Clinical trial NCT02349633
Conditions: Non-Small Cell Lung Cancer
Keywords: EGFRm - Epidermal Growth Factor Receptor Mutation Advanced EGFRm (del19 or L858R +/- T790M NSCLC
Sponsor: Pfizer
Start date: 2015-05-14; Completion date: 2020-05-28
Enrollment: 65 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 1/2 study of PF-06747775 as a single agent and in combination with other cancer treatments in patients with advanced EGFRm NSCLC. The overall clinical study consists of a Phase 1 single agent dose-escalation and expansion part to determine the RP2D of PF-06747775 single agent in patients with previously-treated EGFRm NSCLC followed by sequential evaluations of PF-06747775 at the RP2D in 3 different clinical scenarios as detailed below:

* Cohort 1: Phase 2 evaluation of PF-06747775 as a single agent in previously untreated patients with advanced EGFRm NSCLC,
* Cohort 2: Phase 1b single arm evaluation of PF-06747775 in combination with palbociclib (Cohort 2A) followed by Phase 2 randomized evaluation of PF 06747775 in combination with palbociclib vs PF-06747775 single agent (Cohort 2B) in previously-treated patients with EGFRm NSCLC with a secondary T790M mutation (del 19 and T790M or L858R and T790M), and
* Cohort 3: Phase 1b evaluation of PF-06747775 in combination with avelumab in previously-treated patients with EGFRm NSCLC with a secondary T790M mutation (del 19 and T790M or L858R and T790M).

Detailed description:
There remains an unmet medical need to develop EGFR TKI agents that effectively target both the single activating mutations of del 19 and L858R, and the secondary resistance mutation T790M, while sparing WT EGFR. Drugs active against the resistance mutation will enable molecularly targeted therapy with a more favorable toxicity profile than the current standard of cytotoxic chemotherapy platinum based doublets. Furthermore, by having a wide margin of selectivity favoring the EGFR mutants versus WT EGFR, PF 06747775 is likely to be positioned to improve patient outcomes from an efficacy and safety perspective.

Arms: arm 1: Cohort 1 will be initiated (current dose 200 mg) arm 2: Cohort 2A will evaluate PF-06747775 200 mg by mouth (PO) daily (QD) in combination with palbociclib continuous PO QD dosing in 21-day cycles. The starting dose (DL1) for palbociclib will be 100 mg PO daily. Dose finding will follow mTPI method with adjustments using DLT rate. arm 3: Cohort 2B will be initiated once the RP2D of the PF-06747775 and palbociclib combination is determined. arm 4: Cohort 3 combination is PF-06747775 200 mg PO QD and avelumab 10 mg/kg IV Q2W in 28-day (4-week) cycles. Dose finding will follow the mTPI design. Once RP2D of PF-06747775 in combination with avelumab is determined, the Dose Expansion Phase will be opened.
Interventions: intervention 1: PF-06747775 intervention 2: Palbociclib intervention 3: Avelumab
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol documents:
Prot_000.pdf: 
PF-06747775
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Final Protocol Amendment 4, 19 Dec 2016 
PFIZER CONFIDENTIAL
Page 1
PHASE 1/2 OPEN-LABEL STUDY OF PF-06747775 (EPIDERMAL GROWTH 
FACTOR RECEPTOR T790M INHIBITOR) IN PATIENTS WITH ADVANCED 
EPIDERMAL GROWTH FACTOR RECEPTOR MUTANT 
(DEL 19 OR L858R T790M) NON-SMALL CELL LUNG CANCER
Compound:
PF-06747775
Compound Name:
Not Applicable (N/A)
United States (US) Investigational New 
Drug (IND) Number:
Non-IND Amendment
European Clinical Trials Database 
(EudraCT) Number:
N/A
Universal Trial Number: 
N/A
Protocol Number: 
B7971001
Phase:
Phase 1 / 2
This document contains confidential information belonging to Pfizer.  Except as otherwise 
agreed to in writing, by accepting or reviewing this document, you agree to hold this 
information in confidence and not copy or disclose it to others (except where required by 
applicable law) or use it for unauthorized purposes.  In the event of any actual or suspected 
breach of this obligation, Pfizer must be promptly notified.


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Document History
Document
Version Date
Summary of Changes and Rationale
Original protocol
24 December 2014
N/A
Amendment 1
19 March 2015
The Food and Drug Administration (FDA)
requested changes clarifying conditions for 
continuing investigational therapy after 
Response Evaluation Criteria in Solid Tumors 
(RECIST) progression.
Additional clarification of pharmacokinetic (PK)
timepoints options (For sites closed on weekends 
follow the Schedule of Activities [SOA]
regarding the addition of PK timepoints. Note 
that the PK sample at 192 hrs., if collected, 
should be prior to dose on Day 1).
Grammatical and typographic corrections for 
increased clarity. 
Due to a recent update to the Pfizer Protocol 
template, Sections 8 (Adverse Event [AE]
Reporting) and 15.1 (Communication of Results 
by Pfizer) were revised accordingly.
Due to the number of dosing cohorts, the number 
of patients to be enrolled in the dose escalation 
portion of Phase 1 will be increased in size from 
30 patients to 36 patients in order to align with 
the statistical design.
Exclusion criteria text added to Concomitant 
Treatment section.
In Japan, after completion of Cycle 1, patients 
will be asked to sign an additional consent 
document for confirmation of the patient’s 
willingness to continue participation in this study 
before starting Cycle 2.
Update to Appendix 3: AE Management 
Guidelines - Keratoconjunctivtis Guideline per 
FDA request.
Version updated from DRAFT dated 11 March 
2015 to FINAL dated 19 March 2015 after 
confirmation from FDA.


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Version Date
Summary of Changes and Rationale
Per FDA comments on 19 March 2015, patients 
taking strong P-glycoprotein inhibitors are 
excluded from the study. Patients are also to 
avoid the use of the drugs that are strong P-gp 
inhibitors during the study. P-gp abbreviation 
added to the list.
Amendment 2
02 October 2015
Abbreviation list updated.
Table of Content updated to reflect table number 
changes.
Grammatical and typographic corrections for 
increased clarity.
Schedule of Activities (SOAs) were tabled 
sequentially to provide better flow. References 
and links to these tables were updated 
throughout the entire  protocol. Wording changes 
within some of the footnotes were added for 
clarity and accuracy.
Footnotes were updated in Phase 1 Table 1:

Footnote 4 – baseline signs and symptoms 
including grade will be captured on the 
Medical History case report form (CRF) not 
the Adverse Event CRF (and other tables 
were this footnote applies).

Footnote 14 – 15 unstained formalin-fixed, 
paraffin-embedded (FFPE) sections (vs 10). 
Contact Sponsor for lesser amounts of tissue. 
(also referenced in section 7.3).

Footnote 29 – added: Blood samples for 4-β-
hydroxycholesterol /cholesterol analysis: 
Three (3) mL of blood will be collected in 
lithium heparin tubes for the analysis of 4-β-
hydroxycholesterol and cholesterol as 
outlined in Table 2 through Table 6.
Table 3 and 4 – final footnote added providing 
guidance post the completion of the drug-drug 
interaction(DDI) sub studies:


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Summary of Changes and Rationale

Following completion of the sub-study, 
patients will continue on once daily dosing of 
PF-06747775 at the Recommend Phase 2 
Dose (RP2D). Starting on Cycle 2 Day 1, 
following the pre-dose PK draw, patients 
who have completed the sub-study will 
continue to complete study assessments as 
outlined in Table 1 (Phase 1 Schedule of 
Activities), without additional scheduled PK 
or 4-ß hydroxycholesterol /cholesterol 
assessments. 
Statistical Design changed from Bayesian Model 
Averaging (BMA)-Continuous Reassessment 
Method (CRM) to CRM due to the limitations of 
the BMA-CRM on dose skipping and availability 
of valid software for BMA-CRM – see 
Section 9.2 reference 19.
Sections 3.3 to 3.5.3 were updated to reflect 
similar changes made to the SOA tables for the 
maximum tolerated dose (MTD) and DDI sub-
studies (added clarity and accuracy).
Inclusion Criterion 3 was amended to denote that 
the measurable lesion must not have been 
previously irradiated.
Inclusion Criterion 4 was amended to request 
15 unstained sections (vs 10 sections) but if a 
lesser amount of tissue is available, contact the 
Sponsor.
Exclusion Criterion 1 was amended as follows: 
Previously diagnosed brain metastases, unless 
the patient has completed the treatment that is 
clinically indicated, if any, and has recovered 
from the acute effects of any treatment that was 
delivered prior to study registration, have 
discontinued corticosteroid treatment for these 
metastases prior to registration and are 
neurologically stable. 


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Exclusion Criterion 4 was amended to add 
clarity to the timeframe around discontinuation 
of epidermal growth factor receptor (EGFR) 
tyrosine kinase inhibitors (TKIs). Patients must 
discontinue for a minimum of:

2 days prior to registration for erlotinib or 
afatinib, or 3 days for gefitinib if they will be 
part of the lead-in single dose PF-06747775 
PK study (Phase 1 Dose Escalation Single 
and Multiple dose PK and electrocardiogram
(ECG) Assessments; Phase 1 Sildenafil at 
MTD and Japan PK sub-studies) Please 
contact the Sponsor for direction for any 
other EGFR TKI.

5 half-lives, or 5 days, (whichever is longer), 
prior to registration if they will be starting on 
continuous PF-06747775 dosing directly 
(Phase 1 PK sub-studies at RP2D except 
Japan).
Section 5.3 – added a notation that drugs used 
for the DDI and MTD studies will be supplied by 
the study site personnel (not the sponsor).
Section 5.4 was amended for accuracy and 
clarity:  PF-06747775 will be administered once 
daily (QD) on a continuous basis at 
approximately the same time each day, with the 
exception of the single dose lead-in period for 
those patients participating in the Phase 1 dose 
escalation cohorts. PF-06747775 is to be taken 
with a breakfast of 200-300 calories with 240 
mL (8 ounces) of water.  Food and liquids other 
than water are allowed 2 hours after dose. For 
PK sub-studies administration instructions may 
vary (see Section 3.5.1, 3.5.2, and 3.5.3).  
Following completion of PK sub-study (if 
applicable), patients will continue on once daily 
dosing of PF-06747775 as described above.
Section 7 was amended to add the following 
language similar to that added to the footnotes 
for the DDI sub-studies:


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Version Date
Summary of Changes and Rationale

Patients participating in any of the PK sub-
studies, including the sildenafil sub-study 
(MTD expansion cohort), the food 
effect/rifampin DDI sub-study, or the antacid 
effect/itraconazole DDI sub-study, will 
complete PK assessments as outlined in the 
SOA (See Table 3, Table 4, or Table 5). 
Upon completion of the sub-study portion, no 
additional scheduled PK or 
4-β-hydroxycholesterol/cholesterol 
assessments are required, and patients will 
continue to complete all other study 
assessments as outlined in Table 1 (Phase 1 
Schedule of Activities),with the exceptions 
noted on the relevant SOA footnotes.
Section 7.3 was amended to added clarifying 
language.
Amendment 3
20 September 2016
The original Phase 2 portion of the study (open-
label, multi-center, single-arm study of 
PF-06747775 at the RP2D for assessment of 
antitumor activity in patients with advanced 
EGFRm [del 19 or L858R] non-small cell lung 
cancer [NSCLC] with T790M [del 19 and 
T790M or L858R and T790M]) was revised 
extensively.  Instead of the original Phase 2 
study design, the protocol was amended to 
include sequential evaluation of the RP2D in 
3 different clinical scenarios following 
completion of Phase 1 portion of the study.  
These scenarios are as follows:

Cohort 1: Phase 2 evaluation of 
PF-06747775 as a single agent in previously 
untreated patients with advanced EGFRm 
NSCLC, 

Cohort 2: Phase 1b single arm evaluation of 
PF-06747775 in combination with 
palbociclib (Cohort 2A) followed by Phase 2 
randomized evaluation of PF-06747775 in 
combination with palbociclib vs 
PF-06747775 single agent (Cohort 2B) in 


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Summary of Changes and Rationale
previously-treated patients with EGFRm 
NSCLC with a secondary T790M mutation 
(del 19 and T790M or L858R and T790M), 
and

Cohort 3: Phase 1b evaluation of 
PF-06747775 in combination with avelumab 
in previously-treated patients with EGFRm 
NSCLC with a secondary T790M mutation 
(del 19 and T790M or L858R and T790M).

Additionally, the Japan-specific protocol 
requirements were updated to enable this 
amended protocol to be opened for 
enrollment in Japan.  PK assessments were 
updated to upcoming patient cohorts and 
additional assessments were added for Japan-
only sites.

Several sections of the protocol were 
modified as a result of the study design 
change.  A high-level summary of the major 
changes made by section are as follows: 

Abbreviations list updated.

Protocol Summary updated.

Schedule of Activites (SOA) updated.

New SOA Tables 8 through 13 added.

Section 1, Introduction, updated.

Background information on combination 
agents (palbociclib and avelumab) added.

Rationale for combination starting doses 
and benefit-risk assessment for 
evaluation of the combinations added.

Section 2, Study Objectives and Endpoints, 
modified to include objectives and endpoints 
specific to the revised study design.


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Version Date
Summary of Changes and Rationale

Section 3, Study Design, modified to include 
details specific to the revised study design.

Section 4, Patient Selection, modified to 
include details specific to the revised study 
design.

Entry criteria modified for new Cohorts.  
In addition, Inclusion Criterion 2 was 
modified to allow for enrollment of 
patients with EGFR mutation status 
determined by plasma sample.

Dietary restriction guidelines added.

Section 5, Study Treatments, updated.

Screen failure guidelines added.

Treatment allocation methods updated.

Drug supplies (preparation and 
dispensing, administration, food 
requirements, dose modifications) 
updated to include details for 
combination agents.

Allowed concomitant treatments updated.

Section 6, Study Procedures, updated with 
details specific to revision of entry criterion 
allowing enrollment of patients based on 
EGFR mutation status determined by plasma 
sample.

Section 7, Assessments, updated with details 
specific to revised study design.

Section 9, Data Analysis/Statistical Methods, 
updated with details specific to revised study 
design.

Section 16, References, updated.


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Version Date
Summary of Changes and Rationale

Appendices updated to include:

List of Drugs Known to Predispose to 
Torsade de Pointes (Appendix 5).

Immune-related Response Criteria Derived 
from RECIST 1.1 (irRECIST) (Appendix 6).

Detailed Dose Escalation/De-Escalation 
Scheme for mTPI Design Based on 30% 
Toxicity Rate (Appendix 7).
Amendment 4-for 
Japan Only
19 Dec 2016

Added a Japanese patient-only Lead-In 
Cohort (LIC) to investigate the safety, 
tolerability and PK of PF-06747775 in 
Japanese patients (Appendix 8) per 
requirement from PMDA.

Deleted the table; Japan Only: Single-Agent 
PF-06747775 in Previously Untreated EGFR 
Mutant NSCLC: Phase 2 Cohort 1 
SCHEDULE OF ACTIVITIES per 
requirement from PMDA.

Corrected typographical errors and made
minor updates to the text for clarity
throughout the document.
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities, institutional review boards/ethics committees 
(IRBs/ECs), etc.


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ABBREVIATIONS
This is a list of abbreviations that may be used in the protocol. 
Abbreviation
Term
Ab
Antibody
ACRIN
American College of Radiology Imaging Network
ADA
Anti-drug antibody
ADCC
Antibody-dependent cell-mediated cytotoxicity
ADL
Activities of daily living
AE
Adverse event
A/G
Albumin/globulin
AIDS
Acquired immunodeficiency syndrome 
ALT
Alanine transaminase
ALP
Alkaline phosphatase
ANC
Absolute neutrophil count
ANOVA
Analysis of variance
ASCO
American Society of Clinical Oncology
AST
Aspartate transaminase
AUC
Area under the curve
AUCinf
Area under the curve from zero to infinite time
AUCtau
Area under the curve at steady state
AV
Atrioventricular
BA
Bioavailability
BBS
Biospecimen banking system
BCS
Biopharmaceutics classification system
BICR
Blinded Independent Central Review
BID
Twice daily
BOR
Best overall response
BP
Blood pressure
BUN
Blood urea nitrogen
C
Cycle
cfDNA
Cell-free DNA
Ceff
Efficacious concentration
CI
Confidence interval
CL
Clearance
CL/F
Apparent clearance
CLIA
Clinical Laboratory Improvement Amendments
Cmax
Maximum concentration 
CNS
Central Nervous System
CPK
Creatinine phosphokinase
CRF
Case report form
CR
Complete response
CRA
Cytokine release assay


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Abbreviation
Term
CRM
Continual Reassessment Method
CSA
Clinical study agreement
 
CSF
Colony stimulating factor
CSR
Clinical study report
CT
Computed tomography
CTA
Clinical trial application
CTC
Common Toxicology Criteria
CTCAE
Common Terminology Criteria for Adverse Events
CTLA 4
Cytotoxic T lymphocyte-associated antigen 4
Ctrough
Concentration at steady state
CV
Coefficient of variation
CYP
Cytochrome P450
D
Day
DAI
Dosage and administration instructions
DCR
Disease control rate
DDI
Drug-drug interaction
del 19
Exon 19 deletion
DL
Dose level
DLT
Dose limiting toxicity
DMC
Data monitoring committee
DNA
Deoxyribonucleic acid
DOR
Duration of response
DU
Dispensible unit
EC
Ethics committee
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
EDP
Exposure during pregnancy
EDTA
Edetic acid (ethylenediaminetetraacetic acid)
eg
For example
EGFR
Epidermal growth factor receptor
EGFRm
Epidermal growth factor receptor- mutant
ER
Estrogen receptor
EU
European Union Drug 
EudraCT
European Union Drug Regulating Authorities Clinical Trials
Fc
Fragment crystalline
FDA
Food and Drug Administration (United States)
FDAAA
Food and Drug Administration Amendments Act (United States)
FFPE
Formalin-fixed paraffin-embedded 
FSH
Follicle stimulating syndrome
GCP
Good Clinical Practice
GGT
Gamma-glutamyltransferase
CCI


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Abbreviation
Term
GI
Gastrointestinal 
gm
Grams
GMP
Good Manufacturing Practice
GSTM1
Glutathione S-transferase Mu 1
G-CSF
Granulocyte-colony stimulating factor
HBV
Hepatitis B virus
hCG
Human chorionic gonadotropin
HCV
Hepatitis C virus
HER2
Human epidermal growth factor receptor 2
HDPE
High density polyethylene
Hgb
Hemoglobin
HIV
Human immunodeficiency virus
HNSTD
Highest non-severely toxic dose
HR
Heart rate
HR
Hormone receptor
IB
Investigator’s brochure
ICH
International Conference on Harmonisation
ID
Identification
IFN
Interferon
Ig
Immunoglobulin
IHC
Immunohistochemistry
IL
Interleukin
ILD
Interstitial lung disease
IND
Investigational new drug 
INR
International normalized ratio
IP
Investigational product
ir
Immune-related
irAE
Immune-related adverse event
IRB
Institutional review board
IRC
Internal review committee
irRECIST
Immune-related Response Evaluation Criteria in Solid Tumors
IRR
Infusion-related reaction
IRT
Interactive response technology
IUD
Intrauterine device
IV
Intravenous
IVD
In vitro diagnostic (product)
L858R
Point mutation in exon 21
LFT
Liver function test
LIC
Lead-in cohort
LPD
Local product document
LSFV
Last subject first visit
LSLV
Last subject last visit
LVEF
Left ventricular ejection fraction


