. Triggered Requirements..........................................................................................83
8. ADVERSE EVENT REPORTING......................................................................................83
8.1. Adverse Events........................................................................................................83
8.2. Reporting Period .....................................................................................................84
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8.3. Definition of an Adverse Event...............................................................................84
8.4. Medication Errors....................................................................................................85
8.5. Abnormal Test Findings..........................................................................................85
8.6. Serious Adverse Events...........................................................................................86
8.6.1. Protocol-Specified Serious Adverse Events...............................................87
8.6.2. Potential Cases of Drug-Induced Liver Injury............................................87
8.7. Hospitalization ........................................................................................................88
8.8. Severity Assessment................................................................................................89
8.9. Causality Assessment..............................................................................................89
8.10. Exposure During Pregnancy..................................................................................90
8.11. Occupational Exposure .........................................................................................91
8.12. Withdrawal Due to Adverse Events (See Also the Section on Patient 
Withdrawal)...............................................................................................................91
8.13. Eliciting Adverse Event Information ....................................................................92
8.14. Reporting Requirements........................................................................................92
8.14.1. Serious Adverse Event Reporting Requirements .....................................92
8.14.2. Non-Serious Adverse Event Reporting Requirements .............................92
8.15. Medical Device Complaint Reporting Requirements ...........................................92
8.16. Sponsor’s Reporting Requirements to Regulatory Authorities.............................93
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................93
9.1. Data Analysis ..........................................................................................................93
9.1.1. Phase 1b......................................................................................................93
9.1.2. Phase 2........................................................................................................93
9.1.3. Analysis Sets...............................................................................................93
9.2. Statistical Methods and Properties ..........................................................................94
9.2.1. Phase 1b......................................................................................................94
9.2.2. Statistical Methods for Dose Escalation/De-Escalation (Phase 1b) ...........95
9.2.3. Statistical Method for Estimating the MTD and RP2D (Phase 1b)............97
9.2.4. Phase 2........................................................................................................97
9.3. Sample Size Determination.....................................................................................97
9.4. Efficacy Analysis ....................................................................................................98
9.4.1. Analysis of Progression-Free Survival (PFS).............................................98
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9.4.2. Analysis of Objective Overall Response (ORR: CR or PR).......................98
9.4.3. Analysis of Duration of Objective Response (DR). ...................................99
9.4.4. Analysis of Overall Survival (OS)..............................................................99
9.4.5. Statistical Methods for Interim Analysis ....................................................99
9.5. Analysis of Pharmacokinetics and Pharmacodynamics ........................................100
9.5.1. Analysis of PF-04136309 Pharmacokinetics............................................100
9.5.2. Analysis of Pharmacodynamics................................................................100
9.5.3. Population Pharmacokinetic Analysis or 
Pharmacokinetic/Pharmacodynamic (PK/PD) Modeling ..............................101
9.6. Safety Analysis......................................................................................................101
9.6.1. Analysis of the Primary Endpoint.............................................................102
9.6.2. Analysis of Secondary Safety Endpoints..................................................102
9.6.2.1. Electrocardiogram ...................................................................102
9.7. Analysis of Other Endpoints .................................................................................104
9.8. Data Safety Monitoring Committee ......................................................................104
9.9. Interim Analysis ....................................................................................................104
10. QUALITY CONTROL AND QUALITY ASSURANCE...............................................105
11. DATA HANDLING AND RECORD KEEPING ...........................................................105
11.1. Case Report Forms/Electronic Data Record .......................................................105
11.2. Record Retention.................................................................................................106
12. ETHICS............................................................................................................................106
12.1. Institutional Review Board /Ethics Committee...................................................106
12.2. Ethical Conduct of the Study ..............................................................................107
12.3. Patient Information and Consent.........................................................................107
12.4. Patient Recruitment.............................................................................................107
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP .........................................................................................................................108
13. DEFINITION OF END OF TRIAL.................................................................................108
13.1. End of Trial in a Member State...........................................................................108
13.2. End of Trial in All Participating Countries .........................................................108
14. SPONSOR DISCONTINUATION CRITERIA ..............................................................108
15. PUBLICATION OF STUDY RESULTS........................................................................108
15.1. Communication of Results by Pfizer ..................................................................108
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15.2. Publications by Investigators ..............................................................................109
16. REFERENCES ................................................................................................................111
LIST OF TABLES
Table 1.
Schedule of Activities for Phase 1b/2...................................................................29
Table 2.
Pharmacokinetic and Pharmacodynamic Sampling Schedule..............................36
Table 3.
Recommended Dose Modifications for Neutropenia and/or 
Thrombocytopenia................................................................................................52
Table 4.
Recommended Dose Modifications for Non Hematological Toxicities...............53
Table 5.
Available Doses....................................................................................................68
Table 6.
Laboratory Test.....................................................................................................76
Table 7.
Biomarker Collections and Analyses....................................................................80
Table 8.
Decision Rules......................................................................................................96
APPENDICES
Appendix 1. RECIST (Response Evaluation Criteria In Solid Tumors) version 
1.1 Guidelines.....................................................................................................115
Appendix 2. National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) ..................................................................................120
Appendix 3. ECOG Performance Status................................................................................121
Appendix 4. Sample Patient Study Drug Log........................................................................122
Appendix 5. Neurotoxicity Examination...............................................................................123
Appendix 6. EORTC Quality of Life Questionnaire C30......................................................124
Appendix 7. EORTC Quality of Life Questionnaire CIPN20 ...............................................126
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PROTOCOL SUMMARY
Background and Rationale:
Progress in basic and translational immunology has confirmed the importance of the immune 
system in cancer progression and in its treatment and has renewed interest in immune-based 
therapy for cancer, including pancreatic cancer. The main cellular components contributing 
to the immunosuppressive microenvironment include myeloid-derived suppressor cells 
(MDSC), tumor associated macrophages (TAM), mast cells, and T regulatory cells (Treg).1,2
Of these, MDSC comprise a heterogeneous population of the immature cells arising from the 
myeloid lineage, and they are considered to be the key in orchestrating the suppressive tumor 
microenvironment. Myeloid-derived suppressor cells are increased in many pathological 
conditions such as infections, inflammatory disease, sepsis, traumatic shock, and pancreatic
cancer.3,4  Myeloid-derived suppressor cells are observed with increased prevalence in the 
peripheral blood and in the tumor microenvironment of patients with solid tumors, including 
pancreatic cancer.5 Moreover, the number of circulating MDSC significantly correlates with 
clinical state and metastatic tumor burden6, and elimination of MDSC has been shown to 
improve antitumor activity.7,8,9,10 Because MDSC are proven to be one of the main 
mechanisms of tumor evasion from the immune system, the pharmacological modulation of 
MDSC and prevention of their appearance or infiltration to solid tumors represent potential 
novel and innovative therapeutic strategies in cancer.9,11,12,13,14,15,16
While the mechanisms responsible for MDSC expansion and trafficking to tumors is not 
entirely understood, it has been shown that MDSCs express Chemokine (C-C motif) receptor 
2 (CCR2) and that the Chemokine (C-C motif) ligand 2 (CCL2)/CCR2 signaling axis 
contributes to tumor progression through the CCR2 mediated MDSC recruitment and/or 
accumulation.17,18,19
PF-04136309 is an orally active CCR2 antagonist. It is selective for CCR2 against a panel of 
human chemokine receptors. When evaluated against human monocytes and human whole 
blood, PF-04136309 blocked CCR2 mediated signal transduction, chemotaxis and CCL2 
binding at similar concentrations. While initially developed for the treatment of acute and 
chronic pain and liver fibrosis, the focus of development is now on oncological indications.
Not only do MDSCs express the chemokine receptor CCR2, but in murine models of 
pancreatic cancer, it has been shown that MDSCs are upregulated in the tumor bearing host, 
promote tumor growth, suppress antitumor immunity and when depleted result in increased 
survival.5 Additionally it has been shown that CCR2 is upregulated on MDSC in both the 
circulation and tumor and that PF-04136309 can effectively block MDSC recruitment 
resulting in significantly reduced tumor growth.
Based on these findings it is hypothesized that CCR2 may be a promising therapeutic target 
in pancreatic cancer, a tumor associated with a marked up regulation of MDSCs in the tumor 
microenvironment in both mouse models and human patients.
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Beside the potential interest in terms of anti-tumor efficacy, the expression of CCL2 and 
CCR2 is upregulated by dorsal root ganglia neurons in rodent models of neuropathic pain. 
CCL2 increases the excitability of nociceptive neurons after a peripheral nerve injury, and 
disruption of CCL2 signaling blocks the development of neuropathic pain.20 Furthermore, 
several authors reported that induction of CCL2 and its receptor CCR2 in primary sensory 
neurons contributes to paclitaxel-induced peripheral neuropathy (CIPN).21,22 Activation of 
paracrine CCL2/CCR2 signaling between dorsal root ganglion neurons plays a critical role in 
the development of paclitaxel-induced peripheral neuropathy. Preclinically, paclitaxel 
induces increased expression of CCL2 in spinal astrocytes. Local blockade of CCL2/CCR2 
signaling by anti-CCL2 antibody or CCR2 antisense oligodeoxynucleotides significantly 
attenuates paclitaxel CIPN phenotypes including mechanical hypersensitivity and loss of 
intraepidermal nerve fibers in hindpaw glabrous. Targeting CCL2/CCR2 signaling could be 
a novel therapeutic approach.22 A potential beneficial effect of PF-04136309 on paclitaxel-
CIPN will be assessed through European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire-Chemotherapy-Induced Peripheral Neuropathy 20 (EORTC 
CIPN20) questionnaire23,24,25,26,27 and National Cancer Institute Common Terminology 
Criteria For Adverse Events (NCI-CTC AE).25,26,27,28
Complete information for PF-04136309 may be found in the Single Reference Safety 
Document (SRSD), which for this study is the Investigator Brochure.
The SRSD for Gemcitabine (Gemzar®) is the Eli Lilly United Kingdom (UK) Summary of 
Product Characteristics (SmPC).
The SRSD for nab-paclitaxel (Abraxane®) is the US Package Insert (USPI).
Biomarker Rationale:
The objective of biomarker collections and analyses is to provide evidence of target 
engagement (TE), pharmacodynamic activity and proof of mechanism (POM) of 
PF-04136309 in combination with nab-paclitaxel + gemcitabine. This will provide data to 
inform dose selection, characterize the relationship between PF-04136309 TE, 
pharmacodynamic activity, and any observed anti-tumor effects. Furthermore, this may 
enable the identification of patients and/or tumor phenotypes most likely to respond to 
PF-04136309, nab-paclitaxel + gemcitabine combination therapy.
Target engagement will be assessed using a flow cytometry assay to measure the inhibition 
of extracellular signal regulated kinase (ERK) kinase phosphorylation in whole blood 
samples exposed to the CCR2 ligand, CCL2, ex vivo. If sufficient data is collected to 
characterize TE at the Recommended Phase 2 Dose (RP2D) in Phase 1b, this assessment will 
not be included in Phase 2 of the study.  
Tumor-associated macrophages (TAMs), of which MDSCs are an important subset, have 
been shown to support both primary tumor survival and eventual metastases by inhibiting 
anti-tumor immunity, establishing a toleragenic microenvironment and seeding sites of 
metastases.20,30,31 Tumor-associated macrophages are derived from CD14+CCR2+ 
inflammatory monocytes (IMs) which leave the bone marrow and traffic to the tumor and 
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sites of metastases in response to production of the CCR2 ligand, chemokine ligand-2 
(CCL2).32 Once resident in this tissue, these monocytes convert to a TAM phenotype which 
inhibits anti-tumor T cell activity and promotes the shift to a toleragenic tumor 
microenvironment.33,34 Inhibition of CCR2 activity by PF-04136309 has been shown in pre-
clinical and clinical studies to increase the ratio of IMs in the bone marrow to that in the 
peripheral blood, deplete TAMs from primary tumors and inhibit metastases to lung and 
liver.39 Evidence for this mechanism being active during PF-04136309, nab-paclitaxel + 
gemcitabine combination therapy will be provided by measurement of IM and TAM in the 
peripheral blood, bone marrow aspirates and fine-needle aspirates (FNAs) or core needle 
biopsy of metastases and/or primary tumor by flow cytometry.
Accumulation of the CCR2 ligand, CCL2, has been associated with a rebound of metastases 
after cessation of antibody-mediated blockade of CCR2 in pre-clinical breast cancer 
models.38 Plasma samples will be collected and analyzed for CCL2, cytokines and 
chemokines by immunoassay to monitor for CCL2 accumulation and potential effects on 
adaptive immunity. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Objectives and Primary Endpoint:
Objectives:
Phase 1b Dose Finding Objectives 
Primary Objectives

To evaluate the safety and tolerability of PF-04136309 in combination with nab-
paclitaxel + gemcitabine in patients with metastatic pancreatic ductal carcinoma.
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
To characterize the dose limiting toxicities (DLTs) and overall safety profile of 
escalated doses of PF-04136309 and the associated schedule.

To determine the maximum tolerated dose (MTD) of PF-04136309 and select the 
Recommended Phase 2 Dose (RP2D).
Secondary Objectives

To evaluate the pharmacokinetics (PK) of PF-04136309 when given in combination 
with nab-paclitaxel + gemcitabine in combination. 

To characterize the ex vivo inhibition of CCL2-induced ERK kinase phosphorylation 
as a measure of target engagement following treatment with PF-04136309 in 
combination with nab-paclitaxel + gemcitabine at each dose level.
 
 
 
 
 
 
 
 
 
 
 
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Phase 2 Randomized Double Blinded Placebo Control Study
Primary Objective

To assess the enhancement of efficacy of PF-04136309 in combination with nab-
paclitaxel + gemcitabine versus nab-paclitaxel + gemcitabine + placebo in terms of 
progression free survival (PFS).  
Secondary Objectives

To assess the enhancement of efficacy of PF-04136309 in combination with nab-
paclitaxel + gemcitabine versus nab-paclitaxel + gemcitabine + placebo in terms of 
Overall Survival (OS). 

To assess the enhancement of efficacy of PF-04136309 in combination with nab-
paclitaxel + gemcitabine versus nab-paclitaxel + gemcitabine + placebo in terms of 
Objective Response Rate (ORR) and duration of response.

To evaluate the safety and tolerability of PF-04136309 in combination with nab-
paclitaxel + gemcitabine.

To evaluate the population PK of PF-04136309 given in combination with nab-
paclitaxel + gemcitabine. 

To validate the proof of mechanism of PF-04136309 in combination with nab-
paclitaxel + gemcitabine compared to nab-paclitaxel + gemcitabine + placebo.

To evaluate to evaluate the improvement of peripheral neurotoxicity induced by nab-
paclitaxel by the addition of PF-04136309 to the combination therapy of nab-
paclitaxel + gemcitabine.
 
 
 
 
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Endpoints 
Phase 1b Dose Finding Endpoints
Primary Endpoint

Dose Limiting Toxicities (DLTs) in order to determine the MTD and RP2D.

Adverse Events as characterized by type, frequency, severity (as graded by National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE)
v 4.03) timing, seriousness and relationship to study therapy.

Lab abnormalities as characterized by type, frequency, severity (as graded by NCI 
CTCAE v 4.03) and timing.
Secondary Endpoints

PK parameters of PF-04136309 after multiple dosing, including Cmax,ss, Tmax, 
AUCtau,ss, Cmin,ss, CLss/F, and as data permit, t1/2 and Vss/F.

Ex vivo inhibition of CCL2-induced ERK kinase phosphorylation in the peripheral 
blood.
 
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Phase 2 Randomized Study
Primary Endpoint

Progression Free Survival (PFS).
Secondary Endpoints

Overall Survival (OS).

Adverse events as characterized by type, frequency, severity (as graded by NCI 
CTCAE v.4.03), timing, seriousness and relationship to study treatment.

Laboratory abnormalities as characterized by type, frequency, severity (as graded by 
NCI CTCAE v. 4.03) and timing.

Objective response rate (ORR).

Duration of Response. [The rate of progression-free survival at 1 year, the rate of 
disease control (confirmed response or stable disease for ≥16 weeks)].

Time to progression with the double combination PF-04136309 + gemcitabine 
(maintenance therapy) after interruption of nab-paclitaxel.

Trough PF-04136309 concentrations.

Pharmacodynamic markers in metastatic tumors and bone marrow: Pre-biopsy – Post-
biopsy after 1 or 2 cycles of PF-04136309 + nab-paclitaxel + gemcitabine or nab-
paclitaxel + gemcitabine + placebo.

Peripheral neurological adverse events as characterized by frequency, severity (as 
graded by NCI CTCAE v.4.03 and by self-assessment according to the European 
Organization for Research and Treatment of Cancer Quality of Life Questionnaire-
Chemotherapy-Induced Peripheral Neuropathy 20 (EORTC QLQ-CIPN20)), and 
timing.
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Study Design
This is a multi-center Phase 1b/2 study in the first-line treatment of patients with metastatic 
pancreatic ductal adenocarcinoma (mPDA). 
The Phase 1b will be open label as patients will receive ascending doses of PF-04136309 in 
combination with nab-paclitaxel + gemcitabine. The phase 2 will be controlled, randomized 
and double blinded as patients will be randomized to receive PF-04136309 in combination 
with nab-paclitaxel + gemcitabine (ARM A) versus nab-paclitaxel + gemcitabine + placebo 
(ARM B).
-Phase 1b study: Open label dose finding.
This study will include a dose finding phase.  In the dose finding phase, patients will be 
enrolled in cohorts of 2 to 4 patients, starting with 750 mg BID of PF-04136309.  A new 
cohort of n=2 to 4 patients exposed to the same dose 750 mg twice daily (BID) could be 
opened after safety has been established for at least the first cycle in all patients in the 
previous cohort.  Escalation to a higher dose (eg 1000 mg BID) will require that at least 
n=6 patients are dosed at 750 mg BID and no more than 1 experienced a DLT.
An MTD may not be identified, as DLTs may not be observed after administration of this 
investigational agent. Based on safety data, and, PK and PD data, dose escalation may 
continue up to a predefined Maximum Feasible Dose (ie, 1000 mg BID) or Phase 2 
recommended dose.
Dose levels may include de-escalation (500 mg BID) if a high number of the patients (ie,
>33%) receiving 750 mg BID experiences a DLT related to PF-04136309.  Based on safety 
and other results (eg, PK) from patients enrolled in the dose escalation cohorts, a dose level 
will be selected to be further evaluated as the Recommended Phase 2 Dose (RP2D). A 
minimum of 6 to 12 patients will be treated at this dose level to establish it as the RP2D.
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-Phase 2 study: Randomized double blinded placebo control.
Ninety-two patients will be randomized with a 1:1 to receive PF-04136309 in combination 
with nab-paclitaxel + gemcitabine (ARM A; n=46) versus nab-paclitaxel + gemcitabine + 
placebo (ARM B; n=46). Randomization will be stratified by site (two strata: the site of 
University of Rochester, and other sites). 
The primary objective will be the enhancement of efficacy in terms of PFS.  
In both studies, treatment may continue until progression of disease (PD) unacceptable 
toxicity or patient refusal, whichever comes first. After 6 months, in case of neurological or 
hematological chronic ≥ Grade 2 toxicity, nab-paclitaxel may be stopped and gemcitabine + 
PF-04136309 or gemcitabine + placebo will be continued until disease progression or 
patient’s or investigator’s decision. If gemcitabine is not well tolerated, treatment may be 
continued with PF-04136309 alone until disease progression or patient’s or investigator’s 
decision.
The proof of mechanism of action of PF-04136309 will be assessed by the comparison of at 
least 12 paired (optional) biopsies in each treatment arm, bone marrow aspirates and 
peripheral blood (pre- and post- treatment in the Phase 2 study). Their optional collection 
will provide baseline, pre-dose core needle biopsy or fine needle aspirate (only if a CNB
sample collection from a metastatic site is not feasible) and/or bone marrow aspirates, and a 
core needle biopsy or FNA, and/or bone marrow aspirates following the completion of 
Cycle 1 at C1D28 [±7 days] or at C2D28 [±7 days] if collection at Cycle 1 is not obtained.
Serial blood samples will be collected from patients enrolled in the Phase 1b cohorts to 
determine the multiple dose PK of PF-04136309 given in combination with nab-paclitaxel + 
gemcitabine.  Sparse PK sampling will be performed for patients enrolled in the Phase 2 
portion of the study to evaluate the population PK of PF-04136309.  
Study Treatment
Dose Rationale
PF-04136309 was studied in healthy subjects after a single oral dose over the dose range of 
1 to 1000 mg, and after repeated oral administration at 5 to 500 mg twice daily (BID) for 
14 consecutive days.  These doses were generally safe and well tolerated with no dose 
limiting adverse events.  Using phosphorylation of ERK (pERK) as a whole blood biomarker 
for the pharmacologic inhibition of CCR2 inhibition, these studies showed that PF-04136309 
maximally suppressed pERK phosphorylation in whole blood monocytes for at least 12 hours 
at doses ≥150 mg, which suggest a complete or near complete saturation of circulating CCR2 
at doses ≥150 mg BID.
PF-04136309 at a dose of 500 mg BID has been combined with FOLFIRINOX 
chemotherapy in a Phase 1/2 study39 in 39 patients with borderline and locally advanced 
pancreatic cancer. The study design did include 6 patients treated with FOLFIRINOX alone. 
Comparison of toxicities between the 2 groups of patients showed that the combination of 
PF-04136309 and chemotherapy was well tolerated with most of the observed adverse events 
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being attributed to the chemotherapy.  Also, it was observed that PF-04136309 at 500 mg 
BID inhibited the migration of IMs from the bone marrow to the tumor, and depleted tumor 
infiltrating regulatory T cells.  
While the mechanisms responsible for MDSCs expansion and trafficking to tumors are not 
entirely understood, it has been shown that MDSCs express CCR2 and that the CCL2/CCR2 
signaling axis contributes to tumor progression through the CCR2-mediated MDSC 
recruitment and/or accumulation.  No data is available regarding the exposure-response 
relationship of PF-04136309 for CCR2 occupancy on MDSCs in the tumor.
Previous non-oncology and oncology studies have shown that repeated administration of 
PF-04136309 at 500 mg BID appears to be safe and pharmacologically active. Doses higher 
than 500 mg, (ie, 750 mg and 1000 mg) have been evaluated as single dose but not following 
repeated administration. In the phase 1 escalation phases, no DLTs have been reported and 
toxicities were mild.
Given the uncertainty whether the PF-04136309 exposure achieved after 500 mg BID dosing 
would be able to maximally occupy CCR2 in the tumor, the dose finding in the present study 
will start with the PF-04136309 dose of 750 mg BID, to be given in combination with
nab-paclitaxel + gemcitabine. The PF-04136309 dose of 1000 mg BID is considered as the 
maximal feasible dose for the study. Strict de-escalation rules will apply and lower dose 
levels may be explored.
The PF-04136309 or placebo for this study will be oral administration twice a day for 28 
consecutive days each cycle.
Nab-paclitaxel and gemcitabine will be administered according to the approved dosing 
schema in this indication.
In each cycle, nab-paclitaxel will be administered first as an intravenous infusion over 
30-40 minutes on Days 1, 8 and 15 followed by 1 week of no treatment (Schedule 3/1).  The 
dose of nab-paclitaxel will be 125 mg/m2.
Gemcitabine will be administered immediately after nab-paclitaxel, as an intravenous 
infusion over 30 minutes on Days 1, 8 and 15 of each cycle, followed by 1 week of no 
treatment (Schedule 3/1).  The dose of gemcitabine will be 1000 mg/m2.
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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.
Table 1.
Schedule of Activities for Phase 1b/2
Screen1
(28 days) 
Cycle 1
(28 days)
Subsequent Cycles
(28 Days)
End of 
Treatment 
(EOT)28
Follow-
up29
Protocol Activity
Day 1
Day 
2
Days
3, 4
Day 8
Day 
15
Day 
16
Day 
22
Day 
28
Day 1
Day 8
Day 
15
Day 
28
Allowable Visit Window 
days
±1
±1
±1
-1
day/+3
days
-1
day/+3
days
±1
±3
±3
±3
-1
day/+3
days
-1
day/+3
days
±3
Scans ±7 
±7
±7
Informed Consent2
X
Medical History3
X
Physical Examination4/Vital Signs6
X
X
X
X
X
X
X
X
(X)
Baseline Signs and Symptoms5
X
Height
X
Weight
X
X
X
X
X
X
X
X
X
ECOG Performance Status7
X
X
X
X
Laboratory Studies
Hematology8
X
X
X
X
X
X
X
X
X
(X)
Blood Chemistry9
X
X
X
X
X 
X
X
X
X
(X)
Coagulation10
X
X
X
X
(X)
Urinalysis11
X
X
X
X
(X)
Pregnancy Test12
X
X
X
X
(X)
Immunoglobulin (IgG, IgA, IgM)
X
X
X
X
X
X
(X)
Viral disease screen where required 
by regulations13
X
12-lead ECG14
X
X
X
(day 
3 
only)
X 
X 
(C2, C3)
X
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Table 1.
Schedule of Activities for Phase 1b/2
Screen1
(28 days) 
Cycle 1
(28 days)
Subsequent Cycles
(28 Days)
End of 
Treatment 
(EOT)28
Follow-
up29
Protocol Activity
Day 1
Day 
2
Days
3, 4
Day 8
Day 
15
Day 
16
Day 
22
Day 
28
Day 1
Day 8
Day 
15
Day 
28
Allowable Visit Window 
days
±1
±1
±1
-1
day/+3
days
-1
day/+3
days
±1
±3
±3
±3
-1
day/+3
days
-1
day/+3
days
±3
Scans ±7 
±7
±7
Registration and Treatments
Registration15
X
PF-0413630916
Day 1 to Day 28
Day 1 to Day 28
Nab-paclitaxel (Nab-P)17
X
X
X
X
X
X
Gemcitabine (GEM)18
X
X
X
X
X
X
Tumor Assessments
CT or MRI Scans19
X
(-7 days)
X 
(±7 days)
To be 
assessed 
every 
8 weeks –
efficacy 
assessment 
starts at 
the end 
Cycle 2 
Day 28 
prior to 
start of 
Cycle 3
(X)
(X)
Other Clinical Assessments
Adverse Events (AEs)20
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant Medications21
X
X
X
X
X
X
X
X
X
X
X
X
X
Core Needle Biopsy from a 
Metastatic Site22
X
X
(+/-7
days)
X (Day 28 
+/- 7 days 
of Cycle 2,
study day 
56 only)
(X)
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Table 1.
Schedule of Activities for Phase 1b/2
Screen1
(28 days) 
Cycle 1
(28 days)
Subsequent Cycles
(28 Days)
End of 
Treatment 
(EOT)28
Follow-
up29
Protocol Activity
Day 1
Day 
2
Days
3, 4
Day 8
Day 
15
Day 
16
Day 
22
Day 
28
Day 1
Day 8
Day 
15
Day 
28
Allowable Visit Window 
days
±1
±1
±1
-1
day/+3
days
-1
day/+3
days
±1
±3
±3
±3
-1
day/+3
days
-1
day/+3
days
±3
Scans ±7 
±7
±7
Fine-needle Aspirate (FNA) of 
Primary Tumor (only if Core 
Needle Biopsy of a metastatic site 
not viable).23
X
X
(+/-7 
days)
+/- 7 days 
of Cycle 2, 
study day 
56 only)
Bone Marrow Aspirate (BMA)24
X
X 
[+/-7 
days]
X (Day 28 
+/- 7 of 
Cycle 2 
(study 
day 56) 
only 
Blood for biomarker analyses25
See Pharmacokinetic (PK) and Pharmacodynamic Sampling Schedule Table 2 below
Blood for PF-04136309 PK26      
See Pharmacokinetic (PK) and Pharmacodynamic Sampling Schedule Table 2 below 
Retained Pharmacogenomic Blood 
Sample27    
X
X (pre-dose 
C3D1 only)
Serum for CA19-9
X
X 
X
Follow-up29
X
Survival30
X
Quality of Life Questionnaires
(EORTC QLQ-C30 in combination 
with QLQ-CIPN20)31
X
(-2 days)
X (C2, C3, 
C4, etc.)
X
X
Legend: (X) = Optional activity to be executed only if applicable.  C = Cycle 
Abbreviations: AEs = adverse events; β-HCG=Beta Human Chorionic Gonadotropin; BMA=Bone Marrow Aspirate; C = cycle; CNB= Core Needle Biopsy; CT 
= computed tomography; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EORTC QLQ-C30=European Organization for Research 
and Treatment of Cancer Quality of Life Questionnaire C30; EORTC QLQ-CIPN20=European Organization for Research and Treatment of Cancer Quality of 
Life Questionnaire-Chemotherapy-Induced Peripheral Neuropathy 20; EOT = End of Treatment; FNA = fine needle aspiration; GEM = Gemcitabine; 
HbsAg=hepatitis B surface antigen; HbcAb=hepatitis B core antibody; HCVAb=Hepatitis C virus antibody; HIV=human immunodeficiency virus; IgA = 
Immunoglobulin A;  IgG = Immunoglobulin G; IgM = Immunoglobulin M; MRI =  magnetic resonance imaging; Nab-P = Nab-Paclitaxel; PK = 
pharmacokinetics; QLQ = Quality of Life Questionnaire
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Footnotes (Schedule of Activities)
1.
Screening: To be conducted within 28 days prior to treatment start.
2.
Informed Consent: Must be obtained prior to undergoing any study specific procedures.
3.
Medical History: To include date of diagnosis and information on prior anti-tumor treatments, surgeries, radiotherapy and recurrence date.
4.
Physical Examination: Examination of major body systems including a neurological examination (See Appendix 5) and body weight. Height is measured at 
screening visit only. A neurological examination will be performed as part of the physical examination at Cycle 1 Day (prior to dosing), Day 1 on all 
subsequent cycles (prior to dosing), EOT, and at the Follow-up visit.
5.
Baseline Signs and Symptoms: Patients will be asked about any signs and symptoms experienced within 14 days prior to study entry.  Baseline signs and 
symptoms will be recorded on the Baseline Signs and Symptoms (BSS) Adverse Events case report form (CRF) page.
6.
Vital Signs: Includes temperature, blood pressure (BP), and pulse rate (PR) to be recorded in the sitting position after approximately 5 minutes of rest. 
7.
ECOG Performance Status: ECOG performance scale is available in Appendix 3.
8.
Hematology: No need to repeat on C1D1 if screening assessment performed within 7 days prior to that date.  The list of required laboratory tests is provided 
in Section 7.1.3.1 Laboratory Safety Assessments. 
9.
Blood Chemistry: No need to repeat full blood chemistry on C1D1 if screening assessment performed within 7 days prior to that date.  During Cycle 1, liver 
function tests, (AST, ALT, and bilirubin) must be checked on Days 8 and 15 (before dosing nab-paclitaxel and gemcitabine), and Day 22 to assess for events 
qualifying as dose limiting toxicities (DLTs).  During Cycle 1, renal function (creatinine) must be checked on Days 8 and 15 before dosing nab-paclitaxel 
and gemcitabine.  From Cycle 2 onwards, liver (AST, ALT, and bilirubin) and renal (creatinine) function tests must be performed only before dosing nab-
paclitaxel and gemcitabine.  For patients with Grade ≥3 AST/ALT, close clinical monitoring with an increased frequency of relevant blood testing should be 
undertaken, eg, every 2 - 3 days.  The list of required laboratory tests is provided in Section 7.1.3, Laboratory Safety Assessments. 
10. Coagulation: No need to repeat on C1D1 if screening assessment performed within 7 days prior to that date.  The list of required laboratory tests is provided 
in Section 7.1.3 Laboratory Safety Assessments. 
11. Urinalysis: No need to repeat on C1D1 if screening assessment performed within 7 days prior to that date.  The list of required urine laboratory tests is 
provided in Section 7.1.3, Laboratory Safety Assessments. 
12. Pregnancy Test: Pregnancy tests (serum/urine) for female patients of child bearing potential.  Test may also be repeated as per request of Institutional 
Review Board/Independent Ethics Committee (IRB/IECs), if required by local regulations.  FSH will be done at Screening only in females who are 
amenorrheic for at least 12 consecutive months.  See Section 7.1.1 Pregnancy Testing for further details.
13. Viral disease screening tests: HBsAg, HbcAb, HCVAb, and HIV to be conducted by local laboratory where required by local regulations or if warranted by 
patient history.
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14. Triplicate 12-lead ECG: At each time point, 3 consecutive 12-lead ECGs will be performed approximately 2 minutes apart to determine mean QTc interval.  
ECGs will be collected at the following timepoints: Screening, Cycle 1 Day 1 (pre-dose and 1 hr post-dose), Cycle 1 Day 3 (pre-dose, 1 and 4 hrs post-dose), 
Cycle 1 Day 22 (pre-dose, 1 and 4 hrs post-dose), Day 1 of Cycles 2 and 3 at pre-dose and 1 hr post-dose, and at the End of Treatment Visit.
After Cycle 3, ECGs can be performed as clinically indicated.  All ECG collection time points are with respect to PF-04136309 morning dosing.  When 
coinciding with blood sample draws for 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 QTc is prolonged (value of >480 msec), the ECGs should be re-evaluated by a qualified person at the institution for 
confirmation; further guidance is provided in the Section 7.1.6.
15. Registration: Patient identification number and dose level allocation to be operated by the Sponsor (see Section 5.1, Allocation to Treatment).
16. PF-04136309 treatment: Treatment will be administered in 28-day cycles.  PF-04136309 will be administered twice daily on a continuous basis.  Treatment 
will continue until PD, unacceptable toxicity or patient refusal, whichever occurs first.  If PD occurs during treatment, continuation of one or more 
combination agents may continue, under the following conditions: (a) presence of reasonable evidence of clinical benefit; (b) absence of any relevant 
toxicity; and (c) after discussion with the Sponsor. The patient will be reminded not to take their dose at home on clinic days (Cycle 1 days 1, 2, 3, 4, 8, 15, 
16, and 22, and subsequent cycles days 1, 8, and 15), but to bring their bottle into clinic so that study drug may be administered after study visit assessments 
are completed, PK samples have been collected and nab-paclitaxel and gemcitabine have been administered prior to the PF-04136309 or placebo dosing.  
PF-04136309 or placebo should be taken approximately the same time each day, approximately 12 hours apart. The allowable treatment window for 
PF-04136309 or placebo is ±4 hours.  PF-04136309 dosing should not be taken sooner than 8 hours and no more than 16 hours following the last 
PF-04136309 dosing.     
17. Nab-Paclitaxel treatment: Treatment will be administered in 28-day cycles.  Nab-paclitaxel will be administered first, on Days 1, 8 and 15 of each cycle 
followed by 1 week off treatment (Schedule 3/1).  Treatment will continue until PD, unacceptable toxicity or patient refusal, whichever occurs first.  If PD 
occurs during treatment, continuation of one or more combination agents may continue, under the following conditions: (a) presence of reasonable evidence 
of clinical benefit; (b) absence of any relevant toxicity; and (c) after discussion with the Sponsor. 
18. Gemcitabine treatment: Treatment will be administered in 28-day cycles. Gemcitabine will be administered immediately after nab-paclitaxel, on Days 1, 
8 and 15 of each cycle followed by 1 week off treatment (Schedule 3/1).  Treatment will continue until PD, unacceptable toxicity or patient refusal, 
whichever occurs first.  If PD occurs during treatment, continuation of one or more combination agents may continue, under the following conditions: 
(a) presence of reasonable evidence of clinical benefit; (b) absence of any relevant toxicity; and (c) after discussion with the Sponsor. 
19. Tumor Assessments: Tumor assessments will include all known or suspected disease sites.  CT or MRI scans are to be performed every 8 weeks – efficacy 
assessments start at the end of Cycle 2 Day 28, prior to the start of Cycle 3.  The allowable time window for disease assessments is 7 days while on 
treatment and up to -7 days for screening (ie, the screening time window is up to 35 days prior to registration).  Brain CT or MRI scan for patients with 
known or suspected brain metastases; bone scan and/or bone X-rays for patients with known or suspected bone metastases. Tumor assessment should be 
repeated at the end of treatment visit if more than 8 weeks have passed since the last evaluation.  When the study treatment is discontinued for reasons other 
than disease progression or patient refusal, patients will be followed and have tumor assessments performed every 8 weeks until (a) disease progression or 
death, (b) patient refusal or (c) start of another anti-cancer treatment, whichever occurs first.  Tumor assessments should be fixed according to the calendar, 
regardless of treatment delays.  Responses of CR or PR must be confirmed by repeat assessment no less than 4 weeks after the criteria for response are first 
met.
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20. Adverse Events: Adverse Events (AEs) should be documented and recorded at each visit using NCI CTCAE version 4.03.  Patients must be followed for 
AEs according to Section 8.1.  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 study drug are to be reported to the Sponsor.
21. Concomitant Medications: Concomitant medications and treatments must be recorded on the CRF.
22. Core Needle Biopsy (CNB): Optional, paired collections (at least 12 paired sampled in each treatment arm of Phase 2) of Core Needle Biopsy from a site of 
major metastases will be performed at Screening and at Cycle 1 Day 28 (±7 days) or at Cycle 2 Day 28 (±7 days) , study day 56  only, if C1D28 sample not 
obtained.  A Core Needle Biopsy sample collection from a a metastatic site will be performed unless it poses a safety risk to the patient, in the opinion of the 
Investigator and only after discussion with the Sponsor (refer to Section 7.3 for further guidance).  An end of treatment CNB collection of a metastatic site 
may also be collected if agreement from patient, Investigator and Sponsor is obtained.  Details for handling of these samples including processing, storage, 
and shipment will be provided in the central laboratory manual. A summary of planned analysis for CNB is provided in Section 9.5.2.
23. Fine-Needle Aspirate (FNA): Fine-needle aspirate will be collected only if a Core Needle Biopsy from a metastatic site is not viable.  Optional paired 
collections will be performed at Screening and at Cycle 1 Day 28 (±7 days) or at Cycle 2 Day 28 (±7 days), study day 56  only, if C1D28 sample not 
obtained. An end of treatment FNA collection from the primary tumor may also be collected if agreement from patient, Investigator and Sponsor is obtained.  
Details for handling of these samples including processing, storage, and shipment will be provided in the central laboratory manual. A summary of planned 
analysis for FNA is provided in Section 9.5.2.
24. Bone Marrow Aspirate: An optional bone marrow aspirate will be performed at Screening and repeated at Cycle 1 Day 28 (±7 days) or at Cycle 2 Day 28 
(±7 days), study day 56 only, if C1D28 sample not obtained.
25. Blood for Biomarker Analyses – see Table 2 outlining activities.
26. Pharmacokinetics – see Section 7.2 for Table outlining activities.
27. Banked Biospecimens: A 4 mL whole blood sample will be collected at the Screening Visit and Day 1 of Cycle 3 pre-dose (±3 days) to be retained for 
potential pharmacogenomic/biomarker analyses related to drug response, unless prohibited by local regulations or ethics committee decision.  Samples may 
be used to identify or characterize cells, DNA, RNA, or protein markers known or suspected to be of relevance to the mechanisms of action, or the 
development of resistance to PF-04136309, or the identification of those patients who might preferentially benefit from treatment with PF-04136309 Patients 
will be asked to indicate on the consent form whether they will allow this sample to be also used for the Optional Pharmacogenomic Research as described 
in the Section 7.5.
28. End of Treatment: Obtain these assessments if not completed in the last week.  Tumor assessment should be repeated at the end of treatment visit if more 
than 8 weeks have passed since the last evaluation.
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29. Follow-up: At least 28 days, and no more than 35 days after discontinuation of treatment, patients will return to undergo review of concomitant medications 
and assessment for resolution of any treatment related toxicity.  Patients continuing to experience toxicity 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.  When the study treatment is 
discontinued for reasons other than disease progression or patient refusal, patients will be followed and have tumor assessments performed every 8 weeks 
until (a) disease progression or death, (b) patient refusal or (c) start of another anti-cancer treatment, (whichever occurred first).
30. Survival: After treatment discontinuation, patient survival status will be collected every 3 months until death (telephone contact acceptable).
31. EORTC QLQ-C30 in combination with QLQ-CIPN20: Questionnaires will be completed prior to any study or medical procedure on Cycle 1 Day 1
(-2 day window), Day 1 of all subsequent cycles, and at the End of Treatment visit. One final questionnaire will be completed 4 weeks after discontinuation 
of IP during the Follow-up Visit.  All self-assessment questionnaires must be completed by the patients while in the clinic and cannot be taken home.
Interviewer administration in the clinic may be used under special circumstances (see Appendix 6 and Appendix 7).
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PHARMACOKINETIC AND PHARMACODYNAMIC SAMPLING SCHEDULE
Table 2.
Pharmacokinetic and Pharmacodynamic Sampling Schedule
Screen
(28 days) 
Cycle 1
(28 days)
Subsequent Cycles
(28 Days)
End of 
Treatment 
Follow-up 
Protocol Activity
Day 
1
Day   
2
Day   
3
Day   
4
Day 
8
Day
15
Day 
16
Day
22
Day 1
(±3 days)
Day 8
Day 
15
Allowable Visit Windows
days
±1
±1
±1
±1
-1
day/
+3
days
-1
day/+
3 days
±1
±3
±3
-1
day/+
3 days
-1
day/
+3
days
±7
±7
Pharmacokinetic Assessments
PK of PF-04136309 (whole blood)1
X
X
X
X
X
X 
X
Target Engagement Biomarker
Ex vivo CCL2-induced Phospho ERK 
(whole blood)2
X
X 
[pre-
dose]
X
[pre-
dose]
X 
[pre-
dose]
Pharmacodynamic and Immunophenotyping Biomarkers
Immune Cell Phenotyping (whole 
blood)3
X
X 
X
X
X
X (Cycles 2, 
3, 4, 7, 10)
X
CCL2, Cytokines, Chemokines (whole 
blood)5
X
X 
X
X
X
X (Cycles 2,
3, 4, 7, 10)
X
X
TBNK Absolute Counts (whole blood)
X
X
X
X
X
X
(X)
C Reactive Protein (hsCRP)
X
X
X
X
X
X
(X)
 