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Abbreviation
Term
mAb
Monoclonal antibody
MD
Multiple dose
MedDRA
Medical Dictionary for Regulatory Activities
MFD
Maximum feasible dose
MRI
Magnetic resonance imaging
MTD
Maximum tolerated dose
mTPI
Modified toxicity probability interval
MUGA
Multigated acquisition scan
N/A
Not applicable
Nab
Neutralizing antibody
NCI 
National Cancer Institute 
NGS
Next-generation sequencing
NK
Natural killer
NOAEL
No observed adverse effect level
NSCLC
Non-small cell lung cancer
NTI
Narrow therapeutic index
OBD
Optimal biological dose
OR
Objective response
ORR
Objective response rate
OS
Overall survival
PBMC
Peripheral blood mononuclear cell
PBPK
Physiologically-based pharmacokinetic modeling
PHA
Phytohemagglutinin
pT
Target probability
PCD
Primary completion date
PD
Progressive disease
PD-1
Programmed cell death protein-1
PD-L2
Programmed death ligand-2
PET
Positron emission tomography
PFS
Progression-free survival
P-gp
P-glycoprotein
PK
Pharmacokinetic
PO
By mouth (oral administration)
PPI
Proton pump inhibitor
PR
Partial response
PS
Performance status
PT
Prothrombin time
PTEN
Phosphate and tensin homolog
PTT
Partial thromboplastin time
Q2W
Every 2 weeks
QD
Every day
CC
I
CCI


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Abbreviation
Term
QT
Time between the start of the Q wave and the end of the T wave
R
Ratio
Rac
Observed accumulation ratio
Rss
Steady state accumulation ratio
RBC
Red blood cell
RECIST
Response Evaluation Criteria in Solid Tumor
RGQ
Rotor-Gene Q 5plex
RNA
Ribonucleic acid
RP2D
Recommended Phase 2 dose
R-R interval
R-R interval (heart rate)
SAE
Serious adverse event
SAP
Statistical analysis plan
SC
Subcutaneous
SD
Single dose
SD
Stable disease
SIB
Suicidal ideation and behavior
SOA
Schedule of Activities
SPC
Summary of product characteristics
SRSD
Single reference safety document
SRS
Stereotactic radiosurgery
STD10
Severely toxic dose
SST
Serum separator tube
T
Time
t1/2
Half-life
TBR
Tumor background ratio
TCR
Tissue cross reactivity
TdP
Torsade de Pointes
TEAE
Treatment-emergent adverse event
TIL
Tumor infiltrating lymphocyte
TKI
Tyrosine kinase inhibitor
TLS
Tumor lysis syndrome
Tmax
Maximum concentration
TSH
Thyroid stimulating hormone
TTP
Time to progression
ULN
Upper limit of normal
UPM
Unit probability mass
US
United States
USPI
United States package insert
UTN
Universal Trial Number
UV
Ultraviolet 
UVB
Ultraviolet B light
v
Version
Vz/F
Volume of distribution


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Abbreviation
Term
WBC
White blood cell count
WT
Wild type


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STUDY SCHEMA*
* Approximate enrollment totals indicated.
EGFRm = epidermal growth factor receptor mutant; NSCLC = non-small cell lung cancer; PK = 
pharmacokinetic; RP2D = Recommended Phase 2 Dose


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PROTOCOL SUMMARY:
INDICATION
Advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor 
(EGFR) activating mutations (exon 19 deletion [del 19] or point mutation in exon 
21 [L858R]).   
BACKGROUND AND RATIONALE
Epidermal growth factor receptor -mutant (EGFRm) NSCLC accounts for approximately 
20% of NSCLC, representing a conservative estimate of 100,000 to 200,000 newly 
diagnosed cases per year globally.  Two frequent and mutually exclusive primary mutations, 
EGFR L858R and EGFR del 19, together accounting for approximately 85% of all cases, are 
oncogenic drivers, and are strong predictive biomarkers of response to EGFR tyrosine kinase 
inhibitors (TKIs).  First-line treatment of EGFRm NSCLC patients with currently approved 
EGFR TKIs provides excellent response rates and disease control for 11 to 14 months, but 
patients invariably become resistant to these therapies and their disease progresses.  For 
patients with resistant tumors, approximately 60% harbor a second mutation in the EGFR 
kinase domain (T790M), concurrently with the primary activating mutation.  Thus, in efforts 
to discover and develop improved EGFR TKIs, these double-mutant EGFR variants, 
L858R/T790M and del 19/T790M, are key drug development targets in addressing 
resistance, and sparing wild type (WT) EGFR is essential in preventing dose-limiting toxicity
(DLT).
PF-06747775 is a molecularly-targeted, rationally-designed, third generation EGFR TKI.  In 
recombinant enzyme assays and cellular assays, PF-06747775 is a highly potent and 
irreversible inhibitor against the EGFR double-mutants (L858R/T790M and del 19/T790M)
and single-mutants (L858R and del 19) and a weak inhibitor of WT EGFR.  This inhibitory
potency on mutant targets is paralleled by subsequent inhibition of the EGFR downstream 
signaling axis, induction of apoptosis, and viable cell decline.  In xenograft mouse models, 
PF-06747775 demonstrates tumor growth inhibition and regression at well-tolerated doses in 
disease-relevant models driven by EGFR double- and single-mutants.  The antitumor efficacy 
of PF-06747775 is dose-dependent and shows a strong correlation with pharmacodynamic 
(PD) inhibition of EGFR phosphorylation, inhibition of EGFR-mediated downstream 
signaling, and induction of apoptosis.  Using multiple in vitro approaches to assess non-target 
kinase selectivity, PF-06747775 demonstrates the potential for high kinase selectivity, with 
only 7 out of 273 (3%) tested non-target kinases showing the potential for inhibition by 
PF-06747775 at pharmacologically-relevant concentrations. 
Additionally, the compound has a preclinical safety profile which suggests that 
PF-06747775 can achieve an adequate therapeutic index based on the predicted efficacious 
concentration (Ceff ) in patients.
There remains an unmet medical need to develop EGFR TKI agents that effectively target 
both the single activating mutations of del 19 and L858R, and the secondary resistance 
mutation T790M, while sparing WT EGFR.  Drugs active against the resistance mutation 
will enable molecularly-targeted therapy with a more favorable toxicity profile than the 


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current standard of cytotoxic chemotherapy platinum-based doublets.  Furthermore, by 
having a wide margin of selectivity favoring the EGFR mutants versus WT EGFR, 
PF-06747775 is likely to be positioned to improve patient outcomes from an efficacy and 
safety perspective.
Palbociclib is a first-in-class CDK4/6 inhibitor conditionally approved in the United States 
(US) for use in combination with letrozole or fulvestrant for advanced estrogen-receptor (ER) 
positive, human epidermal growth factor receptor 2 (HER2) negative breast cancer.  By 
inhibiting CDK4/6 and subsequently downstream signaling through Rb protein that controls 
the cell cycle, palbociclib prevents actively proliferating cells from completing the cell 
division cycle, resulting in an arrest of tumor growth.  EGFR TKIs inhibit phosphorylation of 
EGFR, thereby inhibiting downstream cell signaling through the EGFR axis including AKT, 
MEK/ERK, and transcription of cell cycle related genes such as cyclin D1 and E2F target 
genes, resulting in the induction of apoptosis and inhibition of proliferation in EGFR-
dependent tumor cells.   It is hypothesized that combination of the EGFR TKI PF-06747775 
with palbociclib in EGFRm NSCLC could further impede tumor growth with increased 
efficacy over the EGFR TKI alone.  This potential increased efficacy may reflect better 
inhibition of cell cycle progression with the combination.
In vitro and in vivo assessment of the combination of PF-06747775 and palbociclib showed 
increased efficacy over PF-06747775 alone in NSCLC models representing the first-line 
EGFRm and second-line T790M-resistant patient populations.  Mechanistic studies suggest 
the combination effect predominantly relies on the addition of the pro-apoptotic effect of 
PF-06747775 plus the anti-proliferative effect of both agents.  These studies support clinical 
testing of the PF-06747775 palbociclib combination for increased clinical benefit in EGFRm
NSCLC
Separately, recent evidence has shown that tumors require suppression of the host immune 
system for continued growth and spread.
The development of agents targeting the interaction of programmed cell death protein-1
(PD-1) and its ligands has shown promise in the treatment of various cancers including 
NSCLC. Substantial clinical activity was observed with anti-PD-1 antibodies nivolumab and 
pembrolizumab, with an objective response rate of 15% and 20%, respectively, and long 
duration of response in unselected heavily pretreated NSCLC patients.  
Although immune checkpoint inhibitors, including avelumab, are demonstrating promising 
activity in a variety of tumor types, there continues to be a need for new therapies.  Tumor-
directed therapies such as chemotherapy and targeted agents improve tumor antigenicity by 
inducing cell death, providing the basis for potential synergy with immune checkpoint 
inhibitors. 
Recent studies in genetically-engineered mouse models demonstrate that EGFR mutations 
promote tumorigenesis not only by stimulating tumor cell proliferation, but also by 
suppressing antitumor immunity, in part by upregulating PD-1 on tumor-infiltrating T cells 
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Tagrisso® (osimertinib) is a third generation EGFR TKI with a similar activity profile to 
PF-06747775, along with numerous differences between the compounds.  Tagrisso combined 
with the anti-programmed death ligand-1 (PD-L1) durvalumab was tested in patients with 
advanced EGFRm NSCLC in the Phase 1b TATTON study and the Phase 3 CAURAL study.  
While promising tumor responses were seen with the combination, it was too early to tell if 
the combination response was any different from single agent Tagrisso, and both studies 
revealed an increased incidence of interstitial lung disease (ILD).  The TATTON study 
preliminary results indicated a 38% rate of ILD including 5 cases of Grade 3/4 in severity.  
Enrollment was suspended and both trials were put on hold in order to further assess the risk 
associated with the combination.  It is not known currently what causes increased risk of ILD 
but causality due to the interaction of Tagrisso and durvalumab cannot be ruled out.
Tagrisso has been approved for single agent use and carries a warning and precaution on the 
label for ILD/pneumonitis, occurring in 3.3% of patients.  In clinical testing of PF-06747775 
to date, no ILD/pneumonitis adverse events (AE) have been observed.  
Compared with anti-PD-1 antibodies that target T cells, avelumab is an anti-PD-L1 antibody 
that targets tumor cells.  Avelumab is expected to have fewer side effects, including a lower 
risk of autoimmune related safety issues, as blockade of PD-L1 leaves the programmed death 
ligand-2 (PD-L2)/PD-1 pathway intact to promote peripheral self-tolerance.  The anti-PD-1 
antibodies pembrolizumab and nivolumab do carry a low risk of immune-related (ir) 
pneumonitis, with overall incidence of <3%.  Hence the combination of PF-06747775 plus 
avelumab in patients with EGFRm NSCLC has the potential to differentiate from other 
EGFR TKI / anti-PD-1/-L1 combinations via an improved safety profile, especially clinically 
significant lung injury.
STUDY OBJECTIVES AND ENDPOINTS
This study has separate primary and secondary objectives and endpoints for the Phase 1 and 
each of the subsequent sections of the study.
Objectives
Phase 1
Primary Objective

To evaluate safety and tolerability at increasing dose levels of PF-06747775 as a 
single agent in order to estimate the maximum tolerated dose (MTD) and the 
recommended Phase 2 dose (RP2D) in patients with advanced EGFRm NSCLC (del 
19 or L858R, with or without T790M) following 1 prior line of therapy, which must 
have included an approved EGFR TKI. 
Secondary Objectives

To evaluate the overall safety profile of PF-06747775;

To characterize the effects of single-agent PF-06747775 on QTc intervals;


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•
To characterize single dose and steady state pharmacokinetic (PK) profiles of 
single-agent PF-06747775;
•
To evaluate the effect of PF-06747775 at steady state on the exposure of a single dose 
of sildenafil, a Cytochrome P450 3A4 (CYP3A4) probe;
•
To characterize the effect of food on the exposure of PF-06747775 at the RP2D;
•
To characterize the effect of esomeprazole, a proton pump inhibitor, on the exposure 
of PF-06747775 at the RP2D;
•
To characterize the effect of itraconazole, a strong CYP3A4 inhibitor on the exposure 
of PF-06747775 at RP2D;
•
To characterize the effect of rifampin, a strong CYP3A4 inducer on the exposure of 
PF-06747775 at the RP2D;
•
To assess in plasma the presence/absence of EGFR mutations;
•
To evaluate the anti-tumor activity of PF-06747775 in both T790M-positive and 
T790M-negative EGFRm NSCLC tumors;
•
To evaluate tumor tissue biomarkers including, but not limited to, EGFR mutation by 
next generation sequencing.
 
Phase 1b/2
Primary Objectives
Cohort 1 – PF-06747775 Single-Agent in Patients with Previously Untreated 
EGFRm NSCLC
•
To assess the anti-tumor activity (objective response rate; ORR) of 
PF-06747775 single agent in patients with EGFRm NSCLC (del 19 or L858R, with
or without T790M).
Cohort 2A –PF-06747775 plus Palbociclib: Dose Finding
•
To evaluate safety and tolerability and establish the RP2D of PF-06747775 plus 
palbociclib in patients with EGFRm NSCLC with a secondary T790M mutation (del 
19 and T790M or L858R and T790M).
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Cohort 2B –– PF-06747775 Plus Palbociclib vs PF-06747775 Single Agent 
(Randomized)

To assess the progression free survival (PFS) of PF-06747775 plus palbociclib versus 
PF-06747775 single agent in patients with EGFRm NSCLC with a secondary T790M
mutation (del 19 and T790M or L858R and T790M).
Cohort 3 –PF-06747775 Plus Avelumab: Dose Finding

To evaluate safety and tolerability and establish the RP2D of PF-06747775 plus 
avelumab in patients with EGFRm NSCLC with a secondary T790M mutation
(del 19 and T790M or L858 R and T790M).
Secondary Objectives

To assess duration of response (DOR) and overall survival (OS) probability at 
24 months (all Cohorts);

To assess progression-free survival (PFS) (Cohorts 1, 2A, and 3);

To further characterize the AE profile of PF-06747775 when given as a single agent 
(Cohort 1 and Cohort 2B) and in combination with palbociclib (Cohort 2A and 2B)
and avelumab (Cohort 3);

To further characterize PF-06747775 PK when given as a single agent (Cohort 1 and 
Cohort 2B single-agent patients) and in combination with palbociclib (Cohort 2A and 
2B) and avelumab (Cohort 3);

To characterize the PK of palbociclib in combination with PF-06747775 (Cohort 2A 
and 2B);

To characterize the PK of avelumab in combination with PF-06747775 (Cohort 3);

To further explore the effects of PF-06747775 on QTc intervals when given as a 
single agent (Cohort 1 and Cohort 2B single-agent patients) and in combination with 
palbociclib (Cohort 2A and 2B) and avelumab (Cohort 3);

To assess in tumor and plasma the presence/absence of EGFR mutations
(All Cohorts);

To assess the immunogenicity of avelumab when given in combination with 
PF-06747775 (Cohort 3).


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Japanese Patient-Only Lead In Cohort: 
•
To evaluate the safety and tolerability of PF-06747775 when given as a single agent 
in Japanese patients (RP2D tolerability cohort)
•
To characterize single dose and steady state PK profiles of single agent PF-06747775
in Japanese patients (RP2D tolerability cohort and PK cohort)
Endpoints
Phase 1
Primary Endpoint
•
Cycle 1 DLT.
Secondary Endpoints
•
Overall safety profile of PF-06747775 characterized by type, incidence, severity, 
seriousness, and relationship to study therapy of AE (National Cancer Institute [NCI]
Common Terminology Criteria for Adverse Events [CTCAE] v4.03);
•
Laboratory abnormalities;
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
QT and R-R interval (R-R interval heart rate) for QTc effects of PF-06747775 when 
given as a single agent

Plasma area under the curve from zero to infinite time (AUCinf), maximum 
concentration observed after dose administration (Cmax), half life (t1/2), apparent 
clearance (CL/F), and volume of distribution (Vz/F) of PF-06747775 as a single agent 
after single dose;

Pre-dose concentration at steady state (Ctrough), area under the curve at steady state
(AUCtau), CL/F, observed accumulation ratio (Rac), and steady state accumulation 
ratio (Rss) of PF-06747775 as a single agent after multiple doses;

Plasma AUCinf, Cmax, and CL/F of sildenafil alone and in combination with steady 
state plasma concentrations of PF-06747775;

Plasma AUCtau and Cmax of PF-06747775 at the RP2D under fed and overnight fasted 
conditions;

Plasma AUCtau and Cmax of PF-06747775 at the RP2D alone and after esomeprazole 
treatment;

Plasma AUCtau and Cmax of PF-06747775 at the RP2D alone and after itraconazole 
treatment;

Plasma AUCtau and Cmax of PF-06747775 at the RP2D alone and after rifampin 
treatment;

EGFR mutations in tumor and plasma;

Objective response (OR), confirmed and unconfirmed, per Response Evaluation 
Criteria in Solid Tumors (RECIST) v1.1 for those patients with measurable disease.
Phase 1b/2
Primary Endpoints
Cohort 1 - PF-06747775 Single-Agent in Patients with Previously Untreated 
EGFRm NSCLC

Confirmed OR, per RECISTv 1.1.
Cohort 2A - PF-06747775 Plus Palbociclib: Dose Finding 

Cycle 2 DLT.
Cohort 2B – PF-06747775 Plus Palbociclib vs PF-06747775 Single Agent
(Randomized)

PFS.


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Cohort 3 - PF-06747775 Plus Avelumab: Dose Finding
•
Cycle 1 DLT.
Secondary Endpoints
•
PFS (Cohort 1, Cohort 2A, Cohort 3);
•
ORR (Cohort 2A, Cohort 2B, Cohort 3);
•
DOR (All Cohorts);
•
OS probability at 24 months (All Cohorts);
•
Overall safety profile characterized by type, incidence, severity, seriousness, and 
relationship to study therapy of adverse events (NCI CTCAE v4.03); 
•
Laboratory abnormalities (All Cohorts);
•
PK parameters of PF-06747775 following single and multiple doses as data permit 
when given as a single agent (Cohort 1 and Cohort 2B single-agent patients);
•
PK parameters of PF-06747775 following multiple doses as data permit when given 
in combination with palbociclib and avelumab (Cohort 2 and Cohort 3);
•
PK parameters of palbociclib and avelumab when given in combination with 
PF-06747775 as data permit (Cohort 2 and Cohort 3);
•
QT and RR for QTc effects of PF-06747775 when given as a single agent (Cohort 1
and Cohort 2B single-agent patients) and in combination with palbociclib (Cohort 2) 
and avelumab (Cohort 3);
•
EGFR mutations in tumor and plasma (All Cohorts);
•
Avelumab serum anti-drug antibodies (ADA; neutralizing antibodies) (Cohort 3).
 
 
 
 
 
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Endpoint for Japanese Patient-Only Lead In Cohort
•
Cycle 1 DLT (RP2D tolerability cohort);
•
Overall safety profile of PF-06747775 characterized by type, incidence, severity, 
seriousness, and relationship to study therapy of AE (National Cancer Institute [NCI] 
Common Terminology Criteria for Adverse Events [CTCAE] v4.03);
•
Laboratory abnormalities;
•
PK parameters of PF-06747775 following single and multiple doses as data permit 
when given as a single agent (RP2D tolerability cohort and PK cohort).
STUDY DESIGN
Study Overview
This is a Phase 1/2 study of PF-06747775 as a single agent and  in combination with other 
cancer treatments in patients with advanced EGFRm NSCLC.  The overall clinical study 
consists of a Phase 1 single agent dose-escalation and expansion part to determine the RP2D 
of PF-06747775 single agent in patients with previously-treated EGFRm NSCLC followed 
by sequential evaluations of PF-06747775 at the RP2D in 3 different clinical scenarios as 
detailed below:  
•
Cohort 1: Phase 2 evaluation of PF-06747775 as a single agent in previously 
untreated patients with advanced EGFRm NSCLC, 
•
Cohort 2: Phase 1b single arm evaluation of PF-06747775 in combination with 
palbociclib (Cohort 2A) followed by Phase 2 randomized evaluation of PF-06747775 
in combination with palbociclib vs PF-06747775 single agent (Cohort 2B) in 
previously-treated patients with EGFRm NSCLC with a secondary T790M mutation 
(del 19 and T790M or L858R and T790M), and
•
Cohort 3: Phase 1b evaluation of PF-06747775 in combination with avelumab in 
previously-treated patients with EGFRm NSCLC with a secondary T790M mutation
(del 19 and T790M or L858R and T790M).
Cohorts 2A and 3 will determine the RP2D of PF-06747775 in combination with either 
palbociclib or avelumab, respectively, based on safety and tolerability.  Patients will be 
treated at dose level 1 (DL1) of the combination as noted in Table 14 (Cohort 2A) and
Table 17 (Cohort 3). If the initial doses tested are tolerated, that will be the combination dose 
selected. Determination of the RP2D will be performed using the modified toxicity 
probability interval (mTPI) design as described in Section 3.1.3.1 (Cohort 2A) and
Section 3.1.4 (Cohort 3).  
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For Cohort 2A, after determination of the RP2D for the PF-06747775 and palbociclib 
combination, a randomized evaluation of the combination vs PF-06747775 single agent 
(2:1 ratio) will be initiated (Cohort 2B)
 
 
Figure 1.
Study B7971001 Study Schema*
* Approximate enrollment totals indicated.
EGFRm = epidermal growth factor receptor mutant; NSCLC = non-small cell lung cancer; PK = 
pharmacokinetic; RP2D = Recommended Phase 2 Dose
The status of the EGFR mutations will be determined in all patients using tumor or plasma 
samples obtained at study entry.  Patients providing tumor samples will be enrolled based on 
a local EGFR mutation test that includes the QIAGEN Therascreen® EGFR RGQ PCR Kit, 
Roche cobas® EGFR mutation kit, or a Sponsor-approved laboratory developed test that is 
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validated in a Clinical Laboratory Improvement Amendments (CLIA) laboratory.  Patients 
providing plasma samples will be enrolled based on a local EGFR mutation test that includes
the QIAGEN Therascreen EGFR Plasma RGQ kit, Roche cobas® EGFR mutation test v2 
(US-in vitro diagnostic product [IVD]), Sysmex Inostic’s OncoBEAMTM EGFR test, or a 
Sponsor-approved laboratory developed test that is validated in a CLIA laboratory, which 
will then be retrospectively confirmed by a validated cell-free DNA (cfDNA) test as 
determined by the Sponsor.  All patients — ie, in both Phase 1 and Phase 2 parts of the study 
— will have their tumor’s EGFR mutation status confirmed by the central lab test using 
FDA-approved QIAGEN Therascreen EGFR RGQ PCR kit (tumor-based) or a validated 
cfDNA test as determined by the Sponsor (plasma-based).  The tissue samples may also be 
tested retrospectively using the Thermo Fisher Scientific Oncomine Next Generation 
Sequencing (NGS) cancer panel, which detects exon 19 deletions, exon 20 insertions, T790M 
mutations, and exon 21 (L858R) substitution mutations.
Study design details specific to Phase 1 are provided in Section 3.1.1.  Study design details 
specific to Cohorts 1, 2, and 3 are provided in Section 3.1.2, Section 3.1.3, and Section 3.1.4, 
respectively.
All patients (regardless of Phase or Cohort) will be allowed to continue therapy until disease 
progression or intolerable toxicity, withdrawal of consent, termination of the study by the 
Sponsor, or death.  Treatment continuation beyond objective disease progression is 
acceptable if the Investigator deems the patient to have ongoing clinical benefit.  Treatment 
on PF-06747775 alone is also permitted if the combination is intolerable, but no patients 
may continue on trial on palbociclib or avelumab as single agents. Antitumor activity will be 
determined based on Investigator assessment.  Individual patients’ imaging will be 
prospectively collected for potential follow-up assessment by Blinded Independent Central 
Review (BICR).  
For all patients who have a RECIST response, confirmation of the response is required at 
least 4 weeks after initial assessment of response.
Phase 1
The Phase 1 part of this study is an open label, multi-center, multiple dose, non-randomized, 
safety, PK, 
, and dose escalation study of PF-06747775 as a single agent in patients with 
advanced EGFRm NSCLC (del 19 or L858R, +/- T790M).  PF-06747775 will be 
administered in successive cohorts as a single agent in 21 day cycles.  The dose-escalation 
portion of Phase 1 includes a single dose lead-in period to assess single dose PK of 
PF-06747775, followed by continuous once daily dosing in a 21 day cycle.  The Continual 
Reassessment Method (CRM) will be used to guide the dose assignment and estimate the 
MTD based on cumulative data on DLTs in the first cycle of treatment.  
Phase 1 will include a series of PK sub-studies:
•
A sildenafil sub-study (PF-06747775 will be assessed for
CYP3A4 induction/inhibition, utilizing sildenafil as the CYP3A4 substrate);
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•
A food-drug and a CYP3A4 drug-drug interaction (DDI) PK sub-study 
(CYP3A4 induction interaction with rifampin);
•
An antacid-drug and a CYP3A4 drug-drug interaction PK sub-study 
(CYP3A4 inhibition interaction with itraconazole).
Phase 2 Cohort 1
Upon determination of the RP2D of PF-06747775 single agent, Cohort 1 will be initiated.  
Cohort 1 of the study is an open-label, multi-center, single-arm Phase 2 evaluation of 
PF-06747775 single agent in previously untreated patients with advanced EGFRm (del 19 or 
L858R, with or without T790M) NSCLC.
Phase 1b/2 Cohort 2
Cohort 2 will be initiated upon completion of the antacid effect and itraconozole DDI PK 
sub-study.  Cohort 2 of the study consists of a Phase 1b single-arm evaluation of the safety, 
PK
of the RP2D of PF-06747775 in combination with palbociclib (Cohort 2A) 
followed by a Phase 2 randomized evaluation of antitumor activity and safety of the 
combination vs PF-06747775 single agent (Cohort 2B).  Both Cohort 2A and Cohort 2B will 
enroll patients with previously-treated advanced EGFRm NSCLC (del 19 and T790M or 
L858R and T790M).  
Cohort 2A will evaluate PF-06747775 200 mg by mouth (PO) daily (QD) in combination 
with palbociclib continuous PO QD dosing in 21-day cycles. The starting dose (DL1) for 
palbociclib will be 100 mg PO daily. 
Dose finding will follow mTPI method with adjustments using DLT rate.
Phase 2 Cohort 2B will be initiated once the RP2D of the PF-06747775 and palbociclib 
combination is determined. Approximately 39 patients will be randomized in a 2:1 ratio to 
receive either PF-06747775 plus palbocicib combination or PF-06747775 single agent.  
Approximately 49 patients will be enrolled to test this combination (10 patients in Cohort 2A 
and 39 patients [26 PF-06747775 plus palbociclib and 13 PF-06747775 single agent] in 
Cohort 2B).  
Cohort 3
Cohort 3 will be initiated upon completion of enrollment to Cohort 2.  Cohort 3 of the study 
consists of a Phase 1b single-arm evaluation of the safety, PK,
 of the RP2D of 
PF-06747775 administered PO QD in combination with avelumab administered 
intravenously (IV) every 2 weeks (Q2W) in previously-treated patients with advanced 
EGFRm NSCLC (del 19 and T790M or L858R and T790M).  
The starting dose level (DL1) for the Cohort 3 combination is PF-06747775 200 mg PO QD 
and avelumab 10 mg/kg IV Q2W in 28-day (4-week) cycles.
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Dose finding will follow the mTPI design.  Once RP2D of PF-06747775 in combination with 
avelumab is determined, the Dose Expansion Phase will be opened. In Cohort 3, a total of 
approximately 20 patients will be enrolled to assess the safety, PK,
 
 of the combination.
The Schedule of Activities (SOA) Tables outline the study treatments including separate 
SOA for each phase/group of the study and for the Phase 1 PK sub-studies.
Japanese Patient-Only Lead In Cohort
This study will include a Japanese patient lead in cohort (LIC) to evaluate the safety, 
tolerability and PK of PF-06747775 in Japanese patients with advanced EGFRm NSCLC at 
RP2D (PF-06747775 200 mg) when given as a single agent. This Japanese LIC will consists 
of 2 cohorts; RP2D tolerability cohort and PK cohort. The RP2D tolerability cohort will be 
enrolled first. Up to 3 patients will be enrolled and treated at RP2D. If no DLT is observed, 
no additional patients will be enrolled in this cohort. If a DLT is observed in 1 of the initial 3 
treated patients, then 3 additional patients will be enrolled and treated. Following 1 cycle (21 
days) of treatment, a safety review will be performed by Japanese investigators and the 
Sponsor to determine whether the emerging data from this cohort will support inclusion of 
patients at Japanese sites in Phase 2 (Cohort 1) and Phase 1b/2 (Cohort 2A, 2B and 3). After 
tolerability in Japanese patients has been confirmed in the RP2D tolerability cohort, an 
additional PK cohort will be initiated. In the second PK cohort, 3 patients will be enrolled 
and they will receive 100 mg single dose followed by once daily continuous dosing at the 
RP2D. In both cohorts, blood samples will be collected for PK assessment (See Appendix 8).
SCHEDULE OF ACTIVITIES
The Schedule of Activities (SOA) tables provide 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.
The SOA Tables has been organized by Study Phase and Cohort.  Further, the schedules of 
activities for PK and electrocardiogram (ECG) assessments have been added outside of the 
primary SOAs for clarity.
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Table 1.
PHASE 1 SCHEDULE OF ACTIVITIES
Phase 1
Lead-in 
PK 
CYCLE 1
(21 days)
CYCLE 2
(21 days)
CYCLE 3
(21 days)
End of 
Treatment26
Follow-up27
Visit Identifier
Screening2
(Day -8)
Day 11
Day 11
Day 1
Day 1
Visit Window
28 days 
from 
registration
3
1
4
2
2
3
+7
Informed consent3
X
Tumor history
X
Medical history
X
Physical examination 
X
X
X
X
Baseline signs and symptoms4
X
Height
X
Weight
X
X
X
X
Vital signs5
X
X
X
X
X
X
X
X
Performance status (ECOG)6
X
X
X
X
X
X
X
Laboratory
Hematology7
X
(X)
X
X
X
Blood Chemistry8
X
(X)
X
X
X
Coagulation9
X
(X)
X
Urinalysis10
X
(X)
X
Pregnancy test11
X
X
X
X
X
(12-lead) ECG 12
X
See Table 2
Registration and Treatment
Registration13
X
PF-0674777514
X
Once daily, PO, continuous
Tumor assessments 
CT or MRI imaging15
X
X every other 
cycle (every 
6 weeks) 
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Phase 1
Lead-in 
PK 
CYCLE 1
(21 days)
CYCLE 2
(21 days)
CYCLE ≥3
(21 days)
End of 
Treatment26
Follow-up27
Visit Identifier
Screening2
(Day -8)
Day 11
Day 11
Day 1
Day 1
Visit Window
≤28 days 
from 
registration
±3
±1
±4
±2
±2
±3
+7
Other clinical assessments
Adverse Events16
X
X
X
X
X
X
X
Concomitant treatments and 
non-drug supportive 
interventions17
X
X
X
X
X
X
X
Other samplings
Pharmacokinetics
Sildenafil sub-study19
See Table 3
PF-06747775 single and 
multiple dose 
pharmacokinetics20
See Table 2
Food Effect 
sub-study21
See Table 4
Antacid effect sub-study22
See Table 5
CYP3A4 sub-studies23
See Table 4 and Table 5
 
 
Plasma samples for mutation 
analysis28
X
X (Every 
3 cycles)
X
Blood samples for  4-β-
hydroxycholesterol / 
cholesterol analysis29
See Table 2 through Table 5
Abbreviation: CT = computed tomography; ECG = electrocardiogram; MRI = magnetic resonance imaging
Footnotes 
1.
Day relative to start of study treatment (Day 1).
2.
Screening: to be obtained within 28 days prior to registration.
3.
Informed Consent: must be obtained prior to undergoing any study specific procedures unless considered standard of care.
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4.
Baseline Signs & Symptoms: patients will be asked about any signs and symptoms experienced within the past 14 days of registration.  Baseline signs and 
symptoms (including NCI CTCAE grade if applicable) will be recorded on the Medical History case report form (CRF) page.
5.
Vital Signs: vital signs include blood pressure (BP) and heart rate (HR).
6.
Performance status: use Eastern Cooperative Oncology Group (ECOG) – see Appendix 2.
7.
Hematology: See Section 7.1.4 for specific required tests.  No need to repeat on Cycle 1 Day 1 (C1D1) if screening assessment performed within 7 days 
prior to that date. 
8.
Blood Chemistry: See Section 7.1.4 for specific required tests.  No need to repeat on C1D1 if baseline assessment performed within 7 days prior to that 
date.
9.
Coagulation: See Section 7.1.4 for specific required tests.  No need to repeat on C1D1 if screening assessment performed within 7 days prior to that date.
10. Urinalysis: See Section 7.1.4 for specific required tests.  Dipstick is acceptable.  Microscopic analyses if dipstick abnormal.  No need to repeat on C1D1 if 
baseline assessment performed within 7 days prior to that date. 
11. Serum/Urine Pregnancy Test: For female patients of childbearing potential, ie. who do not fit the definition of “female patients who are not of childbearing 
potential” in inclusion criterion 13, a pregnancy test, with sensitivity of at least 25 mIU/mL, and assayed in a certified laboratory, will be performed on two 
occasions prior to starting study therapy - once at the start of screening and once at the baseline visit, immediately before investigational product 
administration.  Pregnancy tests will also be routinely repeated at every cycle during the active treatment period, at the end of study therapy and additionally 
whenever one menstrual cycle is missed or when potential pregnancy is otherwise suspected.  Additional pregnancy tests may also be undertaken if 
requested by institutional review board/ethics committee (IRB/ECs) or if required by local regulations.
12. Triplicate 12-lead ECG: At each time point, three consecutive 12-lead ECGs will be performed approximately 2 minutes apart to determine mean QT 
interval corrected by Fridericia’s formula (QTcF interval).  When coinciding with blood sample draws for pharmacokinetics (PK), ECG assessment should 
be performed prior to blood sample collection, such that the blood sample is collected at the nominal time (ie, the timing of the PK collections over rides the 
timing of the ECG collections).  ECG assessments pre-dose should happen prior to breakfast. If the mean QTcF is prolonged (value of >500 msec), the 
ECGs should be re-evaluated by a qualified person at the institution for confirmation.  Additional triplicate ECGs may be performed as clinically indicated.  
ECG assessments will be performed in the dose escalation cohorts at screening, pre-dose and 2 hrs. post dose on Day -8, pre-dose and 2 hrs. post dose on 
Day 11 of Cycle 1, and pre-dose on Days 1 of Cycles 2 to 4.  The 2 hrs. post dose ECG assessment is intended to target Cmax, this time point may be 
re-assessed as data emerge.  See Table 2 for detailed information.
13. Registration: “randomization” patient number and dose level allocation operated by Pfizer Inc.  Registration will be within 2 days prior to the Day -8 single 
dose lead-in as appropriate.  (see Section 5.2).
14. Study Treatment: PF-06747775 will be taken with a breakfast of 200-300 calories in the morning every day at approximately the same time.  More 
information is provided under Study Treatments section. 
15. CT or MRI Tumor Assessments: Baseline tumor assessments should be within 28 days of first dose of treatment.  Tumor assessments will include all 
known or suspected disease sites.  Imaging may include chest, abdomen and pelvis CT or MRI scans.  Minimally, chest, liver and adrenals must be imaged.  
Brain scans are required at baseline and every assessment if intra-cerebral disease is present; if no intra-cerebral disease is found at baseline, then brain 
imaging is only required on study if clinically indicated.  Bone scans will be performed at baseline if clinically indicated and on-study as appropriate to 
follow disease.  Tumor assessment should be completed every 6 weeks (2 cycles) and repeated at the End of Treatment visit if more than 6 weeks have 
passed since the last evaluation.  For all patients with RECIST measurable disease who have a RECIST response, confirmation of the response is required at 
least 4 weeks after initial assessment of response.


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16. Adverse Event (AE) Assessments: Adverse events should be documented and recorded at each visit using the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0.  Patients must be followed for AEs for 28 days after the last treatment administration or 
until all drug related toxicities have resolved, whichever is later; or earlier than 28 days should the patient commence another anticancer therapy in the 
meantime. For serious adverse events (SAEs), the active reporting period to Pfizer or its designated representative begins from the time that the patient 
provides informed consent, which is obtained prior to the patient’s participation in the study, ie, prior to undergoing any study-related procedure and/or 
receiving investigational product, through and including 28 calendar days after the last administration of the investigational product.  Serious adverse events 
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 serious adverse events that the investigator believes have at least a reasonable possibility of being related to investigational product are to be reported to 
the sponsor.
17. Concomitant Treatments: all concomitant medications and Non Drug Supportive Interventions should be recorded in the CRF.
  
 
 
 
 
19. Sildenafil sub-study (Phase 1 only at RP2D): Sildenafil (SDF) sub-study will be performed at the MTD (expansion cohort) of Phase 1.  See Table 3 for 
detailed information.
20. PF-06747775 single dose and multiple dose pharmacokinetics: serial blood samples will be collected after single and multiple doses (steady state) of 
PF-06747775 to characterize their pharmacokinetic behavior in the dose escalation.  Patients participating in any of the PK sub-studies will not be part of 
this assessment.  See Table 2 for detailed information. 
21. Food effect sub-study (Phase 1 only at RP2D): in a subset of patients (12) enrolled at the PF-06747775 RP2D, a PK sub-study characterizing the potential 
effect that a high fat high calorie meal could have on the absorption of PF-06747775 will be performed prior to the starting of the Phase 2 portion.  Each 
patient will serve as their own control in which PF-06747775 will be administered in the morning under either “fed” or “overnight fasted” (≥10 hrs.) 
conditions.  The testing order for fed versus fasted conditions will be as follows: the first 6 patients to participate in this sub-study will be tested under fed 
followed by fasted conditions, the next 6 patients will be tested under fasted followed by fed conditions.  Patients participating in the food effect sub-study 
will also participate in the rifampin DDI sub-study that will follow as a fixed sequence design.  See Table 4 for detailed information.
22. Antacid effect sub-study (Phase 1 only at RP2D): in a subset of patients (12) enrolled at the PF-06747775 RP2D, a PK sub-study characterizing the 
potential effect that acid reducing agents could have on the absorption of PF-06747775 treatment will be performed prior to the starting of the Phase 
2 portion.  Each patient will serve as their own control in a fixed sequence.  PF-06747775 treatment will be administered once daily in the morning under 
fasted conditions followed by 4 consecutive days of  PF-06747775 QD + esomeprazole (antacid).  In the morning of the fifth day of antacid treatment, PK 
blood samples will be collected for a 24 hr. period.  Patients participating in the antacid effect sub-study will also participate in the itraconazole DDI 
sub-study (fixed sequence).  See Table 5 for detailed information.
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23. CYP3A4 sub-studies (Phase 1 only at RP2D): in a subset (12) of patients enrolled at the RP2D, two PK sub-studies characterizing the potential effect that 
CYP3A4 inhibitors and inducers could have on the exposure of PF-06747775 treatment will be performed prior to the starting of the Phase 2 portion.  Each 
patient will serve as their own control in a fixed sequence.  PF-06747775 treatment will be administered in combination with either itraconazole (inhibitor) 
or rifampin (inducer) after either the antacid effect or food effect sub-study has been performed.  Itraconazole or rifampin will be given for 5 or 
12 consecutive days in combination with PF-06747775.  In the morning of the fifth or twelfth day of either CYP3A4 inhibitor or inducer treatment, PK 
blood samples will be collected for a 24 hr. period.  See Table 4 and Table 5 for detailed information.
 