 
Legend: (X) = Optional activity to be executed only if applicable.  C = Cycle 
Footnotes (Pharmacokinetic and Pharmacodynamic Sampling Schedule)
1.
Pharmacokinetic blood sampling:  
Phase 1b Dose Escalation Cohorts: blood samples for determination of the PF-04136309 concentrations will be collected at the following timepoints:

Cycle 1 Day 1:  within 6 hours prior to the first PF-04136309 dose on Cycle 1 Day 1;

Cycle 1 Day 2 and Day 8: within 30 minutes prior to the morning dose of PF-04136309;

Cycle 1 Day 15: 0 hour (within 30 minutes prior to the morning dose of PF-04136309), and 0.5, 1, 2, 3, 4, and 6 hours after the morning dose;
CCI
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
Cycle 1 Day 16: within 30 minutes prior to the morning dose of PF-04136309;

Day 1 of Cycle 2 and subsequent cycles: within 30 minutes prior to the morning dose of PF-04136309;

End of Treatment visit.
Phase 2: blood samples for determination of the PF-04136309 concentrations will be collected at the following timepoints:

Cycle 1 Day 1:  within 6 hours prior to the first PF-04136309 dose on Cycle 1 Day 1;

Cycle 1 Day 2, Day 8, Day 15: within 30 minutes prior to the morning dose of PF-04136309;

Day 1 of Cycle 2 and subsequent cycles: within 30 minutes prior to the morning dose of PF-04136309;

End of Treatment visit.
On days when patients have clinical visits where PK assessments are to be obtained, the morning dose of PF-04136309 should be held (NOT taken) prior to 
the study visit. On those days, the PF-04136309 morning dose can be taken after the study procedures required immediately prior to the morning dose have 
been performed.
A PK sample should be collected matched with a biomarker sample any time an unscheduled/optional biomarker sample or FNA or core needle biopsy 
[±2 hrs] is collected.
PK samples collected from patients randomized to receive nab-paclitaxel + gemcitabine + placebo (ARM B) will not be analyzed.
2.
Target Engagement: A 3 mL whole blood sample will be collected on Cycle 1 Day 1 pre-dose, 2 and 6 hours post-dose, Day 1, 12 hour (pre-second BID 
dose-optional collection, ±4 hours dependent on last dose), Day 2, pre-dose (24 hour, ±4 hours dependent on last dose), Day 3, pre-dose (48 hour, ±4 hours
dependent on last dose) and Day 4, pre-dose (72 hour, ±4 hours dependent on last dose).  The ex vivo inhibition of CCL2-induced, ERK phosphorylation by 
PF-04136309 will be measured in whole blood using flow cytometry.
3.
Immune Cell Phenotyping: A 10 mL whole blood sample will be collected at screening, Days 1 (pre-dose), Day 2, 8, and 15 of Cycle 1, Day 1 of Cycles 2, 
3, 4, 7, 10, and at End of Treatment.  An additional 6 mL whole blood sample will be collected at Cycle 1 Day 1 and Cycle 2 Day 1 (both pre-dose). 
Immune cell phenotypes and functionality associated with anti-tumor immunity and immune regulation (eg, CD14+/CCR2+ monocytes) will be measured by 
flow cytometry and/or immunoassays.
4.
RNA Profiling Peripheral Blood: A 2-2.5 mL whole blood sample will be collected at Day 1 (pre-dose), Day 2, 8, and 15 of Cycle 1, Day 1 (pre-dose) of 
Cycles 2, 4, 7 and at End of Treatment.  Will be collected to assess the expression profile of immune and tumor-related transcripts.
5.
Monitoring of CCL2 and immune regulatory cytokines: A 4.5 mL whole blood sample will be collected at screening, Days 1 (pre-dose), Day 2, 8, 15, 22 
of Cycle 1, Day 1 of Cycles 2, 3, 4, 7, 10, at End of Treatment and Follow-up to measure levels of the CCR2 Ligand, CCL2, and immunomodulatory 
cytokines.
6.
T Cell Repertoire in Peripheral Blood: 4 mL whole blood sample will be collected at Screening, Day 1 (pre-dose), Day 8 and Day 15 of Cycle 1, Day 1
and Day 15 of Cycle 2, Day 1 of Cycles 4, 7, and End of Treatment. DNA may be isolated and be submitted to sequencing of T cell receptor genes.
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1. INTRODUCTION
Progress in basic and translational immunology has confirmed the importance of the immune 
system in cancer progression and in its treatment and has renewed interest in immune-based 
therapy for cancer, including pancreatic cancer.  The main cellular components contributing 
to the immunosuppressive microenvironment include myeloid-derived suppressor cells 
(MDSC), tumor associated macrophages (TAM), mast cells, and T regulatory cells (Treg).1,2  
Of these, MDSC comprise a heterogeneous population of the immature cells arising from the 
myeloid lineage, and they are considered to be the key in orchestrating the suppressive tumor 
microenvironment.  Myeloid-derived suppressor cells are increased in many pathological 
conditions such as infections, inflammatory disease, sepsis, traumatic shock, and pancreatic 
cancer.3,4  Myeloid-derived suppressor cells are observed with increased prevalence in the 
peripheral blood and in the tumor microenvironment of patients with solid tumors, including 
pancreatic cancer.5  Moreover, the number of circulating MDSC significantly correlates with 
clinical state and metastatic tumor burden6, and elimination of MDSC has been shown to 
improve antitumor activity.7,8,9,10 Because MDSC are proven to be one of the main 
mechanisms of tumor evasion from the immune system, the pharmacological modulation of 
MDSC and prevention of their appearance or infiltration to solid tumors represent potential 
novel and innovative therapeutic strategies in cancer.9,11,12,13,14,15,16
While the mechanisms responsible for MDSC expansion and trafficking to tumors is not 
entirely understood, it has been shown that MDSCs express CCR2 and that the CCL2/CCR2 
signaling axis contributes to tumor progression through the CCR2 mediated MDSC 
recruitment and/or accumulation.17,18,19
1.1. Mechanism of Action/Indication
PF-04136309 is an orally active CCR2 antagonist.  It is selective for CCR2 against a panel of 
human chemokine receptors.  When evaluated against human monocytes and human whole 
blood, PF-04136309 blocked CCR2 mediated signal transduction, chemotaxis and CCL2 
binding at similar concentrations.  While initially developed for the treatment of acute and 
chronic pain and liver fibrosis, the focus of development is now on oncological indications.
1.2. Background and Rationale
1.2.1. Study Rationale
Not only do MDSCs express the chemokine receptor CCR2, but in murine models of 
pancreatic cancer, it has been shown that MDSCs are upregulated in the tumor bearing host, 
promote tumor growth, suppress antitumor immunity and when depleted result in increased 
survival.5  Additionally it has been shown that CCR2 is upregulated on MDSC in both the 
circulation and tumor and that PF-04136309 can effectively block MDSC recruitment 
resulting in significantly reduced tumor growth.
Based on these findings it is hypothesized that CCR2 may be a promising therapeutic target 
in pancreatic cancer, a tumor associated with a marked up regulation of MDSCs in the tumor 
microenvironment in both mouse models and human patients.
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Beside the potential interest in terms of anti-tumor efficacy, the expression of CCL2 and 
CCR2 is upregulated by dorsal root ganglia neurons in rodent models of neuropathic pain. 
CCL2 increases the excitability of nociceptive neurons after a peripheral nerve injury, and 
disruption of CCL2 signaling blocks the development of neuropathic pain.20  Furthermore, 
several authors reported that induction of CCL2 and its receptor CCR2 in primary sensory 
neurons contributes to paclitaxel-induced peripheral neuropathy (CIPN).21,22 Activation of 
paracrine CCL2/CCR2 signaling between dorsal root ganglion neurons plays a critical role in 
the development of paclitaxel-induced peripheral neuropathy. Preclinically, paclitaxel 
induces increased expression of CCL2 in spinal astrocytes. Local blockade of CCL2/CCR2 
signaling by anti-CCL2 antibody or CCR2 antisense oligodeoxynucleotides significantly 
attenuates paclitaxel CIPN phenotypes including mechanical hypersensitivity and loss of 
intraepidermal nerve fibers in hindpaw glabrous. Targeting CCL2/CCR2 signaling could be a 
novel therapeutic approach.22 A potential beneficial effect of PF-04136309 on paclitaxel-
CIPN will be assessed through EORTC CIPN20 questionnaire23,24,25,26,27 and NCI-CTC 
AE.25,26,27,28
Complete information for PF-04136309 may be found in the Single Reference Safety 
Document (SRSD), which for this study is the Investigator Brochure.
The SRSD for Gemcitabine (Gemzar®) is the Eli Lilly UK Summary of Product 
Characteristics (SmPC).
The SRSD for nab-paclitaxel (Abraxane®) is the US Package Insert (USPI).
1.2.2. Dose Rationale
PF-04136309 was studied in healthy subjects after a single oral dose over the dose range of 
1 to 1000 mg, and after repeated oral administration at 5 to 500 mg twice daily (BID) for 
14 consecutive days.  These doses were generally safe and well tolerated with no dose 
limiting adverse events.  Using phosphorylation of ERK (pERK) as a whole blood biomarker 
for the pharmacologic inhibition of CCR2 inhibition, these studies showed that PF-04136309 
maximally suppressed pERK phosphorylation in whole blood monocytes for at least 12 hours 
at doses ≥150 mg, which suggest a complete or near complete saturation of circulating CCR2 
at doses ≥150 mg twice per day (BID).
PF-04136309 at a dose of 500 mg BID has been combined with FOLFIRINOX (fluorouracil, 
leucovorin calcium, irinotecan hydrochloride, and oxaliplatin) chemotherapy in a Phase 1/2 
study (NCT01413022)39 in 39 patients with borderline and locally advanced pancreatic 
cancer.  The study design did include 6 patients treated with FOLFIRINOX alone. 
Comparison of toxicities between the 2 groups of patients showed that the combination of 
PF-04136309 and chemotherapy (cohort B + expansion phase) was well tolerated with most 
of the observed adverse events being attributed to the chemotherapy.  The most commonly 
reported treatment-related haematological adverse events (AEs) in the cohort B + expansion 
phase (N=39) included neutropenia n=28 (21.8%) all grade and n=26 (66.7%) ≥Grade 3.  The 
most commonly reported treatment-related non-hematological AEs in the cohort B + 
expansion phase included: fatigue n=26 (66.7%) all grade and n=1 (2.6%) ≥Grade 3.  Also, it 
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was observed that PF-04136309 at 500 mg BID inhibited the migration of inflammatory 
monocytes from the bone marrow to the tumor, and depleted tumor infiltrating regulatory 
T-cells.  
While the mechanisms responsible for MDSCs expansion and trafficking to tumors are not 
entirely understood, it has been shown that MDSCs express CCR2 and that the CCL2/CCR2 
signaling axis contributes to tumor progression through the CCR2-mediated MDSC 
recruitment and/or accumulation.  No data is available regarding the exposure-response 
relationship of PF-04136309 for CCR2 occupancy on MDSCs in the tumor.
Previous non-oncology and oncology studies have shown that repeated administration of 
PF-04136309 at 500 mg BID appears to be safe and pharmacologically active. Doses higher 
than 500 mg, ie, 750 mg and 1000 mg have been evaluated as single dose but not following 
repeated administration. In the phase 1 escalation phases, no DLTs have been reported and 
toxicities were mild.
Given the uncertainty whether the PF-04136309 exposure achieved after 500 mg BID dosing 
would be able to maximally occupy CCR2 in the tumor, the dose finding in the present study 
will start with the PF-04136309 dose of 750 mg BID, to be given in combination with
nab-paclitaxel and gemcitabine.  The dose of 1000 mg BID is considered as the maximal 
feasible dose for the study. Strict de-escalation rules will apply and lower dose levels may be 
explored.
Nab-paclitaxel and gemcitabine will be administered according to the approved dosing 
schema in this indication.
1.2.3. Biomarker Rationale  
The objective of biomarker collections and analyses is to provide evidence of target 
engagement (TE) pharmacodynamic activity and proof of mechanism (POM) of 
PF-04136309 in combination with nab-paclitaxel + gemcitabine. This will provide data to 
characterize the relationship between PF-04136309 TE, pharmacodynamic activity, and any 
observed disease modifying effects. Furthermore, this may enable the identification of 
patients and/or tumor phenotypes most likely to respond to PF-04136309, nab-paclitaxel + 
gemcitabine combination therapy.
Target engagement will be assessed using a flow cytometry assay to measure the inhibition 
of ERK kinase phosphorylation in whole blood samples exposed to the CCR2 ligand, CCL2, 
ex vivo. If sufficient data is collected to characterize TE at the RP2D in Phase 1b, this 
assessment will not be included in Phase 2 of the study.  Tumor-associated macrophages 
(TAMs) have been shown to support both primary tumor survival and eventual metastases by 
inhibiting anti-tumor immunity, establishing a toleragenic microenvironment and seeding 
sites of metastases.20,30,31  Tumor-associated macrophages are derived from CD14+CCR2+ 
inflammatory monocytes (IMs) which leave the bone marrow and traffic to the tumor and 
sites of metastases in response to production of the CCR2 ligand, CCL2.32  Once resident in 
this tissue, these monocytes convert to a TAM phenotype which inhibits anti-tumor T cell 
activity and promote the shift to a toleragenic tumor microenvironment.33,34  Inhibition of 
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CCR2 activity by PF-0413609 has been shown in pre-clinical and clinical studies to increase 
the ratio of IMs in the bone marrow to that in the peripheral blood, deplete TAMs from 
primary tumors and inhibit metastases to lung and liver.  Evidence for this mechanism being 
active during PF-04136309, nab-paclitaxel + gemcitabine combination therapy will be 
provided by measurement of IM and TAM in the peripheral blood, bone marrow aspirates 
and fine-needle aspirates (FNAs) or core needle biopsy of metastases and/or primary tumor 
by flow cytometry.
Accumulation of the CCR2 ligand, CCL2, has been associated with a rebound of metastases 
after cessation of antibody-mediated blockade of CCR2 in pre-clinical breast cancer 
models.38  Plasma samples will be collected and assayed for CCL2, cytokines and 
chemokines by immunoassay to monitor for CCL2 accumulation and potential effects on 
components of adaptive immunity. 
 
 
 
 
 
 
 
2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Objectives
2.1.1. Phase 1b Dose Finding Objectives 
Primary Objectives

To evaluate the safety and tolerability of PF-04136309 in combination with nab-
paclitaxel + gemcitabine in patients with metastatic pancreatic ductal carcinoma.

To characterize the Dose Limiting Toxicities (DLTs) and overall safety profile of 
escalated doses of PF-04136309 and the associated schedule.

To determine the maximum tolerated dose of PF-04136309 and select the 
Recommended Phase 2 Dose (RP2D).
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Secondary Objectives

To evaluate the pharmacokinetics (PK) of PF-04136309 when given in combination 
with nab-paclitaxel + gemcitabine in combination. 

To characterize the ex vivo inhibition of CCL2-induced ERK kinase phosphorylation 
as a measure of target engagement following treatment with PF-04136309 in 
combination with nab-paclitaxel + gemcitabine at each dose level.
 
 
 
 
 
 
 
 
 
 
 
 
2.1.2. Phase 2 Randomized Double Blinded Placebo Controlled Study
Primary Objective

To assess the enhancement of efficacy of PF-04136309 in combination with nab-
paclitaxel + gemcitabine versus nab-paclitaxel + gemcitabine + placebo in terms of 
PFS.   
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Secondary Objectives

To assess the enhancement of efficacy of PF-04136309 in combination with nab-
paclitaxel + gemcitabine versus nab-paclitaxel + gemcitabine + placebo in terms of 
OS.

To assess the enhancement of efficacy of PF-04136309 in combination with nab-
paclitaxel + gemcitabine versus nab-paclitaxel + gemcitabine + placebo in terms of 
ORR and duration of response.

To evaluate the safety and tolerability of PF-04136309 in combination with nab-
paclitaxel + gemcitabine.

To evaluate the population PK of PF-04136309 given in combination with nab-
paclitaxel + gemcitabine. 

To validate the proof of mechanism of PF-04136309 in combination with nab-
paclitaxel + gemcitabine compared to nab-paclitaxel + gemcitabine + placebo.

To evaluate to evaluate the improvement of peripheral neurotoxicity induced by nab-
paclitaxel by the addition of PF-04136309 to the combination therapy of nab-
paclitaxel + gemcitabine.
 
 
 
 
 
 
 
 
 
 
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
To explore the effects of PF-04136309 in combination with nab-paclitaxel + 
gemcitabine on the prevalence and diversity of tumor antigenic epitopes in tumor 
tissue.

To correlate the levels of tumor markers, including but not limited to CA19.9 with 
clinical response.
2.2. Endpoints 
2.2.1. Phase 1b Dose Finding Endpoints
Primary Endpoint

Dose Limiting Toxicities (DLTs) in order to determine the MTD and RP2D.
Adverse Events as characterized by type, frequency, severity (as graded by NCI 
CTCAE v 4.03) timing, seriousness and relationship to study therapy.

Lab abnormalities as characterized by type, frequency, severity (as graded by NCI 
CTCAE v 4.03) and timing.
Secondary Endpoints

PK parameters of PF-04136309 after multiple dosing, including Cmax,ss, Tmax, 
AUCtau,ss, Cmin,ss, CLss/F, and as data permit, t1/2 and Vss/F.

Ex vivo inhibition of CCL2-induced ERK kinase phosphorylation in the peripheral 
blood.
 
 
 
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2.2.2. Phase 2 Randomized Double Blinded Placebo Controlled Study Endpoints
Primary Endpoint

Progression Free Survival (PFS).
Secondary Endpoints

Overall Survival (OS).  

Adverse events as characterized by type, frequency, severity (as graded by NCI 
CTCAE v.4.03), timing, seriousness and relationship to study treatment.

Laboratory abnormalities as characterized by type, frequency, severity (as graded by 
NCI CTCAE v. 4.03) and timing.

Objective response rate (ORR).

Duration of Response. [The rate of progression-free survival at 1 year, the rate of 
disease control (confirmed response or stable disease for ≥16 weeks)].

Time to progression with the double combination PF-04136309 and gemcitabine 
(maintenance therapy) after interruption of nab-paclitaxel.

Trough PF-04136309 concentrations.

PD markers in metastatic tumors and bone marrow: Pre-biopsy – Post-biopsy after 1 
or 2 cycles of PF-04136309 + nab-paclitaxel + gemcitabine or nab-paclitaxel + 
gemcitabine + placebo.

Peripheral neurological adverse events as characterized by frequency, severity (as 
graded by NCI CTCAE v.4.03 and by self-assessment according to the EORTC QLQ-
CIPN20 questionnaire), and timing.
 
 
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
Presence or levels of expression of several tumor biomarkers and their relationship to 
clinical responsiveness (including but not limited to tumor markers, CA 19.9).
3. STUDY DESIGN
3.1. Study Overview
This is a multi-center Phase 1b/2 study in the first line treatment of patients with mPDA. 
The Phase 1b will be open label as patients will receive ascending doses of PF-04136309 in 
combination with nab-paclitaxel + gemcitabine.  The Phase 2 will be controlled, randomized 
and double blinded as patients will be randomized to receive PF-04136309 in combination 
with nab-paclitaxel + gemcitabine (ARM A) versus nab-paclitaxel + gemcitabine + placebo 
(ARM B: Standard of Care).
-Phase 1b study: Open label dose finding.
In the dose finding phase, patients will be enrolled in cohorts of 2 to 4 patients, starting with 
750 mg BID of PF-04136309 for the first cohort.  A new cohort of n=2 to 4 patients exposed 
to the same dose 750 mg BID could be opened after safety has been established for at least 
the first cycle in all patients in the previous cohort.  A higher dose level at 1000 mg BID may 
also be explored.  
If at the dose level of 750 mg BID, more than 33% (ie, >1/3, >2/6) of the patients 
experiences a DLT related to PF-04136309 (see Section 3.3 and 9.2.2), a lower dose level of 
500 mg BID may be evaluated.  
The dose escalation in this stage may not be able to identify a MTD, as DLTs may not be 
frequently observed after administration of this investigational agent.  Based on safety and 
other results (eg, PK) from patients enrolled in the dose escalation cohorts, a dose level will 
be selected to be further evaluated as the Recommended Phase 2 Dose (RP2D).  A minimum 
of 6 patients, up to 12 patients, will be treated at this dose level to establish it as the RP2D.
-Phase 2 study:  Randomized double blinded placebo control.
Approximately 92 patients will be randomized with a 1:1 to receive PF-04136309 in 
combination with nab-paclitaxel + gemcitabine (ARM A; n=46) versus nab-paclitaxel + 
gemcitabine + placebo (ARM B; n=46). Randomization will be stratified by site (two strata: 
the site of University of Rochester, and other sites). 
The primary objective will be the enhancement of efficacy in terms of PFS (see
Section 9.4.1).
In both studies, treatment may continue until progression of disease (PD) unacceptable 
toxicity or patient refusal, whichever comes first.  After 6 months, in case of neurological or 
hematological chronic ≥ Grade 2 toxicity, nab-paclitaxel may be stopped and gemcitabine + 
PF-04136309 will be continued until disease progression or patient’s or investigator’s 
decision. If gemcitabine is not well tolerated, treatment may be continued with PF-04136309 
alone until disease progression or patient’s or investigator’s decision.
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The proof of mechanism of action of PF-04136309 will be assessed by the comparison of at 
least 12 paired (optional) biopsies from each treatment arm, bone marrow aspirates and 
peripheral blood (pre- and post- treatment in the Phase 1b and Phase 2 study). Their optional 
collection will provide baseline, pre-dose core needle biopsy (CNB) from a metastatic site, or 
fine-needle aspirate (FNA) from the primary tumor tissue, if a sample from the metastatic 
site is not viable, and/or bone marrow aspirates. Paired CNB, or FNA, and/or bone marrow 
aspirates will be collected following the completion of Cycle 1 at C1D28 [±7 days] or at 
C2D28 [±7 days] if the collection at Cycle 1 is not obtained.
Serial blood samples will be collected from patients enrolled in the Phase 1b cohorts to 
determine the multiple dose PK of PF-04136309 given in combination with nab-paclitaxel + 
gemcitabine.  Sparse PK sampling will be performed for patients enrolled in the Phase 2 
portion of the study to evaluate the population PK of PF-04136309.  
One of the key elements of this study is the possibility to evaluate potential molecular targets 
that could be modified in vivo by the drug combination used in this study. In the 
combination setting, this is especially important for PF-04136309 and nab-paclitaxel +
gemcitabine, as their MTDs as single agents may exceed the MTD required to induce a 
maximal effect in combination. 
The biomarker studies will be used to help understand the in vivo mechanism of action of the 
agents studied as well as potential mechanisms of resistance.  The studies may help in the 
future development of PF-04136309 as a single agent, or in combination with other 
compounds.
3.2. Dose Finding and Stopping Rules (Phase 1b)
A modified toxicity probability interval method (mTPI) targeting a DLT rate of 27.5% with 
an equivalence interval (22.5%-32.5%) will be utilized in order to estimate MTD.  Patients 
will be enrolled in cohorts of 2-4, starting with 750 mg BID of PF-04136309 for the first 
cohort. A higher dose at 1000 mg BID may be explored after evaluation of the Cycle 1 
safety and other results from patients enrolled at 750 mg BID. Escalation to a higher dose 
(eg 1000 mg BID) will require that at least 6 patients are dosed at 750 mg BID and no more 
than 1 experienced a DLT.  If more than 33% of the patients (ie, >1/3, >2/6) at the dose level 
of 750 mg BID experience a DLT related to PF-04136309, a lower dose level at 500 mg BID 
will be evaluated.  
After evaluating the safety and other results (eg, PK) from patients enrolled in the dose 
escalation cohorts, a dose level will be selected to be further evaluated as the Recommended 
Phase 2 Dose (RP2D).  A minimum of 6 patients, up to 12 patients, will be treated at this 
dose level to establish it as the RP2D.  To further evaluate safety and pharmacodynamics, the 
number of patients enrolled during this part of the study (Phase 1b) may be N up to 20.  The 
study will stop if all PF-04136309 doses explored appear to be overly toxic.
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3.3. Dose Limiting Toxicity (DLT)
DLTs will be defined as any of the following events described below that occur in the first 
cycle of treatment (Day 1 through 28) and are attributed (ie, judged to be at least possibly 
related) to the combination of PF-04136309 with nab-paclitaxel and gemcitabine where 
relationship with the combination cannot be ruled out.  DLTs will be classified according to 
CTCAE version 4.03.
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 neutropenic infection;

Grade ≥3 thrombocytopenia with Grade ≥2 bleeding;

Grade 4 thrombocytopenia.
Non-Hematologic:

Grade 3 toxicities, except: 

Nausea and vomiting responding to prophylaxis and/or treatment and lasting less 
than 7 days from each chemotherapy infusion period;  

Diarrhea responding to treatment and lasting less than 7 days; 

Grade 3 Fatigue lasting less than 7 days;

Grade 3 QTc prolongation (QTc >500 msec) will be considered a DLT only if 
persisting after correction of any reversible causes.  So, Grade 3 QTc prolongation 
will first require repeat testing, re-evaluation by a qualified person, and correction 
of reversible causes such as electrolyte abnormalities or hypoxia for confirmation;

Grade 3 aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) 
increase lasting ≤7 days.

All Grade 4 toxicities;

Delay of more than 2 weeks (14 calendar days) in receiving the next scheduled cycle due 
to persisting treatment-related toxicities.
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A subject is classified as DLT-evaluable if he/she experiences a DLT or if he/she otherwise 
in the absence of a DLT receives at least 85% of the planned doses of each study drug in the 
first 28 day cycle.  If a subject is withdrawn from study for any reason other than a DLT prior 
to completion of the 28-day safety observation period, a replacement subject will be assigned 
the same dose as the replaced subject. 
Adverse Effects of Interest are defined as those adverse events that fulfill the same grade and 
terms that would qualify as a DLT but occur beyond the protocol defined 28-day DLT 
window. Any Adverse Event of Interest that occurs should be reported to Pfizer as they 
occur and entered into the electronic case report form (eCRF).
3.4. Late Onset Toxicity and Toxicities
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.
3.5. Maximum Tolerated Dose/Recommended Phase 2 Dose
These 2 concepts may be determined after a full evaluation of safety and efficacy data from 
patients treated in the escalation phase of the study.
3.6. Recommended Dose Modifications
Every effort should be made to administer study treatment 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. 
Dose modifications may occur in 3 ways:
Within a cycle: dosing interruption until adequate recovery and dose reduction, if required, of 
study drugs 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 a subsequent cycle based on worst 
toxicity experienced in the previous cycle.
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3.7. Dose Interruptions/Delays/Reductions
3.7.1. PF-04136309-Induced Dose Interruptions and Delays
PF-04136309 does not have to be interrupted in case of hematologic toxicity or peripheral 
neurotoxicity with the exception for Grade 4 hematological toxicity (see Table 3.
Recommended Dose Modifications for Neutropenia and/or Thrombocytopenia). 
PF-04136309 should be interrupted in case of > Grade 2 non-hematologic or non-peripheral 
neurological toxicity, potentially due to PF-04136309.
3.7.2. Chemotherapy-Induced Dose Interruptions and Delays 
A new chemotherapy cycle (both agents) may not start (Cycle Day 1) until the following 
parameters have been met:

ANC 1,500/µL;

Platelets count 100,000/µL;

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).
PF-04136309 and gemcitabine cannot be administered until the following parameters have 
been met:

AST and ALT ≤2.5 x ULN; ≤5.0 x ULN if liver involvement by the tumor.
In addition, gemcitabine cannot be administered until:

Creatinine ≤1.0 x ULN or estimated creatinine clearance ≥60 mL/min as calculated 
using the method standard for the institution.
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 starting of the next cycle is delayed for toxicities attributable only to nab-paclitaxel and/or 
gemcitabine, the administration of PF-04136309 may continue until the next administration 
of chemotherapy.
Nab-paclitaxel may be administered if hematological toxicities are recovered to the criteria 
reported above.  See Table 4. Recommended Dose Modifications for Non Hematological 
Toxicities for guidelines on liver and renal function tests.
Gemcitabine administration must be omitted until liver and renal function tests return to the 
above reported value.  If liver and renal toxicities persist beyond 14 days, gemcitabine as 
well as nab-paclitaxel and PF-04136309 should be interrupted.
If a treatment interruption continues beyond Day 28 of the current cycle, then the day when 
nab-paclitaxel and/or gemcitabine are restarted will be counted as Day 1 of the next cycle. 
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Overall, if toxicities (hematologic and non-hematologic) do not revert to acceptable levels as 
defined above, chemotherapy resumption must be delayed.  The 14 days of treatment delay 
does not include the one week of no treatment in each 3/1 cycle of chemotherapy.  A 
treatment delay or interruption of more than 14 days due to lack of recovery will result in 
discontinuation of the patient from treatment unless discussed and agreed with the sponsor. 
Treatment resumption for patients recovering from treatment-related toxicities after 14 days 
can be considered only if there is a reasonable evidence of clinical benefit from one or more 
compounds, the safety of continuing one or more compounds is adequate, and after 
discussion with the Sponsor (including a discussion of which treatment will continue). 
3.7.3. Dose Reductions
PF-04136309, nab-paclitaxel or gemcitabine doses may need to be reduced when treatment is 
resumed following dose interruption or cycle delay due to toxicity.
Table 5.
Available Doses lists available doses for dose modifications of each drug. 
No specific dose reductions are recommended for Grade 1 and 2 treatment-related toxicities, 
with the exception of some drug-related, non-hematological toxicities that are Grade ≥2, as 
reported in Table 4.  However, Investigators should always manage their patients according 
to their medical judgment based on the particular clinical circumstances.
Dose reductions from the starting dose of 1 or 2 doses will be allowed, depending on the type 
and severity of toxicity encountered.  Patients requiring dose reductions to exposure levels of 
PF-04136309 <250 mg, nab-paclitaxel <75 mg/m2, gemcitabine <600 mg/m2 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 CRF. 
Recommended dose reductions for neutropenia and/or thrombocytopenia at the start of a 
cycle or within a cycle are illustrated in Table 3. 
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Table 3.
Recommended Dose Modifications for Neutropenia and/or 
Thrombocytopenia
Cycle
Day
ANC 
(cells/mm
3)
PLT 
(cells/mm3)
Action on 
Nab-Paclitaxel
Dosing*
Action on 
Gemcitabine 
Dosing*
Action on 
PF-04136309
Dosing
Day 1
≥ 1500
AND
≥ 100,000
Treat as planned
Treat as planned
Treat as 
planned
<1500
OR
<100,000
Delay dose by 
1 week until 
recovery; if 
recovery is not 
observed in 
1 week, delay by 
one additional 
week. If recovery 
is not observed 
after 2 weeks of 
delay, discontinue 
or discuss with 
Sponsor
Delay dose by 
1 week until 
recovery;
if recovery is not 
observed in 1 week, 
delay by one 
additional week. If 
recovery is not 
observed after 
2 weeks of delay, 
discontinue or 
discuss with 
Sponsor
No change
Day 8
≥1000
AND
75,000
Resume full dose
Resume full dose
No change
500 to 
<1000
OR
50,000 to 
<75,000
No delay, 
1 dose level 
No delay,
1 dose level
No change
<500
OR
<50,000
Hold dose 
Hold dose 
Withhold until 
recovery
Day 15: If Day 8 chemotherapy was administered (any dose)
≥1000
AND
75,000
Resume full dose, 
even if the Day 
8 dose was 
reduced 
Resume full dose, 
even if the Day 
8 dose was reduced 
No change
500 to 
<1000
OR
50,000 to 
<75,000
No delay; if  the 
Day 8 dose was 
reduced, give 
same dose as Day 
8; if Day 8 dose 
was not reduced, 
1 dose level;  
No delay; if  the 
Day 8 dose was 
reduced, give same 
dose as Day 8; if 
Day 8 dose was not 
reduced, 1 dose 
level;  
G-CSF permitted 
based on 
Investigator 
judgment
No change
<500
OR
<50,000
Hold dose; 
G-CSF permitted 
based on 
Investigator 
judgment
Hold doses; 
G-CSF permitted 
based on 
Investigator 
judgment
Withhold until 
recovery
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Table 3.
Recommended Dose Modifications for Neutropenia and/or 
Thrombocytopenia
Cycle
Day
ANC 
(cells/mm
3)
PLT 
(cells/mm3)
Action on 
Nab-Paclitaxel
Dosing*
Action on 
Gemcitabine 
Dosing*
Action on 
PF-04136309
Dosing
Day 15: If Day 8 chemotherapy was withheld
>1000
OR
75,000
No delay; 
1 dose levels from 
Day 1;
No delay; 2 dose 
levels from Day 1;
G-CSF permitted 
based on 
Investigator 
judgment
No change
500 to 
<1000
OR
50,000 to 
<75,000
No delay; 
2 dose levels from 
Day 1;
No delay; 2 dose 
levels from Day 1;
G-CSF permitted 
based on 
Investigator 
judgment
No change
<500
OR
<50,000
Hold dose;  
G-CSF permitted 
based on 
Investigator 
judgment
Hold dose;  
G-CSF permitted 
based on 
Investigator 
judgment
Withhold until 
recovery
Abbreviations: ANC = Absolute Neutrophil Count; G-CSF = granulocyte-colony stimulating factors ; PLT= Platelet 
Primary prophylactic use of granulocyte-colony stimulating factor (G-CSF) is not permitted
until following completion of Cycle 2.  
Recommended dose reductions for non-hematological toxicities at the start of a cycle or 
within a cycle are illustrated in Table 4.
Table 4.
Recommended Dose Modifications for Non Hematological Toxicities
Toxicity (NCI CTCAE 
version 4.0)
Nab-Paclitaxel
Gemcitabine
PF-04136309
Infections
Febrile Neutropenia 
Grade 3
Withhold until fever resolves 
and ANC 1500; then resume 
at next lower dose level 
Withhold until fever resolves 
and ANC1500; then resume at 
next lower dose level
Withhold until 
recovery
Sepsis Grade 4
(with or without 
neutropenia)
Withhold until resolution of 
sepsis and ANC 1500;
then resume at next lower 
dose level or discontinue as 
per Investigator judgment.
Withhold until resolution of 
sepsis and ANC 1500);
then resume at next lower dose 
level or discontinue as per 
Investigator judgment.
Withhold until 
recovery
Nervous System Disorders
Peripheral Neuropathy 
Grade 2
Withhold until Grade 1; 
then resume at next lower 
dose level or discontinue as 
per Investigator judgment. 
Continue treatment.
No dose reduction.
No change
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Table 4.
Recommended Dose Modifications for Non Hematological Toxicities
Toxicity (NCI CTCAE 
version 4.0)
Nab-Paclitaxel
Gemcitabine
PF-04136309
Skin & Subcutaneous Tissue Disorders  
Grade 2
Withhold until Grade 1;
then resume at next lower 
dose level; 
Withhold until Grade 1;
then resume at next lower dose 
level; 
Withhold until Grade 
≤1 then resume at the 
same dose level; if 
toxicity recurs Grade 
≥2 withhold until 
Grade ≤1 then 
resume at the same 
dose level or next 
lower dose level per 
Investigator’s 
judgment.
Grade 3
Withhold until Grade ≤1 then 
resume at the next lower dose 
level.
Withhold until Grade ≤1 then 
resume at the next lower dose 
level.
Withhold until Grade 
≤1 then resume at the 
next lower dose level.
Grade 4
Discontinue
Discontinue
Discontinue
Lung Disorders
Interstitial Pneumonitis 
Grade ≥2
Discontinue after ruling out 
infectious etiology 
Discontinue after ruling out 
infectious etiology 
Withhold until 
recovery
Pulmonary Embolism
Grade >2(a)
Withhold until recovery; 
then resume at next lower 
dose level or discontinue as 
per Investigator judgment
Discontinue
Withhold until 
recovery; 
then resume at next 
lower dose level or 
discontinue as per 
Investigator 
judgment
Gastrointestinal Disorders
Stomatitis Grade 3
Withhold until Grade 1;
then resume at next lower 
dose level
Withhold until Grade 1;
then resume at next lower dose 
level
Withhold until 
recovery
Stomatitis Grade 4
Discontinue
Discontinue
Withhold until 
recovery
Diarrhea Grade 3
(despite maximal medical 
therapy)
Withhold until Grade 1;
then resume at next lower 
dose level
Withhold until Grade 1;
then resume at next lower dose 
level
Withhold until 
Grade 1;
then resume at next 
lower dose level
Diarrhea Grade 4
(despite maximal medical 
therapy)
Discontinue
Discontinue
Discontinue
Nausea or Vomiting 
Grade ≥3
(despite maximal medical 
therapy and lasting more 
than 7 days)
Withhold until Grade 1;
then resume at next lower 
dose level
Withhold until Grade 1;
then resume at next lower dose 
level
Withhold until 
Grade 1;
then resume at next 
lower dose level
Metabolic Disorders
Hypophosphatemia 
Grade ≥3
(despite maximal 
replacement therapy)
No change
No change
No change
Immune System Disorders
Hypersensitivity 
reactions Grade ≥3 (b)
Discontinue
Discontinue
Discontinue 
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Table 4.
Recommended Dose Modifications for Non Hematological Toxicities
Toxicity (NCI CTCAE 
version 4.0)
Nab-Paclitaxel
Gemcitabine
PF-04136309
Renal and Urinary Disorders(c)
Creatinine >1.0 x ULN or 
estimated creatinine 
clearance <60 mL/min as 
calculated 
No change 
Delay dose by 1 week until 
recovery, then resume at the 
next lower dose level; If no 
recovery by 2 weeks, 
discontinue
No change
Creatinine increase 
Grade ≥3
Withhold until Grade 1;
then resume to next lower 
dose level
Discontinue
Withhold until 
Grade 1;
then resume to next 
lower dose level
Hepatic Disorders(d)
AST and/or ALT 
>2.5 - 10 x ULN if no 
liver involvement;
>5.0 - 10 x ULN if liver 
involvement 
No change 
Delay dose by 1 week until 
recovery to Grade 1 or 
baseline (ie, ≤2.5 or ≤5.0 x ULN 
if liver involvement by the 
tumor), then resume at the next 
lower dose level. If no recovery 
by 2 weeks, discontinue.
No change –
Investigator may 
discuss with the 
Sponsor the need to 
withhold until 
recovery
AST and ALT
>10 x ULN
Withhold until Grade 1 or 
baseline, then resume at next 
lower dose level or 
discontinuation
Discontinue
Withhold until 
Grade 1 or 
baseline, then resume 
at next lower dose 
level or 
discontinuation per 
Investigator’s 
judgment.
Other Non-Hematological Toxicities
Grade ≥3
Withhold until Grade 1;
then resume at next lower 
dose level 
Withhold until Grade 1;
then resume at next lower dose 
level
Withhold until 
Grade 1;
then resume at next 
lower dose level
Abbreviations: ANC = Absolute Neutrophil Count;  AST = Aspartate Aminotransferase;  ALT = Alanine 
Aminotransferase;  ULN = upper limit of normal
(a). If a patient develops pulmonary embolism, only low-molecular weight heparin may be used for treatment.  Oral 
anticoagulants and oral anti-thrombins are excluded from use. 
(b). Severe reactions, such as hypotension requiring treatment, dyspnea requiring bronchodilators, angioedema, or 
generalized urticaria require immediate discontinuation of study drug administration and aggressive symptomatic 
therapy. 
(c). Gemcitabine must be used with caution in patients with renal impairment.  Cases of hemolytic uremic syndrome 
and/or renal failure (some fatal) have occurred with gemcitabine treatment.  
(d). In the case of moderate to severe hepatic impairment, before implementing any dose modification, disease 
progression in the liver should be excluded.
4. PATIENT SELECTION
This study can fulfill its objectives only if appropriate subjects are enrolled.  The following 
eligibility criteria are designed to select subjects for whom participation in the study is 
considered appropriate.  All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether a particular subject is suitable for this protocol.   
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4.1. Inclusion Criteria
Patient eligibility should be reviewed and documented by an appropriately qualified 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. Histologically or cytologically-proven diagnosis of metastatic ductal adenocarcinoma 
of the pancreas.  
2. All patients must provide a baseline tumor sample at registration.  This can be an 
archival sample if collected within 1 year of study enrollment.  If an archival sample 
is not available, patients must have a metastatic biopsy collected at the screening 
visit.
3. Patient must have received no previous radiotherapy, surgery, chemotherapy or 
investigational therapy for the treatment of pancreatic metastatic disease.  Prior 
treatment with Fluorouracil (5-FU) or 5-FU prodrug or gemcitabine administered as 
a radiation sensitizer or immune therapy at the exception of modulators of monocyte 
or TAM function in the adjuvant setting is allowed (with or without continued post 
radiation gemcitabine treatment as adjuvant chemotherapy), provided at least 3 
months have elapsed since completion of the last dose and no lingering toxicities are 
present.  Patients having received cytotoxic doses of any other chemotherapy in the
pancreatic adjuvant setting are not eligible for this study.
4. Measurable disease as per RECIST v. 1.1. 
5. Life expectancy 12 weeks.
6. Patients with clinically significant ascites may enter.
7. Resolved acute effects of any prior therapy to baseline severity or Grade ≤1 NCI 
CTCAE except for AEs not constituting a safety risk by Investigator judgment. 
8. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1.
9. Age ≥18 years.
10. Adequate Bone Marrow Function, including:

Absolute Neutrophil Count ≥1,500/μL or ≥1.5 x 109/L;

Platelets ≥100,000/μL or ≥100 x 109/L; Hemoglobin ≥9 g/dL. 
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11. Adequate Renal Function, including:

Serum creatinine ≤1.0 x upper limit of normal (ULN) or estimated creatinine 
clearance ≥60 mL/min as calculated using the method standard for the institution.
12. Adequate Liver Function, including:

Total serum bilirubin ≤1.0 x ULN unless the patient has documented Gilbert’s 
syndrome;

Aspartate and Alanine Aminotransferase (AST and ALT) ≤2.5 x ULN; ≤5.0 x 
ULN if there is liver involvement by the tumor.
13. Acceptable coagulation parameters as demonstrated by prothrombin time (PT) and 
partial thromboplastin time (PTT) within ±15% normal limits.
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 2 highly effective method(s) of contraception 
throughout the study and for at least 28 days after the last dose of PF-04136309 and 
for 6 months after last dose of nab-paclitaxel, gemcitabine, or both.   
16. Evidence of a personally signed and dated informed consent document indicating that 
the patient (or a legal representative) has been informed of all pertinent aspects of the 
study.
17. Patients who are willing and able to comply with scheduled visits, treatment plan, 
laboratory tests, and other study procedures.
4.2. Exclusion Criteria
Patients with any of the following characteristics/conditions will not be included in the study:
1. Patients with known symptomatic brain metastases requiring steroids.  Patients with 
previously diagnosed brain metastases are eligible if they have completed their 
treatment and have recovered from the acute effects of radiation therapy or surgery 
prior to study entry, have discontinued corticosteroid treatment for these metastases 
for at least 4 weeks and are neurologically stable. 
2. Prior therapy with modulators of monocyte or TAM function.
3. Participation in other studies involving investigational drug(s) (Phases 1-4) within 
4 weeks of registering for the current study and/or during study participation.
4. Any surgery (not including minor procedures such as placement of port-a-caths) 
within 4 weeks of registering for the current study.
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5.
Diagnosis of any second malignancy within the last 3 years, except for adequately 
treated basal cell carcinoma, or squamous cell skin carcinoma or in-situ cervical 
carcinoma. 
6. Known hypersensitivity to nab-paclitaxel or to any of the excipients.
7. Known hypersensitivity to gemcitabine or to any of the excipients. 
8. Any one of the following currently or in the previous 6 months: myocardial 
infarction, severe/unstable angina, coronary/peripheral artery bypass graft, 
symptomatic congestive heart failure, cerebrovascular accident, transient ischemic 
attack; symptomatic pulmonary embolism; congenital long QT syndrome, torsades de 
points, arrhythmias (including sustained ventricular tachyarrhythmia and ventricular 
fibrillation), right bundle branch block and left anterior hemiblock (bifascicular 
block), ongoing cardiac dysrhythmias of NCI CTCAE Grade 2, atrial fibrillation of 
any grade, or QTc interval >470 msec at screening. 
9. Concurrent administration of herbal preparations. 
10. Use of oral anticoagulants.  Use of subcutaneous anti-coagulation is allowed. 
Concurrent use of potent or moderate inhibitors or inducers of CYP3A4 and/or 
CYP2C8.  
11. 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. 
12. History of interstitial lung disease, or slowly progressive dyspnea and unproductive 
cough, sarcoidosis, silicosis, idiopathic pulmonary fibrosis, pulmonary 
hypersensitivity pneumonitis or multiple allergies.
13. Other severe acute or chronic medical or psychiatric condition, including recent 
(within the past year) or active suicidal ideation or behavior) or 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.
14. Pregnant female patients; breastfeeding female patients; males patients with partners 
currently pregnant, male patients able to father children and female patients of 
childbearing potential who are unwilling or unable to use two (2) highly effective 
methods of contraception as outlined in this protocol for the duration of the study and 
for 28 days after last dose of PF-04136309, and for 6 months after last dose of nab-
paclitaxel, gemcitabine, or both.  
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15. Patients who are investigational site staff members directly involved in the conduct of 
the trial 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 trial.
4.3. Lifestyle Guidelines 
4.3.1. Contraception
In this study, male subjects who are able to father children and female subjects who are of 
childbearing potential will receive PF-04136309, which the teratogenic risk is currently 
unknown and chemotherapeutic agents that have been associated with teratogenic risk.  Two 
(2) methods of highly effective contraception must be used throughout the study and 
continued for at least 28 days after the last dose of PF-04136309, and for 6 months after last 
dose of nab-paclitaxel, gemcitabine, or both.  The investigator or his or her designee, in 
consultation with the subject, will confirm the subject has selected 2 appropriate methods of 
contraception for the individual subject and his or her partner from the list of permitted 
contraception methods (see below) and instruct the subject in their consistent and correct use.  
Subjects need to affirm that they meet the criteria for the correct use of at least 2 of the 
selected methods of contraception.  The investigator or his or her designee will discuss with 
the subject the need to use highly effective contraception consistently and correctly according 
to the Schedule of Activities and document such conversation in the subject’s chart.  In 
addition, the investigator or his or her designee will instruct the subject to call immediately if 
a selected contraception method is discontinued or if pregnancy is known or suspected in the 
subject or the subject’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, transdermal, or implanted hormonal 
methods of contraception are allowed provided the subject 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 / 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 as described 
below.  
Female subjects of non-childbearing potential must meet at least one of the following 
criteria:
a.
Achieved postmenopausal status, defined as follows: cessation of regular menses 
for at least 12 consecutive months with no alternative pathological or 
physiological cause; status may be confirmed by having a serum 
follicle-stimulating hormone (FSH) level confirming the post-menopausal state;  
b. Have undergone a documented hysterectomy and/or bilateral oophorectomy;
c.
Have medically confirmed ovarian failure.
All other female subjects (including females with tubal ligations) will be 
considered to be of childbearing potential.
All sexually active male subjects must agree to prevent potential transfer of and exposure to 
drug through semen to their partners by using a condom consistently and correctly, beginning 
with the first dose of investigational product and continuing for at least 28 days after the last 
dose.
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/team study portal.
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.
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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 
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
5.1.1. Phase 1b Dose-finding 
In Phase 1b (dose-finding study), eligible patients will be enrolled to receive PF-04136309 in 
combination with nab-paclitaxel + gemcitabine in an open-labeled, unblinded manner.  
Patients will be successively assigned to the next available treatment slot at a PF-04136309 
dose level decided on after the previous cohort’s safety evaluation and ongoing observations 
of earlier enrolled patients.  In the dose finding study, patients will be enrolled in cohorts of 
2 to 4 patients, starting with 750 mg BID of PF-04136309 for the first cohort.  A higher dose 
level of PF-04136309 at 1000 mg BID may be explored.
Dose level allocation in Phase 1b will be performed by the sponsor after patients have given 
their written informed consent and have completed the necessary baseline assessments. The 
Investigator or designee will enroll the patient according to the procedure described in the 
Study Manual.  The Sponsor will assign a patient identification number, which will be used 
on all Case Report Form (CRF) pages and other study-related documentation or 
correspondence referencing that patient. 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 enrolment;

specification of the dose level for that patient; and

permission to proceed with dosing the patient.
The sponsor or designee will notify the other sites of the inclusion of a new patient, and will 
inform study sites about the next possible enrollment date.
5.1.2. Phase 2 Randomized
In the Phase 2 randomized double blinded placebo control study, patients will be assigned to 
one of the following treatments following a randomization ratio 1:1:

Arm A: Nab-Paclitaxel + Gemcitabine + PF-04136309 oral daily BID.