 
26. End of Treatment visit: Obtain these assessments if not completed in the last week (last 6 weeks for tumor assessments).
27. 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, 
vital signs, and assessment for resolution of any treatment related toxicity.  Patients continuing to experience toxicity at this point following discontinuation 
of treatment will continue to be followed at least every 4 weeks until resolution or determination, in the clinical judgment of the investigator, that no further 
improvement is expected. 
28. Plasma Samples for Mutation Analysis: Two, 10 mL blood draws in K2EDTA tubes will be collected at screening, every three cycles and at End of 
Treatment and processed for plasma according to the Study Manual to be used for mutation analysis, including, but  not necessarily limited to, the EGFR 
gene.
29. Blood samples for 4-β-hydroxycholesterol /cholesterol analysis: Three (3) mL of blood will be collected in lithium heparin tubes for the analysis of
4-β-hydroxycholesterol and cholesterol as outlined in Table 2 through Table 5.
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Table 2.
Phase 1 Single and Multiple Dose PK and ECG Assessments for Phase 1 Dose Escalation Cohorts. 
Patients Participating in any of the PK Sub-Studies will not be Part of this Assessment.
Visit 
Identifier
Lead-in
Day -8 (3)
Cycle 1
Day-7
Cycle 1
Day -6
Cycle 1
Day -5
/ -4*
Cycle 1
Day -3*
/ -2*
Cycle 1
Day -1*
/ 1*
Cycle 1
Day 
1 - 10
Cycle 1
Day 11 (± 4)
Cycle 
1 Day 12
Cycle 
1 Day 
13 - 21
Cycles 
2 - 4
Day 1
Hours Post 
Dose
0a 1
2
4
6
8
24
48
72/96*
120*/
144*
168*/
192*
Pre-
doseb
0a
1
2
4
6
8
Pre-
doseb
0a
0a
Pre-doseb
PF-
06747775
Dosec
X
X
X
X
X
PK blood 
samplingd
X X X X X
X
X
X
X
X
X
X X X X X
X
X
12-lead 
ECGe
X
X
X
X
X
4--hydroxy
-cholesterol/
cholesterolf
X
X
X
a.
0 hrs. Dose time: dose time of PF-06747775 that triggers the defined post dose sample collection times.
b.
Pre-dose sample collection: before study treatment dose.
c.
PF-06747775 dose: PF-06747775 dose will be given in the morning with a breakfast of 200-300 calories, at approximately the same time once daily in 
21 day cycles. Food is allowed 2 hrs. after dose. 
d.
PK blood sampling for PF-06747775 analysis:  On Day -8, 4 mL of blood in K2EDTA tubes will be collected as shown above for single dose PK analysis.  
On Day 11 of Cycle 1, 4 mL of blood in K2EDTA tubes will be collected as shown above for multiple dose PK analysis.  On Day 1 of Cycles 2 to 4, 4 mL of 
blood in K2EDTA tubes will be collected prior to PF-06747775 dose (pre-dose) for steady state PK analysis.
e.
Triplicate 12-lead ECG: At each time point, three consecutive 12-lead ECGs will be performed approximately 2 minutes apart.  When coinciding with 
blood sample draws for pharmacokinetics (PK), ECG assessment should be performed prior to blood sample collection, such that the blood sample is 
collected at the nominal time (ie, the timing of the PK collections over rides the timing of the ECG collections).  ECG assessments pre-dose should happen 
prior to breakfast.  If the mean QTcF is prolonged (value of >500 msec), the ECGs should be re-evaluated by a qualified person at the institution for 
confirmation.  Additional triplicate ECGs may be performed as clinically indicated.  ECG assessments will be performed at pre-dose and 2 hrs. post dose on 
Day -8, pre-dose and 2 hrs. post dose on Day 11 of Cycle 1, and pre-dose on Days 1 of Cycles 2 to 4.  The 2 hrs. post dose ECG assessment is intended to 
target Cmax, this time point may be re-assessed as data emerge.
f.
Blood sampling for 4--hydroxycholesterol and cholesterol analysis: 3 mL blood collected in Lithium heparin tubes pre-dose.
*     In order to accommodate weekends, only 3 of these 5 timepoints (Day -4, Day -3, Day -2, Day -1, Day 1) should be collected. This pertains to all sites. 
The PK sample at 192 hrs, if collected, should be prior to dose on Day 1.
Abbreviations: PK = pharmacokinetic.


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Table 3.
Phase 1 Sildenafil Sub-Study (Phase 1 only at MTD Expansion Cohort).
Visit Identifier 
Lead-in
Day -8 (± 3)
Cycle 1
Day -7
Cycle 1
Day 1 - 10
Cycle 1
Day 11 (± 4)
Cycle 1
Day 12
Cycle 1 Days 
12 - 21
Hours Post Dose
0a
0.5
1
2
3
4
6
8
24
0a
Pre-
doseb
0a
0.5
1
2
3
4
6
8
Pre-doseb
0a
Sildenafil dosec
X
X
PF-06747775 Dosed
X
X
X
PK blood samplinge
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
4--hydroxy-
cholesterol/
cholesterolf
X
X
a.
0 hrs. Dose time: dose time of sildenafil or PF-06747775 that triggers the defined post dose sample collection times.
b.
Pre-dose sample collection: before study treatment dose.
c.
Sildenafil dose: a single 25 mg dose of sildenafil will be given in the morning at approximately the same time on Day -8 and on Day 11 of 
Cycle 1 following a ≥10 hr. overnight fast; food is allowed 2 hrs. after dose. On Day 11 of Cycle 1, PF-06747775 will be given together with sildenafil (see
Section 3.5.1).
d.
PF-06747775 dose: PF-06747775 at the MTD dose will be given in the morning, with a breakfast of 200-300 calories, at approximately the same time once 
daily in 21 day cycles.  On Day 11 of Cycle 1, PF-06747775 will be given in the morning with sildenafil following a ≥10 hr. overnight fast. Food is allowed 
2 hrs. after dose.
e.
PK blood sampling for PF-06747775 and sildenafil analysis: On Day -8, 4 mL of blood in K2EDTA tubes will be collected for PK analysis.  On Day 11, 
a PK blood sample will be collected prior to the dose of sildenafil + PF-06747775 (pre-dose).  After sildenafil and PF-06747775 dose, 4 mL of blood in 
K2EDTA tubes will be collected as shown above for PK analysis.
f.
Blood sampling for 4--hydroxycholesterol and cholesterol analysis: 3 mL blood collected in Lithium heparin tubes pre-dose.
Following completion of sub-study, patients will continue on once daily dosing of PF-06747775 at the MTD.  Starting on Cycle 2 Day 1, patients who have 
completed the sub-study will continue to complete study assessments as outlined in Table 1 (Phase 1 Schedule of Activities), without any additional scheduled 
PK or 4--hydroxycholesterol /cholesterol assessments.
Abbreviation: PK = pharmacokinetic.


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Table 4.
Phase 1 Food Effect and Rifampin DDI Sub-Studies (Phase 1 only at the RP2D).  
Visit 
Identifier 
Cycle 1
Day 8
(fasted-fed & fed-fasted)
Cycle 1
Day 9
(fasted-fed & fed-fasted)
Cycle 1
Day 10
Cycle 1
Day 10 - 20
Cycle 1
Day 21
Cycle 
2
Day 1
Hours Post 
Dose
Pre-
dosea
0b
1
2
4
6
8
Pre-
dosea
0b
1
2
4
6
8
Pre-dosea
-2
0b
-2 
Pre-
dosea
0b
1
2
4
6 8
Pre-
dosea
PF-06747775
dosec
X
X
Xd
X
Rifampin 
Dosed
Xd
Xd
PK blood 
samplinge
X
X X X X
X
X
X
X
X
X
X
X
X
X
X
X X X
X
4-β-hydroxy-
cholesterol/
Cholesterolf
X
X
a.
Pre-dose sample collection: before study treatment dose.
b.
0 hrs. Dose time: dose time of PF-06747775 that triggers the defined post dose sample collection times.
c.
PF-06747775 dose: PF-06747775 at the RP2D will be given in the morning, starting on Cycle 1 Day 1, with a breakfast of 200-300 calories (see
Section 3.5.2), at approximately the same time once a day in 21 day cycles.  On Days 8 and 9 of Cycle 1, following ≥10 hr overnight fast, PF-06747775 will 
be given either  while fasting or with a high-fat, high-calorie meal.  The testing order for fasted versus fed conditions will be as follows: the first 6 patients to 
participate in this sub-study will be tested under fasted followed by fed conditions, the next 6 patients will be tested under fed followed by fasted conditions.  
Food is allowed 4 hrs. after dose in both fasted and fed conditions. A fixed sequence with rifampin treatment will happen after the fasted/fed portions have 
been completed.
d.
Rifampin dose: On Days 10 to 20 of Cycle 1, a 600 mg dose of rifampin will be given to patients at approximately the same time in the morning 2 hours 
prior to breakfast.  On Day 21 of Cycle 1, following ≥10 hr overnight fast, a pre-dose sample should be collected followed by rifampin + 
PF-06747775 treatment. Food is allowed 4 hrs. after dose.
e.
PK blood sampling for PF-06747775 analysis: On Day 8 of Cycle 1, 4 mL PK blood samples in K2EDTA tubes will be collected pre and post dose as 
shown above.  On Day 9 of Cycle 1, 4 mL PK blood sample in K2EDTA tubes will be collected pre and post dose as shown above.  On day 21 of Cycle 1, 
4 mL PK blood sample in K2EDTA tubes will be collected pre and post dose as shown above.  
f.
Blood sampling for 4--hydroxycholesterol and cholesterol analysis: 3 mL blood collected in Lithium heparin tubes pre-dose.
Following completion of the sub-study, patients will continue on once daily dosing of PF-06747775 at the R2PD. Starting on Cycle 2 Day 1, following the pre-
dose PK draw, patients who have completed the sub-study will continue to complete study assessments as outlined in Table 1 (Phase 1 Schedule of Activities),
without additional scheduled PK or 4--hydroxycholesterol /cholesterol assessments.
Abbreviations: PK = pharmacokinetic.


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Table 5.
Phase 1 Antacid Effect and Itraconazole DDI Sub-Studies (Phase 1 only at the RP2D).  
Visit Identifier
Cycle 1
Day 8
Cycle 1
Day 9
Cycle 1
Day 
10 - 12
Cycle 1
Day 13
(antacid)
Cycle 1
Day 14
Cycle 
1
Day 
15 - 16
Cycle 1
Day 
17 - 20
Cycle 1
Day 21
Cycle 
2
Day 1
Hours Post Dose
Pre-
dosea 0b 1 2 4
6
8 -2
Pre-
dosea
0b
-2
0b
-2
Pre-
dosea
0b
1
2
4 6
8
Pre-
dosea
0b
0b
0b
-3
Pre-
dosea 0b 1
2 4 6 8
Pre-
dosea
PF-06747775
dosec
X
X
X
X
X
X
X
X
Esomeprazole dosed
X
X
X
Itraconazole dosee
X
X
PK blood samplingf
X
X X X X X
X
X
X
X
X X
X
X
X
X X X X X
X
4--hydroxy-
cholesterol/
Cholesterolg
X
X
a.
Pre-dose sample: before study treatment dose.
b.
0 hrs. Dose time: dose time of PF-06747775 that triggers the defined post dose sample collection times.
c.
PF-06747775 dose: PF-06747775 at the RP2D will be given in the morning, starting on Cycle 1 Day 1, with a breakfast of 200-300 calories (see Section 3.5.3), at 
approximately the same time once a day in 21 day cycles.  Each patient will serve as their own control in a fixed sequence.  A washout period of 3 days prior to dosing 
itraconazole is required to restore the pH of the stomach (C1 D14 - 16).  During this washout period, PF-06747775 will be given daily in the morning with a breakfast of 
200-300 calories. Food is allowed 2 hrs. after dose. A minimum of 12 patients (PK evaluable) are required for this study.
d.
Esomeprazole dose: on Days 9-12 of Cycle 1, a 40 mg dose of esomeprazole (antacid) will be given to patients 2 hrs. prior to breakfast and PF-06747775.  On Day 13 of 
Cycle 1, patients will take 40 mg of esomeprazole at home without food (fasted) prior to arriving at the clinic, then a PK blood sample will be collected prior to dose 
(pre-dose), then patients will receive PF-06747775 with a breakfast of 200-300 calories, approximately 2 hrs. after esomeprazole dose. Food is allowed 2 hrs. after dose of 
PF-06747775.
e.
Itraconazole dose: On days 17 to 20 of Cycle 1, a 200 mg dose of itraconazole + PF-06747775 should be given with a breakfast of 200-300 calories in the morning at 
approximately the same time of the day.  On day 21 of Cycle 1, 3 hrs. prior to the administration of PF-06747775 treatment, 200 mg of itraconazole should be taken at home 
without food (fasted) prior to arriving at the clinic, then a pre-dose PK blood sample will be collected approximately 3 hrs. post itraconazole dose, followed by 
PF-06747775 treatment with a breakfast of 200-300 calories. Food is allowed 2 hrs. after dose.
f.
PK Blood sampling for PF-06747775 analysis: On Day 8 of Cycle 1, a 4 mL PK blood sample in K2EDTA tubes will be collected prior to dose (pre-dose) then patients will 
receive PF-06747775 treatment, and 4 mL PK blood samples in K2EDTA tubes will be collected as shown above.  On Day 13 of Cycle 1, a 4 mL PK blood sample in 
K2EDTA tubes will be collected prior to dose (pre-dose, 2 hrs. after esomeprazole administration) then patients will receive PF-06747775, and 4 mL PK blood sample in 
K2EDTA tubes will be collected as shown above.  On Day 21 of Cycle 1, a 4 mL PK blood sample in K2EDTA tubes will be collected prior to dose of PF-06747775
(pre-dose, 3 hrs. after itraconazole administration) then patients will receive PF-06747775, and 4 mL PK blood samples in K2EDTA tubes will be collected as shown above. 
Blood sampling for 4--hydroxycholesterol and cholesterol analysis: 3 mL blood collected in Lithium heparin tubes pre-dose.
Following completion of sub-study, patients will continue on once daily dosing of PF-06747775 at the R2PD. Starting on Cycle 2 Day 1, following the pre-dose PK draw, patients 
who have completed the sub-study will continue to complete study assessments as outlined in Table 1 (Phase 1 Schedule of Activities), without additional scheduled PK or 
4--hydroxycholesterol /cholesterol assessments.
Abbreviations: PK = pharmacokinetic.


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Table 6.
Single-Agent PF-06747775 in Previously-Untreated EGFRm NSCLC: Phase 2 Cohort 1 SCHEDULE OF 
ACTIVITIES
Phase 2
LEAD-IN 
PK
CYCLE 1
(21 days)
CYCLE 2
(21 days)
CYCLES ≥3
(21 days)
End of 
Treatment23
Follow- up24
Visit Identifier
Screening2
Day -4
Day 10
Day 11
Day 1
Day 1
Visit Window
28 days from 
registration
1
4
2
2
3
+7
Informed consent3
X
Tumor history
X
Medical history
X
Physical examination
X
(X)
X
X
Baseline signs and symptoms4
X
Height
X
Weight
X
X
X
X
Vital signs5
X
X
X
X
X
X
X
Performance status (ECOG)6
X
X
X
X
X
X
X
Contraception check7
X
(X)
X
X
X
Laboratory
Hematology8
X
(X)
X
X
X
Blood Chemistry9
X
(X)
X
X
X
Coagulation10
X
(X)
X
Urinalysis11
X
(X)
X
Pregnancy test12
X
X
X
X
X
12-Lead ECG13
X
X (See 
Table 7)
See Table 7
X
Registration and Treatment
Registration14
X
PF-0674777515
X
Once daily PO continuous
Tumor assessments 
CT or MRI imaging16
X
X and every 
other cycle 
(every 6 weeks) 
+/- 7 days
X
Other clinical assessments
Adverse Events17
X
X
X
X
X
X
Concomitant treatments and non-drug 
supportive interventions18
X
X
X
X
X
X


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Phase 2
LEAD-IN 
PK
CYCLE 1
(21 days)
CYCLE 2
(21 days)
CYCLES ≥3
(21 days)
End of 
Treatment23
Follow- up24
Visit Identifier
Screening2
Day -4
Day 10
Day 11
Day 1
Day 1
Visit Window
≤28 days from 
registration
±1
±4
±2
±2
±3
+7
Other samplings
 
Pharmacokinetics20
X (See 
Table 7)
See Table 7
Genotyping sample22
X
Plasma Samples for Mutation 
Analysis25
X
Cycle 5 only
X
 