Arm B: Nab-Paclitaxel + Gemcitabine + Placebo oral daily BID.
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Randomization will be stratified by site (two strata: the site of University of Rochester, and 
other sites). 
The doses of nab-paclitaxel and gemcitabine will be as described in Section 5.4.2 and 
Section 5.4.3.  The dose of PF-04136309 will be the RP2D determined in the Phase 1b 
portion of the study.
During the randomized portion of the study, the assignment of patient identification numbers 
and the allocation of patients to treatment groups may be managed via the use of an 
automated Interactive Response Technology (IRT) system or another equivalent system 
provided by the Sponsor.  Further information on the procedure for patient management for 
the Phase 2 portion of the study will be described in the Study Manual.
Treatment allocation will be blinded to the patient, investigator and the sponsor.
5.2. Patient Compliance
5.2.1. PF-04136309 and Placebo
Patients will be instructed to record daily administration of study drug (PF-04136309 or 
placebo) in a patient diary provided by the Sponsor.  Missed or changed doses and dates of 
all missed doses need to be annotated.
Patients will be required to return all unused study medication at the beginning of each cycle.  
The number of tablets (PF-04136309 or placebo) returned by the patient at the end of the 
cycle will be counted, documented and recorded. Compliance of outpatient dosing will be 
assessed by site personnel by review of the patient’s dosing diary and by tablet counts for 
remaining tablets at each visit.
Any deviations in compliance should be discussed by the investigator and Pfizer study team 
and an assessment will be made as to whether the patient may continue in the study or be 
withdrawn.
5.2.2. Nab-paclitaxel and Gemcitabine
For assessing compliance of nab-paclitaxel and gemcitabine, the site should complete the 
required dosage Preparation Record located in the Study Manual.  The use of the Preparation 
Record is preferred, but it does not preclude the use of an existing appropriate clinical site 
documentation system.  The existing clinical site's documentation system should capture all 
pertinent /required information on the preparation and administration of the dose.  This may 
be used in place of the Preparation Record after approval from the Sponsor.
5.3. Investigational Product Supplies 
Additional information can be found in the Investigational Product Manual.
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5.3.1. Dosage Form(s) and Packaging
PF-04136309 and placebo will be supplied by Pfizer as formulated 125 mg tablet or 
matching placebo tablet for oral administration.  The sponsor will supply the oral drug 
formulation to sites in high-density polyethylene (HDPE) bottles.  Labeling will occur 
according to local regulatory requirements.
In each cycle, nab-paclitaxel will be administered first as an intravenous infusion over 
30-40 minutes on Days 1, 8 and 15 followed by 1 week of no treatment (Schedule 3/1).  The 
dose of nab-paclitaxel will be 125 mg/m2.
Gemcitabine will be administered immediately after nab-paclitaxel, as an intravenous 
infusion over 30 minutes on Days 1, 8 and 15 of each cycle, followed by 1 week of no 
treatment (Schedule 3/1).  The dose of gemcitabine will be 1000 mg/m2.
Nab-paclitaxel and gemcitabine to be administered during this study will be branded or 
generic product available in the local region.  Nab-paclitaxel and gemcitabine will be 
procured by the study sites unless local regulations or other limitations require direct 
provision of background therapy by the Sponsor.  Nab-paclitaxel and gemcitabine are to be 
stored, prepared and administered according to locally approved product labeling.
Study centers will receive a supply of Clinical Trial Material upon screening or confirmation 
of study enrollment of the first patient along with instructions on how to confirm drug 
receipt.  Resupplies will be made during the course of the study based on patient need.  The 
details on drug supply will be provided in the Study Manual.  The study monitor should be 
contacted for any issues related to drug supplies.
5.3.2. Preparation and Dispensing
Only qualified personnel who are familiar with procedures that minimize undue exposure to 
them and to the environment should undertake the preparation, handling, and safe disposal of 
chemotherapeutic agents.
5.3.2.1. PF-04136309 and Placebo
Site personnel must ensure that patients clearly understand the dosing directions for self-
medication.  A Patient Dosing Diary and Instruction Card will be included in the Study 
Manual and will provide detailed instructions for daily administration of study drug and will 
be used for patients to record dosing compliance.  An example of the diary is provided in 
Appendix 4.
5.3.2.2. Nab-paclitaxel
Nab-paclitaxel will be prepared and administered according to the package insert and product 
labeling. Inject the appropriate amount of reconstituted nab-paclitaxel into an empty, sterile 
intravenous bag [plasticized polyvinyl chloride (PVC) containers, PVC or non-PVC type 
intravenous bag]. The use of specialized di-(2-ethylhexyl)phthalate (DEHP)-free solution 
containers or administration sets is not necessary to prepare or administer nab-paclitaxel
infusions. The use of an in-line filter is not recommended.
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Nab-paclitaxel is a cytotoxic drug, and, as with other potentially toxic paclitaxel compounds, 
caution should be exercised in handling it.  The use of gloves is recommended.  If nab-
paclitaxel (lyophilized cake or reconstituted suspension) contacts the skin, the skin must be 
washed immediately and thoroughly with soap and water.  Following topical exposure to 
paclitaxel, events may include tingling, burning and redness.  If nab-paclitaxel contacts 
mucous membranes, the membranes should be flushed thoroughly with water.  Procedures 
for proper handling and disposal of anti-cancer drugs should be considered.  
Investigational product should be prepared and 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.
5.3.2.3. Gemcitabine
Gemcitabine will be prepared and administered according to see the package insert and 
product labeling.
Caution should be exercised in handling and preparing gemcitabine for injection. The use of 
gloves is recommended.  If a solution of gemcitabine for injection contacts the skin or 
mucosa, the skin must be washed immediately and thoroughly with soap and water, or the 
mucosa must be rinsed with copious amounts of water alone.  Procedures for proper handling 
and disposal of anti-cancer drugs should be considered.
Investigational product should be prepared and 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
5.4.1. PF-04136309
The starting dose for PF-04136309 in the Phase 1b portion will be 750 mg BID.  
PF-04136309 is to be administered orally, on a continuous basis, twice daily (BID) in 28-day 
cycles.  Available dose levels are described in Table 5.
PF-04136309 or placebo should be taken approximately the same time each day, 
approximately 12 hours apart. The allowable treatment window for PF-04136309 or placebo 
is ±4 hours.  PF-04136309 dosing should not be taken sooner than 8 hours and no more than 
16 hours following the last PF-04136309 dosing. The patient will be reminded not to take 
their dose at home on clinic days, but to bring their bottle into clinic so that study drug may 
be administered after study visit assessments are completed, PK samples have been collected 
and nab-paclitaxel and gemcitabine have been administered prior to the PF-04136309 or 
placebo dosing.
Patients will swallow the investigational product whole, and will not manipulate or chew the 
investigational product prior to swallowing.
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Patient should be instructed to take their study medication, PF-04136309 or placebo, with at 
least 6-ounces (180 mL) of water. There is no requirement for fasting as a result of the 
A9421019 study, which evaluated the effect of food on the PK of PF-04136309, indicating 
no significant effect of food on the PK of PF-04136309. 
If a patient 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 vomits any time after taking a dose, he/she must be instructed not to “make it up”
but to resume subsequent doses as prescribed.  
If a patient inadvertently takes 1 extra dose during a day, the patient should not take the next 
dose of PF-04136309.  
On days where the morning dose of PF-04136309 or placebo is held due to a specific study 
visit (Cycle 1 Days 1, 2, 3, 4, 8, 15, 16, and 22, and subsequent cycle visits Days 1, 8 and 15) 
the 2nd BID dosing should be taken no sooner than 8 hours, and no later than 16 hours post 
the first BID dosing (allowable treatment window ±4 hours).
Treatment will continue until PD, unacceptable toxicity or patient refusal, whichever occurs 
first.  If PD occurs during treatment, continuation of one or more combination agents may 
continue, under the following conditions: (a) presence of reasonable evidence of clinical 
benefit; (b) absence of any relevant toxicity; and (c) after discussion with the Sponsor.
5.4.2. Nab-paclitaxel
Treatment will be administered in 28-day cycles.  In each cycle, nab-paclitaxel will be 
administered first, as an intravenous infusion over 30-40 minutes on Days 1, 8 and 
15 followed by 1 week of no treatment (Schedule 3/1).  The dose of nab-paclitaxel will be 
125 mg/m2.  Administer nab-paclitaxel according to the package insert and product labeling.
Treatment will continue until PD, unacceptable toxicity or patient refusal, whichever occurs 
first.  If PD occurs during treatment, continuation of one or more combination agents may 
continue, under the following conditions: (a) presence of reasonable evidence of clinical 
benefit; (b) absence of any relevant toxicity; and (c) after discussion with the Sponsor.
5.4.3. Gemcitabine
Treatment will be administered in 28-day cycles.  Gemcitabine will be administered 
immediately after nab-paclitaxel, on Days 1, 8 and 15 of each cycle followed by 1 week off 
treatment (Schedule 3/1). The dose of gemcitabine will be 1000 mg/m2. Administer 
gemcitabine according to the package insert and product labeling.
Treatment will continue until PD, unacceptable toxicity or patient refusal, whichever occurs 
first.  If PD occurs during treatment, continuation of one or more combination agents may 
continue, under the following conditions: (a) presence of reasonable evidence of clinical 
benefit; (b) absence of any relevant toxicity; and (c) after discussion with the Sponsor. 
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5.4.4. Recommended Dose Modifications
Every effort should be made to administer study treatment 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. 
Dose modifications may occur in 3 ways:
Within a cycle: dosing interruption until adequate recovery and dose reduction, if required, of 
study drugs 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 a subsequent cycle based on worst 
toxicity experienced in the previous cycle.
5.4.5. Dosing Interruptions/Delays/Reductions
5.4.5.1. PF-04136309-Induced Dose Interruptions and Delays
PF-04136309 does not have to be interrupted in case of hematologic toxicity until Grade 3 or 
peripheral neurotoxicity.  PF-04136309 should be interrupted in case of ≥Grade 2 non-
hematologic or non-peripheral neurological toxicity, potentially due to PF-04136309.
5.4.5.2. Chemotherapy-Induced Dose Interruptions and Delays 
A new chemotherapy cycle (both agents) may not start until the following parameters have 
been met:

ANC 1,500/µL;

Platelets count 100,000/µL;

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).
PF-04136309 and gemcitabine cannot be administered until the following parameters have 
been met:

AST and ALT ≤2.5 x ULN; ≤5.0 x ULN if liver involvement by the tumor.
In addition, gemcitabine cannot be administered until:

Creatinine ≤1.0 x ULN or estimated creatinine clearance ≥60 mL/min as calculated 
using the method standard for the institution.
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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 starting of the next cycle is delayed for toxicities attributable only to nab-paclitaxel and/or 
gemcitabine, the administration of PF-04136309 should not be interrupted and may continue 
until the next administration of chemotherapy.
Nab-paclitaxel may be administered if hematological toxicities are recovered to the criteria 
reported above, despite the fact that liver and renal function tests do not meet the criteria for 
re-treatment, as outlined above. 
Gemcitabine administration must be omitted until liver and renal function tests return to the 
above reported value.  If liver and renal toxicities persist beyond 14 days, gemcitabine as 
well as nab-paclitaxel and PF-04136309 should be interrupted. 
If a treatment interruption continues beyond Day 28 of the current cycle, then the day when 
nab-paclitaxel and/or gemcitabine are restarted will be counted as Day 1 of the next cycle. 
Overall, if toxicities (hematologic and non-hematologic) do not revert to acceptable levels as 
defined above, chemotherapy resumption must be delayed.  The 14 days of treatment delay 
does not include the one week of no treatment in each 3/1 cycle of chemotherapy.  A 
treatment delay or interruption of more than 14 days due to lack of recovery will result in 
discontinuation of the patient from treatment unless discussed and agreed with the sponsor. 
Treatment resumption for patients recovering from treatment-related toxicities after 14 days 
can be considered only if there is a reasonable evidence of clinical benefit from one or more 
compounds, the safety of continuing one or more compounds is adequate, and after 
discussion with the Sponsor (including a discussion of which treatment will continue). 
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 
Dose Interruptions/Delays/Reductions, Section 3.7. 
Doses may be held as needed until toxicity resolution.  Depending on when the adverse event 
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 adverse event 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 >2 weeks, treatment resumption will be decided in consultation with 
the sponsor.  
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5.4.6. Dose Reductions
However, investigators should always manage their patients according to their medical 
judgment based on the particular clinical circumstances.
PF-04136309, nab-paclitaxel or gemcitabine doses may need to be reduced when treatment is 
resumed following dose interruption or cycle delay due to toxicity.
Table 5.
Available Doses lists available doses for dose modifications of each drug. 
Table 5.
Available Doses
PF-04136309 or 
Placebo
(mg/BID)
Nab-Paclitaxel 
(mg/m2)
Gemcitabine 
(mg/m2)
750 or 1000
125
1000
500 
100
800
250
75
600
No specific dose reductions are recommended for Grade 1 and 2 treatment-related toxicities, 
with the exception of some drug-related, non-hematological toxicities that are Grade ≥2, as 
reported in Table 4.  However, Investigators should always manage their patients according 
to their medical judgment based on the particular clinical circumstances.
Dose reductions from the starting dose of 1 or 2 doses will be allowed, depending on the type 
and severity of toxicity encountered.  Patients requiring dose reductions to exposure levels of 
PF-04136309 <250 mg, nab-paclitaxel <75 mg/m2, gemcitabine <600 mg/m2 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 CRF. 
Recommended dose reductions for neutropenia and/or thrombocytopenia at the start of a 
cycle or within a cycle are illustrated in Table 3.
Primary prophylactic use of granulocyte-colony stimulating factors is not permitted during 
Cycles 1 and 2 but they may be used to treat treatment emergent neutropenia as indicated by 
the current American Society of Clinical Oncology (ASCO) guidelines.42 G-CSF may be 
used prophylactically after completion of 2 treatment cycles.
Recommended dose reductions for non-hematological toxicities at the start of a cycle or 
within a cycle are illustrated in Table 4.
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5.5. Investigational Product Storage 
The investigator, or an approved representative (eg, pharmacist) will ensure that all 
investigational products, including any comparator and/or marketed 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.  See the dosage and administration instructions (DAI), package insert, or equivalent for 
storage conditions of the product once reconstituted and/or diluted.
Storage conditions stated in the single reference safety document (SRSD) (eg, investigator 
brochure [IB], core data sheet [CDS], United States package insert [USPI], summary of 
product characteristics [SPC], or local product document [LPD]) 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.  
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. 
The Investigational Product Manual should be referenced for any additional guidance on 
storage conditions and actions to be taken when conditions are outside the specified range.
Receipt of materials, door opening and closing, and other routine handling operations where 
the product(s) are briefly out of the temperature range described in the labeling are not 
considered excursions. More specific details will be provided to the sites separately.  
Site staff will instruct patients on the proper storage requirements for take home study 
treatment. 
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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 bottles of study medication at the beginning of each 4 week period.  The number of tablets
remaining will be documented and recorded.  Patient compliance is covered in Section 5.2.
5.7. 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.
5.8. Concomitant Treatment(s)
Concomitant treatment considered necessary for the patient’s well-being may be given at 
discretion of the treating physician.
All concomitant treatments, blood products, as well as non-drug interventions (eg, 
paracentesis) received by patients from screening until the end of study visit must be 
recorded on the CRF.  
Because inhibition of CYP3A4 isoenzymes may increase PF-04136309 exposure leading to a 
potential increases in toxicities, the use of known strong/moderate inhibitors (Strong CYP3A4 
Inhibitors: grapefruit juice or grapefruit/grapefruit related citrus fruits (eg, Seville oranges, 
pomelos), ketoconazole, miconazole, itraconazole, voriconazole, posaconazole, 
clarithromycin, telithromycin, indinavir, saquinavir, ritonavir, nelfinavir, amprenavir, 
fosamprenavir, nefazodone, lopinavir, troleandomycin, mibefradil, conivaptan; Moderate 
CYP3A4 inhibitors: Erythromycin, verapamil, atazanavir, fluconazole, darunavir, diltiazem, 
delavirdine, aprepitant, imatinib, tofisopam, ciprofloxacin, cimetidine)41 are not permitted 
from 10 days prior to the first dose of PF-04136309 until study treatment discontinuation 
(OR) caution should be warranted with co-administration with PF-04136309.  
PF-04136309 metabolism may be induced when taking strong CYP3A4 inducers (eg, 
phenobarbital, rifampin, phenytoin, carbamazepine, rifabutin, rifapentin, clevidipine, 
St. John’s Wort)41 resulting in reduced plasma concentrations.  Therefore co-administration 
of PF-04136309 in combination with these and other strong CYP3A4 inducers is not 
permitted from 10 days prior to the first dose of PF-04136309 until study treatment 
discontinuation (OR) caution should be warranted with co-administration with PF-04136309.
Caution should be exercised when administering nab-paclitaxel concomitantly with 
medicines known to inhibit (eg, ketoconazole and other imidazole antifungals, erythromycin, 
fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) or induce 
(eg, rifampicin, carbamazepine, phenytoin, efavirenz, and nevirapine) either CYP2C8 or 
CYP3A4.
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5.8.1. 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.
Palliative radiotherapy on study is permitted for the treatment of painful bony lesions 
providing the lesions were known at the time of study entry and the investigator clearly 
indicates that the need for palliative radiotherapy is not indicative of disease progression.  In 
view of the current lack of data about the interaction of PF-04136309 with radiotherapy, 
PF-04136309 treatment should be interrupted during palliative radiotherapy, stopping 7 days
before and resuming treatment 7 days after completion of radiotherapy.
5.8.2. 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.  
5.8.3. Hematopoietic Growth Factors
Erythropoietin may be used at the investigator’s discretion for the supportive treatment of 
anemia. 
5.8.4. Anti-Diarrheal, Anti Emetic Therapy
Supportive care may include premedication with antiemetics to limit gemcitabine treatment-
related nausea and vomiting. Primary prophylaxis of diarrhea, nausea and vomiting is
permitted in the first cycle.  Primary prophylaxis in subsequent cycles is at the investigator’s 
discretion.  The choice of the prophylactic drug is up to the investigator with sponsor 
approval and assuming the drug is not included in the Concomitant Treatment(s) section, as 
well as the duration of treatment, assuming there is no known or expected drug-drug 
interaction.  If so, then it must be approved by the sponsor.
5.8.5. 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. 
5.8.6. Corticosteroids  
Chronic, systemic corticosteroid use for palliative or supportive purposes is not permitted.  
Acute emergency administration, topical applications, inhaled sprays, eye drops, or local 
injections of corticosteroids are allowed.
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5.8.7. Surgery 
Caution is advised on theoretical grounds for any surgical procedures during the study.  The 
appropriate interval of time between surgery and PF-04136309 required to minimize the risk 
of impaired wound healing and bleeding has not been determined.  Stopping PF-04136309 is 
recommended at least 14 days prior to surgery.  Post-operatively, the decision to reinitiate
PF-04136309 treatment should be based on a clinical assessment of satisfactory wound 
healing and recovery from surgery.
6. STUDY PROCEDURES 
6.1. Screening
All patients being considered for the study and eligible for screening must sign an informed 
consent for the study before completing any study-specific procedures.  A patient 
identification number will be assigned.  The investigator (or appropriate delegate at the site) 
will obtain informed consent from each patient in accordance with the procedures described
in the Schedule of Activities and Section 12.3 on Patient Information and Informed Consent.  
Informed consent must be obtained prior to undergoing any study specific procedures. 
Patients will be screened within 28 days prior to administration of the study treatment to 
confirm that they meet the patient selection criteria for the study. 
Medical history will include the date of diagnosis and information on prior anti-tumor 
treatments, surgeries, radiotherapy and recurrence date.
Patients will be asked about any signs and symptoms experienced within 14 days prior to 
study entry.  Baseline signs and symptoms will be recorded on the BSS Adverse Events 
(AEs) case report form (CRF) page.
The required screening assessments and laboratory tests are summarized in the Schedule of 
Activities and Section 7.1.3.  Following completion of the screening assessments and 
confirmation of eligibility, patients may be enrolled.
6.2. Study Period.
For treatment period procedures, see Schedule of Activities and ASSESSMENTS Section.
6.3. End of Treatment
For end of treatment procedures, see Schedule of Activities and ASSESSMENTS Section.  
End of Treatment procedures should be completed if not done in the last calendar week.  
Tumor assessments should be repeated at the End of Treatment visit if more than 8 weeks 
have passed since the last evaluation.
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6.4. Follow-up Visit
For follow-up procedures, see Schedule of Activities and ASSESSMENTS Section.
At least 28 days, and no more than 35 days after discontinuation of treatment, patients will 
return to undergo review of concomitant medications and assessment for resolution of any 
treatment related toxicity.  Patients continuing to experience toxicity 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.  When the study treatment is 
discontinued for reasons other than disease progression or patient refusal, patients will be 
followed and have tumor assessments performed every 8 weeks until (a) disease progression 
or death, (b) patient refusal or (c) start of another anti-cancer treatment, (whichever occurred 
first).
In the event a patient is unable to return to the clinic for the follow-up visit, telephone contact 
with the patient to assess adverse events and concomitant medications and treatment is 
expected.  If laboratory assessments are needed to follow-up unresolved adverse events, 
retrieval of assessments performed at an institution local to the patient is acceptable.
6.5. Patient Withdrawal
The reason for a patient’s discontinuation from treatment will be documented in the end of 
study/withdrawal CRF.  Patients will be followed for at least 28 days after the last dose of 
study drug for adverse events. 
Patients may withdraw from treatment at any time at their own request, they may be 
withdrawn at the discretion of the investigator or sponsor for safety or behavioral reasons, or 
the inability of the subject 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;

Global deterioration of health status requiring discontinuation;

Adverse event;

Medication error without associated adverse event;

Significant protocol violation;

Lost to follow-up;

Patient no longer willing to participate in study;

Study terminated by Sponsor;

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;

Patient refusal for 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 the patient to return all unused investigational 
product(s), request the patient to return for a final visit, if applicable and follow-up with the 
patient regarding any unresolved adverse events (AEs).
If the patient refuses further visits, and the patient withdraws consent for disclosure of future 
information or for further contact, 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.
6.6. Survival Follow-up
After treatment discontinuation, patient survival status will be collected every 3 months until 
death (telephone contact acceptable).
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 adverse events (AEs), serious adverse events 
(SAEs), vital signs and physical examination, electrocardiogram (ECG [12-lead]), laboratory 
assessments, including pregnancy tests and verification of concomitant treatments.
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7.1.1. Pregnancy Testing
Nonclinical fertility and early embryonic and pre- and postnatal development studies have 
not been completed with PF-04136309.  In the absence of definitive studies, the potential 
risks to the developing embryo and foetus are undetermined; therefore, PF-04136309 should 
not be administered in pregnant women.  Moreover, PF-04136309 should not be 
administered to women of childbearing potential in the absence of 2 forms of contraception.  
In addition, pregnancy testing prior to enrollment and at follow up will be employed for any 
suitable patient participating in the clinical study.
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 the 
baseline visit, immediately before investigational product administration.  Following a 
negative pregnancy result at screening, appropriate contraception must be commenced and a 
further negative pregnancy result will then be required at the baseline 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 hCG test, the patient will be withdrawn from treatment but may 
remain in the study. Additional pregnancy tests may also be undertaken if requested by 
IRB/ECs or if required by local regulations.
7.1.2. Adverse Events
Assessment of adverse events will include the type, incidence, severity (graded by the 
National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE
version 4.03) timing, seriousness, and relatedness.
Adverse events that occur during the study, including baseline signs and symptoms, will be 
recorded on the BSS adverse events CRF page.
7.1.3. Laboratory Safety Assessment
7.1.3.1. Hematology and Blood Chemistry  
Hematology and blood chemistry tests will include the parameters presented in Table 6
Blood tests will be drawn at the time points described in Schedule of Activity table and 
analyzed at local laboratories.  Additional blood tests may be performed at the investigator's 
discretion for the purpose of planning treatment administration, dose modification, or 
following adverse events.  There is no need to repeat hematology, chemistry, coagulation or 
urinalysis samples on Cycle 1 Day 1 (C1D1) if screening assessment performed within 
7 days prior to that date.
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Table 6.
Laboratory Test
Hematology
Chemistry
Urinalysis
Other
Hemoglobin
Hematocrit
RBC count
MCV
MCH
MCHC
Platelet count
WBC count
Total neutrophils (Abs or %)
Eosinophils (Abs or %)
Monocytes (Abs or %)
Basophils (Abs or %)
Lymphocytes (Abs or %)
BUN/urea and Creatinine
Glucose (fasting)
Calcium
Sodium
Potassium
Chloride
Total CO2 (Bicarbonate)
AST, ALT
Total Bilirubin
Alkaline phosphatase
Uric acid
Albumin
Total protein
Magnesium
Phosphorous or Phosphate
pH
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Leukocyte esterase
Urobilinogen
Urine bilirubin
Microscopya
Urine dipstick for urine  
protein: If positive 
collect 24-hr and 
microscopic (Reflex 
Testing)
Urine dipstick for urine 
blood: If positive collect 
a microscopic (Reflex 
Testing)
FSHb
HbsAg, HbcAb, HCVc,d
HIVc,d
β-hCGe
IgG, IgA, and IgMf
CA-19.9g
Biomarker Collectionh
Addition Test
Coagulation
Additional Tests (Needed 
for Hy’s law)***
PT or INR
PTT
AST, ALT (repeat)
Total bilirubin (repeat)
Albumin (repeat)
Alkaline phosphatase 
(repeat)
Direct bilirubin
Indirect bilirubin
Creatine kinase
GGT
PT/INR
Total bile acids
Acetaminophen drug and/or 
protein adduct levels
a.
Only if urine dipstick is positive for blood, protein, nitrites or leukocyte esterase.
b. At Screening only, in females who are amenorrheic for at least 12 consecutive months. 
c. At Screening only.
d. Viral disease screening test to be conducted by local laboratory where required by local regulations or if warranted by 
patient history.
e. Serum or urine β-hCG for females of childbearing potential.
f. Samples collected at Cycle 1 Days 1, 8 and 15, and at subsequent Cycles Days 1 and 15, EOT and follow-up.
g. Samples collected at Cycle 1 Days 1 and 22 and at subsequent even Cycles on Day 1 and at EOT.
h. See Table 7.
*** 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, alkaline phosphatase, total bile acids and acetaminophen drug and/or protein 
adduct levels. 
HBsAg, HbcAb, HCVAb, and HIV testing to demonstrate eligibility to be conducted by local 
laboratory where required by local regulations or if warranted by patient history.  In all other 
countries, testing should be considered if a patient is at risk for having undiagnosed infection 
(for example due to history of injection drug use or due to geographic location).  Testing will 
be conducted by the local laboratory.
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7.1.4. Vital Signs and Physical Examination
Patients will have a physical examination of major body systems to include weight, vital 
signs (BP, PR to be recorded in the sitting position after approximately 5 minutes of rest), 
assessment of ECOG performance status and height; height will be measured at screening 
only. Weight will be obtained at Screening, Days 1, 8, and 15 of every cycle, and at the EOT
and Follow-up visits.  A neurological examination will be performed as part of the physical 
examination at Cycle 1 Day (prior to dosing), Day 1 on all subsequent cycles (prior to 
dosing), EOT, and at the Follow-up visit (see Appendix 5).  
7.1.5. European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire C30 (QLQ-C30) in combination with the Chemotherapy-Induced 
Peripheral Neuropathy-20 Questionnaire (EORTC QLQ-CIPN20)
Questionnaires will be completed prior to any study or medical procedure on Cycle 1 Day 1
(-2 day window), Day 1 of all subsequent cycles, and at the End of Treatment visit. One 
final questionnaire will be completed 4 weeks after discontinuation of IP during the Follow-
up Visit.  All self-assessment questionnaires must be completed by the patients while in the 
clinic and cannot be taken home. Interviewer administration in the clinic may be used under 
special circumstances.
7.1.6. Triplicate (12-Lead) Electrocardiogram
Triplicate 12-lead (with a 10-second rhythm strip) tracing will be used for all ECGs.  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 (>480 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 >480 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 480 msec.  If QTcF 
interval reverts to less than 480 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
480 msec the investigational product will be held until the QTcF interval decreases to 
≤480 msec and to within 20 msec of baseline.  Additionally, 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.  
Patients will then restart the investigational product at the next lowest dose level.  If the 
QTcF interval has still not decreased to 480 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. 
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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. 
After Cycle 3, ECGs can be performed as clinically indicated.  All ECG collection time 
points are with respect to PF-04136309 morning dosing.  
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). A 15-min window for each ECG 
collection is allowed around the nominal ECG time point.
7.2. Pharmacokinetics Assessments
7.2.1. Blood for PF-04136309 Pharmacokinetic Analysis
Phase 1b Dose Escalation Cohorts: Blood samples for determination of the PF-04136309 
concentrations will be collected at the following timepoints:

Cycle 1 Day 1: within 6 hours prior to the first PF-04136309 dose on C1D1;

Cycle 1 Day 2 and Day 8: within 30 minutes prior to the morning dose of 
PF-04136309;

Cycle 1 Day 15: 0 hour (within 30 minutes prior to the morning dose of 
PF-04136309, and 0.5, 1, 2, 3, 4, and 6 hours after the morning dose;

Cycle 1 Day 16: within 30 minutes prior to the morning dose of PF-04136309;

Day 1 Cycle 2 and subsequent cycles: within 30 minutes of the morning dose of 
PF-04136309;

End of Treatment.
Phase 2: Blood samples for determination of the PF-04136309 concentrations will be 
collected at the following timepoints:

Cycle 1 Day 1: within 6 hours prior to the first PF-04136309 dose on Cycle 1 Day 1;

Cycle 1 Day 2, Day 8, Day 15: within 30 minutes prior to the morning dose of 
PF-04136309;

Day 1 of Cycle 2 and subsequent cycles: within 30 minutes prior to the morning dose 
of PF-04136309;
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
End of treatment.
On days when patients have clinical visits where PK assessments are to be obtained, the 
morning dose of PF-04136309 should be held (NOT taken) prior to the study visit.  On those 
days, the PF-04136309 morning dose can be taken after the study procedures required 
immediately prior to the PF-04136309 morning dose have been performed (including 
completion of the nab-paclitaxel and gemcitabine intravenous administration).
A PK sample should be collected matched with a biomarker sample any time an 
unscheduled/optional biomarker sample or FNA or core needle biopsy (±2 hours) is 
collected.
PK samples collected from patients randomized to receive nab-paclitaxel + gemcitabine + 
placebo will not be analyzed.
Blood samples (4 mL whole blood) sufficient to provide at least 1 mL of plasma will be 
collected into appropriately labeled tubes containing K2-EDTA as an anticoagulant for PK 
analysis of PF-04136309 as outlined in the Schedule of Activities (PHARMACOKINETIC 
AND PHARMACODYNAMIC SAMPLING SCHEDULE).  On days when patients have 
clinical visits where PK assessments are to be obtained, the morning dose of PF-04136309 
should be held (NOT taken) prior to the study visit, until the pre-dose PK sample on the day 
has been collected.  The exact time of the morning dose administration on the days of 
PF-04136309 PK sampling will be recorded in the CRF. The exact time of PK sample 
collection will also be recorded in the CRF.  PK sampling schedule may be modified based 
on emerging PK data. 
In addition to samples collected at the scheduled times, an additional blood sample should be 
collected from patients experiencing unexpected and/or serious AE’s and the date and time of 
blood sample collection and of last dosing prior to PK collection documented in the CRF.
Blood samples for PF-04136309 PK will be placed on ice and centrifuged at 4oC to obtain 
plasma within 10 minutes of blood sample collection. Plasma will be stored in appropriately
labeled screw-capped polypropylene tubes at approximately -20°C within 1 hour of 
collection.
Where noted in the Schedule of Activities, blood samples for PF-04136309 concentrations 
will be collected at approximately the same time as other assessments such as 
pharmacodynamic samples, ECGs and bone marrow aspirate collections etc., wherever 
possible. 
All efforts will be made to obtain the PK samples at the scheduled nominal time relative to 
dosing.  However, the exact time of the sample collection will always be noted on the CRF.  
If a scheduled blood sample collection cannot be completed for any reason, the missed 
sample time may be re-scheduled with agreement of the clinical investigator, patient, and 
sponsor.
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PK samples collected from patients receiving PF-04136309 will be assayed for PF-04136309 
using a validated analytical method in compliance with Pfizer standard operating procedures.  
PK samples collected from patients randomized to receive nab-paclitaxel, gemcitabine plus
Placebo (ARM B in Phase 2) will not be analyzed. Details regarding the collection, 
processing, storage and shipping of the blood samples will be provided in the study manual.
As part of the understanding of the PK of investigational product, PK samples may be used 
for potential qualitative and/or quantitative metabolite analyses and/or evaluation of the 
bioanalytical methods of PF-04136309. These data will be used for internal exploratory 
purposes and will not be included in the clinical report.
7.3. Biomarker and Pharmacodynamic Assessments
Optional, paired collections of core needle biopsy from a metastatic site or fine-needle 
aspirates (FNAs) from the primary tumor tissue (if sample collection from a metastatic site is 
not viable) will be performed on at least 12 patients in each treatment arm at screening and at 
the end of Cycle 1 Day 28 (±7 days) or at the end Cycle 2 Day 28 (±7 days), study Day 56, if 
sample not collected at C1D28. Core-needle biopsies or FNAs will be optional for patients 
participating in the Phase 1b cohorts.  For Phase 2 dose expansion cohorts, core-needle 
biopsies or FNAs will be optional; however, at least 12 paired biopsies will have to be 
available and fully assessable in each treatment arm, Arm A and Arm B, to allow the 
comparison.  An optional bone marrow aspirate (BMA) will be performed on at least
12 patients at Screening and at the end of Cycle 1 Day 28 (±7 days) or at the end Cycle 2 
Day 28 (±7 days), study Day 56 if sample not collected at C1D28.
Samples will be analyzed using the type of assays as described in Table 7 for evidence of
PF-04136309 pharmacodynamic activity and immunophenotyping of tumors and patients.  
Additional pathway-related markers (eg, a,b,c) may be included as pre-clinical studies or 
literature reports further elucidate the mechanism of action of PF-04136309 or the relevant 
signaling pathway or as new technology becomes available.  
Table 7 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 Lab Manual for details of sample preparation.
Table 7.
Biomarker Collections and Analyses
Biomarker
Sample Type
Analysis
Target Occupancy (3 mL)
Whole Blood
Ex vivo inhibition of CCL2-
induced, ERK phosphorylation by 
flow cytometry
Immune Cell Phenotypes (10 mL)
Core needle biopsy from a 
metastatic site or FNA from the 
primary tumor tissue; bone 
marrow aspirates; peripheral 
blood
CD14+CCR2+ monocytes and 
other  immune cell phenotypes by 
flow cytometry
CCL2, Cytokines, Chemokines 
and immune regulatory cytokines 
(4.5 mL)
Whole Blood for Plasma
preparation
The CCR2 ligand, CCL2, and 
other  immunomodulatory 
chemokines and cytokines by 
immunoassay
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Biomarker
Sample Type
Analysis
Transcriptional Profile RNA 
Profiling Peripheral Blood 
(2-2.5 mL)
Core needle biopsy from a 
metastatic site or FNA from the 
primary tumor tissue; bone 
marrow aspirates; peripheral 
blood (RNA)
RNA will be analyzed for 
expression profile of immune- and 
tumor-related transcripts.
T cell Repertoire in Peripheral 
Blood (4 mL)
Core needle biopsy from a 
metastatic site or FNA from the 
primary tumor tissue; peripheral 
blood (DNA)
DNA will be submitted to TCR 
sequencing analysis
Tumor Epitope Profile
Core needle biopsy from a 
metastatic site or FNA from the 
primary tumor tissue (DNA)
DNA will be submitted to whole 
exome sequencing analysis
7.4. Tumor Response Assessments
Tumor assessments will include all known or suspected disease sites.  Imaging may include 
chest, abdomen and pelvis computed tomography (CT) or magnetic resonance imaging 
(MRI) scans; brain CT or MRI scan for patients with known or suspected brain metastases; 
bone scan and/or bone X-rays for patients with known or suspected bone metastases.
CT or MRI scans are to be performed every 8 weeks – efficacy assessments start at the end of 
Cycle 2 Day 28, prior to the start of Cycle 3.  The allowable time window for disease 
assessments is 7 days while on treatment and up to -7 days for screening (ie, the screening 
time window is up to 35 days prior to registration).  Tumor assessment should be repeated at 
the end of treatment visit if more than 8 weeks have passed since the last evaluation.  When 
the study treatment is discontinued for reasons other than disease progression or patient 
refusal, patients will be followed and have tumor assessments performed every 8 weeks until 
(a) disease progression or death, (b) patient refusal or (c) start of another anti-cancer 
treatment, whichever occurs first.  Tumor assessments should be fixed according to the 
calendar, regardless of treatment delays.  For patients enrolled in the Phase 2 cohorts, 
responses of CR or PR must be confirmed by repeat assessment no less than 4 weeks after 
the criteria for response are first met.  The same imaging technique used to characterize each 
identified and reported lesion at baseline will be employed in the following tumor 
assessments.
Assessment of response will be made using RECIST version 1.1 (Appendix 1).
All patients’ files and radiologic images must be available for source verification and for 
potential peer review. Central review of imaging studies and clinical information 
documenting disease status will be performed to verify recurrence of mPDA or occurrence of 
secondary tumor. 
It is important to the integrity of the study that all imaging studies are forwarded to the
central review laboratory as each patient enrolls and progresses through the study.  Materials 
to be forwarded for independent review are all imaging studies performed on study,
preferably in digital format on compact disc, optical disc, or via process as specified in the 
Core Imaging Study Manual. All digital media must be in Digital Imaging and 
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Communications in Medicine (DICOM) format. Films may be forwarded for review if 
necessary; all films must be originals (second original films acceptable) rather than copies of 
films. Further information on materials to be forwarded for independent review is provided 
in the Core Imaging Study Manual.
7.5. Banked Biospecimens 
Studying the variation in genetic markers and other biomarkers may help to explain some of 
the variability in response seen with some drugs among different individuals.  This is referred 
to as pharmacogenomics/biomarker research.  Comparing the deoxyribonucleic acid (DNA), 
ribonucleic (RNA), protein, and metabolite variation patterns of patients who respond well 
and those who respond poorly to treatment may help to better define the most appropriate 
group of patients in which to target a given treatment. Collecting biospecimens for 
exploratory pharmacogenomics/biomarker research analyses and retaining them in the Pfizer 
BioBank makes it possible to better understand the drug’s mechanism of action and to seek 
explanations for differences in, for example, exposure, efficacy, tolerability, or safety not 
anticipated prior to the beginning of the study. Providing these biospecimens is a required 
study activity for study sites and patients, unless prohibited as such by local regulations or 
ethics committee decision. 
To protect patients’ confidentiality, the banked biospecimens and data generated from them 
will be coded with the patient’s study identification (ID) number.  Samples will be kept in a 
facility accessible only by swiping a badge.  Data will be stored on password-protected 
computer systems.  The key between the code and the patient’s personal identifiers will be 
held at the study site; the researchers using the biospecimens and data generated from them 
will not have access to the key nor any personally identifying information.  Biospecimens 
will be used only for the purposes described here and in the informed consent 
document/patient information sheet; any other uses require additional ethical approval.  
Unless a time limitation is required by local regulations or ethical requirements, 
biospecimens will be stored indefinitely to allow for future research on the topics described 
here, including research conducted during the lengthy drug development process and also 
post-marketing research.  Patients can withdraw their consent for the use of their 
biospecimens at any time by making a request to the investigator, in which case any 
remaining biospecimen will be destroyed; data already generated from the biospecimens will 
continue to be stored to protect the integrity of existing analyses.  It is very unlikely that 
results generated from the biospecimens will have any clinical, diagnostic, or therapeutic 
implications for the individual study participants.  Patients are notified in the informed 
consent document/patient information sheet that their results will not be given to them, unless 
required by local laws or regulations, in which case results will be returned via the 
investigator.  Results will not be provided to family members or other physicians; nor will 
they be recorded in the patient’s medical record.  There is no intention to contact patients 
after completion of the clinical study.
A 4 mL blood sample Prep D1 (K2 edetic acid (ethylenediaminetetraacetic acid) (EDTA) 
whole blood collection optimized for DNA analysis) will be collected at the Screening and 
Cycle 3, Day 1 (pre-dose) visit to be retained for potential pharmacogenomics/biomarker 
analyses related to drug response, unless prohibited by local regulations or ethics committee 
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decision.  For example, putative safety biomarkers, drug metabolizing enzyme genes, drug 
transport protein genes, or genes thought to be related to the mechanism of drug action may 
be examined. 
The Banked Biospecimen will be collected from all patients unless prohibited by local 
regulations.  Detailed collection, processing, storage and shipment instructions are provided 
in the central laboratory manual.
It is possible that the use of these biospecimens may result in commercially viable products.  
Patients will be advised in the informed consent document/patient information sheet that they 
will not be compensated in this event.
7.5.1. Additional Research
Unless prohibited by local regulations or ethics committee decision, patients will be asked to 
indicate on the consent form whether they will allow the banked biospecimens to also be 
used for the following research:

Investigations of the disease under study in the clinical study, and related conditions;

Biospecimens may be used as controls.  This includes use in case-control studies of 
diseases for which Pfizer is researching drug therapies; use in characterizing the 
natural variation amongst people in genes, RNA, proteins, and metabolites; and use in 
developing new technologies related to pharmacogenomics/biomarkers.  
Patients need not provide additional biospecimens for the uses described in this section; the 
biospecimens specified in Section 7.3 will be used.  Patients may still participate in the 
clinical study if they elect not to allow their banked biospecimens to be used for the 
additional purposes described in this section. 
7.6. Assessment of Suicidal Ideation and Behavior 
This section is not applicable. 
7.7. Triggered Requirements 
This section is not applicable. 
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 
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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;

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:
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
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;

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: 
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
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 
Severity Assessment).
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.
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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).
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 
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cases confirmed on repeat testing as meeting the laboratory criteria defined above, with no 
other cause for liver function test (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 a 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: 

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;
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
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
Investigators will report adverse events using concise medical terminology (verbatim) as well 
as collect on the CRF the appropriate Common Terminology Criteria for Adverse Events 
(CTCAE) (Version 4.03, Publish Date: 14 June 2010, 
http://ctep.cancer.gov/reporting/ctc.html) listed in the Cancer Therapy Evaluation Program.  
The investigator will use the following definitions of severity in accordance with the current 
CTCAE version to describe the maximum intensity of the adverse event.  
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.
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 
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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 woman (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 
to termination of pregnancy).
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 
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terminated fetus should be assessed by gross visual inspection (unless pre-procedure 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 
page.
When a patient withdraws because of an SAE, the SAE must be reported in accordance with 
the reporting requirements defined below.
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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.
8.15. Medical Device Complaint Reporting Requirements
This section is not applicable.
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8.16. 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
9.1. Data Analysis
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. The information may include details of missing and, if applicable, 
unused and spurious data.  Deviations from the statistical plan will be reported in the clinical 
study report.
This study is divided into 2 phases: 

Phase 1b: dose finding phase, and

Phase 2: randomized, double blinded, placebo controlled study.
9.1.1. Phase 1b
Patients will participate in a dose-escalation part aimed at estimating the MTD and RP2D.  
The sample size for this component of the study will vary depending on the number of DLTs 
observed.  
9.1.2. Phase 2
In the Phase 2 randomized study PFS will be the primary endpoint.
This randomized Phase 2 study is designed to determine whether Arm A is superior to 
Arm B. This trial is designed to detect a hazard ratio of 0.55 with 80% power at a two-sided 
0.2 level of significance. 
9.1.3. Analysis Sets 
Data Analysis will be performed on the following analysis population.
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 randomized patients. This is equivalent to the ITT 
(intent-to-treat) population.
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3. Per protocol analysis set (evaluable for MTD and RP2D).
The per protocol analysis set includes all enrolled patients who receive at least one dose 
of study treatment and who do not have major protocol deviations during first cycle.  
Patients with important protocol deviations during the first cycle of treatment are not 
evaluable for the MTD or RP2D assessment and will be replaced as needed. Important
protocol deviations may include failure to satisfy major entry criteria (eg, confirmation of 
the target disease; signed informed consent) or use of other anticancer treatments during 
the active treatment and disease follow-up phases other than as defined/allowed in this 
protocol.
4. Modified Intent-to-Treat (mITT) Population.
The modified intent-to-treat (mITT) is the analysis population that will follow the ITT 
principle and include subjects receiving at least 1 dose of study medication with baseline 
assessment and at least 1 post baseline assessment. The mITT population may be used 
for PD, biomarkers analyses and anti-tumor assessment.
5. PK analysis sets
The PK concentration population is defined as all patients receiving PF-04136309 
treatment, have no major protocol deviations affecting the PK assessment, and have at 
least 1 post-dose sample with measurable drug concentration.
6. Tumor Biopsies analysis sets
Tumor biopsies will be performed in the Phase 2 randomized study pre-treatment and
post- treatment after 1 or 2 cycles.  At least 12 paired biopsies will have to be available 
and fully assessable in each arm, arm A and arm B, to allow the comparison.  
9.2. Statistical Methods and Properties
9.2.1. Phase 1b
Patients will participate in a dose-escalation part aimed at estimating the MTD and RP2D.  
The sample size for this component of the study will vary depending on the number of DLTs 
observed.  This study phase has been designed to establish the Maximum Tolerated Dose 
(MTD) defined as the dose that yields approximately 27.5% probability of DLT and 
considers equivalent doses that yield probability of DLT in the interval (Equivalence 
Interval) 22.5% to 32.5%. The 27.5% target and the Equivalence Interval are chosen based 
on safety considerations and is considered appropriate based on simulations and expert input 
(see Sections 9.2.3 and 9.2.4).  
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9.2.2. Statistical Methods for Dose Escalation/De-Escalation (Phase 1b)
Many alternative designs have been proposed to the standard 3+3 design for Phase 1 dose 
escalation studies that improve its accuracy, efficiency and statistical validity. 
The modified toxicity probability interval (mTPI) design43 uses a Bayesian statistics 
framework and a beta/binomial hierarchical model to compute the posterior probability of 
3 dosing intervals that reflect the relative difference between the toxicity rate of each dose 
level to the target rate (pT = 0.275). 
The prior distribution of DLT is set as a beta (0.5,0.5) and the threshold probability for early 
termination and dose exclusion is set to 0.95 as suggested in the mTPI design.43  Doses with 
an incidence of DLT>33% (eg, 4 out of 10) cannot be selected as MTD although is allowed 
by the mTPI method. If the toxicity rate of the currently used dose level is far smaller than 
27.5%, the mTPI will recommend escalating the dose level; if it is close to 27.5%, the mTPI 
will recommend continuing at the current dose; if it is far greater than 27.5%, the mTPI will 
recommend de-escalating the dose level. Being a model-based design, mTPI automatically 
and appropriately tailors dose-escalation and de-escalation decisions. Target size for each 
cohort will be n= 2 to 4 patients as described in mTPI design.43  All the dose-escalation 
decisions for a given trial can be pre-calculated under the mTPI design and presented in a
two-way table. The decision rules to “dose escalate” (E), “no change in dose” (S), “dose de-
escalate” (D) or “dose de-escalate, unacceptable toxicity” (U) are described in Table 8.
Decision Rules.
Cohorts of patients could receive doses already tested but a dose that is associated with 
decision “Dose de-escalate, unacceptable toxicity” cannot be revisited and no more patients 
should be treated at this dose or higher doses for the remainder of the trial.
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Table 8.
Decision Rules
Number of Patient Treated at a Dose Level
Number of 
Patients 
Having DLT
n=2
n=3
n=4
n=5
n=6
n=7
n=8
n=9
n=10
n=11
n=12
N=13
N=14
N=15
0
E
E
E
E
E
E
E
E
E
E
E
E
E
E
1
S
S
S
E
E
E
E
E
E
E
E
E
E
E
2
U
D
S
S
S
S
S
S
S
S
E
E
E
E
3
U
U
D
D
S
S
S
S
S
S
S
S
E
4
U
U
U
U
D
D
D
D
S
S
S
S
5
U
U
U
U
U
D
D
D
D
D
S
6
U
U
U
U
U
U
U
D
D
D
7
U
U
U
U
U
U
U
U
U
D: De-escalate the dose; E: Escalate the dose; S: Stay at the dose; U: Unacceptable toxicity
Note: Starting dose is 750 mg BID. Escalation to a higher dose (eg 1000 mg BID) will require that at least 6 patients are dosed at 
750 mg BID and no more than 1 experienced a DLT.
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9.2.3. Statistical Method for Estimating the MTD and RP2D (Phase 1b)
An MTD may not be identified, as DLTs may not be frequently observed after administration 
of this investigational agent. Dose escalation may continue up to a predefined Maximum 
Feasible Dose (MFD) (eg 1000 mg) and the escalation is halted without a maximum tolerated 
dose (MTD) estimate. The study will continue accruing until one of the three stopping 
conditions below is triggered.  
The algorithm will stop if any of the following criteria is met:
1. MTD or RP2D has been identified with sufficient accuracy: at least 6 to 12 patients 
have been accumulated on a dose that is currently estimated to be the MTD or RP2D; 
or
2. All doses explored appear to be overly toxic.
Due to binomial data variability in small samples, DLTs may be observed in a first cohort(s) 
by chance even when the true Probability (DLT) is fairly low.  This could result in the 
estimated posterior DLT rate to exceed the targeted very early in the trial, triggering an early 
stop when very few patients (eg 3) have been treated.  To prevent stopping the trial 
prematurely in such cases, a step-down option with a lower dose of 500 mg added to the dose 
grid. 
9.2.4. Phase 2
In the Phase 2 randomized study PFS will be the primary endpoint.
This randomized Phase 2 study is designed to determine whether Arm A is superior to 
Arm B. This trial is designed to detect a hazard ratio of 0.55 with 80% power at a two-sided 
0.2 level of significance. 
9.3. Sample Size Determination
Phase 1b: The number of patients to be enrolled in the study will depend upon the observed 
safety profile, which will determine the number of patients at each dose level and the number 
of dose levels explored. It is envisaged that the maximum sample size at the RP2D would be 
N=12 (see Section 9.2.3). To further evaluate safety and pharmacodynamics, the number of 
patients enrolled during this part of the study (Phase 1b) may be N up to 20.
Phase 2: Ninety-two (92) patients will be randomized in a 1:1 ratio Arm A versus Arm B. 
Median PFS in patients enrolled in the control arm (Arm B) is expected to be approximately 
5.5 months. A total of 92 patients and 57 events are required for a log-rank test to have an 
overall 1-sided significance level of 0.1 (alpha=0.2) and power of 0.80.  This assumes an 
82% improvement in median PFS from 5.5 months to 10 months and an HR=0.55.  Predicted 
accrual is approximately n=7 patients per month and the predicted dropout rate is 
approximately 15% at 1 year. This sample size is also based on a planned non-binding 
Interim analysis that will be conducted when 60% of the PFS events are observed, by using 
Lan-DeMets alpha spending function (see Section 9.4.5). In addition, contingent upon 
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rejection of the null hypothesis for the PFS endpoint, this sample size allows to apply the log-
rank test to have an overall 1-sided significance level of 0.1 and power of 0.63 to 
demonstrate improvement of OS after 50 deaths are observed, assuming improvement in 
median OS from 8.5 months to 13.5 months and an HR=0.63.
9.4. Efficacy Analysis
9.4.1. Analysis of Progression-Free Survival (PFS)
PFS is defined as the time from randomization to first documentation of objective tumor
progression or to death due to any cause, whichever occurs first. PFS data will be censored
on the day following the date of the last on treatment (including 28 day follow-up period
after last dose) tumor assessment documenting absence of progressive disease for patients
who do not have objective tumor progression and who do not die due to any cause while on
treatment or who are given antitumor treatment other than the study treatment prior to
observing objective tumor progression. Patients lacking an evaluation of tumor response
after randomization will have their event time censored on the date of randomization with
duration of 1 day. PFS will be compared between the 2 treatment arms using a one-sided log-
rank test with a significance level of 0.1 (alpha=0.2). Cox proportional hazard models will 
be used to calculate the HR and to explore the potential influences of the baseline factors (eg,
age, gender and ethnic origin) on PFS. The PFS probability at 1 year will be estimated for 
each treatment arm using the Kaplan-Meier method and the 2-sided 80% and 90% 
confidence interval for the log [-log(1-year PFS probability)] will be calculated using a 
normal approximation and then back transformed to give the confidence interval for the 
1-year PFS rate itself.  Analyses of PFS will be conducted when n=57 PFS events are 
observed. An Interim Analysis (IA) will be conducted based on PFS after 34 patients have 
had an event, which is 60% of the total required number of events (ie, 57 events). Efficacy, 
in terms of PFS, would be declared at the time of the IA if the HR surpasses the IA boundary 
for efficacy that is HR≤0.533. Futility, in terms of PFS, would be declared at the time of IA 
if the HR surpasses the IA boundary for futility that is HR >0.863.
9.4.2. Analysis of Objective Overall Response (ORR: CR or PR)
ORR is defined as the proportion of patients with confirmed complete response (CR) or
confirmed partial response (PR) according to RECIST, relative to all randomized patients
who have baseline measurable disease. Confirmed responses are those that persist on repeat
imaging study ≥4 weeks after initial documentation of response. Patients who do not have
on-study radiographic tumor re-evaluation or who die, progress, or drop out for any reason
prior to reaching a CR or PR will be counted as non-responders in the assessment of ORR.  A 
patient, who initially meets the criteria for a PR and then subsequently becomes a confirmed 
CR, will be assigned a best response of CR.  
ORR, CR and PR point estimates for each treatment arm will be provided along with the 
corresponding 2-sided 95% confidence intervals using an exact method.44  The difference 
between the two treatments in Phase 2 will be estimated and the corresponding 80% and 95% 
confidence intervals will be constructed using an exact method.45
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9.4.3. Analysis of Duration of Objective Response (DR).
DR is defined as the time from the first documentation of objective tumor response to the
first documentation of objective tumor progression or to death due to any cause, whichever
occurs first. DR data will be censored on the day following the date of the last on treatment
(including 28 day follow-up period after last dose) tumor assessment documenting absence of
progressive disease for patients who do not have objective tumor progression and who do not 
die due to any cause while on treatment or who are given antitumor treatment other than the 
study treatment prior to observing objective tumor progression. Patients who achieve a PR
and then a CR will have times calculated using the date of the PR as the first day. DR will
only be calculated for the subgroup of patients with objective response.
Estimates of the DR curves from the Kaplan-Meier method will be presented.  This method 
will be applied to derive the median event time and a confidence interval for the median for 
each treatment arm.  
9.4.4. Analysis of Overall Survival (OS)
OS is defined as the time from date of randomization to date of death due to any cause. For
patients not expiring, their survival times will be censored at the last date they are known to
be alive. Patients lacking data beyond the day of randomization will have their survival
times censored at the date of randomization with duration of 1 day.
For the main analysis, OS in each arm will be assessed using the Kaplan-Meier method and 
treatment arms will be compared by using a log-rank test (alpha=0.2) in the intent-to-treat 
population. Although this study is not powered to detect significant differences in Overall 
Survival at the time of the primary analyses of PFS, analyses of OS (similarly to the analyses 
described in Section 9.4.1), with a statistical power = 63%, will be conducted after 50 deaths 
are observed, assuming an HR=0.63 and improvement in median OS from 8.5 months to 
13.5 months. First type error will not be inflated as this statistical comparison will be 
conducted conditionally upon rejection of the null hypothesis for the PFS endpoint (see
Section 9.4.1).
9.4.5. Statistical Methods for Interim Analysis 
A non-binding Interim Analysis (IA) will be conducted based on PFS after 34 patients have 
had an event, which is 60% of the total required number of events (ie, 57 events). Efficacy, 
in terms of PFS, would be declared at the time of the IA if the HR surpasses the IA boundary 
for efficacy that is HR≤0.533.  Futility, in terms of PFS, would be declared at the time of IA 
if the HR surpasses the IA boundary for futility that is HR>0.863.  Lan-DeMets alpha 
spending function with the O’Brien-Fleming boundaries46,47 was used to define both the 
boundaries for efficacy and futility.  This function spends the type-1 error very sparingly in 
the beginning but rapidly increase the pace of spending as the trial nears completion.
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9.5. Analysis of Pharmacokinetics and Pharmacodynamics 
9.5.1. Analysis of PF-04136309 Pharmacokinetics
The concentration-time data of PF-04136309 will be summarized by descriptive statistics 
(n, mean, standard deviation, median, minimum, and maximum) according to dose level.
For patients enrolled in the Phase 1 dose finding cohorts, the concentration-time data of 
PF-04136309 within the 12-hour dose interval on Day 15 (with the pre-dose sample collected 
on Day 16 as the 12-hour post dose sample) will be analyzed for individual patients using 
non-compartmental methods.  The noncompartmental analysis will estimate PK parameters 
including Cmax,ss, Tmax, AUCtau,ss, Cmin,ss, CLss/F, and as data permit, t1/2 and Vss/F.  The PK 
parameters will be summarized using descriptive statistics according to dosing cohort. 
The concentration-time data of PF-04136309 from all patients enrolled in the study will be 
using nonlinear mixed effect modeling.  The modeling-based analysis will estimate the 
typical value and variability for PK parameters including oral clearance (CL/F) and apparent 
volume of distribution (V/F).  Also, the influence of selected potential covariates on the PK 
parameters will be explored as appropriate; the potential covariates to be explored will 
include selected demographics (eg, body weight, age, sex) and selected patient characteristics 
(eg, baseline CCR2 expression, baseline CCL2 level, ECOG performance status, liver 
function markers).   
Population PK assessment will be conducted with the concentration-time data of 
PF-04136309 from all patients, using the nonlinear mixed effect modeling approach in 
accordance with regulatory guidances.  A structural PK model based on data from the 
Phase 1b portion will be used.  The population PK analysis will estimate typical value and 
variability for PK parameters including oral clearance (CL/F) and apparent volume of 
distribution (Vd/F).  Also, the influence of selected potential covariates on the PK parameters 
will be explored as appropriate; the potential covariates to be explored will include selected 
demographics (eg, body weight, age, sex) and selected patient characteristics (eg, baseline 
CCR2 expression, baseline CCL2 level, ECOG performance status, liver function markers).
The detailed procedures for the population PK analysis, including the model implementation 
and evaluation, will be described prospectively in the Population Modeling Analysis Plan 
(PMAP).  The results of the analysis will be summarized in a Population Modeling and 
Analysis Report (PMAR), separate from the clinical study report.
9.5.2. Analysis of Pharmacodynamics 
For FNA and core-biopsy 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.
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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/anti-cancer efficacy.
The percentage change from baseline for pharmacodynamics biomarkers over the period of 
the study will be tabulated by individual. The mean change from baseline values over time 
per cohort will also be tabulated. Data will be presented in tabular and/or graphical format 
and summarized descriptively. Changes from baseline in biomarker readouts will be 
correlated with pharmacokinetic and clinical measures, as appropriate. Pharmacodynamic 
biomarkers submitted to these analyses may include, but not be limited to:

Proportions of IM, TAM and other immune cell type of interest in peripheral blood, 
bone marrow and paired tumor biopsy.