Survival27
X
Abbreviation: →= ongoing/continuous event; AEs = adverse events; C = cycle; CT = computed tomography; ECG = electrocardiogram; MRI =  magnetic 
resonance imaging
Footnotes
1.
Day relative to start of study treatment (Day 1).
2.
Screening: to be obtained within 28 days prior to registration.
3.
Informed Consent: must be obtained prior to undergoing any study specific procedures unless considered standard of care.
4.
Baseline Signs & Symptoms: patients will be asked about any signs and symptoms experienced within the past 14 days of registration.  Baseline signs and 
symptoms (including  NCI CTCAE grade, if applicable) will be recorded on the Medical History case report form (CRF) page.
5.
Vital signs: vital signs include blood pressure (BP) and heart rate (HR).  Vital signs will be taken and recorded during the site clinic visit. 
6.
Performance status: use Eastern Cooperative Oncology Cohort (ECOG) – see Appendix 2.
7.
Contraception Check: Male patients who are able to father children, and female patients who are of childbearing potential will need to affirm that they 
meet the criteria for correct use of 2 of the selected methods of contraception.  The investigator or his or her designee will discuss with the patient the need to 
use 2 highly effective contraception methods consistently and correctly, and document such conversation in the patient’s chart.  In addition, the investigator 
or his or her designee will instruct the patient to call immediately if one or both selected contraception methods are discontinued, or if pregnancy is known or 
suspected in the patient or the patient’s partner.
8.
Hematology: See Section 7.1.4 for specific required tests.  No need to repeat on Cycle 1 Day 1 (C1D1) if baseline assessment performed within 7 days prior 
to that date.
9.
Blood Chemistry: See Section 7.1.4 for specific required tests.  No need to repeat on C1D1 if baseline assessment performed within 7 days prior to that 
date.
10. Coagulation: See Section 7.1.4 for specific required tests.  No need to repeat on C1D1 if baseline assessment performed within 7 days prior to that date.
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11. Urinalysis: See Section 7.1.4 for specific required tests.  Dipstick is acceptable.  Microscopic analyses if dipstick abnormal.  No need to repeat on C1D1 if 
baseline assessment performed within 7 days prior to that date.
12. Serum/Urine Pregnancy Test: For female patients of childbearing potential, ie, who do not fit the definition of “female patients who are not of childbearing 
potential” in inclusion criterion 13, a serum or urine pregnancy test, with sensitivity of at least 25 mIU/mL and assayed in a certified laboratory>, will be 
performed on two occasions prior to starting study therapy - once at the start of screening and once at the baseline visit, immediately before investigational 
product administration.  Pregnancy tests will also be routinely repeated at every cycle during the active treatment period, at the end of study therapy and 
additionally whenever one menstrual cycle is missed or when potential pregnancy is otherwise suspected.  Additional pregnancy tests may also be 
undertaken if requested by institutional review board/ethics committee (IRB/ECs) or if required by local regulations.
13. Triplicate 12-Lead ECGs: At each time point, three consecutive 12-lead ECGs will be performed approximately 2 minutes apart to determine mean QTcF 
interval.  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 (ie, the timing of the PK collections over rides the timing of the ECG collections). ECG assessments pre-dose should 
happen prior to breakfast. If the mean QTcF is prolonged (value of >500 msec), the ECGs should be re-evaluated by a qualified person at the institution for 
confirmation.  Additional triplicate ECGs may be performed as clinically indicated.  ECG assessments will be performed according to the schedule outlined 
in Table 7.  
14. Registration: Patients will be enrolled according to a computer generated pseudo-random code.  Randomization numbers will be assigned by a central 
web-based randomization system operated by Pfizer Inc. 
15. Study Treatment: The recommended Phase 2 Dose (RP2D) of PF-06747775 will be given with a breakfast of 200-300 calories in the morning every day at 
approximately the same time once daily in 21 day cycles. 
16. CT or MRI Tumor Assessments: Baseline assessments must be within 28 days of first study treatment.  Tumor assessments will include all known or 
suspected disease sites.  Tumor response will be assessed per RECIST v1.1.  Imaging may include chest, abdomen and pelvis CT or MRI scans.  Minimally, 
chest, liver and adrenals must be imaged.  Brain scans are required at baseline and every assessment if intra-cerebral disease is present; if no intra-cerebral 
disease is found at baseline, then brain imaging is only required on study if clinically indicated.  Bone scans will be performed at baseline if clinically 
indicated and on-study as appropriate to follow disease.  For all patients with RECIST measurable disease who have a RECIST response, confirmation of the 
response is required at least 4 weeks after initial assessment of response. Tumor assessment should be repeated at the End of Treatment visit if more than 
6 weeks have passed since the last evaluation.  For patients that have discontinued the treatment period due to reasons other than disease progression: Tumor 
assessments must continue until documented progression of disease by investigator. Patients who discontinue treatment without PD should continue to have 
tumor assessments performed every 6 weeks until PD is confirmed by investigator regardless of subsequent anti-cancer treatments.
17. Adverse Event (AE) Assessments: Adverse events should be documented and recorded at each visit using the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTC AE) version 4.0.  Patients must be followed for AEs for 28 days after the last treatment administration 
or until all drug related toxicities have resolved, whichever is later; or earlier than 28 days should the patient commence another anticancer therapy in the 
meantime.  For serious adverse events (SAEs), the active reporting period to Pfizer or its designated representative begins from the time that the patient 
provides informed consent, which is obtained prior to the patient’s participation in the study, ie, prior to undergoing any study-related procedure and/or 
receiving investigational product, through and including 28 calendar days after the last administration of the investigational product.  Serious adverse events 
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 serious adverse events that the investigator believes have at least a reasonable possibility of being related to investigational product are to be reported to 
the Sponsor.
18. Concomitant Treatments: all concomitant medications and Non Drug Supportive Interventions should be recorded in the CRF.


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20. PK Sampling: serial blood samples will be collected after single and multiple doses of PF-06747775 to characterize PK behavior. See Table 7 for more 
detailed information.
  
 
 
 
22. Genotyping sample: A 4 mL blood in K2 edetic acid (ethylenediaminetetraacetic acid, EDTA) optimized for DNA analysis will be collected at the baseline 
visit for genotyping analysis.
23. End of Treatment visit: Obtain these assessments if not completed in the last week (last 6 weeks for tumor assessments). 
24. 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, 
vital signs, and assessment for resolution of any treatment related toxicity.  Patients continuing to experience toxicity at this point following discontinuation 
of treatment will continue to be followed at least every 4 weeks until resolution or determination, in the clinical judgment of the investigator, that no further 
improvement is expected.  For patients that have discontinued the treatment period due to reasons other than disease progression: Tumor assessments will 
continue to be performed every 6 weeks during long term follow up until documented disease progression, start of a new anti-cancer treatment, death or lost 
to follow-up (whichever occurs first).  All patients will be followed for at least 24 months after initial dose of last patient treated. 
25. Plasma Samples for Mutation analysis: Two, 10 mL blood specimens will be collected at screening, Cycle 5 Day 1, and at End of Treatment and 
processed for plasma preparation according to the Study Manual and will be used for mutation analysis, including, but possibly not limited to, the EGFR 
gene.
 
27. Survival: Will be performed every 2 months for up to 24 months after PD or new anti-cancer therapy has commenced (telephone contact is acceptable).
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Table 7.
SINGLE-AGENT PF-06747775: Cohort 1 Phase 2 PK and ECG Assessments
Visit Identifier
Lead-in
Cycle 1
Cycles 2 - 4
Day
-4
-3
-2
-1
1 (± 1)
Day 11 (± 4)
12
1
(± 2)
Hours Post Dose
0a
1
2
4
6
8
24
48
72
96f 
(Pre-
Doseb)
0a
Pre-
Doseb
1
2
4
6
24 (Pre-Doseb)
Pre-Doseb
PF-06747775 Dosec
X
X
Once daily PO continuous, with breakfast
PK blood samplingd
X
X
X
X
X
X
X
X
Xb
X
X
X
X
X
Xb
Xb
12-Lead ECGe
X
X
X
X
X
X
a.
0 hrs. Dose time: dose time of PF-06747775 triggers the defined post dose sample collection times.
b.
Pre-dose sample collection: before study treatment dose.
c.
PF-06747775 dose: PF-06747775 dose will be given in the morning with a breakfast of 200-300 calories, at approximately the same time once daily in 
21 day cycles starting continuous dosing on Cycle 1 Day 1. On days in which pre-dose ECG or PK assessments are conducted, dosing should occur in clinic 
with breakfast after pre-dose ECGs are completed and pre-dose PK samples are drawn. Food is allowed 2 hrs. after dose. 
d.
PK blood sampling for PF-06747775 analysis: On Day -4, 4 mL of blood in K2EDTA tubes will be collected as shown above for single dose PK analysis.  
On Day 1 of Cycle 1, (96 hr post lead-in dose) a PK sample will be taken before dose of PF-06747775 (the start of continuous daily dosing). On Day 11 of 
Cycle 1, 4 mL of blood in K2EDTA tubes will be collected as shown above for multiple dose PK analysis.  On Day 1 of Cycles 2 - 4, 4 mL of blood in 
K2EDTA tubes will be collected prior to PF 06747775 dose (pre-dose) for steady state PK analysis.
e.
Triplicate 12-Lead ECG: At each time point, three consecutive 12-lead ECGs will be performed approximately 2 minutes apart.  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 (ie, the timing of the PK collections over rides the timing of the ECG collections).  ECG assessments pre-dose should happen prior to breakfast.  If the 
mean QTcF is prolonged (value of >500 msec), the ECGs should be re-evaluated by a qualified person at the institution for confirmation.  Additional 
triplicate ECGs may be performed as clinically indicated.  ECG assessments will be performed at pre-dose and 2 hrs. post dose on Day -4, pre-dose and 
2 hrs. and 6 hrs. post dose on Day 11 of Cycle 1, and pre-dose on Days 1 of Cycles 2 - 4.  The 2 hrs. post dose ECG assessment is intended to target Cmax, 
this time point may be re-assessed as data emerge.
f.
If the -1 day window is utilized for the Cycle 1 Day 1 visit, then the 72 hrs. PK blood draw should occur prior to the dose of PF-06747775, which starts the 
once daily continuous dosing; in this case the 96 hrs. PK blood draw will not be completed.
Abbreviations: PK = pharmacokinetic; PO = by mouth; QTcF = QT interval corrected by Fridericia’s formula.


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Table 8.
PF-06747775 + Palbociclib: Cohort 2A and Cohort 2B SCHEDULE OF ACTIVITIES 
Visit Identifier
Screening2
Treatment Phase
(1 Cycle = 21 days)
End of 
Treatment24
Post-Treatment 
Follow-up25
CYCLES 1 and 2
CYCLES 3
Study Day:
28 days from 
registration
Day 11
Day 15
Day 1
Visit Time Window: 
2 days
(except Cycle 1)
2 days
±3 days
±3 days
+7 days
Informed Consent3
X
Tumor History4
X
Medical History
X
Physical Examination5
X
X
X
X
X
Baseline Signs and Symptoms6
X
Height
X
Weight
X
X
X
Vital Signs7
X
X
X
X
X
ECOG Performance Status8
X
X
X
X
Contraception Check9
X
X
X
X
Laboratory
Hematology10
X
(X)
X
X
X
Blood Chemistry10
X
(X)
X
X
Coagulation10
X
(X)
X
X
Urinalysis10
X
(X)
X
X
Pregnancy Test11
X
X
X
X
12-Lead ECG12
X
See Table 9 and Table 10
Registration and Treatment
Registration13
X
PF-0674777514
Once daily, PO continuous
Palbociclib14
Once daily, PO continuous
Tumor Assessments
CT or MRI imaging15
X
X, then every other cycle 
(Q6W) ±7 days
X
Other Clinical Assessments
Adverse Events16
Monitored and Recorded Continuously
Concomitant treatments and non-drug 
supportive interventions17
X
X
X
X
X


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Visit Identifier
Screening2
Treatment Phase
(1 Cycle = 21 days)
End of 
Treatment24
Post-Treatment 
Follow-up25
CYCLES 1 and 2
CYCLES ≥3
Study Day:
≤28 days from 
registration
Day 11
Day 15
Day 1
Visit Time Window: 
±2 days
(except Cycle 1)
±2 days
±3 days
±3 days
+7 days
Special Laboratory Studies
PF-06747775 and Palbociclib 
Pharmacokinetics18
See Table 9 and Table 10
Banked Biospecimens19
X
Genotyping sample21
X
Tumor Tissue Specimen21
X (Mandatory)
X (optional)
Plasma Samples for Mutation 
Analysis22
X
X (C5 only)
X
Survival26
X
Abbreviations: CT = computed tomography; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; PO = by mouth (oral administration); 
Q6W = every 6 weeks; MRI = magnetic resonance imaging; MTD=Maximum Tolerated Dose; TK=Thymidine Kinase.
1.
Day relative to start of study treatment (Day 1).
2.
Screening: to be obtained within 28 days prior to registration.
3.
Informed Consent: must be obtained prior to undergoing any study specific procedures unless considered standard of care.
4.
Tumor History: To include information on prior anticancer treatments.
5.
Physical Examination: A full physical examination including an examination of all major body systems (including general appearance, head, ears, eyes, 
nose, mouth, throat, neck, thyroid, lungs, heart, breasts, abdomen, and musculoskeletal), height (at screening only), weight, blood pressure and pulse rate, 
which may be performed by a physician, registered nurse or other qualified health care provider, will be required at Screening.  Symptom directed physical 
examinations, blood pressure and pulse rate assessment will be performed at all other timepoints.
6.
Baseline Signs/Symptoms: patients will be asked about any signs and symptoms experienced within the past 14 days of registration.  Baseline signs and 
symptoms (including NCI CTCAE grade, if applicable) will be recorded on the Medical History case report form (CRF) page.
7.
Vital signs: vital signs include blood pressure (BP) and heart rate (HR).  Vital signs will be taken and recorded during the site clinic visit. 
8.
ECOG Performance Status: see Appendix 2.
9.
Contraception Check: Male patients who are able to father children, and female patients who are of childbearing potential will need to affirm that they 
meet the criteria for correct use of 2 of the selected methods of contraception.  The investigator or his or her designee will discuss with the patient the need to 
use 2 highly effective contraception methods consistently and correctly, and document such conversation in the patient’s chart.  In addition, the investigator 
or his or her designee will instruct the patient to call immediately if one or both selected contraception methods are discontinued, or if pregnancy is known or 
suspected in the patient or the patient’s partner.
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10. Hematology, Coagulation, Blood Chemistry, and Urinalysis: See Section 7.1.4 for specific required tests.  No need to repeat on C1D1 if baseline 
assessment performed within 7 days prior to that date.  For urinalysis, dipstick is acceptable; microscopic analysis to be performed if dipstick is abnormal.  
Additional blood tests should be performed where needed for the purpose of evaluating potential DLTs or other adverse events.  In particular, if a patient has 
Grade 3 neutropenia, a complete blood count (CBC) should be performed with greater frequency as clinically indicated.
11. Pregnancy Test: For female patients of childbearing potential, ie, who do not fit the definition of “female patients who are not of childbearing potential” in 
inclusion criterion 13, a serum or urine pregnancy test, with sensitivity of at least 25 mIU/mL and assayed in a certified laboratory>, will be performed on 
two occasions prior to starting study therapy   once at the start of screening and once at the baseline visit, immediately before investigational product 
administration.  Pregnancy tests will also be routinely repeated at every cycle during the active treatment period, at the end of study therapy and additionally 
whenever one menstrual cycle is missed or when potential pregnancy is otherwise suspected.  Additional pregnancy tests may also be undertaken if 
requested by institutional review board/ethics committee (IRB/ECs) or if required by local regulations.
12. Triplicate 12-Lead ECG: At each time point, three consecutive 12-lead ECGs will be performed approximately 2 minutes apart to determine mean QTcF 
interval. When coinciding with blood sample draws for pharmacokinetics (PK), ECG assessment should be performed prior to blood sample collection, such 
that the blood sample is collected at the nominal time (ie, the timing of the PK collections over rides the timing of the ECG collections). ECG assessments 
pre-dose should happen prior to breakfast. If the mean QTcF is prolonged (value of >500 msec), the ECGs should be re-evaluated by a qualified person at 
the institution for confirmation. Additional triplicate ECGs may be performed as clinically indicated. ECG assessments will be performed according to the 
schedule outlined in Table 9 and Table 10.
13. Registration: A patient is considered enrolled when all screening procedures have been completed, the patient has satisfied the requirements of all 
inclusion/exclusion criteria, and the completed registration form has been approved by the Sponsor.  Allocation of patients to treatment groups will proceed 
through the use of an Interactive Response Technology (IRT) system.  For Cohort 2B , patients will be enrolled in a 2:1 ratio to either PF-06747775 in 
combination with palbociclib or PF-06747775 single agent.  
14. Study Treatment: PF-06747775 and palbociclib will be taken at the same time along with a breakfast of 200-300 calories at approximately the same time 
each morning.  On visits in which patients undergo pre-dose PK collection, study treatments should be taken in clinic after any pre-dose assessments are 
completed.  More information is provided in Section 5.4.3.
15. CT or MRI Tumor Assessments: Baseline assessments must be within 28 days of first study treatment.  Tumor assessments will include all known or 
suspected disease sites.  Tumor response will be assessed per RECIST v1.1.  Imaging may include chest, abdomen and pelvis CT or MRI scans.  Minimally, 
chest, liver and adrenals must be imaged.  Brain scans are required at baseline and every assessment if intra-cerebral disease is present; if no intra-cerebral 
disease is found at baseline, then brain imaging is only required on study if clinically indicated.  Bone scans will be performed at baseline if clinically 
indicated and on-study as appropriate to follow disease.  For all patients with RECIST measurable disease who have a RECIST response, confirmation of the 
response is required at least 4 weeks after initial assessment of response. Tumor assessment should be repeated at the End of Treatment visit if more than 
6 weeks have passed since the last evaluation.  For patients that have discontinued the treatment period due to reasons other than disease progression: Tumor 
assessments must continue until documented progression of disease by investigator. Patients who discontinue treatment without PD should continue to have 
tumor assessments performed every 6 weeks until PD is confirmed by investigator regardless of subsequent anti-cancer treatments.


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16. Adverse Event (AE) Assessments: Adverse events should be documented and recorded at each visit using the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTC AE) version 4.0.  Patients must be followed for AEs for 28 days after the last treatment administration 
or until all drug related toxicities have resolved, whichever is later; or earlier than 28 days should the patient commence another anticancer therapy in the 
meantime.  For serious adverse events (SAEs), the active reporting period to Pfizer or its designated representative begins from the time that the patient 
provides informed consent, which is obtained prior to the patient’s participation in the study, ie, prior to undergoing any study-related procedure and/or 
receiving investigational product, through and including 28 calendar days after the last administration of the investigational product.  Serious adverse events 
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 serious adverse events that the investigator believes have at least a reasonable possibility of being related to investigational product are to be reported to 
the sponsor.
17. Concomitant Treatments: all concomitant medications and Non Drug Supportive Interventions should be recorded in the CRF.
18. Blood Sample for Pharmacokinetics: Cohort 2A: Blood samples will be collected after multiple doses of PF-06747775 and palbociclib to characterize 
their pharmacokinetic behavior according to the assessments outlined in Table 9. Cohort 2B: Blood samples will be collected after multiple doses (steady 
state) of PF-06747775 and palbociclib to characterize their pharmacokinetic behavior according to the assessments outlined in Table 10. 
 
 
19. Banked Biospecimen: Unless prohibited by local regulations, a blood specimen (Prep D1: 4 mL K2 EDTA whole blood collection optimized for DNA 
analysis will be collect at screening.࠼
20. Genotyping sample: A 4 mL blood in K2 edetic acid (ethylenediaminetetraacetic acid, EDTA) optimized for DNA analysis will be collected at the baseline 
visit for genotyping analysis.
21. Tumor Tissue Specimen: A mandatory archived formalin-fixed, paraffin-embedded (FFPE) tumor tissue block must be provided that is of sufficient size to 
allow, if possible, for sectioning of fifteen (15) 5-micron tissue sections. If an FFPE tumor tissue block cannot be provided, sites should try to provide 
fifteen (15) unstained slides each containing a 5-micron tissue section cut serially from the same FFPE block. If archived FFPE tissue is not available, a de 
novo (ie, fresh) tumor sample must be obtained in accord with local institutional practice for tumor biopsies. Archived or de novo tumor tissue from 
cytologic sampling (eg, fine needle aspiration, including FFPE cell pellet material), is not adequate and should not be submitted. Acquisition of the 
mandatory tumor tissue and submission to the Sponsor-designated Central Laboratory (see Study Manual) can be completed outside the 28-day screening 
window, but is required for enrollment.  Please ensure the newest available specimen is submitted (eg, if a patient had a biopsy post-EGFR TKI progression, 
that sample should be submitted.  If the T790M presence was diagnosed by plasma samples only, then the initial diagnostic biopsy may be submitted to 
fulfill the tissue specimen collection requirement.  An optional de novo (ie, fresh biopsy) tumor sample will be collected at End of Treatment if a patient 
discontinues due to disease progression. Tumor tissue from cytologic sampling (eg, fine needle aspiration, including FFPE cell pellet material), is not 
adequate.
22. Plasma Samples for Mutation analysis: Two, 10 mL blood specimen will be collected at screening, Cycle 5 Day 1, and at End of Treatment and processed 
for plasma preparation according to the Study Manual and will be used for mutation analysis, including, but possibly not limited to, the EGFR gene.
 