CCL2 levels in the peripheral blood.

Relative expression of immune-related transcripts in tumor tissue and peripheral 
blood.

Expression level of tumor biomarkers including but not limited to CA 19.9.
9.5.3. Population Pharmacokinetic Analysis or Pharmacokinetic/Pharmacodynamic 
(PK/PD) Modeling 
Pharmacokinetic and pharmacodynamic 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-04136309 exposure and biomarkers or significant safety endpoints.  
The results of these analyses, if performed, may be reported separately.
9.6. Safety Analysis
Adverse events, ECGs, blood pressure, pulse rate, continuous cardiac monitoring, and safety 
laboratory data will be reviewed and summarized on an ongoing basis during the study to 
evaluate the safety of subjects.  Any clinical laboratory, ECG, BP, and PR abnormalities of 
potential clinical concern will be described.  Safety data will be presented in tabular and/or 
graphical format and summarized descriptively, where appropriate.
Medical history and physical examination and neurologic examination information, as 
applicable, collected during the course of the study will be considered source data and will 
not be required to be reported, unless otherwise noted.  However, any untoward findings 
identified on physical and/or neurologic examinations conducted after the administration of 
the first dose of study medication will be captured as an adverse event, if those findings meet 
the definition of an adverse event. Data collected at Screening that is used for 
inclusion/exclusion criteria, such as laboratory data, ECGs and vital signs will be considered 
source data, and will not be required to be reported, unless otherwise noted.  Demographic 
data collected at Screening will be reported.
Summaries and analyses of safety parameters will include all patients in the Safety Analysis 
Set.
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9.6.1. Analysis of the Primary Endpoint
Phase 1b: 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 and RP2D as described in the STUDY DESIGN section.  Adverse Events 
constituting DLTs will be listed per dose level.
Adverse Events
Adverse Events (AEs) will be graded by the investigator according to the Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03 and coded using the 
Medical Dictionary for Regulatory Activities (MedDRA).  The focus of AE summaries will 
be on Treatment Emergent Adverse Events, 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, serious AE (SAE), treatment related AE, 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 (Cycle 1 and Cycles beyond 1). 
Laboratory Test Abnormalities
The number and percentage of patients who experienced 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 
(Cycle 1 and Cycles beyond 1).  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. 
Phase 2: PFS is the primary endpoint (see Section 9.4.1).
9.6.2. Analysis of Secondary Safety Endpoints
9.6.2.1. Electrocardiogram
The analysis of ECG results will be based on patients in the safety analysis set with baseline 
(Screening) and on-treatment ECG data.
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 (default correction), Bazett’s, and possibly a study specific factor, as appropriate].  
Data will be summarized and listed for QT, HR, response rate (RR), PR, QRS, QTcF (and 
other correction factors, eg, QTcB as appropriate), and by study arm and dose.  Individual 
QT` (all evaluated corrections) intervals will be listed by study arm time and dose.  The most 
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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 
study arm 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 (one or more 
correction method will be used) 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.
9.6.2.2. Analyses of Peripheral Neurological Adverse Events, EORTC QLQ-C30 and 
QLQ-CIPN20 Questionnaires
Summary statistics, including frequencies, means, medians, range will be conducted. Times 
to neurotoxic events will be calculated, and Kaplan- Meier techniques will be employed to 
evaluate differences in treatment arms. Multi-variate analysis to adjust for some parameters 
may be conducted, if deemed appropriate.
Response to all questions of EORTC QLQ-30 and QLQ-CIPN20 questionnaires will be 
shown in percentage.  Logistic regression analyses may be conducted at each visit to detect 
potential differences regarding neuropathy problems at the corresponding visit (EORTC 
QLQ-CIPN20 or QLQ-30 (except the last two questions on global health status); answer 
categories “quite a bit” or “very much” combined) between the two treatments in Phase 2.
Summary statistics will be provided by treatment for the raw scores of functional, Symptom 
and global health status raw subscales in QLQ-C30 as well as for linearly converted scores 
on the scale of 0-100 for these subscales. Summary statistics will also be provided for the 
raw scores of sensory, motor and automic scales raw subscales in QLQ-CIPN20 as well as 
for linearly converted scores on the scale of 0-100 for these subscales. Analysis of covariance 
(ANCOVA) models which include covariates of treatment and baseline may be employed to 
compare the two treatments by visit in each of the three-category scales of QOL-C30 and 
each of the three-category scales of QLQ-CIPN20.
Details of analyses of peripheral neurological adverse events, EORTC QLQ-C30 and QLQ-
CIPN20 questionnaire will be provided in the SAP.
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9.7. Analysis of Other Endpoints
Analyses of ORR, DR, OS and other Pharmacokinetics and Pharmacodynamics endpoints are 
described in Section 9.4.2, 9.4.4 and 9.5 respectively.
9.8. Data Safety Monitoring Committee 
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 is 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.
An external Data Monitoring Committee (DMC) will be established for the Phase 2 portion 
study. The external DMC will evaluate efficacy and safety data and make a recommendation 
about early termination due to observed results of the study.
9.9. Interim Analysis  
Phase 1/b: This is a sponsor-open study.  The Sponsor will conduct reviews of the data 
during the course of the study for the purpose of safety assessment, facilitating dose-
escalation decisions, facilitating PK/PD modeling, and/or to support clinical development.
Phase 2: The Phase 2 portion of the study is a double-blind randomized, multi-center, 
comparative safety and efficacy assessment of PF-04136309 in combination with nab-
paclitaxel + gemcitabine versus SOC: nab-paclitaxel + gemcitabine + placebo in patients 
with mPDA.
Safety: An external DMC will monitor the safety of the patients on a periodic basis. The 
DMC will determine whether the trial should be terminated based on ongoing reviews of 
safety data. 
Efficacy: The external DMC will also evaluate efficacy data and make a recommendation 
about early termination due to observed results of the study (see Section 9.4.5). Unblinded 
results will be reviewed by a designated limited number of experts. Refer to the study’s Data 
Blinding Plan and/or Statistical Analysis Plan for specific details including delineation of 
members who will be involved in these unblinded reviews as well as steps to be instituted 
ahead of initiation of any unblinded review to ensure study integrity is maintained. 
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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 institutional review board (IRB)/ethics committee (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.
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.
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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 International Conference on Harmonisation
(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.  
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.
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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 1996 and 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.
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 when applicable, 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.  All advertisements must be approved by the study Sponsor prior to 
use.
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.
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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
13.1. End of Trial in a Member State
End of trial in a Member State of the European Union (EU) is defined as the time at which it 
is deemed that a sufficient number of patients have been recruited and completed the study as 
stated in the regulatory application (ie, clinical trial application (CTA)) and ethics application 
in the Member State.  Poor recruitment (recruiting less than the anticipated number in the 
CTA) by a Member State is not a reason for premature termination but is considered a 
normal conclusion to the study in that Member State.
13.2. End of Trial in All Participating Countries 
End of trial in all participating countries is defined as the time at which all patients enrolled 
in the study have completed the last study visit and data from those visits have been reviewed 
by the investigator or designee.
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-04136309 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 one week.  As directed by Pfizer, all study 
materials must be collected and all CRFs completed to the greatest extent possible.
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. 
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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 prespecified protocol or was terminated.
EudraCT
Pfizer posts 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.
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.
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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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22. Zhang H, Boyette-Davis JA, Kosturakis AK, et al. Induction of monocyte 
chemoattractant protein-1 (MCP-1) and its receptor CCR2 in primary sensory neurons 
contributes to paclitaxel-induced peripheral neuropathy. J Pain 2013; 14(10):1031-44.
23. Postma TJ, Aaronson NK, Heimans JJ, et al. The development of an EORTC quality of 
life questionnaire to assess chemotherapy-induced peripheral neuropathy: the QLQ-
CIPN20. Eur J Cancer 2005; 41(8):1135-9.
24. Lavoie Smith EM, Barton DL, Qin R, et al. Assessing patient-reported peripheral 
neuropathy: the reliability and validity of the European Organization for Research and 
Treatment of Cancer QLQ-CIPN20 Questionnaire. Qual Life Res 2013; 22(10):2787-99.
25. Loprinzi CL, Qin R, Dakhil SR, et al. Phase III Randomized, Placebo-Controlled, 
Double-Blind Study of Intravenous Calcium and Magnesium to Prevent Oxaliplatin-
Induced Sensory Neurotoxicity (N08CB/Alliance). J Clin Oncol 2014; 32(10):997-1005.
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26. Pachman DR, Qin R, Seisler DK, et al. Clinical Course of Oxaliplatin-Induced 
Neuropathy: Results From the Randomized Phase III Trial N08CB (Alliance). J Clin
Oncol 2015; 33(30):3416-22.
27. Leal AD, Qin R, Atherton PJ, et al. North Central Cancer Treatment Group/Alliance Trial 
N08CA-The Use of Glutathione for Prevention of Paclitaxel/Carboplatin-Induced 
Peripheral Neuropathy. Cancer 2014; 120(12):1890-7.
28. Puttabasavaiah S, Heshan L, Qin R, et al. A comparison of simple single-item measures 
and the NCI Common Toxicity Criteria version 3.0 measure of peripheral neuropathy. J 
Clin Oncol 2012; 30(Suppl 15):Abstr 1557.
29. Mitchem JB, Brennan DJ, Knolhoff BL et al. Targeting tumor-infiltrating macrophages 
decreases tumor-initiating cells, relieves immunosuppression, and improves 
chemotherapeutic responses. Cancer Res. 2013 Feb 1;73(3):1128-41.
30. Chanmee T, Ontong P, Konno K, Itano N Tumor-associated macrophages as major 
players in the tumor microenvironment. Cancers (Basel). 2014 Aug 13;6(3):1670-90.
31. Mantovani A, Sica A. Macrophages, innate immunity and cancer: balance, tolerance, and 
diversity. Curr Opin Immunol. 2010 Apr;22(2):231-7.
32. Franklin RA, Liao W, Sarkar A, The cellular and molecular origin of tumor-associated 
macrophages. Science. 2014;344(6186):921-5.
33. Chanmee T, Ontong P, Konno K, Itano N Tumor-associated macrophages as major 
players in the tumor microenvironment. Cancers (Basel). 2014 Aug 13;6(3):1670-90.
34. Mantovani A, Sica A. Macrophages, innate immunity and cancer: balance, tolerance, and 
diversity. Curr Opin Immunol. 2010 Apr;22(2):231-7.
35. Y Ji, P Liu, Y Li, and BN Bekele. A modified toxicity probability interval method for 
dose-finding trials. Clinical Trials 2010;7:653-66.
36. M. Fanale, L. Fayad, B. Pro, F. Samaniego, M. Liboon, C. Nunez, S. Horowitz, P. 
Anderlini, U. Popat, Y. Ji, LW. Kwak, and A. Younes. Phase I study of bortezomib plus 
ICE (BICE) for the treatment of relapsed/refractory Hodgkin lymphoma. British Journal 
of Haematology 2011;154:284-286.
37. Dykstra R, Robertson T. An algorithm for isotonic regression for two or more 
independent variables. Ann Stat. 1982;10:708-716.
38. Bonapace L, Coissieux MM, Wyckoff J, et al. Cessation of CCL2 inhibition accelerates 
breast cancer metastasis by promoting angiogenesis. Nature 2014; 515(7525):130-3.
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39. Wang-Gillam, et al. Phase 1b study of FOLFIRINOX plus PF-04136309 in patients with 
borderline resectable and locally advanced pancreatic adenocarcinoma(PC). J Clin Oncol 
2015; 3(Suppl):Abstr 338.
40. Von Hoff DD, Ervin T, Arena FP, et al.  Increased survival on pancreatic cancer with 
nab-paclitaxel plus gemcitabine.  N Engl J Med 2013;369(18):1691-703.
41. “Metabolism and Transport, Drug Interaction Database,” Department of Pharmaceutics, 
University of Washington. www.druginteractioninfo.org. Accessed May 2009.
42. 2006 Update of Recommendations for the Use of White Blood Cell Growth Factors: An 
Evidence-Based Clinical Practice Guideline. JCO Jul 1, 2006:3187-3205.
43. Ji Y & Wang SJ.  Modified toxicity probability interval design: A safer and more reliable 
method than the 3+3 design for practical Phase 1 trials.  J Clin. Onc. 2013;31:1-12.
44. Blyth, C. R. and Still, H. A. (1983). Binomial Confidence Intervals. Journal of the 
American Statistical Association 78, 108–116.
45. Chan, I. S. F. and Zhang, Z. (1999), "Test-Based Exact Confidence Intervals for the 
Difference of Two Binomial Proportions," Biometrics, 55, 1202–1209.
46. DeMets DL, Lan KK. Interim analysis: the alpha spending function approach. Stat Med 
1994; 13(13-14):1341-52; discussion 1353-6.
47. Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika 
1983; 70:659-63.
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Appendix 1. RECIST (Response Evaluation Criteria In Solid Tumors) version 
1.1 Guidelines
Adapted from E.A. Eisenhauer, et al: New response evaluation criteria in solid tumours: 
Revised RECIST guideline (version 1.1). European Journal of Cancer 45 (2009) 228–247. 
CATEGORIZING LESIONS AT BASELINE
Measurable Lesions
Lesions that can be accurately measured in at least one dimension.

Lesions with longest diameter twice the slice thickness and at least 10 mm or greater 
when assessed by CT or MRI (slice thickness 5-8 mm).

Lesions with longest diameter at least 20 mm when assessed by Chest X-ray. 

Superficial lesions with longest diameter 10 mm or greater when assessed by caliper.

Malignant lymph nodes with the short axis 15 mm or greater when assessed by CT.
NOTE: The shortest axis is used as the diameter for malignant lymph nodes, longest 
axis for all other measurable lesions. 
Non-measurable disease
Non-measurable disease includes lesions too small to be considered measurable (including 
nodes with short axis between 10 and 14.9 mm) and truly non-measurable disease such as
pleural or pericardial effusions, ascites, inflammatory breast disease, leptomeningeal disease, 
lymphangitic involvement of skin or lung, clinical lesions that cannot be accurately measured 
with calipers, abdominal masses identified by physical exam that are not measurable by 
reproducible imaging techniques.

Bone disease: Bone disease is non-measurable with the exception of soft tissue 
components that can be evaluated by CT or MRI and meet the definition of 
measurability at baseline. 

Previous local treatment: A previously irradiated lesion (or lesion subjected to other 
local treatment) is non-measurable unless it has progressed since completion of 
treatment.
Normal sites

Cystic lesions: Simple cysts should not be considered as malignant lesions and should 
not be recorded either as target or non-target disease.  Cystic lesions thought to 
represent cystic metastases can be measurable lesions, if they meet the specific 
definition above.  If non-cystic lesions are also present, these are preferred as target 
lesions.
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
Normal nodes: Nodes with short axis <10 mm are considered normal and should not 
be recorded or followed either as measurable or non-measurable disease.
Recording Tumor Assessments 
All sites of disease must be assessed at baseline.  Baseline assessments should be done as 
close as possible prior to study start.  For an adequate baseline assessment, all required scans 
must be done within 28 days prior to treatment and all disease must be documented 
appropriately.  If baseline assessment is inadequate, subsequent statuses generally should be 
indeterminate.
Note: For the patient population being evaluated in this protocol, the baseline assessment 
may be completed within 6 weeks prior to randomization. 
Target lesions
All measurable lesions up to a maximum of 2 lesions per organ, 5 lesions in total, 
representative of all involved organs, should be identified as target lesions at baseline.  
Target lesions should be selected on the basis of size (longest lesions) and suitability for 
accurate repeated measurements.  Record the longest diameter for each lesion, except in the 
case of pathological lymph nodes for which the short axis should be recorded.  The sum of 
the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions 
at baseline will be the basis for comparison to assessments performed on study. 

If two target lesions coalesce the measurement of the coalesced mass is used.  If a 
large target lesion splits, the sum of the parts is used.

Measurements for target lesions that become small should continue to be recorded.  If 
a target lesion becomes too small to measure, 0 mm should be recorded if the lesion is 
considered to have disappeared; otherwise a default value of 5 mm should be 
recorded.
NOTE: When nodal lesions decrease to <10 mm (normal), the actual measurement 
should still be recorded.
Non-target disease 
All non-measurable disease is non-target. All measurable lesions not identified as target 
lesions are also included as non-target disease.  Measurements are not required but rather 
assessments will be expressed as ABSENT, INDETERMINATE, PRESENT/NOT 
INCREASED, INCREASED.  Multiple non-target lesions in one organ may be recorded as a 
single item on the case report form (eg, ‘multiple enlarged pelvic lymph nodes’ or ‘multiple 
liver metastases’).
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OBJECTIVE RESPONSE STATUS AT EACH EVALUATION
Disease sites must be assessed using the same technique as baseline, including consistent 
administration of contrast and timing of scanning.  If a change needs to be made the case 
must be discussed with the radiologist to determine if substitution is possible.  If not, 
subsequent objective statuses are indeterminate. 
Target disease

Complete Response (CR): Complete disappearance of all target lesions with the 
exception of nodal disease.  All target nodes must decrease to normal size (short axis 
<10 mm).  All target lesions must be assessed.

Partial Response (PR): Greater than or equal to 30% decrease under baseline of the 
sum of diameters of all target measurable lesions.  The short diameter is used in the 
sum for target nodes, while the longest diameter is used in the sum for all other target 
lesions.  All target lesions must be assessed. 

Stable: Does not qualify for CR, PR or Progression.  All target lesions must be 
assessed.  Stable can follow PR only in the rare case that the sum increases by less 
than 20% from the nadir, but enough that a previously documented 30% decrease no 
longer holds. 

Objective Progression (PD): 20% increase in the sum of diameters of target 
measurable lesions above the smallest sum observed (over baseline if no decrease in 
the sum is observed during therapy), with a minimum absolute increase of 5 mm. 

Indeterminate. Progression has not been documented, and 

one or more target measurable lesions have not been assessed; 

or assessment methods used were inconsistent with those used at baseline;

or one or more target lesions cannot be measured accurately (eg, poorly visible 
unless due to being too small to measure);

or one or more target lesions were excised or irradiated and have not reappeared 
or increased. 
Non-target disease

CR: Disappearance of all non-target lesions and normalization of tumor marker 
levels. All lymph nodes must be ‘normal’ in size (<10 mm short axis).

Non-CR/Non-PD: Persistence of any non-target lesions and/or tumor marker level 
above the normal limits. 
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
PD: Unequivocal progression of pre-existing lesions. Generally the overall tumor 
burden must increase sufficiently to merit discontinuation of therapy.  In the 
presence of SD or PR in target disease, progression due to unequivocal increase in 
non-target disease should be rare. 

Indeterminate: Progression has not been determined and one or more non-target 
sites were not assessed or assessment methods were inconsistent with those used 
at baseline.
New Lesions 
The appearance of any new unequivocal malignant lesion indicates PD.  If a new lesion is 
equivocal, for example due to its small size, continued assessment will clarify the etiology.  
If repeat assessments confirm the lesion, then progression should be recorded on the date of 
the initial assessment.  A lesion identified in an area not previously scanned will be 
considered a new lesion.
Supplemental Investigations

If CR determination depends on a residual lesion that decreased in size but did not 
disappear completely, it is recommended the residual lesion be investigated with 
biopsy or fine needle aspirate.  If no disease is identified, objective status is CR.

If progression determination depends on a lesion with an increase possibly due to 
necrosis, the lesion may be investigated with biopsy or fine needle aspirate to clarify 
status. 
Subjective progression
Patients requiring discontinuation of treatment without objective evidence of disease 
progression should not be reported as PD on tumor assessment CRFs.  This should be 
indicated on the end of treatment CRF as off treatment due to Global Deterioration of Health 
Status.  Every effort should be made to document objective progression even after 
discontinuation of treatment. 
Table 1. Objective Response Status at each Evaluation
Target Lesions
Non-target Disease
New Lesions
Objective status
CR
CR
No
CR
CR
Non-CR/Non-PD
No
PR
CR
Indeterminate or Missing
No
PR
PR
Non-CR/Non-PD, 
Indeterminate, or Missing
No
PR
SD
Non-CR/Non-PD, 
Indeterminate, or Missing
No
Stable
Indeterminate or 
Missing
Non-PD
No
Indeterminate
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
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If the protocol allows enrollment of patients with only non-target disease, the following table 
will be used:
Table 2. Objective Response Status at each Evaluation for Patients with Non-Target Disease Only
Non-target Disease
New Lesions
Objective status
CR
No
CR
Non-CR/Non-PD
No
Non-CR/Non-PD
Indeterminate
No
Indeterminate
Unequivocal progression
Yes or No
PD
Any
Yes
PD
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Appendix 2. National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE)
The NCI CTCAE (Version 4.03 date June 14, 2010) has been placed in the Study Manual for 
this protocol.  Alternatively, the NCI CTCAE may be reviewed on-line at the following NCI 
website: http://ctep.cancer.gov/reporting/ctc.html
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Appendix 3. ECOG Performance Status
Grade
ECOG Performance Status
0
Fully active, able to carry on all pre-disease performance without restriction.
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, eg, light house work, office work.
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities.  Up and about more than 50% of waking hours.
3
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours.
4
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed 
or chair.
5
Dead.
*As published in Am J Clin Oncol 5:649-655, 1982.
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Appendix 4. Sample Patient Study Drug Log
Complete this Patient Study Drug Log to ensure all doses are accounted for.
Patient Number: _______ - ________
Date
(DD/MMM/YYYY)
Dose
Reasons for missed doses, description of any 
symptoms, or other.
Morning 
(AM)
Night 
(PM)
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Appendix 5. Neurotoxicity Examination
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Appendix 6. EORTC Quality of Life Questionnaire C30
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Appendix 7. EORTC Quality of Life Questionnaire CIPN20
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SAP_001.pdf: 
Protocol A9421018 (PF-04136309) 
Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
Page 1
PROTOCOL A9421018
PHASE 1B/2 STUDY OF PF-04136309 IN COMBINATION WITH GEMCITABINE
AND NAB-PACLITAXEL IN PATIENTS WITH PREVIOUSLY UNTREATED
METASTATIC PANCREATIC DUCTAL ADENOCARCINOMA
STATISTICAL ANALYSIS PLAN 
(SAP)
Version:
1.0
Author: 
(Early Oncology Development and Clinical Research Statistics, Cambridge, 
MA, USA)
Date:     8-APR-2016
PPD
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................3
APPENDICES...........................................................................................................................4
1. VERSION HISTORY............................................................................................................5
2. INTRODUCTION.................................................................................................................5
2.1. Study Objectives .......................................................................................................5
2.2. Study Design.............................................................................................................7
2.2.1. Phase 1b study: open label dose finding.......................................................7
2.2.2. Phase 2: a randomized double blinded placebo control study......................8
3. ENDPOINTS AND COVARIATES: DEFINITIONS AND CONVENTIONS...................9
3.1. Primary Endpoint(s)..................................................................................................9
3.2. Secondary Endpoint(s)..............................................................................................9
3.3. Exploratory Endpoints ............................................................................................10
3.4. Covariates ...............................................................................................................11
4. ANALYSIS SETS...............................................................................................................11
4.1. Full Analysis Set.....................................................................................................11
4.2. Safety Analysis Set .................................................................................................11
4.3. ‘PER PROTOCOL’ Analysis Set ...........................................................................11
4.4. PK Analysis Set ......................................................................................................11
4.4.1. PK Concentration Set .................................................................................11
4.4.2. PK Parameter Set........................................................................................11
4.5. PD Biomarker Analysis Set ....................................................................................11
4.6. Modified Intent-to-Treat Set...................................................................................12
4.7. Treatment Misallocations........................................................................................12
4.8. Protocol Deviations.................................................................................................12
5. GENERAL METHODOLOGY AND CONVENTIONS ...................................................12
5.1. Statistical Hypotheses .............................................................................................12
5.2. Statistical Decision Rules .......................................................................................12
5.2.1. Part 1b.........................................................................................................12
5.2.2. Phase 2........................................................................................................14
5.3. General Methods.....................................................................................................15
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5.3.1. Analyses for Time to Event Data ...............................................................15
5.3.2. Analyses for Binary Data ...........................................................................16
5.3.3. Analyses for Continuous Data....................................................................16
5.4. Methods to Manage Missing Data ..........................................................................16
5.4.1. Missing Dates.............................................................................................16
5.4.2. Efficacy Analysis .......................................................................................16
5.4.3. Pharmacokinetics........................................................................................16
5.4.4. Pharmacodynamic and health outcome parameters ...................................17
6. ANALYSES AND SUMMARIES......................................................................................17
6.1. Standard Analyses...................................................................................................17
6.2. Analysis of Primary Endpoints ...............................................................................19
6.2.1. DLT(Part 1) ................................................................................................19
6.2.2. Safety Endpoints.........................................................................................20
6.2.3. PFS (Phase 2) .............................................................................................20
6.3. Analysis for Other Endpoints..................................................................................21
6.3.1. Other Efficacy Endpoints Analysis ............................................................21
6.3.2. Pharmacokinetics Analyses........................................................................22
6.3.3. Analysis of Pharmacodynamics..................................................................23
6.3.4. Population Pharmacokinetic Analysis or
Pharmacokinetic/Pharmacodynamic (PK/PD) Modeling (Phase 1b and 
Phase 2)............................................................................................................24
6.3.5. Analysis of Peripheral Neurological Adverse Events and EORTC 
QOL-C30 and QLQ-CIPN20 Questionaire (Phase 2).....................................24
6.4. ECG and Vital Sign Data Analysis.........................................................................25
7. INTERIM ANALYSES.......................................................................................................26
8. REFERENCES....................................................................................................................27
9. APPENDICES.....................................................................................................................28
LIST OF TABLES
Table 1.
………………………………………………………………………………......13
Table 2.
Progression Free Survival and Duration of Response..........................................30
Table 3.
Time to Progression with the double combination PF-04136309 and 
gemcitabine (maintenance therapy) after interruption of nab-paclitaxel .............30
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Table 4.
Objective Response Status at each Evaluation.....................................................36
Table 5.
Objective Response Status at each Evaluation for Patients with Non-Target 
Disease Only.........................................................................................................37
APPENDICES
Appendix 1. Details of Definitions of Endpoints ....................................................................28
Appendix 2. Time to Event Data Analysis Censoring Rules ..................................................30
Appendix 3. Categorical Classes for ECG and Vital Signs.....................................................32
Appendix 4. RECIST 1.1 Tumor Assessment Criteria............................................................33
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1. VERSION HISTORY
This is the first version of statistical analysis plan, based on the protocol amendment dated Nov. 
25, 2015 [1]. 
2. INTRODUCTION
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in study A9421018.  This document may modify the plans outlined in the protocol; 
however, any major modifications of the primary endpoint definition or its analysis will also be 
reflected in a protocol amendment.
2.1. Study Objectives
Phase 1b (Dose Finding) Objectives
Primary Objectives

To evaluate the safety and tolerability of PF-04136309 in combination with nab 
paclitaxel and gemcitabine in patients with metastatic pancreatic ductal carcinoma.