24. End of Treatment Visit: Obtain these assessments if not completed in the last week (last 6 weeks for tumor assessments).
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25. 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, 
vital signs, and assessment for resolution of any treatment related toxicity.  Patients continuing to experience toxicity at this point following discontinuation 
of treatment will continue to be followed at least every 4 weeks until resolution or determination, in the clinical judgment of the investigator, that no further 
improvement is expected.  For patients that have discontinued the treatment period due to reasons other than disease progression: Tumor assessments will 
continue to be performed every 6 weeks during long term follow up until documented disease progression, start of a new anti-cancer treatment, death or lost 
to follow-up (whichever occurs first).  All patients will be followed for at least 24 months after initial dose of last patient treated.
26. Survival: Will be performed every 2 months for up to 24 months after PD or new anti-cancer therapy has commenced (telephone contact is acceptable).


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Table 9.
PF-06747775 + Palbociclib: Cohort 2A (Phase 1b) – PK and ECG Assessments
Visit Identifier 
Cycle
1
Cycle 
2
Cycles 
3 – 4
Day
1
15
(± 2)
16
1
(± 2)
15
(± 2)
1
(± 3)
Hours Post Dose
Pre-
Doseb
0a
Pre-
Doseb
1
2
4
6
24
(Pre-Doseb)
Pre-Doseb
Pre-Doseb
2
Pre-Doseb
Palbociclib Dosec
X
Once daily PO continuous, with breakfast
PF-06747775 Dosed
X
Once daily PO continuous, with breakfast
PK blood sampling 
(PF-06747775 and 
palbociclib)e
X
X
X
X
X
X
X
X
X
X
12-Lead ECGf
X
X
X
X
X
X
X
X
a.
0 hrs. Dose time: dose time of PF-06747775 and palbociclib triggers the defined post dose sample collection times.
b.
Pre-dose sample collection: before dose of PF-06747775 and palbociclib.
c.
Palbociclib dose: palbociclib dose will be given in the morning along with PF-06747775 and breakfast, at approximately the same time once daily in 21 day 
cycles.  On Day 15 of Cycle 1 and Cycle 2, both PF-06747775 and palbociclib will be given in clinic with breakfast after pre-dose ECG is completed and 
pre-dose PK blood samples have been drawn, then post-dose samples will be collected as above. See Section 5.4.3.2 for more details.
d.
PF-06747775 dose: PF 06747775 dose will be given in the morning, with a breakfast of 200-300 calories, at approximately the same time once daily in 
21 day cycles.  On Day 15 of Cycle 1 and Cycle 2, both PF-06747775 and palbociclib will be given in clinic with breakfast after pre-dose ECG is completed 
and pre-dose PK blood samples have been drawn, then post-dose samples will be collected as above.  Food is allowed 2 hrs. after dose.  
e.
PK blood sampling for PF-06747775 and palbociclib analysis: On Cycle 1 Day 15, 4 mL of blood in K2EDTA tubes will be collected for PK analysis of 
both PF-06747775 and palbociclib at each time shown above.  On Cycle 1 Day 16, a PK blood sample will be collected prior to the dose of PF-06747775 
and palbociclib (pre-dose).  On Day 1 of Cycles 2 – 4, pre-dose PK samples will be collected, and on Day 15 of Cycle 2 PK blood samples will be collected 
pre-dose and 2 hrs. post-dose.  In the event a patient is only receiving one agent, please contact Sponsor for further direction on PK blood draws.
f.
Triplicate 12-Lead ECG: At each time point, three consecutive 12 lead ECGs will be performed approximately 2 minutes apart.  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 (ie, the timing of the PK collections over rides the timing of the ECG collections).  ECG assessments pre-dose should happen prior to breakfast.  If the 
mean QTcF is prolonged (value of >500 msec), the ECGs should be re-evaluated by a qualified person at the institution for confirmation.  Additional 
triplicate ECGs may be performed as clinically indicated.  ECG assessments will be performed at pre-dose on Day 1 of Cycle 1; at pre-dose and 2 and 
6 hours post dose on Day 15 of Cycle 1; at pre-dose and 2 hours post dose on Day 15 of Cycle 2; and pre-dose on Days 1 of Cycles 2 - 4.  The 2-hour. post-
dose ECG assessment is intended to target Cmax of PF-06747775; this time point may be re-assessed as data emerge.
Abbreviations: PK = pharmacokinetic; PO = by mouth; QTcF = QT interval corrected by Fridericia’s formula.


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Table 10. PF-06747775 + Palbociclib: Cohort 2B (Phase 2) – PK and ECG Assessments
Visit Identifier
Cycle 1
Cycles 2 - 4
Day
1
15 (± 2)
1 (± 3)
Hours Post Dose
Pre-doseb
0a
Pre-doseb
2
Pre-doseb
2
Palbociclib Dose
(patients randomized to combination only)c
X
Once daily PO continuous, with breakfast
PF-06747775 Dosed
(all patients)
X
Once daily PO continuous, with breakfast
PK blood sampling for palbociclib (patients 
randomized to combination only)e
X
X
X
X
PK blood sampling for PF-06747775f 
(all patients)
X
X
X
X
12-Lead ECG (all patients)g
X
X
X
X
X
a.
0 hrs. Dose time: dose time of PF-06747775 and palbociclib (if applicable) that triggers the defined post dose sample collection times.
b.
Pre-dose sample collection: before dose of PF-06747775 and palbociclib (if applicable).
c.
Palbociclib dose (patients randomized to combination only): palbociclib dose will be given in the morning along with PF-06747775 and breakfast, at 
approximately the same time once daily in 21 day cycles.  On Day 15 of Cycle 1 and Day 1 of Cycles 2 - 4, both PF-06747775 and palbociclib will be given 
in clinic with breakfast after pre-dose ECG is completed and pre-dose PK blood samples have been drawn.  See Section 5.4.3.2 for  more details.
d.
PF-06747775 dose (all patients): PF-06747775 dose will be given in the morning, with a breakfast of 200 - 300 calories, at approximately the same time 
once a day in 21 day cycles.  On Day 15 of Cycle 1 and Day 1 of Cycles 2 - 4, PF-06747775 and palbociclib (if applicable) will be given in clinic with 
breakfast after pre-dose ECG is completed and pre-dose PK blood samples have been drawn.  Food is allowed 2 hrs. after dose.  
e.
PK blood sampling for palbociclib analysis (patients randomized to combination only): On Day 15 of Cycle 1 and Day 1 of Cycles 2 - 4, a 4 mL PK 
blood sample in K2EDTA tubes will be collected prior to dose of PF 06747775 and palbociclib (pre-dose) for PK analysis of both PF-06747775 and 
palbociclib, then patients will receive PF-06747775 and palbociclib treatment and then at 2 hrs. post dose another 4 mL PK blood sample will be collected..  
In the event a patient is only receiving one agent, please contact Sponsor for further direction on PK blood draws.
f.
PK blood sampling for PF-06747775 analysis (all patients): On Day 15 of Cycle 1 and Day 1 of Cycles 2 - 4, a 4 mL PK blood sample in K2EDTA tubes 
will be collected prior to dose (pre-dose) for PK analysis of PF-06747775 and palbociclib (if applicable), then patients will receive PF-06747775 treatment 
and then at 2 hrs. post dose another 4 mL PK blood sample will be collected.  
g.
12-Lead ECG (all patients): At each time point, three consecutive 12-lead ECGs will be performed approximately 2 minutes apart.  When coinciding with 
blood sample draws PK, ECG assessment should be performed prior to blood sample collection, such that the blood sample is collected at the nominal time 
(ie, the timing of the PK collections over rides the timing of the ECG collections).  ECG assessments pre-dose should happen prior to breakfast.  If the mean 
QTcF is prolonged (value of >500 msec), the ECGs should be re-evaluated by a qualified person at the institution for confirmation.  Additional triplicate 
ECGs may be performed as clinically indicated.  ECG assessments will be performed at pre-dose on Cycle 1 Day 1, and at pre-dose and 2 hrs. post dose on 
Day 15 of Cycle 1 and Day 1 of Cycles 2 - 4.  The 2 hrs. post dose ECG assessment is intended to target Cmax of PF-06747775; this time point may be re-
assessed as data emerge.
Abbreviation: PK = pharmacokinetic; PO = by mouth; QTcF = QT interval corrected by Fridericia’s formula.


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Table 11.
PF-06747775 + Avelumab: Cohort 3 (Phase 1b) SCHEDULE OF ACTIVITIES 
Visit Identifier
Screening2
Treatment Phase
(1 Cycle = 28 days)
Post-Treatment
CYCLES 1-2
CYCLES 3
Study Day
28 days 
from 
registration
Day 1
Day 15
Day 1
Day 15 End of Treatment/
Withdrawal32
30-day
Follow-up33 90-Day Follow-
up Telephone 
Contact33
Visit Time Window (days):1
2 days 
(except Cycle 1)
2 days
2 days
2 days
2 days
3 days
7 days
Informed Consent3
X
Tumor History History4
X
Medical History
X
Physical Examination5
X
X
X
X
Baseline Signs and Symptoms6
X
Height
X
Weight
X
X
X
X
X
Vital signs7
X
X
X
X
X
X
ECOG Performance Status8
X
X
X
X
Contraception Check9
X
X
X
X
Laboratory
Hematology10
X
(X)
X
X
X
X
Blood Chemistry10
X
(X)
X
X
X
X
Coagulation10
X
(X)
X
X
X
X
Urinalysis10
X
(X)
X
Thyroid Function Test and ACTH11
X
X
X (then every 
2 cycles)
X
X
ANA, ANCA, RF
X
If clinically indicated
HBV, HCV testing
X
Pregnancy test12
X
X
X
X
12-Lead ECG13
X
See Table 12
X
Registration and Treatment 
Registration14
X
Administration of PF-0674777515
Once daily PO continuous, with breakfast
Administration of avelumab15
X
X
X
X


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Visit Identifier
Screening2
Treatment Phase
(1 Cycle = 28 days)
Post-Treatment
CYCLES 1-2
CYCLES ≥3
Study Day
≤28 days 
from 
registration
Day 1
Day 15
Day 1
Day 15 End of Treatment/
Withdrawal32
30-day
Follow-up33 90-Day Follow-
up Telephone 
Contact33
Visit Time Window (days):1
±2 days 
(except Cycle 1)
±2 days
±2 days
±2 days
±2 days
±3 days
±7 days
Tumor assessments
CT or MRI imaging16
X
X, then every 
other cycle 
(Q8W) 
±7 days
X
Other Clinical Assessments
Adverse Events17
X
Concomitant treatments and non-drug 
supportive interventions18
X
Special Laboratory Studies
PF-06747775 Phamacokinetics19
See Table 12
Avelumab Pharmacokinetics20
See Table 12
(Up to Cycle 3, then every 3 cycles thereafter)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Visit Identifier
Screening2
Treatment Phase
(1 Cycle = 28 days)
Post-Treatment
CYCLES 1-2
CYCLES 3
Study Day
28 days 
from 
registration
Day 1
Day 15
Day 1
Day 15 End of Treatment/
Withdrawal32
30-day
Follow-up33 90-Day Follow-
up Telephone 
Contact33
Visit Time Window (days):1
2 days 
(except Cycle 1)
2 days
2 days
2 days
2 days
3 days
7 days
Whole Blood Biospecimen for TCR 
Sequencing29
X
X
X (Cycles 3, 
4, 7, and 10)
X
X
Whole Blood for Target Occupancy30
X (Cycle 1 Day 1, 
Cycle 1 Day 2, 
Cycle 2 Day 1)
X (Cycles 3, 
4, 7, and 10)
X
Blood for avelumab ADA 
(Immunogenicity) Testing31
See Table 12
(Up to Cycle 3, then every 3 cycles thereafter)
X
X 
Survival34
X
Abbreviations: CT = computed tomography; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; PO = by mouth (oral administration); 
Q8W = every 8 weeks; MRI = magnetic resonance imaging; MTD=Maximum Tolerated Dose; TK=Thymidine Kinase.
1.
Visit Time Windows: Day is relative to start of PF-06747775 and avelumab study treatment (Day 1).  If avelumab is delayed, the cycle start is relative to 
PF-06747775.  A cycle length is 4 weeks (28 days).
2.
Screening: to be obtained within 28 days prior to registration.
3.
Informed Consent: must be obtained prior to undergoing any study specific procedures unless considered standard of care.
4.
Tumor History: To include information on prior anticancer treatments.
5.
Physical Examination: A full physical examination including an examination of all major body systems (including general appearance, head, ears, eyes, 
nose, mouth, throat, neck, thyroid, lungs, heart, breasts, abdomen, and musculoskeletal), height (at screening only), weight, blood pressure and pulse rate, 
which may be performed by a physician, registered nurse or other qualified health care provider, will be required at Screening.  Symptom directed physical 
examinations, blood pressure and pulse rate assessment will be performed at all other timepoints.
6.
Baseline Signs/Symptoms: patients will be asked about any signs and symptoms experienced within the past 14 days of registration.  Baseline signs and 
symptoms (including NCI CTCAE grade, if applicable) will be recorded on the Medical History case report form (CRF) page.
7.
Vital Signs: vital signs include blood pressure (BP) and heart rate (HR).  Vital signs will be taken and recorded during the site clinic visit.
8.
ECOG Performance Status: See Appendix 2.
9.
Contraception Check: Male patients who are able to father children, and female patients who are of childbearing potential will need to affirm that they 
meet the criteria for correct use of 2 of the selected methods of contraception.  The investigator or his or her designee will discuss with the patient the need to 
use 2 highly effective contraception methods consistently and correctly, and document such conversation in the patient’s chart.  In addition, the investigator 
or his or her designee will instruct the patient to call immediately if one or both selected contraception methods are discontinued, or if pregnancy is known or 
suspected in the patient or the patient’s partner.


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10. Hematology, Coagulation, Blood Chemistry, and Urinalysis: See Section 7.1.4 for specific required tests.  No need to repeat on C1D1 if baseline 
assessment performed within 7 days prior to that date.  For urinalysis, dipstick is acceptable; microscopic analysis to be performed if dipstick is abnormal.  
Additional blood tests should be performed where needed for the purpose of evaluating potential DLTs or other adverse events. In particular, if a patient has 
Grade 3 neutropenia, a complete blood count (CBC) should be performed as clinically indicated.
11. Thyroid Function Tests: Free T4, TSH, and ACTH will be performed at Screening, Day 1, and then every 8 weeks thereafter during the Treatment Phase, 
and at the End of Treatment and 30-day Follow-up visits after last administration of study treatment unless performed in the prior 8 weeks.  
12. Pregnancy Test: For female patients of childbearing potential, ie, who do not fit the definition of “female patients who are not of childbearing potential” in 
inclusion criterion 13, a serum or urine pregnancy test, with sensitivity of at least 25 mIU/mL and assayed in a certified laboratory>, will be performed on 
two occasions prior to starting study therapy once at the start of screening and once at the baseline visit, immediately before investigational product 
administration.  Pregnancy tests will also be routinely repeated at every cycle during the active treatment period, at the end of study therapy and additionally 
whenever one menstrual cycle is missed or when potential pregnancy is otherwise suspected.  Additional pregnancy tests may also be undertaken if 
requested by institutional review board/ethics committee (IRB/ECs) or if required by local regulations.
13. Triplicate 12-Lead ECG: At each time point, three consecutive 12-lead ECGs will be performed approximately 2 minutes apart to determine mean QT 
interval corrected by Fridericia’s formula (QTcF interval).  When coinciding with blood sample draws for pharmacokinetics (PK), ECG assessment should 
be performed prior to blood sample collection, such that the blood sample is collected at the nominal time (ie, the timing of the PK collections over rides the 
timing of the ECG collections).  ECG assessments pre-dose should happen prior to breakfast.  If the mean QTcF is prolonged (value of >500 msec), the 
ECGs should be re-evaluated by a qualified person at the institution for confirmation.  Additional triplicate ECGs may be performed as clinically indicated.  
ECG assessments will be performed at screening and according to Table 12. 
14. Registration: A patient is considered enrolled when all screening procedures have been completed, the patient has satisfied the requirements of all 
inclusion/exclusion criteria, and the completed registration form has been approved by the Sponsor.  Allocation of patients to treatment groups will proceed 
through the use of an Interactive Response Technology (IRT) system.
15. Study Treatment: PF-06747775 will be taken with a breakfast of 200-300 calories in the morning every day at approximately the same time in 28-day 
cycles.  Avelumab will be given as a 1-hour infusion every 2 weeks. On visits in which patients undergo pre-dose PK collection, study treatments should be 
taken in clinic after any pre-dose assessments are completed. More information is provided in Section 5.4.3.
16. CT or MRI Tumor Assessments: Baseline assessments must be within 28 days of first study treatment.  Tumor assessments will include all known or 
suspected disease sites.  Tumor response will be assessed per RECIST v1.1.  Imaging may include chest, abdomen and pelvis CT or MRI scans.  Minimally, 
chest, liver and adrenals must be imaged.  Brain scans are required at baseline and every assessment if intra-cerebral disease is present; if no intra-cerebral 
disease is found at baseline, then brain imaging is only required on study if clinically indicated.  Bone scans will be performed at baseline if clinically 
indicated and on-study as appropriate to follow disease.  For all patients with RECIST measurable disease who have a RECIST response, confirmation of the 
response is required at least 4 weeks after initial assessment of response. Tumor assessment should be repeated at the End of Treatment visit if more than 
8 weeks have passed since the last evaluation.  For patients that have discontinued the treatment period due to reasons other than disease progression: Tumor
assessments should continue to be performed every 8 weeks during long term follow up until documented disease progression, start of a new anti-cancer 
treatment, death or lost to follow-up.
17. Adverse Event (AE) Assessments: Adverse events should be documented and recorded at each visit using the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTC AE) version 4.0.  Patients must be followed for AEs for 28 days after the last treatment administration 
or until all drug related toxicities have resolved, whichever is later; or earlier than 28 days should the patient commence another anticancer therapy in the 
meantime.  For serious adverse events (SAEs), the active reporting period to Pfizer or its designated representative begins from the time that the patient 
provides informed consent, which is obtained prior to the patient’s participation in the study, ie, prior to undergoing any study-related procedure and/or 
receiving investigational product, through and including 28 calendar days after the last administration of the investigational product.  Serious adverse events 


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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 serious adverse events that the investigator believes have at least a reasonable possibility of being related to investigational product are to be reported to 
the sponsor.
18. Concomitant Treatments: all concomitant medications and Non Drug Supportive Interventions should be recorded in the CRF.
19. Blood Sample for PF-06747775 Pharmacokinetics: Blood samples to characterize the pharmacokinetic behavior of PF-06747775 will be collected 
according to Table 12.
 
20. Blood Sample for Avelumab Pharmacokinetics: Pre-dose PK samples for avelumab must be taken before administration of PF-06747775 and avelumab 
and will be collected according to Table 12 until Cycle 3, then every 3 cycles thereafter. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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32. End of Treatment: Obtain these assessments if not completed in the prior week, except for tumor assessments, which need not be repeated if performed 
within the prior 8 weeks. Patients continuing to experience treatment-related toxicity at this point following discontinuation of treatment will continue to be 
followed every 4 weeks until resolution or determination, in the clinical judgment of the investigator, that no further improvement is expected.
33. Safety Follow-up after Last Dose: To occur Day 30 ±3 after the last study treatment administration or until the time of initiation of a new systemic 
anticancer treatment.  The Day 90 Follow-up visit will be conducted as a phone call.  If any concern arises, the patient will be called in for a follow-up visit 
within 5 calendar days for appropriate assessments (as per the investigator’s medical judgment).  
34. Survival: Will be performed every 2 months for up to 24 months after PD or new anti-cancer therapy has commenced (telephone contact is acceptable).
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Table 12. PF-06747775 + Avelumab: Cohort 3 (Phase 1b) – PK and ECG Assessments
Visit Identifier
Cycle 1
Cycles 2 - 3
Day
1
15 (±2)
1 (±2)
Hours Post Dose
Pre-doseb
0a
1 
(EOI)c
Pre-doseb
0a
1 
(EOI) c
Pre-doseb
0a
1 
(EOI)c
Avelumab Administrationd
X
X
X
PF-06747775 Dosee
X
Once daily PO continuous, with breakfast
PK blood sampling for avelumab f
X
X
X
X
X
X
PK blood sampling for PF-06747775g
X
X
12-lead ECGh
X
X
X
X (Cycle 2 only)
ADA blood samplingi
X
X
X
a.
0 hrs. Dose time: Dose time of PF-06747775 triggers the defined post dose sample collection times. Avelumab infusion should begin as soon as possible thereafter.
b.
Pre-dose sample collection: Prior to the dose of PF-06747775 and avelumab administration.
c.
End of Infusion (EOI) PK sample: The 1 hour PK sample for avelumab should be within 30 minutes of the end of infusion (EOI) of avelumab, drawn from the arm opposite 
(contralateral) from that arm which is receiving avelumab infusion. 
d.
Avelumab administration: Avelumab will be given as a 1-hour infusion every 2 weeks in 28 day cycles (as described in Section 5.4.3.3), after pre-dose ECG is completed 
and pre-dose PK and ADA blood samples have been drawn.
e.
PF-06747775 dose:  PF-06747775 will be given in the morning, with a breakfast of 200 - 300 calories, at approximately the same time once a day in 28 day cycles starting on 
Cycle 1 Day 1. On days of avelumab infusion, PF-06747775 will be given in clinic with breakfast after any required pre-dose ECG is completed and any required pre-dose 
PK blood samples have been drawn.  Food is allowed 2 hrs. after dose.  
f.
PK blood sampling for avelumab analysis: A 3.5 mL PK blood sample in a Serum Separator Tube (SST) for avelumab will be collected at pre-dose and at EOI of avelumab 
on Cycle 1 Day 1, on Day 15 of Cycle 1, and on Day 1 of Cycles 2 – 3.  After Cycle 3, pre-dose PK samples will be collected every 3 cycles thereafter.  See Table 11 for more 
details.  For EOI samples, blood should be drawn from the arm opposite (contralateral) from that arm which is receiving avelumab infusion.  In the event a patient is only 
receiving one agent, please contact Sponsor for further direction on PK blood draws.
g.
PK blood sampling for PF-06747775 analysis: A 4 mL PK blood sample in K2EDTA tubes will be collected at pre-dose on Day 15 of Cycle 1 and Day 1 of Cycle 2 – 3.  In 
the event a patient is only receiving one agent, please contact Sponsor for further direction on PK blood draws.
h.
Triplicate 12-Lead ECG: At each time point, three consecutive 12-lead ECGs will be performed approximately 2 minutes apart.  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 (ie, the timing of the PK collections 
over rides the timing of the ECG collections).  ECG assessments pre-dose should happen prior to breakfast.  If the mean QTcF is prolonged (value of >500 msec), the ECGs 
should be reevaluated by a qualified person at the institution for confirmation.  Additional triplicate ECGs may be performed as clinically indicated.  ECG assessments will be 
performed at pre-dose on Day 1 of Cycle 1, Day 15 of  Cycle 1, Day 1 of Cycles 2 – 3, and at EOI on Day 1 of Cycle 2.
i.
Anti-drug antibodies for avelumab: A 3.5 mL sample of blood will be drawn into a Serum Separator Tube (SST) to assess anti-avelumab antibodies prior to avelumab 
administration (pre-dose) on Cycle 1 Day 1 and Day 15, and on Day 1 of Cycles 2 – 3, then every 3 cycles thereafter. Additional samples for ADAs will be collected 30 days 
after the end of therapy. All samples that are positive for ADA may also undergo characterization for neutralizing antibodies (Nab). 
Abbreviation: ADA=anti-drug antibodies; EOI=end of infusion of avelumab; Nab=neutralizing antibodies; PK = pharmacokinetic; PO = by mouth; QTcF = QT interval corrected 
by Fridericia’s formula; SST=serum separator tube.


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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................65
APPENDICES .........................................................................................................................66
1. INTRODUCTION ...............................................................................................................67
1.1. Mechanism of Action/Indication.............................................................................67
1.2. Background and Rationale ......................................................................................67
1.2.1. Non-Small Cell Lung Cancer .....................................................................67
1.2.2. PF-06747775...............................................................................................68
1.2.2.1. PF-06747775 Nonclinical Pharmacokinetic Data.....................68
1.2.2.2. PF-06747775 Nonclinical Safety Data......................................69
1.2.2.3. PF-06747775 Projection of Human Pharmacokinetics .............72
1.2.2.4. PF-06747775 Nonclinical Pharmacology .................................73
1.2.3. Palbociclib ..................................................................................................74
1.2.3.1. Palbociclib Nonclinical Pharmacology Data.............................74
1.2.3.2. Palbociclib Nonclinical Pharmacokinetic Data.........................75
1.2.3.3. Palbociclib Human Pharmacokinetic Data................................76
1.2.3.4. Palbociclib Clinical Data...........................................................76
1.2.4. Avelumab....................................................................................................77
1.2.4.1. Avelumab Nonclincial Data......................................................78
1.2.4.2. Avelumab Human Pharmacokinetics........................................80
1.2.4.3. Avelumab Clinical Experience..................................................80
1.2.5. Rationale for Evaluating PF-06747775 as Single Agent or in 
Combination with Palbociclib or Avelumab in Patients with EGFRm 
NSCLC.............................................................................................................83
1.2.6. Rationale for Selection of the Starting Doses.............................................86
1.2.6.1. PF-06747775.............................................................................86
1.2.6.2. Palbociclib.................................................................................87
1.2.6.3. Avelumab ..................................................................................89
1.2.7. Rationale for Drug-Drug and Food-Drug Interaction Sub-Studies ............89
1.3. Safety Considerations in the Clinical Trial .............................................................90
1.3.1. Benefit-Risk Assessment for PF-06747775 Single Agent..........................90
1.3.2. Benefit-Risk Assessment Combinations with Palbociclib (Cohort 2) 
and Avelumab (Cohort 3) ................................................................................92


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2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................93
2.1. Objectives................................................................................................................93
2.1.1. Phase 1........................................................................................................93
2.1.1.1. Primary Objective .....................................................................93
2.1.1.2. Secondary Objectives................................................................93
2.1.2. Phase 1b/2...................................................................................................94
2.1.2.1. Primary Objectives....................................................................94
2.1.2.2. Secondary Objectives................................................................94
2.1.3. Japanese Patient-Only Lead In Cohort .......................................................95
2.2. Endpoints.................................................................................................................96
2.2.1. Phase 1........................................................................................................96
2.2.1.1. Primary Endpoint(s) ..................................................................96
2.2.1.2. Secondary Endpoints.................................................................96
2.2.2. Phase 1b/2...................................................................................................97
2.2.2.1. Primary Endpoints.....................................................................97
2.2.2.2. Secondary Endpoints.................................................................97
2.2.3. Endpoint for Japanese Patient-Only Lead In Cohort..................................98
3. STUDY DESIGN.................................................................................................................98
3.1. Study Overview.......................................................................................................98
3.1.1. Phase 1......................................................................................................101
3.1.1.1. Starting Dose...........................................................................102
3.1.1.2. Dose Escalation Criteria..........................................................102
3.1.1.3. Dose Levels to be Tested ........................................................104
3.1.2. Cohort 1: Phase 2 Evaluation of PF-06747775 Single Agent in 
Previously Untreated Advanced EGFRm NSCLC ........................................105
3.1.3. Cohort 2: Phase 1b/2 Evaluation of PF-06747775 Plus Palbociclib ........105
3.1.3.1. Cohort 2A................................................................................105
3.1.3.2. Cohort 2B ................................................................................107
3.1.4. Cohort 3: Phase 1b Evaluation of PF-06747775 Plus Avelumab.............107
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3.1.5. Japanese Patient-Only Lead In Cohort .....................................................108
3.2. DLT Definitions ....................................................................................................108
3.2.1. Phase 1 PF-06747775 Single Agent .........................................................109
3.2.2. Phase 1b Cohort 2.....................................................................................109
3.2.3. Phase 1b Cohort 3.....................................................................................110
3.3. Phase 1 MTD Definition .......................................................................................110
3.4. Recommended Phase 2 Dose (RP2D) Definition .................................................111
3.5. Phase 1 Drug Interaction Sub-Studies...................................................................111
3.5.1. Sildenafil Sub-Study.................................................................................111
3.5.2. Food Effect and Rifampin DDI Sub-Study ..............................................111
3.5.3. Antacid Effect and Itraconazole DDI Sub-Study .....................................113
4. PATIENT SELECTION....................................................................................................115
4.1. Inclusion Criteria...................................................................................................115
4.2. Exclusion Criteria..................................................................................................118
4.3. Lifestyle Guidelines ..............................................................................................121
4.3.1. Dietary Restrictions ..................................................................................121
4.3.2. Contraception............................................................................................122
4.3.3. Sun Exposure............................................................................................123
4.3.4. Smoking....................................................................................................123
4.4. Sponsor’s Qualified Medical Personnel................................................................123
5. STUDY TREATMENTS...................................................................................................123
5.1. Screen Failures ......................................................................................................123
5.2. Allocation to Treatment ........................................................................................124
5.3. Patient Compliance ...............................................................................................125
5.4. Drug Supplies........................................................................................................125
5.4.1. Dosage Form(s) and Packaging................................................................125
5.4.1.1. PF-06747775...........................................................................125
5.4.1.2. Palbociclib...............................................................................125
5.4.1.3. Avelumab ................................................................................125
5.4.1.4. Concomitant Agents Used in Phase 1 PK Sub-Studies...........125
5.4.2. Preparation and Dispensing......................................................................126
5.4.2.1. PF-06747775 and Palbociclib .................................................126


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5.4.2.2. Avelumab ................................................................................126
5.4.3. Administration..........................................................................................126
5.4.3.1. PF-06747775...........................................................................126
5.4.3.2. Palbociclib...............................................................................128
5.4.3.3. Avelumab ................................................................................128
5.4.3.4. Concomitant Agents Used in Phase 1 PK Sub-Studies...........128
5.4.4. Food Requirements...................................................................................129
5.4.4.1. Food Requirements for PF-06747775 (Except for the 
Food Effect Cohort).........................................................................129
5.4.4.2. Requirements for PF-06747775 for the Phase 1 Food 
Effect Cohort ...................................................................................129
5.4.4.3. Requirements for PF-06747775 Plus Palbociclib (Cohort 
2)......................................................................................................129
5.4.5. Recommended Dose Modifications..........................................................130
5.4.5.1. PF-06747775...........................................................................130
5.4.5.2. Palbociclib...............................................................................133
5.4.5.3. Avelumab ................................................................................136
5.5. Investigational Drug Storage.................................................................................143
5.6. Drug Accountability..............................................................................................144
5.7. Concomitant Treatment(s).....................................................................................144
5.7.1. Considerations Specific to PF-06747775 .................................................144
5.7.1.1. PF-06747775 in Combination with Palbociclib (Cohort 
2A and 2B) ......................................................................................145
5.7.1.2. PF-06747775 in Combination with Avelumab (Cohort 3)......146
5.7.2. Other Anti-tumor/Anti-cancer or Experimental Drugs.............................146
5.7.3. Supportive Care ........................................................................................147
5.7.4. Anti-Diarrheal and Anti-Emetic Therapy.................................................147
5.7.5. Anti-inflammatory Therapy......................................................................147
5.7.6. Corticosteroids..........................................................................................147
5.7.6.1. Cohort 2A and 2B (PF-06747775 Plus Palbociclib):..............148
5.7.6.2. Cohort 3 (PF-06747775 Plus Avelumab):...............................148
5.7.7. Surgery......................................................................................................148
6. STUDY PROCEDURES ...................................................................................................149


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6.1. Screening...............................................................................................................149
6.2. Study Period ..........................................................................................................150
6.3. Patient Withdrawal................................................................................................150
7. ASSESSMENTS................................................................................................................152
7.1. Safety Assessment.................................................................................................152
7.1.1. Pregnancy Testing ....................................................................................152
7.1.2. Contraception Check ................................................................................153
7.1.3. Adverse Events.........................................................................................153
7.1.4. Laboratory Safety Assessment .................................................................154
7.1.5. Vital Signs and Physical Examination......................................................154
7.1.6. 12-Lead ECG............................................................................................154
7.2. Pharmacokinetics Assessments.............................................................................155
7.2.1. Blood for PK analysis of PF-06747775 and Sildenafil ............................155
7.2.2. Blood for 4-β-Hydroxycholesterol and Cholesterol Analysis ..................156
7.2.3. Blood for Metabolite Profiling of PF-06747775 ......................................157
7.2.4. Blood for PK Analysis of Palbociclib ......................................................157
7.2.5. Blood for PK Analysis of Avelumab........................................................157
7.2.6.1. Shipment of Genotyping Samples...........................................158
7.5. Tumor Response Assessments ..............................................................................160
7.6.2. Additional Research..................................................................................162
8. ADVERSE EVENT REPORTING....................................................................................163
8.1. Adverse Events......................................................................................................163
8.2. Reporting Period ...................................................................................................163
8.3. Definition of an Adverse Event.............................................................................163
8.4. Medication Errors..................................................................................................164
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8.5. Abnormal Test Findings........................................................................................165
8.6. Serious Adverse Events.........................................................................................165
8.6.1. Protocol-Specified Serious Adverse Events.............................................166
8.6.2. Potential Cases of Drug-Induced Liver Injury..........................................166
8.7. Hospitalization ......................................................................................................167
8.8. Severity Assessment..............................................................................................168
8.9. Causality Assessment............................................................................................169
8.10. Exposure During Pregnancy................................................................................169
8.11. Occupational Exposure .......................................................................................170
8.12. Withdrawal Due to Adverse Events (See also the Section Patient 
Withdrawal).............................................................................................................170
8.13. Eliciting Adverse Event Information ..................................................................171
8.14. Reporting Requirements......................................................................................171
8.14.1. Serious Adverse Event Reporting Requirements ...................................171
8.14.2. Non-Serious Adverse Event Reporting Requirements ...........................171
8.14.3. Sponsor’s Reporting Requirements to Regulatory Authorities ..............172
9. DATA ANALYSIS/STATISTICAL METHODS.............................................................172
9.1. Analysis Sets .........................................................................................................172
9.1.1. Safety Analysis Set...................................................................................172
9.1.2. Full Analysis Set.......................................................................................172
9.1.3. Per Protocol Analysis Set (Phase 1 and Cohorts 2A and 3) .....................172
9.1.4. Pharmacokinetic Analysis Sets.................................................................172
9.1.5. Response Evaluable Analysis Set.............................................................173
9.2. Statistical Methods and Properties ........................................................................173
9.2.1. Statistical Methods for Dose Escalation/De-Escalation ...........................173
9.2.1.1. Continual Reassessment Method (Phase 1) ............................173
9.2.1.2. Modified Toxicity Probability Interval (mTPI) (Phase 1b) ....174
9.3. Sample Size Determination...................................................................................175
9.3.1. Phase 1 Sample Size.................................................................................175
9.3.2. Phase 1b/2 Sample Size............................................................................175
9.4. Efficacy Analysis ..................................................................................................176
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9.4.1. Phase 1......................................................................................................176
9.4.2. Phase 1b/2.................................................................................................176
9.5. Analysis of Other Endpoints .................................................................................177
9.5.1. Analysis of Pharmacokinetics...................................................................177
9.5.1.1. Single Dose and Steady State PF-06747775 PK Analysis......177
9.5.1.2. Effect of Food on PF-06747775 Pharmacokinetics ................178
9.5.1.3. Sildenafil Sub-Study: MTD Expansion Cohort ......................178
9.5.1.5. PF-06747775-Esomeprazole Drug-Drug Interaction Study....179
9.5.1.6. PF-06747775-Itraconazole Drug-Drug Interaction Study.......179
9.5.1.7. Palbociclib PK Analysis..........................................................180
9.6. Safety Analysis......................................................................................................181
9.6.1. Analysis of Phase 1 and Phase 1b Primary Endpoint...............................181
9.6.2. Analysis of Secondary Safety Endpoints..................................................182
9.6.2.1. Adverse Events........................................................................182
9.6.2.2. Laboratory Test Abnormalities ...............................................182
9.6.2.3. ECG.........................................................................................182
9.7. Data Safety Monitoring Committee ......................................................................183
10. QUALITY CONTROL AND QUALITY ASSURANCE...............................................183
11. DATA HANDLING AND RECORD KEEPING ...........................................................184
11.1. Case Report Forms/Electronic Data Record .......................................................184
11.2. Record Retention.................................................................................................184
12. ETHICS............................................................................................................................185
12.1. Institutional Review Board (IRB)/Ethics Committee (EC).................................185
12.2. Ethical Conduct of the Study ..............................................................................185
12.3. Patient Information and Consent.........................................................................185
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12.4. Patient Recruitment.............................................................................................186
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP .........................................................................................................................186
13. DEFINITION OF END OF TRIAL.................................................................................186
13.1. End of Trial in a Member State...........................................................................186
13.2. End of Trial in All Other Participating Countries...............................................186
14. SPONSOR DISCONTINUATION CRITERIA ..............................................................186
15. PUBLICATION OF STUDY RESULTS........................................................................187
15.1. Communication of Results by Pfizer ..................................................................187
15.2. Publications by Investigators ..............................................................................187
16. REFERENCES ................................................................................................................189
17. APPENDICES .................................................................................................................195
LIST OF TABLES
Table 1.
PHASE 1 SCHEDULE OF ACTIVITIES............................................................30
Table 2.
Phase 1 Single and Multiple Dose PK and ECG Assessments for Phase 1 
Dose Escalation Cohorts.......................................................................................35
Table 3.
Phase 1 Sildenafil Sub-Study (Phase 1 only at MTD Expansion Cohort)............36
Table 4.
Phase 1 Food Effect and Rifampin DDI Sub-Studies (Phase 1 only at the 
RP2D). ..................................................................................................................37
Table 5.
Phase 1 Antacid Effect and Itraconazole DDI Sub-Studies (Phase 1 only at 
the RP2D). ............................................................................................................38
Table 6.
Single-Agent PF-06747775 in Previously-Untreated EGFRm NSCLC: 
Phase 2 Cohort 1 SCHEDULE OF ACTIVITIES................................................39
Table 7.
SINGLE-AGENT PF-06747775: Cohort 1 Phase 2 PK and ECG 
Assessments..........................................................................................................43
Table 8.
PF-06747775 + Palbociclib: Cohort 2A and Cohort 2B SCHEDULE OF 
ACTIVITIES ........................................................................................................44
Table 9.
PF-06747775 + Palbociclib: Cohort 2A (Phase 1b) – PK and ECG 
Assessments..........................................................................................................49
Table 10.
PF-06747775 + Palbociclib: Cohort 2B (Phase 2) – PK and ECG 
Assessments..........................................................................................................50
Table 11.
PF-06747775 + Avelumab: Cohort 3 (Phase 1b) SCHEDULE OF 
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Table 12.
PF-06747775 + Avelumab: Cohort 3 (Phase 1b) – PK and ECG 
Assessments..........................................................................................................57
Table 13.
Dose Levels for PF-06747775............................................................................104
Table 14.
PF-06747775 and Palbociclib Dose Levels........................................................105
Table 15.
Some Possible Dose Finding Sequences ............................................................106
Table 16.
Dose Escalation/De-Escalation Decision Algorithm..........................................106
Table 17.
PF-06747775 and Avelumab Dose Levels .........................................................107
Table 18.
PF-06747775 Dose Modifications for Drug-Related Toxicity...........................133
Table 19.
Recommended Dose Modifications for Adverse Events Associated with 
Palbociclib ..........................................................................................................134
Table 20.
Recommended Dose Modifications for Neutropenia and/or 
Thrombocytopenia..............................................................................................135
Table 21.
Palbociclib Dose Modifications in the Event of QTc Prolongation ...................135
Table 22.
Treatment Modification for Symptoms of Avelumab Infusion-Related 
Reactions.............................................................................................................137
Table 23.
Management of Avelumab Immune-Related Adverse Events ...........................140
Table 24.
Translational Oncology Assays ..........................................................................160
APPENDICES
Appendix 1. Bone Marrow Reserve in Adults (to be Used in Support of Exclusion of 
>25% Prior Irradiation of the Bone Marrow).....................................................195
Appendix 2. ECOG PS ..........................................................................................................197
Appendix 3. AE Management Guidelines .............................................................................198
Appendix 4. RECIST Version 1.1 .........................................................................................205
Appendix 5. List of Drugs Known to Predispose to Torsade de Pointes...............................210
Appendix 7. Detailed Dose Escalation/De-Escalation Scheme for mTPI Design Based 
on 30% Toxicity Rate. ........................................................................................213
Appendix 8. Japanese Patient-Only Lead In Cohort..............................................................215
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1. INTRODUCTION
1.1. Mechanism of Action/Indication
PF-06747775 is a highly selective epidermal growth factor receptor (EGFR) tyrosine kinase 
inhibitor (TKI) with strong activity against the EGFR mutants (EGFRm), including EGFR 
double-mutants (L858R/T790M and del 19/T790M) and the EGFR single-mutants (L858R
and del 19).  There remains an unmet medical need to develop EGFR TKI agents that 
effectively target both the single activating mutations of del 19 and L858R, and the 
secondary resistance mutation T790M, while sparing wild type (WT) EGFR.  Drugs active 
against the resistance mutation will enable molecularly-targeted therapy with a more 
favorable toxicity profile than the current standard of cytotoxic chemotherapy 
platinum-based doublets.  
The purpose of this Phase 1/2 study is to explore the safety and antitumor activity of 
PF-06747775 as single agent and in combination with palbociclib (PD-0332991) or 
avelumab (MSB00010718C) in patients with advanced EGFRm (del 19 or L858R ± T790M)
non-small lung cancer (NSCLC).  
1.2. Background and Rationale
1.2.1. Non-Small Cell Lung Cancer
EGFRm NSCLC accounts for approximately 20% of NSCLC, representing a conservative 
estimate of 100,000 to 200,000 newly diagnosed cases per year globally.  Two frequent and 
mutually exclusive primary mutations, EGFR L858R and EGFR del 19, together account for 
approximately 85% of all EGFRm cases.1  These somatic EGFR mutants are oncogenic 
drivers and are strong predictive biomarkers of response to EGFR TKIs, such as erlotinib, 
gefitinib, afatinib, and dacomitinib.  All of these EGFR TKIs are dose-limited by their 
potency on WT EGFR.  Inhibition of WT EGFR drives toxicities in epithelia where WT 
EGFR functions in normal adult physiology.2,3 EGFR TKI first-line treatment of EGFRm
NSCLC patients provides excellent response rates and disease control for 11 to 14 months, 
but patients invariably become resistant to these therapies and their disease progresses.  For 
patients with resistant tumors, approximately 60% harbor a second mutation in the EGFR 
kinase domain (T790M) concurrently with the primary activating mutation4 that renders the 
receptor insensitive to inhibition by the EGFR TKIs, thus restoring constitutive signaling 
through the EGFR axis.  Hence, in efforts to discover and develop improved EGFR TKIs, 
these double-mutant EGFR variants, L858R/T790M and del 19/T790M, are key targets in 
addressing resistance, and sparing WT EGFR is essential in preventing dose-limiting 
toxicities (DLTs).
Further complexity identified from clinical observations and nonclinical studies has shown 
the resistant tumor is not simply a homogeneous T790M double-mutant-driven condition.  In 
nonclinical studies, resistant tumor cells appeared to harbor both single- and double-mutant 
EGFR alleles in different ratios, and either single- or double-mutant EGFR may provide 
oncogenic signaling.5 In addition, resistant tumors appeared to contain a heterogeneous mix 
of tumor cells, with some cells containing only single-mutant alleles admixed with other cells 
containing both single- and double-mutant alleles.  Clinical observations supporting this 