To characterize the dose limiting toxicities (DLTs) and overall safety profile of
escalated doses of PF-04136309 and the associated schedule.

To determine the maximum tolerated dose (MTD) of PF-04136309 and select the
Recommended Phase 2 Dose (RP2D).
Secondary Objectives

To evaluate the pharmacokinetics (PK) of PF-04136309 when given in combination
with nab-paclitaxel and gemcitabine in combination.

To characterize the ex vivo inhibition of CCL2-induced ERK kinase phosphorylation as 
a measure of target engagement following treatment with PF-04136309 in combination 
with nab-paclitaxel + gemcitabine at each dose level.
 
 
 
 
CCI
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Phase 2 (Randomized Double Blinded Placebo Control Study) Objectives 
Primary Objectives

To assess the enhancement of efficacy of PF-04136309 in combination with 
nab- paclitaxel and gemcitabine versus nab-paclitaxel + gemcitabine + placebo in terms 
of progression free survival (PFS).
Secondary Objectives

To assess the enhancement of efficacy of PF-04136309 in combination with 
nab- paclitaxel and gemcitabine versus nab-paclitaxel + gemcitabine + placebo in terms 
of Overall Survival (OS).

To assess the enhancement of efficacy of PF-04136309 in combination with 
nab- paclitaxel and gemcitabine versus nab-paclitaxel + gemcitabine + placebo in terms 
of Objective Response Rate (ORR) and duration of response.

To evaluate the safety and tolerability of PF-04136309 in combination with 
nab- paclitaxel + gemcitabine.

To evaluate the population PK of PF-04136309 given in combination with 
nab- paclitaxel + gemcitabine.

To validate the proof of mechanism of PF-04136309 in combination with 
nab- paclitaxel + gemcitabine compared to nab-paclitaxel + gemcitabine + placebo.

To evaluate the improvement of peripheral neurotoxicity induced by nab- paclitaxel by
the addition of PF-04136309 to the combination therapy of nab- paclitaxel plus 
gemcitabine.
C
C
I
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2.2. Study Design
This is a multi-center Phase 1b/2 study in the first line treatment of patients with metastatic
pancreatic ductal adenocarcinoma (mPDA).
The Phase 1b will be open label as patients will receive ascending doses of PF-04136309 in
combination with nab-paclitaxel + gemcitabine.  The Phase 2 will be controlled, randomized
and double blinded as patients will be randomized to receive PF-04136309 in combination with 
nab-paclitaxel + gemcitabine (ARM A) versus nab-paclitaxel + gemcitabine + placebo (ARM 
B: Standard of Care).
2.2.1. Phase 1b study: open label dose finding.
The Phase 1b part of the study is a dose finding phase study.  In the dose finding phase, 
patients will be enrolled in cohorts of 2 to 4 patients, starting with 750 mg BID of 
PF-04136309.  A new cohort of n=2 to 4 patients exposed to the same dose 750 mg twice
daily (BID) could be opened after safety has been established for at least the first cycle in all 
patients in the previous cohort.  Escalation to a higher dose (eg 1000 mg BID) will require that 
at least n=6 patients are dosed at 750 mg BID and no more than 1 experienced a DLT.
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An MTD may not be identified, as DLTs may not be observed after administration of this
investigational agent.  Based on safety data, and, PK and PD data, dose escalation may
continue up to a predefined Maximum Feasible Dose (ie, 1000 mg BID) or Phase
2 recommended dose.
Dose levels may include de-escalation (500 mg BID) if a high number of the patients (ie,>33%) 
receiving 750 mg BID experiences a DLT related to PF-04136309.  Based on safety and other 
results (eg, PK) from patients enrolled in the dose escalation cohorts, a dose level will be
selected to be further evaluated as the Recommended Phase 2 Dose (RP2D).  A minimum of 
6 to 12 patients will be treated at this dose level to establish it as the RP2D.
2.2.2. Phase 2: a randomized double blinded placebo control study 
In the Phase 2 part, ninety-two (92) patients will be randomized with a 1:1 to receive 
PF-04136309 in combination with nab-paclitaxel + gemcitabine (ARM A; n=46) versus 
nab-paclitaxel + gemcitabine + placebo (ARM B; n=46).  The primary objective will be the 
enhancement of efficacy in terms of PFS.
Given the dynamic feature of this design, the exact number of dose arms that will be expanded 
cannot be prespecified, as it will depend on safety and anti-tumor activity.
In both studies, treatment may continue until progression of disease (PD) unacceptable toxicity
or patient refusal, whichever comes first. After 6 months, in case of neurological or
hematological chronic ≥ grade 2 toxicity, nab-paclitaxel may be stopped and gemcitabine +
PF-04136309 will be continued until disease progression or patient’s or investigator’s decision.
If gemcitabine is not well tolerated, treatment may be continued with PF-04136309 alone until
disease progression or patient’s or investigator’s decision.
The proof of mechanism of action of PF-04136309 will be assessed by the comparison of at
least 12 paired (optional) biopsies, bone marrow aspirates and peripheral blood (pre- and
post- treatment in the Phase 1b and Phase 2 study).  Their optional collection will provide
baseline, pre-dose fine-needle aspirate (FNA) or core needle biopsy, and/or bone marrow
aspirates, and FNA or core needle biopsy, and/or bone marrow aspirates following the
completion of Cycle 1 at C1D28 [±7 days] or at C2D28 [±7 days] if collection at Cycle 1 is not
obtained.
Serial blood samples will be collected from patients enrolled in the Phase 1b cohorts to 
determine the multiple dose PK of PF-04136309 given in combination with nab-paclitaxel +
gemcitabine.  Sparse PK sampling will be performed for patients enrolled in the Phase
2 portion of the study to evaluate the population PK of PF-04136309.
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3. ENDPOINTS AND COVARIATES: DEFINITIONS AND CONVENTIONS
3.1. Primary Endpoint(s)
Phase 1b

Dose Limiting Toxicities (DLTs) in order to determine the Maxmimum Tolerated Dose 
(MTD) and Recommended Phase 2 Dose (RP2D).

Adverse Events as characterized by type, frequency, severity (as graded by NCI
CTCAE v 4.03) timing, seriousness and relationship to study therapy. 

Lab abnormalities as characterized by type, frequency, severity (as graded by NCI 
CTCAE v 4.03) and timing.
Phase 2

Progression Free Survival (PFS).
3.2. Secondary Endpoint(s)
Phase 1b

PK parameters of PF-04136309 after multiple dosing, including Cmax,ss, Tmax,
AUCtau,ss, Cmin,ss, CLss/F, and as data permit, t1/2 and Vss/F.

Ex vivo inhibition of CCL2-induced ERK kinase phosphorylation in the peripheral
blood.

Objective tumor response (OR) as assessed using the Response Evaluation Criteria in
Solid Tumor (RECIST) version 1.1.
Phase 2

Overall Survival (OS)

Adverse events as characterized by type, frequency, severity (as graded by NCI
CTCAE v.4.03), timing, seriousness and relationship to study treatment.

Laboratory abnormalities as characterized by type, frequency, severity (as graded by
NCI CTCAE v. 4.03) and timing.

Objective response rate (ORR).

Duration of Response. [The rate of progression-free survival at 1 year, the rate of
disease control (confirmed response or stable disease for ≥16 weeks)].
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
Time to progression with the double combination PF-04136309 and gemcitabine
(maintenance therapy) after interruption of nab-paclitaxel.

Trough PF-04136309 concentrations.

PD markers in metastatic tumors: Pre biopsy – Post biopsy after 2 cycles of

PF-04136309 + nab-paclitaxel + gemcitabine or nab-paclitaxel + gemcitabine +
placebo

Peripheral neurological adverse events as characterized by frequency, severity (as
graded by NCI CTCAE v.4.03 and by self-assessment according to the EORTC 
QOL- CIPN20 questionnaire), and timing.
 
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3.4. Covariates
Biomarker data and baseline characteristics may be considered as covariates in population PK, 
PK/PD and anti-tumor efficacy exploratory analyses. Covariates may also be considered when 
exploring QTc and PK relationship.
4. ANALYSIS SETS
Several analysis sets are defined and will be considered for this study.
4.1. Full Analysis Set
The full analysis set includes all enrolled patients.  This is equivalent to the ITT (intent-to-treat) 
population.
4.2. Safety Analysis Set
The safety analysis set includes all enrolled patients who receive at least one dose of study 
medication.
4.3. ‘PER PROTOCOL’ Analysis Set 
The per protocol analysis set includes all enrolled patients who received at least one dose of
study treatment and who did not have important protocol deviations during the Cycle 1 that 
may impact DLT evaluations.  Patients with the important protocol deviations during the first 
cycle of treatment that may impact DLT evaluations are not evaluable for the MTD or RP2D 
assessment. 
4.4. PK Analysis Set
4.4.1. PK Concentration Set
The PK concentration population is defined as all patients who receive PF-04136309, have no 
protocol deviations affecting the PK assessment, and have at least 1 post-dose concentration 
measurement.
4.4.2. PK Parameter Set
The PK parameter analysis population is defined as all Phase 1b patients treated who have 
sufficient information to estimate at least 1 of the PK parameters of interest.
4.5. PD Biomarker Analysis Set
The PD/Biomarker analysis population is defined as all enrolled patients with at least 1 of the 
PD/Biomarkers evaluated (including both the patients with only pre-treatment data and those
with both pre- and/or post-treatment data) .
C
C
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4.6. Modified Intent-to-Treat Set
The modified intent-to-treat (mITT) population is defined as all the randomized subjects who 
have received at least 1 dose of study medication and have measurable disease baseline 
assessment (within 28 days prior to study entry).  The mITT population will be used for 
anti-tumor assessment.
4.7. Treatment Misallocations 
Subjects who receive the wrong initial dose for whatever reason will be analyzed according to 
the initial dose actually received.  Subjects who receive the wrong dose after the initial dose 
will be analyzed according to the initial dose received.
4.8. Protocol Deviations
The determination of protocol deviations (PDs) and important protocol deviations (IPDs) will
follow Pfizer standard operating procedures.  A full list of PDs, IPDs, and IPDs that are 
excluded from Per-protocol analysis will be determined prior to the database release and be 
included in the CSR. 
5. GENERAL METHODOLOGY AND CONVENTIONS
The phase 1b part of the study is an open-label dose finding study and no interim analysis or 
blinding is planned for the Phase 1b part.  The phase 2 part of the study is a double-blinded 
study and the final analysis for the phase 2 part will be conducted after the last subject last visit 
(LSLV) in the phase 2 part.
5.1. Statistical Hypotheses
Phase 1b (dose finding):
There is no statistical hypothesis. 
Phase 2 Hypothesis: 
H0: Hazard ratio = 1 vs. H1: < 1,
Where Hazard ratio is the hazard ratio for progression free survival between Arm A 
(PF-04136309 + nab-paclitaxel + gemcitabine) and Arm B (nab-paclitaxel + gemcitabine +
placebo). 
5.2. Statistical Decision Rules
5.2.1. Part 1b
Dose esclation and de-esclation
The modified toxicity probability interval (mTPI) design [2] uses a Bayesian statistics
framework and a beta/binomial hierarchical model to compute the posterior probability of
3 dosing intervals that reflect the relative difference between the toxicity rate of each dose level 
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to the target rate (pT = 0.275).  The prior distribution of DLT is set as a beta (0.5,0.5) and the 
threshold probability for early termination and dose exclusion is set to 0.95 as suggested in the 
mTPI design.  Doses with an incidence of DLT>33% (eg, 4 out of 10) cannot be selected as 
MTD although is allowed by the mTPI method. If the toxicity rate of the currently used dose 
level is far smaller than 27.5%, the mTPI will recommend escalating the dose level; if it is 
close to 27.5%, the mTPI will recommend continuing at the current dose; if it is far greater than
27.5%, the mTPI will recommend de-escalating the dose level.  Being a model-based design, 
mTPI automatically and appropriately tailors dose-escalation and de-escalation decisions.  
Target size for each cohort will be n= 2 to 4 patients as described in mTPI design. All the 
dose-escalation decisions for a given trial can be pre-calculated under the mTPI design and 
presented in a two-way table.  The decision rules to “dose escalate” (E), “no change in dose” 
(S), “dose de- escalate” (D) or “dose de-escalate, unacceptable toxicity” (U) are described in 
Table 1.
Cohorts of patients could receive doses already tested but a dose that is associated with decision
“Dose de-escalate, unacceptable toxicity” cannot be revisited and no more patients should be 
treated at this dose or higher doses for the remainder of the trial.
Table 1.
Number of Patient Treated at a Dose Level
Number of
Patients
Having DLT
n=2
n=3
n=4
n=5
n=6
n=7
n=8
n=9
n=10
n=11
n=12
N=13
N=14
N=15
0
E
E
E
E
E
E
E
E
E
E
E
E
E
E
1
S
S
S
E
E
E
E
E
E
E
E
E
E
E
2
U
D
S
S
S
S
S
S
S
S
E
E
E
E
3
U
U
D
D
S
S
S
S
S
S
S
S
E
4
U
U
U
U
D
D
D
D
S
S
S
S
5
U
U
U
U
U
D
D
D
D
D
S
6
U
U
U
U
U
U
U
D
D
D
7
U
U
U
U
U
U
U
U
U
D: De-escalate the dose; E: Escalate the dose; S: Stay at the dose; U: Unacceptable toxicity
Note: Starting dose is 750 mg BID.  Escalation to a higher dose (eg 1000 mg BID) will require that at least
6 patients are dosed at 750 mg BID and no more than 1 experienced a DLT.
Estimating the MTD and RP2D (Phase 1b)
An MTD may not be identified, as DLTs may not be frequently observed after administration
of this investigational agent.  Dose escalation may continue up to a predefined Maximum
Feasible Dose (MFD) (eg 1000 mg) and the escalation is halted without a maximum tolerated
dose (MTD) estimate.  The study will continue accruing until one of the three stopping
conditions below is triggered.
The algorithm will stop if any of the following criteria is met:
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1. MTD or RP2D has been identified with sufficient accuracy: at least 6 to 12 patients
have been accumulated on a dose that is currently estimated to be the MTD or RP2D; or
2. All doses explored appear to be overly toxic.
Due to binomial data variability in small samples, DLTs may be observed in a first cohort(s) by
chance even when the true Probability (DLT) is fairly low.  This could result in the estimated 
posterior DLT rate to exceed the targeted very early in the trial, triggering an early stop when 
very few patients (eg, 3) have been treated.  To prevent stopping the trial prematurely in such 
cases, a step-down option with a lower dose of 500 mg added to the dose grid.
Sample Size (Phase 1b)
The number of patients to be enrolled in the Phase 1b part will depend upon the observed safety
profile, which will determine the number of patients at each dose level and the number of dose 
levels explored. It is envisaged that the maximum sample size at the RP2D would be
N=12 (see Protocol Section 9.2.3). To further evaluate safety and pharmacodynamics, the
number of patients enrolled during this part of the study (Phase 1b) may be N up to 20.
5.2.2. Phase 2
Sample Size (Phase 2)
Ninety-nine (92) patients will be randomized in a 1:1 ratio Arm A versus Arm B.  Median PFS 
in patients enrolled in the control arm (Arm B) is expected to be approximately 5.5 months.  
A total of 92 patients and 57 events are required for a log-rank test to have an overall 1-sided 
significance level of 0.1 (alpha=0.2) and power of 0.80.  This assumes an 82% improvement in 
median PFS from 5.5 months to 10 months and an HR=0.55.  Predicted accrual is 
approximately n=7 patients per month and the predicted dropout rate is approximately 15% at 
1 year.  This sample size is also based on a planned non-binding interim analysis that will be 
conducted when 60% of the PFS events are observed, by using Lan-DeMets O’Brien-Fleming 
error spending function for both Type I and Type II errors.
Decision Rules at the interim and the final analyses (Phase 2)
An interim Analysis (IA) will be conducted based on PFS after 34 patients have had an event, 
which is 60% of the total required number of events (ie, 57 events).
The table below displays the decision rules at the interim and at the end so that the overall Type 
I error is maintained at one-sided 0.10 and power is approximately 80%.  Efficacy in terms of 
HR would be declared at the time of the IA if the HR surpasses the IA boundary for efficacy
that is HR<0.533 (or p-value<0.033).  Futility, in terms of HR, could be declared at the time of 
IA if the HR surpasses the IA boundary for futility that is HR >0.863.
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Look
Information 
fraction
Efficacy Boundary
Futility Boundary
HR scale
Z-score
scale
p-value 
scale
Z-score 
scale
HR scale
Interim
60% (34 events)
0.533
-1.836
0.033
-0.429
0.863
Final
100% (57 events)
0.701
-1.339
0.067
-1.339
0.701
The study will not stop for efficacy regardless whether or not a statistical significance is found 
in the interim analysis.  The final analysis will be performed when all randomized subjects 
have either completed study participation period or withdrawn early or should the study be 
stopped prematurely due to safety reasons.  If statistical significance is claimed at the interim 
analysis, the p-values at the interim will be considered as the primary p-values for the study 
and the efficacy data after the interim analysis will be used for summary, supportive purpose.  
If statistical significance is not claimed at the interim analysis, the efficacy boundaries for the 
final analysis will apply as the inferential base.  In the example that an interim analysis is done 
and no statistical significance is detected at the interim, the statistical significance will be 
claimed at the final analysis if the p-value is less than or equal to 0.067. 
The futility analysis is non-blinding, ie,  the decision whether to stop the trial for futility is not 
bound to the futility boundary in the table.  Even the HR surpasses the IA boundary for futility
that is HR >0.863,  the trial may not stop.  Other related data including other efficacy (such as 
ORR and OS etc.), biomarker data and safety data may be weighed into the decision of 
stopping the trial for futility. 
Both central review and investigator assessment efficacy data will be analyzed in the interim 
analysis.  If the two analyses lead to inconsistent conclusions, the claim of efficacy or futility 
may not be made and the trial may continue as planned. 
5.3. General Methods 
Whilst every effort has been made to pre-specify all analyses in this statistical analysis plan, if 
any additional exploratory analyses be found to be necessary, the analyses and the reasons for 
them will be detailed in the clinical study report (CSR).
Unless otherwise specified, Phase 1b and Phase 2 data will be analyzed separately in all 
analyses.  The baseline value is defined as the value collected at the time closest to, but prior 
to, the start of study drug administration in the first cycle.  All data will be categorized based 
on the scheduled visit at which it was collected.  These visit designators are predefined values 
that appear as part of the visit tab in the eCRF.
5.3.1. Analyses for Time to Event Data
Time to event (DOR, PFS, TTP and OS etc) curves between the two treatment groups will be 
compared with a log-rank test at significance level of 0.1 (one-sided).  Cox model will be used 
to estimate the hazard ratio as well as 2-sided 80% and 95% confidence intervals, and may be 
used to explore the potential influences of the baseline factors (eg, age, gender and ethnic 
origin) on the time to event data.  The time to event data will also be summarized using the 
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Kaplan-Meier method [2].  The Kaplan-Meier estimates for the 1-y PFS and OS rates, and the 
2-sided 80% and 95% confidence intervals of the rates using the Greenwood’s formula [4] will 
be reported. 
5.3.2. Analyses for Binary Data
Point estimates of binary endpoints for each treatment arm will be provided along with the 
corresponding 2-sided 95% confidence intervals using an exact method (Blyth and Still (1983)
[5]).  The difference between the two treatments in Phase 2 will be estimated and the 
corresponding 80% and 95% intervals will be constructed using an exact method (Chan and 
Zhang (1999) [6]). Logistic regression may be employed to compare the two treatments in 
Phase 2. 
5.3.3. Analyses for Continuous Data
Descriptive statistics, such as the mean, standard deviation, coefficient of variation, median, 
minimum, and maximum values, will be provided for continuous endpoints.  Linear or 
non-linear models may be employed to analyze the continuous data. 
5.4. Methods to Manage Missing Data
5.4.1. Missing Dates
In compliance with Pfizer standards, if the day of the month is missing for any date used in a 
calculation, the 1st of the month will be used to replace the missing date unless the calculation 
results in a negative time duration (eg, date of onset cannot be prior to day one date).  In this 
case, the date resulting in 0 time duration will be used.  Pfizer standards are also used if both 
month and day are missing (Jan 1 unless negative time duration).  This excludes the 
pharmacokinetic, ECG, and pharmacodynamic analyses, which will only use the actual date 
collected or if date not available deem the data missing.
5.4.2. Efficacy Analysis
For the time-to-event endpoints, the missing data handling method will be censoring.  
Censoring rules for time-to-event endpoints are detailed in Appendix 2.
5.4.3. Pharmacokinetics
Concentrations below the limit of quantification
In all data presentations (except listings), concentrations below the limit of quantification 
(BLQ) will be set to zero.  (In 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
Patients who experience events that may affect their PK (eg, incomplete dosing due to 
vomitting) may be excluded from the PK analysis. 
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In drug concentration summary tables and plots of median PK profiles (plots of PK profiles 
will only be done for Phase 1b patients), statistics will be calculated with concentrations set to 
missing if one of the following cases is true:
1. A concentration has been reported 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 pharmacokineticist.
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.  If a PK parameter 
cannot be derived from a subject’s concentration data, the parameter will be coded as NC (ie, 
not calculated).  (Note that NC values will not be generated beyond the day that a subject 
discontinues).
In summary tables, statistics will not be presented for a particular treatment group if more than 
50% of the data are NC.  For statistical analyses, 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.
5.4.4. Pharmacodynamic and health outcome parameters
Missing data for the pharmacodynamic and health outcome parameters will be treated as such 
and no imputed values will be derived.
6. ANALYSES AND SUMMARIES
6.1. Standard Analyses
Study Conduct and Patient Disposition
An accounting of the study patients will be tabulated.  The subject evaluation groups will be 
listed.  The Full Analysis Set will be used.
Subject discontinuation from treatment and study will be tabulated and listed separately with 
their reason for discontinuation.  The Safety Analysis Set will be used.
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Baseline Characteristics
Baseline characteristics such as demographics, prior medication, medical history, ECOG 
performance status, and primary diagnosis will be tabulated and listed.  For ECOG 
performance status a shift table (worst post-baseline vs baseline may be produced).  The Safety 
Analysis Set will be used.
Treatment Administration/Compliance
Unless otherwise stated, listings and tables by treatment will be provided and within each 
treatment, the summary for each drug, ie, PF-04136309, nab-paclitaxel, or gemcitabine 
respectively within treatment, will be presented.  Cycle length is 28 days.  Day 1 of a cycle is 
the first date of dose within that cycle.  The safety analysis set will be used.
One may refer to Protocol Section 5.4.5 and 5.4.6 for dosing interruptions, delays and 
reductions for PF-04136309, nab-paclitaxel, or gemcitabine respectively. 
The following will be summarized for each treatment and within treatment for each drug 
(PF-04136309, nab-paclitaxel, or gemcitabine respectively).  For phase 1b data the overall 
summary across treatment will also be presented. 

Number of subjects

Median and range of number of cycles started per subject

Number (%) of subjects starting a cycle (1, 2, 3…)

Number (%) of subjects with cycle delays

Number (%) of dose interruptions (include both known and unknown dates)

Number (%) of subjects with dose reductions

Number (%) of each reason (drug related AE vs AE vs. Other) for cycle delays, dose 
interruptions and dose reductions

Time (in months) on treatment (median, range)
The following will be summarized for each treatment and within treatment for each drug 
(PF-04136309, nab-paclitaxel, or gemcitabine respectively).  For phase 1b data the overall 
summary across treatment will also be presented. 

Total number of cycles started

Number of cycles started per subject (median, range)
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
Number of cycles before 1st delay (median, range)

Number of cycles before 1st reduction (median, range)

Number of cycles before 1st interruption (median, range)
The following will be summarized by cycle.  For phase 1b data the overall summary across 
treatment will also be presented. 

For nab-paclitaxel and gemcitabine respectively, summary statistics (mean, median, 
standard deviation and range) of cumulative prescribed dose, cumulative actual dose, 
relative dose intensity (%), and percent of compliance will be provided by cycle, where
relative dose intensity (%) = cumulative prescribed dose / (planned dose * planned # of 
treatment administrations) * 100%, and percent of compliance (%) = cumulative actual 
dose / cumulative prescribed dose * 100%.

For PF-04136309, the percent of compliance by cycle is calculated as percent of 
compliance (%) = (# of days on PF-04136309) / (# of days should be on PF-04136309) 
* 100%
Listings by subject (ordered by treatment, and within treatment by drug): start date and stop 
date of each dosing period within each cycle (including records with 0 mg), administered total 
daily dose for each period, any missed doses with unknown dates (Y/N), number of missed 
doses with unknown dates, reason for any dosing changes. 
Listings by subject and each cycle (ordered by treatment, and within treatment by drug): cycle 
length, total planned dose, administered total dose, percentage of planned dose, dose delay 
(yes/no), dose reduction (yes/no), and dose interruption (yes/no). 
Prior, Concomitant, and Further Therapies
Prior, concomitant, and further therapies (drug and non-drug treatments) will be coded by the 
World Health Organization (WHO) medical dictionary.  Listings of prior, concomitant, and 
further therapies will be provided separately.
6.2. Analysis of Primary Endpoints
6.2.1. DLT(Part 1)
Dose Limiting Toxicity (DLT) is the primary endpoint of the dose finding component of the 
study, which will be summarized by treatment (PF dose level) using the Per Protocol Analysis 
Set for patients in the dose finding portion of the study.  A listing of the DLTs will also be 
provided.  If necessary, a summary and listing of the DLT by malignancy may be provided 
using the Per Protocol Analysis Set for patients in the MTD expansion portion of the study.
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6.2.2. Safety Endpoints
Adverse Events
Adverse Events (AEs) will be graded by the investigator according to the CTCAE version 
4.03 and coded using the MedDRA [7].  The focus of AE summaries will be on Treatment 
Emergent Adverse Events, those with initial onset or increasing in severity after the first dose 
of study medication.  The number and percentage of patients who experienced any AE, serious 
AE (SAE), treatment related AE, 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 (Cycle 1 and Cycles beyond 1) by treatment in Phase 1b and Phase 2 respectively, and for 
Phase 1b the overall summary will also be presented.  Note that AEs are the primary endpoints 
in phase 1b, but the secondary endpoints in phase 2.  However the analysis methods are the 
same for both so we put them together here.  Pfizer standard on safety data reporting will be 
followed. 
Laboratory Tests Abnormalities
The number and percentage of patients who experienced laboratory test abnormalities will be 
summarized according to worst toxicity grade observed for each laboratory test for each 
treatment for Phase 1b the overall summary will also be presented.  The analyses will 
summarize laboratory tests both in the entire study period and by cycle (Cycle 1 and Cycles 
beyond 1).  Shift tables will be provided to examine the distribution of laboratory 
abnormalities.  The Safety Analysis Set will be used.  For laboratory tests without CTC grade 
definitions, results will be categorized as normal, abnormal high/low or not done.  Note that 
laboratory test abnormalities are the primary endpoints in phase 1b, but the secondary 
endpoints in phase 2.  However the analysis methods are the same for both so we put them 
together here.  Pfizer standard on safety data reporting will be followed.
6.2.3. PFS (Phase 2)
PFS is defined as the time from randomization to first documentation of objective tumor
progression or to death due to any cause, whichever occurs first.  Censoring of the PFS data is 
described in Appendix 2.  PFS will be compared between the 2 treatment arms using a 
one-sided log- rank test with a significance level of 0.1 (two-sided alpha=0.2).  Cox model 
will be used to estimate the hazard ratio as well as 2-sided 80% and 95% confidence intervals, 
and may be used to explore the potential influences of the baseline factors (eg, age, gender and 
ethnic origin) on PFS.  PFS will also be summarized using the Kaplan-Meier method.  The 
Kaplan-Meier estimates for the 1-y PFS rates, and the 2-sided 80% and 95% confidence 
intervals of the rates using the Greenwood’s formula will be reported.  Primary analysis of PFS 
will be based on central review data and sensitivity analyses will also be conducted using 
investigational site tumor assessments.  PFS analysis will be conducted in the mITT population. 
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6.3. Analysis for Other Endpoints
6.3.1. Other Efficacy Endpoints Analysis
Summary tables of the efficacy data including Objective Response Rate (ORR), Progression 
Free Survival (PFS), and Overall Survival (OS), and Duration of Response (DOR) will be 
provided by the groups aforemented.  Efficacy listings will be provided that include best 
response, first CR/PR date, last date with CR or PR, most recent date without progression, 
progression date, death date, date of first response and last tumor assessment date, etc.  
Swimmer plot for individual clinical response and time on treatment, waterfall plot for 
individual tumor size percent change from baseline, and spider plot for individual tumor size 
percent change from baseline over time will be presented.
Objective Response Rate (ORR), Complete Response (CR) and Partial Response (PR)
ORR is defined as the proportion of patients with confirmed complete response (CR) or
confirmed partial response (PR) according to RECIST, relative to all randomized patients who 
have baseline measurable disease.  Confirmed responses are those that persist on repeat
imaging study ≥4 weeks after initial documentation of response.  Patients who do not have 
on-study radiographic tumor re-evaluation or who die, progress, or drop out for any reason
prior to reaching a CR or PR will be counted as non-responders in the assessment of ORR. A
patient, who initially meets the criteria for a PR and then subsequently becomes a confirmed
CR, will be assigned a best response of CR.  ORR, CR and PR point estimates for each 
treatment arm will be provided along with the corresponding 2-sided 95% confidence intervals
using an exact method (Blyth and Still (1983)).  The difference between the two treatments in 
Phase 2 will be estimated and the corresponding 80% and 95% confidence intervals will be 
constructed using an exact method (Chan and Zhang (1999)). 
Overall Survival (OS)
Time to death is defined as the time from date of randomization to death due to any cause.  
Patients will be censored for this endpoint on the date of the last tumor assessment if they do 
not die at that time.  A log-rank test will be used to compare the treatment groups with respect 
to PFS at a 2-sided alpha level of 0.20.  Overall survival will also be summarized using the 
Kaplan-Meier method.  The Kaplan-Meier estimates for the 1-year OS rates, and the 2-sided 
80% and 95% confidence intervals of the rates using the Greenwood’s formula will be reported.  
In addition, Cox model will be used to estimate the hazard ratio and its 80% and 95% CIs for 
the treatment effect.  The analysis for overall survival (OS) will be based on the ITT population. 
Note that although this study is not powered to detect significant differences in Overall
Survival at the time of the primary analyses of PFS, analyses of OS, with a statistical power =
63%, will be conducted after 50 deaths are observed, assuming an HR=0.63 and improvement 
in median OS from 8.5 months to 13.5 months.  First type error will not be inflated as this 
statistical comparison will be conducted conditionally upon rejection of the null hypothesis for 
the PFS endpoint.
Duration of Objective Response (DoR) and Duration of Stable Disease (DoSD)
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DoR is defined as the time from the first confirmed documentation of objective tumor response 
to the first documentation of objective tumor progression or to death due to any cause,
whichever occurs first.  Censoring of the DOR data is the same as for PFS.  DOR will only be 
calculated for the subgroup of patients with objective response.  For Phase 2 data, a log-rank test 
will be used to compare the treatment groups with respect to DOR at a 2-sided alpha level of 
0.20.  In addition, Cox model will be used to estimate the hazard ratio and its 80% and 95% CIs 
for the treatment effect for Phase 2 data.  The Kaplan-Meier estimates for the DoR≥16 weeks, 
and the 2-sided 80% and 95% confidence intervals of the rates using the Greenwood’s formula 
will be reported.  DOR will only be calculated for the subgroup of patients with response (CR 
or PR).
DoSD is defined as the time from the first documentation of stable disease to the first 
documentation of objective tumor progression or to death due to any cause, whichever occurs 
first.  DoSD will be analyzed in the similar fashion as DoR.  DoSD will only be calculated for 
the subgroup of patients with CR,PR or stable disease (SD).
Time to progression (TTP) with the double combination PF-04136309 and gemcitabine
(maintenance therapy) after interruption of nab-paclitaxel
This type of TTP is defined as the time from interruption of nab-paclitaxel to the first 
documentation of objective tumor progression.  Censoring of the TTP data is described in 
Appendix 2.  The Kaplan-Meier survival estimates, together with the number of subjects, 
percentage of subjects to experience the event, and the number and percentage of subjects 
censored will be summarized.  This TTP is only calculated for the subgroup of patients who 
were treated with the maintenance therapy. 
6.3.2. Pharmacokinetics Analyses 
The concentration-time data of PF-04136309 will be summarized by descriptive statistics (n,
mean, standard deviation, median, minimum, and maximum) according to dose level.
For patients enrolled in the Phase 1 dose finding cohorts, the concentration-time data of
PF-04136309 within the 12-hour dose interval on Day 15 (with the pre-dose sample collected
on Day 16 as the 12-hour post dose sample) will be analyzed for individual patients using
non-compartmental methods.  The noncompartmental analysis will estimate PK parameters
including Cmax,ss, Tmax, AUCtau,ss, Cmin,ss, CLss/F, and as data permit, t1/2 and Vss/F.  
The PK parameters will be summarized using descriptive statistics according to dosing cohort.
The concentration-time data of PF-04136309 from all patients enrolled in the study will be
using nonlinear mixed effect modeling.  The modeling-based analysis will estimate the typical
value and variability for PK parameters including oral clearance (CL/F) and apparent volume 
of distribution (V/F).  Also, the influence of selected potential covariates on the PK parameters 
will be explored as appropriate; the potential covariates to be explored will include selected 
demographics (eg, body weight, age, sex) and selected patient characteristics (eg, baseline 
CCR2 expression, baseline CCL2 level, ECOG performance status, liver function markers).
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Population PK assessment will be conducted with the concentration-time data of
PF-04136309 from all patients, using the nonlinear mixed effect modeling approach in
accordance with regulatory guidances.  A structural PK model based on data from the Phase
1b portion will be used.  The population PK analysis will estimate typical value and
variability for PK parameters including oral clearance (CL/F) and apparent volume of
distribution (Vd/F).  Also, the influence of selected potential covariates on the PK parameters 
will be explored as appropriate; the potential covariates to be explored will include selected
demographics (eg, body weight, age, sex) and selected patient characteristics (eg, baseline
CCR2 expression, baseline CCL2 level, ECOG performance status, liver function markers).
The detailed procedures for the population PK analysis, including the model implementation 
and evaluation, will be described prospectively in the Population Modeling Analysis Plan 
(PMAP).  The results of the analysis will be summarized in a Population Modeling and 
Analysis Report (PMAR), separate from the clinical study report.
6.3.3. Analysis of Pharmacodynamics
For FNA and core-biopsy 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 mean change and/or mean percent change from baseline of these same 
parameters will also be calculated and the corresponding error bar plots over time be displayed.  
Other biomarker assay data will be analyzed in a similar fashion. 
The correlations between FNA, core-biopsy samples and other biomarker results, and
pharmacokinetic parameters and measures of anti-tumor/anti-cancer efficacy will be examined.  
And the modeling of pharmacokinetic and pharmacodynamics data as well as 
anti-tumor/anti-cancer efficacy data may include biomarker data as covariates.  
Pharmacodynamic biomarkers submitted to these analyses may include, but not be limited to:

Ex vivo inhibition of CCL2-induced ERK kinase phosphorylation in the peripheral
blood.

Phenotype, relative proportions and CCR2 expression of IMs, TAMs, and other
relevant immune cell subsets in the bone marrow, peripheral blood and tumor tissue.

CCL2 levels in the peripheral blood.

Relative expression of immune-related transcripts in tumor tissue and peripheral blood.

Abundance and diversity of tumor-infiltrating and peripheral blood T cell clones.

Prevalence and diversity of tumor antigenic epitopes.

Presence or levels of expression of several tumor biomarkers and their relationship to
clinical responsiveness (including but not limited to SPARC, tumor markers,CA 19.9).
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6.3.4. Population Pharmacokinetic Analysis or Pharmacokinetic/Pharmacodynamic 
(PK/PD) Modeling (Phase 1b and Phase 2)
Pharmacokinetic and pharmacodynamic 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-04136309 exposure and biomarkers or significant safety endpoints.  The results of 
these analyses, if performed, may be reported separately.
6.3.5. Analysis of Peripheral Neurological Adverse Events and EORTC QOL-C30 and 
QLQ-CIPN20 Questionaire (Phase 2)
Summary statistics, including frequencies, means, medians, range will be reported by treatment 
for peripheral neurological adverse events according to NCI CTCAE v.4.03. Times to 
neurotoxic events may be analyzed by the Kaplan- Meier method. 
Response to all questions of EORTC QOL-30 and QLQ-CIPN20 questionaires will be shown in 
percentage.  Logistic regression analyses may be conducted at each visit to detect potential 
differences regarding neuropathy problems at the correponding visit (EORTC QLQ-CIPN20 or 
QOL-30 (except the last two questions on global health status); answer categories “quite a bit” 
or “very much” combined) between the two treatments in Phase 2.
Summary statistics will be provided by treatment for the raw scores of functional, Symptom 
and global health status raw subscalesin QOL-C30 as well as for linearly coverted scores on the 
scale of 0-100 for these subscales.  Cronbach’s alpha coefficient will be presented for each 
subscale in QOL-C30 and the correlations between the subscales will be also reported.  Note 
The raw score is: RawScore=RS=(I1+I2+…+In)/n, where I1, I2, and In are the n component in 
the categories of functional, symptom or global health status scales. 
The linearly convered score (LCS) for Functional scales is defined as:
Linearly Convered Score =LCS = (1- (RS-1)/Range)) ×100, 
And for Symptom scales or Global health status: 
Linearly Convered Score =LCS = (RS-1)/Range ×100
Summary statistics will also be provided for the raw scores of sensory, motor andautomic 
scales raw subscales in QLQ-CIPN20 as well as for linearly coverted scores on the scale of 
0-100 for these subscales.  Cronbach’s alpha coefficient will be presented for each subscale in 
QLQ-CIPN20 and the correlations between the subscales will be also reported.  For each of the 
scales in QLQ-CIPN20,  
Linearly Convered Score =LCS = (RS-1)/Range ×100
ANCOVA models which include covariates of treatment and baseline may be employed to 
compare the two treatments by visit in each of the three-category scales of QOL-C30 and each 
of the three-category scales of QLQ-CIPN20. 
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6.4. ECG and Vital Sign Data Analysis
The analysis of ECG results will be based on patients in the Safety Analysis Set with baseline
and on-treatment ECG data, and will follow the ICH E14 guidance on the clinical evaluation of 
QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs [8].
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 HR (QTc) using standard correction factors [ie, Fridericia’s
(default correction), Bazett’s, and possibly a study specific factor, as appropriate].  QTcF
interval will be calculated using the Friderica formula, as follows:
3 RR
QT
QTcF 
Data will be summarized and listed for QT, HR, response rate (RR), PR, QRS, QTcF (and/or 
QTcB if deemed appropriate by overall, and dose.  Individual QT` (all evaluated corrections) 
intervals will be listed by study arm 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 study arm 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 (one or more 
correction methods will be used) using maximum CTCAE version 4.03 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.
Changes from baseline for the ECG parameters QT interval, heart rate (HR), QTc interval, PR 
interval and QRS interval will be summarized by treatment and visit.  Categorical data analysis 
will follow Appendix 3. 
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If more than one ECG is collected at a nominal time post dose (for example, triplicate ECGs), 
the mean of the replicate measurements will be used to represent a single observation at that 
time point.  If any of the three individual ECG tracings has a QTc value ≥500 msec, but the 
mean of the triplicates is not ≥500 msec, the data from the subject’s individual tracing will be 
described in a safety section of the study report in order to place the ≥500 msec value in 
appropriate clinical context.  However, values from individual tracings within triplicate 
measurements that are ≥500 msec will not be included in the categorical analysis unless the
average from the triplicate measurements is also ≥500 msec.  Changes from baseline will be
defined as the change between QTc post dose from the time-matched average of the pre-dose
triplicate values on Day 1.
In addition, an attempt will be made to explore and characterize the relationship between 
plasma concentration and QT interval length using a PK/PD modeling approach.  If a PK/PD
relationship is found, the impact of subject factors (covariates) on the relationship will be 
examined.
7. INTERIM ANALYSES
An interim Analysis (IA) will be conducted in the Phase 2 part of the study based on PFS after 
34 patients have had an event, which is 60% of the total required number of events (ie,
57 events).  The decision rules are detailed in Section 5.2.2.
An external Data Monitoring Committee (DMC) will be established for the Phase 2 portion
study.  The external DMC will evaluate efficacy and safety data and make a recommendation 
to Pfizer according the the decision rules as specified in Section 5.2.2.  The logistical issues on 
the interim analysis will be detailed in DMC charter. 
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8. REFERENCES 
1.
A9421018 Protocol Amendment 1, Nov. 25, 2015.  
2.
Ji Y, Wang SJ., Modified toxicity probability interval design: a safer and more reliable 
method than the 3 + 3 design for practical phase I trials, J Clin Oncol., 2013; 
10;31(14):1785-91. 
3.
Kaplan EL, Meier P.  Nonparametric estimation from incomplete observations.  J Am Stat 
Assoc 1958; 53:457-481.
4.
Greenwood, M. (1926) The natural duration of cancer. Reports on Pub-lic Health and 
Medical Subjects 33, 1–26. Her Majesty’s Stationery Office, London.
5.
Blyth, C. R. and Still, H. A. (1983). Binomial Confidence Intervals. Journal of the 
American Statistical Association 78, 108–116.
6.
Chan, I. S. F. and Zhang, Z. (1999), "Test-Based Exact Confidence Intervals for the 
Difference of Two Binomial Proportions," Biometrics, 55, 1202–1209.
7.
NCI Common Terminology Criteria for Adverse Events v4.03 (CTCAE). 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf
8.
ICH E14 - The clinical evaluation of QT/QTc interval prolongation and proarrhythmic 
potential for non-antiarrhythmic drugs.  CHMP/ICH/2/04.
9.
E.A. Eisenhauer, P. Therasseb, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. 
Dancey, S. Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. 
Kaplan, D. Lacombe, J. Verweij: New response evaluation criteria in solid tumours: 
Revised RECIST guideline (version 1.1). European Journal of Cancer 45 (2009) 228–247
10.
Nishino M, Gargano M, Suda M, Ramaiya NH, Hodi FS. Optimizing immune-related
tumor response assessment: does reducing the number of lesions impact response 
assessment in melanoma patients treated with ipilimumab?  J Immunother Cancer
2014;2:17.
11.
Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant 
lymphoma. J Clin Oncol 2007; 25: 579-86. Responses must last for at least 4 weeks off 
treatment.
12.
Guha M:The new era of immune checkpoint inhibitors; Pharm J Volume 293, 18 NOV 
2014, No 7837/8 online URL 200671127
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9. APPENDICES 
Appendix 1. Details of Definitions of Endpoints
DLT Definitions
DLTs will be defined as any of the following events described below that occur in the first 
cycle of treatment (Day 1 through 28) and are attributed (ie, judged to be at least possibly
related) to the combination of PF-04136309 with nab-paclitaxel and gemcitabine where
relationship with the combination cannot be ruled out.  DLTs will be classified according to 
CTCAE version 4.03.
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 neutropenic infection;

Grade ≥3 thrombocytopenia with Grade ≥2 bleeding;

Grade 4 thrombocytopenia.
Non-Hematologic:

Grade 3 toxicities, except:

Nausea and vomiting responding to prophylaxis and/or treatment and lasting less
than 7 days from each chemotherapy infusion period;

Diarrhea responding to treatment and lasting less than 7 days;

Grade 3 QTc prolongation (QTc >500 msec) will be considered a DLT only if
persisting after correction of any reversible causes.  So, Grade 3 QTc prolongation
will first require repeat testing, re-evaluation by a qualified person, and correction of 
reversible causes such as electrolyte abnormalities or hypoxia for confirmation;

Grade 3 aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT)
increase lasting ≤7 days.

All Grade 4 toxicities;
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
Delay of more than 2 weeks in receiving the next scheduled cycle due to persisting
treatment-related toxicities.
A subject is classified as DLT-evaluable if he/she experiences a DLT or if he/she otherwise in 
the absence of a DLT receives at least 85% of the planned doses of each study drug in the first 
28 day cycle.  If a subject is withdrawn from study for any reason other than a DLT prior to 
completion of the 28-day safety observation period, a replacement subject will be assigned the
same dose as the replaced subject.
Adverse Effects of Interest are defined as those adverse events that fulfill the same grade and
terms that would qualify as a DLT but occur beyond the protocol defined 28-day DLT window.  
Any Adverse Event of Interest that occurs should be reported to Pfizer as they occur and 
entered into the electronic case report form (eCRF).
Late Onset Toxicity and Toxicities
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.
Maximum tolerated dose (MTD) and Recommended Phase 2 Dose (RP2D)
The maximum tolerated dose (MTD) is defined as the highest dose with true toxicity
probabilities in the equivalence interval (EI) where the EI is defined as [22.5%-32.5%].  
However, in this study, MTD and RP2D may be determined after a full evaluation of safety and 
efficacy data from patients treated in the escalation phase of the study.  See details in 
Section 5.2.1. 
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Appendix 2. Time to Event Data Analysis Censoring Rules
Table 2.
Progression Free Survival and Duration of Response
Situation
Date of Progression/Censoring1
Outcome
Inadequate baseline assessment 
Randomization date
Censored
No on-study assessments
Randomization date
Censored
Alive, on treatment2 and no 
Progression 
Date of last objective tumor 
assessment
Censored
Progression Documented on or 
between 
scheduled 
tumor 
assessments prior to  treatment 
discontinuation2
Date of first objective tumor 
assessment 
showing 
objective 
progression
Progressed (Event)
Treatment discontinuation for 
undocumented progression
Date of last objective tumor 
assessment 
prior 
to 
discontinuation2
Censored
Treatment discontinuation due 
to toxicity or other reason
Date of last objective tumor 
assessment 
prior 
to 
discontinuation2
Censored
Death prior to first planned 
tumor assessment 
Date of death
Death (Event)            
Death 
without 
objective 
progression prior to treatment 
discontinuation2
Date of death
Death (Event)
                  
Death or progression after 2 or 
more missed tumor assessments
Date of last objective tumor 
assessment prior to the event
Censored
1: For date of censorship, if a tumor assessment takes place over a number of days (eg, 
superficial lesions one day, scans another), the last date is used as the assessment date.
2: or within 28 days of discontinuation of treatment. 
Table 3.
Time to Progression with the double combination PF-04136309 and 
gemcitabine (maintenance therapy) after interruption of nab-paclitaxel
Situation
Date of Progression/Censoring1
Outcome
Inadequate assessment at the 
start of maintenance therapy
the start of maintenance therapy
Censored
No on-study assessments after 
the start of maintenance therapy
the start of maintenance therapy
Censored
Alive, on treatment2 and no 
Progression 
Date of last objective tumor 
assessment
in the maintenance 
therapy period
Censored
Progression Documented on or 
between 
scheduled 
tumor 
assessments prior to  treatment 
Date of first objective tumor 
assessment 
showing 
objective 
progression in the maintenance 
Progressed (Event)
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Table 3.
Time to Progression with the double combination PF-04136309 and 
gemcitabine (maintenance therapy) after interruption of nab-paclitaxel
Situation
Date of Progression/Censoring1
Outcome
discontinuation2
therapy period
Treatment discontinuation for 
undocumented progression
in 
the maintenance therapy period
Date of last objective tumor 
assessment 
prior 
to 
discontinuation2 in 
the 
maintenance therapy period
Censored
Treatment discontinuation due 
to toxicity or other reason in the 
maintenance therapy period
Date of last objective tumor 
assessment 
prior 
to 
discontinuation2 in 
the 
maintenance therapy period
Censored
New
anticancer 
treatment 
<28 days after discontinuation 
of 
treatment 
without 
progression in the maintenance 
therapy period
Date of last objective tumor 
assessment prior to new anticancer 
treatment
in 
the 
maintenance 
therapy period
Censored
Death prior to first planned 
tumor 
assessment 
in 
the 
maintenance therapy period
Start dat of the maintenance 
therapy period
Censored
Death 
without 
objective 
progression prior to treatment 
discontinuation2 in 
the 
maintenance therapy period
Date of last objective tumor 
assessment prior to death in the 
maintenance therapy period
Censored
                  
Progression after 2 or more 
missed tumor assessments in the 
maintenance therapy period
Date of last objective tumor 
assessment prior to the event in the 
maintenance therapy period
Censored
1: For censoring date, if a tumor assessment takes place over a number of days (eg, superficial 
lesions one day, scans another), the last date is used as the assessment date.
2: or within 28 days of discontinuation of treatment.
DOSD and DOR
Censoring rules for DOSD and DOR will be the same as for PFS. 
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Appendix 3. Categorical Classes for ECG and Vital Signs
Categories for QTcB and QTcF
QTcB/QTcF 
(ms)
max. ≤450
450< 
max. 
≤480
480< 
max.≤500
max. >500
QTcB/QTcF 
(ms) increase 
from baseline
max. < 30
30≤ max. <60
max. ≥60
Categories for PR and QRS
PR (ms)
max ≥300
PR 
(ms) 
increase from 
baseline
Baseline 
>200 and 
max. ≥25% 
increase
Baseline 
≤200 and max. 
≥50% increase
QRS (ms)
max ≥200
QRS 
(ms) 
increase from 
baseline
Baseline 
>100 and 
max. ≥25% 
increase
Baseline ≤100 
and 
max. 
≥50% increase
Categories for Vital Signs
Systolic BP (mm Hg)
min. <90
Systolic BP (mm Hg) 
change from baseline
max. 
decrease 
≥30
max. 
increase 
≥30
Diastolic BP (mm Hg)
min. <50
Diastolic BP (mm Hg) 
change from baseline
max. 
decrease 
≥20
max. 
increase 
≥20
Supine pulse rate (bpm)
min. <40
max. >120
Measurements that fulfil these criteria are to be listed in the study report.
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Appendix 4. RECIST 1.1 Tumor Assessment Criteria
Adapted from E.A. Eisenhauer, P. Therasseb, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, 
J. Dancey, S. Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, 
D. Lacombe, J. Verweij: New response evaluation criteria in solid tumours: Revised RECIST 
guideline (version 1.1). European Journal of Cancer 45 (2009) 228–247 [9]. 
CATEGORIZING LESIONS AT BASELINE
Measurable Lesions
Lesions that can be accurately measured in at least one dimension.

Lesions with longest diameter twice the slice thickness and at least 10 mm or greater
when assessed by CT or MRI (slice thickness 5-8 mm).

Lesions with longest diameter at least 20 mm when assessed by Chest X-ray.

Superficial lesions with longest diameter 10 mm or greater when assessed by caliper.

Malignant lymph nodes with the short axis 15 mm or greater when assessed by CT.
NOTE: The shortest axis is used as the diameter for malignant lymph nodes, longest axis 
for all other measurable lesions.
Non-measurable disease
Non-measurable disease includes lesions too small to be considered measurable (including
nodes with short axis between 10 and 14.9 mm) and truly non-measurable disease such as
pleural or pericardial effusions, ascites, inflammatory breast disease, leptomeningeal disease,
lymphangitic involvement of skin or lung, clinical lesions that cannot be accurately measured
with calipers, abdominal masses identified by physical exam that are not measurable by
reproducible imaging techniques.

Bone disease: Bone disease is non-measurable with the exception of soft tissue
components that can be evaluated by CT or MRI and meet the definition of
measurability at baseline.

Previous local treatment: A previously irradiated lesion (or lesion subjected to other
local treatment) is non-measurable unless it has progressed since completion of
treatment.
Normal sites

Cystic lesions: Simple cysts should not be considered as malignant lesions and should
not be recorded either as target or non-target disease. Cystic lesions thought to
represent cystic metastases can be measurable lesions, if they meet the specific
definition above. If non-cystic lesions are also present, these are preferred as target
lesions.
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
Normal nodes: Nodes with short axis <10 mm are considered normal and should not be
recorded or followed either as measurable or non-measurable disease.
Recording Tumor Assessments
All sites of disease must be assessed at baseline. Baseline assessments should be done as close 
as possible prior to study start. For an adequate baseline assessment, all required scans must be
done within 28 days prior to treatment and all disease must be documented appropriately. If
baseline assessment is inadequate, subsequent statuses generally should be indeterminate.
Note: For the patient population being evaluated in this protocol, the baseline assessment may
be completed within 6 weeks prior to randomization.
Target lesions
All measurable lesions up to a maximum of 2 lesions per organ, 5 lesions in total,
representative of all involved organs, should be identified as target lesions at baseline. Target 
lesions should be selected on the basis of size (longest lesions) and suitability for accurate 
repeated measurements. Record the longest diameter for each lesion, except in the case of 
pathological lymph nodes for which the short axis should be recorded. The sum of the 
diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions at 
baseline will be the basis for comparison to assessments performed on study.

If two target lesions coalesce the measurement of the coalesced mass is used.  If a large 
target lesion splits, the sum of the parts is used.

Measurements for target lesions that become small should continue to be recorded.  If a 
target lesion becomes too small to measure, 0 mm should be recorded if the lesion is
considered to have disappeared; otherwise a default value of 5 mm should be recorded.
NOTE: When nodal lesions decrease to <10 mm (normal), the actual measurement
should still be recorded.
Non-target disease
All non-measurable disease is non-target. All measurable lesions not identified as target
lesions are also included as non-target disease. Measurements are not required but rather
assessments will be expressed as ABSENT, INDETERMINATE, PRESENT/NOT
INCREASED, INCREASED.  Multiple non-target lesions in one organ may be recorded as a
single item on the case report form (eg, ‘multiple enlarged pelvic lymph nodes’ or ‘multiple
liver metastases’).
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OBJECTIVE RESPONSE STATUS AT EACH EVALUATION
Disease sites must be assessed using the same technique as baseline, including consistent
administration of contrast and timing of scanning. If a change needs to be made the case must 
be discussed with the radiologist to determine if substitution is possible.  If not, subsequent 
objective statuses are indeterminate.
Target disease

Complete Response (CR): Complete disappearance of all target lesions with the 
exception of nodal disease.  All target nodes must decrease to normal size (short 
axis<10 mm).  All target lesions must be assessed.

Partial Response (PR): Greater than or equal to 30% decrease under baseline of the sum 
of diameters of all target measurable lesions.  The short diameter is used in the sum for 
target nodes, while the longest diameter is used in the sum for all other target lesions.  
All target lesions must be assessed.

Stable: Does not qualify for CR, PR or Progression.  All target lesions must be assessed.  
Stable can follow PR only in the rare case that the sum increases by less than 20% from 
the nadir, but enough that a previously documented 30% decrease no longer holds.

Objective Progression (PD): 20% increase in the sum of diameters of target measurable 
lesions above the smallest sum observed (over baseline if no decrease in the sum is
observed during therapy), with a minimum absolute increase of 5 mm.

Indeterminate. Progression has not been documented, and

one or more target measurable lesions have not been assessed;

or assessment methods used were inconsistent with those used at baseline;

or one or more target lesions cannot be measured accurately (eg, poorly visible
unless due to being too small to measure);

or one or more target lesions were excised or irradiated and have not reappeared or 
increased.
Non-target disease

CR: Disappearance of all non-target lesions and normalization of tumor marker levels.
All lymph nodes must be ‘normal’ in size (<10 mm short axis).

Non-CR/Non-PD: Persistence of any non-target lesions and/or tumor marker level
above the normal limits.
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
PD: Unequivocal progression of pre-existing lesions.  Generally the overall tumor
burden must increase sufficiently to merit discontinuation of therapy.  In the presence of 
SD or PR in target disease, progression due to unequivocal increase in non-target 
disease should be rare.

Indeterminate: Progression has not been determined and one or more non-target sites 
were not assessed or assessment methods were inconsistent with those used at baseline.
New Lesions
The appearance of any new unequivocal malignant lesion indicates PD.  If a new lesion is
equivocal, for example due to its small size, continued assessment will clarify the etiology. If 
repeat assessments confirm the lesion, then progression should be recorded on the date of the 
initial assessment.  A lesion identified in an area not previously scanned will be considered a
new lesion.
Supplemental Investigations

If CR determination depends on a residual lesion that decreased in size but did not 
disappear completely, it is recommended the residual lesion be investigated with biopsy
or fine needle aspirate.  If no disease is identified, objective status is CR.

If progression determination depends on a lesion with an increase possibly due to 
necrosis, the lesion may be investigated with biopsy or fine needle aspirate to clarify 
status.
Subjective progression
Patients requiring discontinuation of treatment without objective evidence of disease
progression should not be reported as PD on tumor assessment CRFs. This should be indicated
on the end of treatment CRF as off treatment due to Global Deterioration of Health Status.  
Every effort should be made to document objective progression even after discontinuation of 
treatment.
Table 4.
Objective Response Status at each Evaluation
Target Lesions
Non-target Disease
New Lesions
Objective status
CR
CR
No
CR
CR
Non-CR/Non-PD
No
PR
CR
Indeterminate or Missing
No
PR
PR
Non-CR/Non-PD,
Indeterminate, or Missing
No
PR
SD
Non-CR/Non-PD,
Indeterminate, or Missing
No
Stable
Indeterminat
e or Missing
Non-PD
No
Indeterminate
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Table 4.
Objective Response Status at each Evaluation
Target Lesions
Non-target Disease
New Lesions
Objective status
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
If the protocol allows enrollment of patients with only non-target disease, the following table
will be used:
Table 5.
Objective Response Status at each Evaluation for Patients with Non-
Target Disease Only
Non-target Disease
New Lesions
Objective status
CR
No
CR
Non-CR/Non-PD
No
Non-CR/Non-PD
Indeterminate
No
Indeterminate
Unequivocal progression
Yes or No
PD
Any
Yes
PD
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