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phenomenon found that continuing initial EGFR TKI upon development of tumor resistance 
provides significant clinical benefit over stopping initial EGFR TKI upon development of
EGFR TKI resistance.6,7,8 It is currently recommended that EGFRm NSCLC patients remain 
on EGFR TKI therapy even after developing resistance.9  To provide the most effective 
disease control in these patients, it is hypothesized that inhibition of both the double-mutants 
and the single-mutants is required.  PF-06747775 was discovered and optimized to meet this 
profile.
1.2.2. PF-06747775
PF-06747775 is a molecularly-targeted, rationally-designed, third generation EGFR TKI.
PF-06747775 shows highly potent cellular activity (inhibition of EGFR phosphorylation in 
patient-derived NSCLC cell models) against double-mutants L858R/T790M and del 
19/T790M and single-mutants L858R and del 19, and is a weak inhibitor of WT EGFR.  
Therefore, WT EGFR-driven PF-06747775 toxicity is anticipated to be very limited with 
strong efficacy against the mutant targets.
In vivo assays employing single- and double-mutant target driven tumor models were used to 
build a quantitative understanding of target modulation and anti-tumor activity as a function 
of plasma exposure of PF-06747775. The efficacious concentration (Ceff) providing tumor 
stasis was determined based on multiple in vivo models and was in close agreement between 
the models as 58 to 139 nM free plasma concentration.
The compound has a preclinical safety profile (Section 1.2.2.2) which suggests that 
PF-06747775 can achieve a good therapeutic index based on the predicted Ceff in patients.
These data suggest that PF-06747775 will have more than adequate potency and exposure to 
produce anti-tumor responses in patients with EGFRm NSCLC, which remains an unmet 
medical need.
1.2.2.1. PF-06747775 Nonclinical Pharmacokinetic Data
The non-clinical pharmacokinetics (PK) of PF-06747775 were characterized by moderate to 
high plasma clearances in mice (53 mL/min/kg) and rats (48 mL/min/kg), and low to 
moderate clearances in dogs (11.6 mL/min/kg). The volume of distribution was 
characterized as low to moderate in rats (0.66 L/kg), dogs (0.94 L/kg) and mice (1.48 L/kg).  
Rapid absorption was observed in all nonclinical species (0.25-1 h).
Using Day 1 toxicokinetic data from the 1-month definitive toxicity studies of PF-06747775, 
the Tmax occurred at 0.5 hours in rats at all doses (≤60 mg/kg) and corresponded with mean 
plasma unbound Cmax of 983 ng/mL at 60 mg/kg.  On Day 1 in the 1-month toxicity studies in 
dogs, Tmax was observed to range from 1.44 to 4.0 hours post dose across all doses 
(≤90 mg/kg) in dogs.  The Tmax appeared delayed at 90 mg/kg relative to lower doses, and 
corresponded with mean plasma unbound Cmax of 836 ng/mL. According to rat brain 
penetration studies conducted at 10 mg/kg PF-06747775 administered by mouth (PO),
PF-06747775 does not distribute into the brain, as evidenced by a mean free brain to plasma 
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1.2.2.2. PF-06747775 Nonclinical Safety Data
PF-06747775 was administered once daily by oral gavage to rats and dogs in toxicity studies 
up to 1 month in duration.  After 1 month of PF-06747775 administration, the severely toxic 
dose (STD10) in rats was 60 mg/kg/day (unbound Day 25 AUC24 of 6310 ng•h/mL); a highest 
non-severely toxic dose (HNSTD) was not identified in dogs at doses 15 mg/kg/day 
(unbound Day 27 AUC24 of 2580 ng•h/mL).  The primary target organs identified in rats 
and/or dogs included the gastrointestinal system, skin, eye, and kidney.  The potential for 
reversibility of all target organ toxicities was established following a 1-month non-dosing 
period.  In genetic toxicology tests, PF-06747775 was not mutagenic or clastogenic, but was 
aneugenic in vitro.  PF-06747775 is also a potential phototoxicant based on ultraviolet (UV) 
B-absorbing properties.
1.2.2.2.1. Gastrointestinal System
Effects on the gastrointestinal system were dose-limiting in rats and dogs.  Repeat-dose oral 
administration of PF-06747775 at 100 mg/kg/day and 60 mg/kg/day in rats and dogs, 
respectively, led to decreased body weight and unscheduled euthanasia.  Histopathological 
examination of these non-tolerated doses revealed gastrointestinal lesions extending from the 
esophagus to the colon of rats, and from the tongue to the colon of dogs.  The lesions 
impacted the epithelial and/or mucosal layers and ranged from minimal atrophy to 
erosions/ulcers.  In the esophagus and nonglandular stomach of rats, the atrophy was 
characterized by thinning of the stratified squamous epithelium and a less dense keratin layer.  
In the glandular stomach, mucosal atrophy was primarily in the pyloric region and was 
characterized by mucosal thinning with attenuation and loss of epithelium.  In rats at 
500 mg/kg/day (after 9 days of dosing) and 30 mg/kg/day (after 29 days of dosing), there 
were erosions/ulcers in the glandular stomach mucosa accompanied by lower glucose and 
potassium compared with baseline values.  Erosions/ulcers may have been a response to
mucosal atrophy, but decreased food consumption may have also contributed10,11 at 
500 mg/kg/day.  Nonadverse mucosal congestion in the glandular stomach and cecum of rats 
at 60 mg/kg/day was also identified.  Similar findings in dogs consisted of minimal to 
moderate erosion/ulceration of the tongue, minimal to moderate erosions in the esophagus 
with minimal atrophy of esophageal epithelium, minimal to moderate duodenal crypt 
dilatation with minimal to mild mucosal atrophy and/or erosions, and minimal to mild crypt 
dilatation in the jejunum, colon, ileum, and cecum.  In the duodenum and ileum, mucosal 
atrophy was characterized by epithelial attenuation, loss, and villar blunting.  In the cecum 
and colon, mucosal atrophy was characterized by epithelial attenuation and loss and collapse 
of surrounding stroma with a slight increase in mononuclear inflammatory cells.
Soft feces were noted in rats at 60 mg/kg/day, and the most common gastrointestinal 
observation in dogs at 15 mg/kg/day was a non-dose related incidence of abnormal (soft, 
mucoid, watery, and/or red-tinged) feces at all dose levels lasting up to 27 days during the 
dosing phase.  Body weight loss and poor condition of dogs at 60 mg/kg/day correlated with 
decreased serum creatinine compared with baseline.  Emesis was also sporadically noted in 
dogs (1 to 5 days of study) with increased incidence (3 to 4 /group) when compared with 
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Microscopic findings which did not fully recover in rats included erosion/ulcer of the 
glandular stomach, and epithelial atrophy of the non-glandular stomach at 60 mg/kg/day, and 
epithelial atrophy of the cecum at 30 mg/kg/day in rats.  After a 1-month recovery phase, 
there was recovery of all clinical observations, body weight and food consumption changes, 
and histology findings at 60 mg/kg/day in dogs.
There were no effects on the liver after repeated dosing of PF-06747775 in nonclinical 
toxicity studies in rats and dogs up to 1-month in duration.
1.2.2.2.2. Skin
Effects on the skin were dose-limiting in dogs after repeat oral dosing.  The severity of 
observations including lameness, footpad lesions and/or swelling after repeat-dose oral 
administration of PF-06747775 at 15 mg/kg/day in dogs led to unscheduled euthanasia.  
Skin lesions/discoloration (red-tinged) were noted on the forepaw, hindpaw, forelimb, 
hindlimb, head, eyelid, ear, abdomen, scrotum, tail tip, and/or cervical, thoracic and inguinal
regions.  While lesions were occasionally noted in association with skin discoloration, there 
was no clear correlation.  Skin lesions and discoloration generally occurred later in the study 
with onset between Days 11 and 23, most often persisting for several days post cessation of 
dose administration or until euthanasia (up to 15 days).  Skin crusting on the scrotum was 
noted with or without skin discoloration or lesions in 1 to 2 males/group with onset between 
Days 22-28 persisting for 1-7 days.  Hair loss from the eyelid, forepaw, and/or hindpaw was 
noted with low incidence (1 to 2/group) in association with red-tinged skin in dogs.  In the 
14_day study in rats, there was microscopic epidermal atrophy at 100 mg/kg/day.  In the 
1-month study in rats, skin hair granulomas which corresponded to the in-life observations of 
swollen lips or muzzles and skin lesions at 60 mg/kg/day, and granulomatous inflammation 
in the Harderian gland at 30 mg/kg/day were due to foreign body reactions from epithelial 
atrophy (ie, atrophic hair follicle epithelium and Harderian gland acinar epithelium).  
Nonadverse findings in the skin of rats included hair loss in multiple regions at 
10 mg/kg/day, tissue swelling (lips, muzzle, and/or anus) at 30 mg/kg/day, and skin 
lesions (muzzle, cervical or dorsal thoracic regions), adnexal atrophy, and crusting of the skin 
at 60 mg/kg/day.  PF-06747775-related microscopic findings that did not recover included 
nonadverse adnexa atrophy of the skin and increased mononuclear cell infiltrate in the 
Harderian gland at 60 mg/kg/day.
1.2.2.2.3. Eye
Ocular effects were dose-limiting in the 14-day exploratory toxicity study in dogs; the female 
dog at 120 mg/kg/day was euthanized on Day 9 due to progressing eye findings of 
conjunctival hyperemia (moderate to severe), corneal edema with mucus/discharge, 
excessive lacrimation, constricted pupil/miosis, sclera congestion, swollen and partially 
closed eyelids, which evolved to central corneal ulceration.  In order to attenuate the 
progression of the ocular observations in the 1-month definitive toxicity study in dogs, a 
lubricant was prophylactically, topically administered to the eyes of all dogs in the study 
starting on Day 1.  As a result, no dogs were euthanized early due to ocular lesions in the 
1-month study.  However, adverse ocular findings were still present at all dose levels 
(15 mg/kg/day).  From the animals available for ophthalmologic examination at the 


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conclusion of the dosing phase, multifocal or diffuse cornea opacities consistent with corneal 
edema21,22 were observed at 15 mg/kg/day, often associated with observations of partially 
closed eyes and/or microscopic findings of minimal to marked atrophy of the corneal 
epithelium in both sexes.  Additionally, a dull appearance of the eye was noted during 
ophthalmologic examination of some dogs suggesting alterations in the precorneal tear film.  
This was consistent with observations of meibomian gland inflammation noted in the eyelids 
of animals that had observations of swollen and/or discolored eyelids and changes in the 
cornea itself.  Changes in eyelids and tear film as well as corneal atrophy have previously 
been associated with EGFR inhibition.12  It is notable that the corneal epithelial atrophy was 
less severe in animals that survived the dosing phase compared to animals that were 
euthanized early.  Similar ocular observations and microscopic findings were also seen in rats 
at doses 60 mg/kg/day.  Multifocal corneal opacities and rough corneal surfaces correlating 
to corneal epithelial atrophy and corneal ulcers/erosions were seen at 30 mg/kg/day.  At the 
end of the recovery phase, findings of corneal opacities in rats and dogs had resolved; 
however, corneal neovascularization (a further progression of the corneal findings) had 
developed in one rat at 60 mg/kg/day.
1.2.2.2.4. Kidney
Kidney findings were only observed at non-tolerated doses (≥100 mg/kg/day) in the 14-day 
exploratory toxicity study in rats.  At ≥100 mg/kg/day in rats, there was PF-06747775-related 
tubular basophilia.  At 500 mg/kg/day there was papillary necrosis and dilatation of tubules.  
Tubular basophilia and tubular dilatation were both bilateral and were associated with 
macroscopic observations of abnormal kidney color (mottled) in 1/5 rats at 500 mg/kg/day.  
The kidney findings were associated with clinical pathology increases in blood urea nitrogen 
(BUN) and/or creatinine.  There were no kidney findings in dogs at any dose in studies up to 
1 month in duration.  These rodent-specific kidney effects are probably based on the 
pharmacology of PF-06747775 (ie, inhibition of EGFR).13,14
1.2.2.2.5. Lymphohematopoietic
Hematological effects that affected both myeloid and erythroid parameters were observed in 
rats and dogs administered PF-06747775; these changes were predominantly associated with 
inflammation or invasion of bacteria as a result of diminished integrity of the epithelial 
barrier in multiple tissues.
In rats, non-adverse differences in clinical pathology parameters, consistent with 
inflammatory changes noted microscopically in the skin, gastrointestinal tract and eye, were 
increased white blood cells, neutrophils, and lymphocytes in females at 30 mg/kg/day, and 
monocytes in males and females at 30 mg/kg/day, and decreased albumin in females at 
30 mg/kg/day, albumin/globulin (A/G) ratio in females at 60 mg/kg/day, and potassium in 
males at 10 mg/kg/day.  In dogs, erosions, ulcers and/or inflammation that occurred in 
multiple tissues including skin, tongue, esophagus, and/or duodenum at 15 mg/kg/day 
correlated with inflammatory changes (typically not dose responsive) that were present in the 
hematology, coagulation, and clinical chemistry parameters and were similar in magnitude in 
animals at scheduled and unscheduled euthanasia.  In dogs at 15 mg/kg/day there were 
increases in monocytes, fibrinogen, and globulin with concurrent decreases in albumin and 


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often total protein indicating an inflammatory response.  The decrease in albumin may also 
be partially attributed to protein loss associated with the ulceration/erosions of epithelial 
surfaces.  In addition at 60 mg/kg/day, due to inflammation in multiple tissues, neutrophils, 
white blood cells, and platelet counts were increased.  The inflammatory changes noted 
above led to non-dose responsive, non-progressive decreases in red cell mass parameters at 
15 mg/kg/day due to suppression of the bone marrow production of red blood cells.  None 
of these hematology, coagulation, or clinical chemistry effects was considered adverse based 
on the characteristics of these responses, which were secondary to the inflammatory changes 
present in the dogs.
Secondary non-adverse morphological changes occurred in the thymus, bone marrow, and 
lymph nodes at 15 mg/kg/day in dogs.  There was mild lymphoid depletion in the thymus in 
a few male dogs consistent with corticosteroid-induced stress15,16 that correlated with 
decreases in lymphocytes and eosinophils in individual animals.  There was increased 
myeloid cellularity of the bone marrow secondary to the inflammation that correlated with 
higher leukocyte counts and fibrinogen.  Also, there were increased lymphocytes in the 
cortex accompanied with increased plasma cells in the popliteal, mandibular, and/or iliac 
lymph nodes, reflecting secondary reactive and functional responses to inflamed 
drainage/regional areas of the skin and digestive system.
1.2.2.2.6. Cardiovascular
Cardiovascular effects were only observed in rats after a single dose.  Oral administration of 
PF-06747775 at 20 mg/kg caused minimally higher systolic, diastolic, and mean blood 
pressure compared with vehicle control values.  The higher blood pressure values persisted 
from 8 - 24 hours post dose and were highest from 20 - 24 hours post dose, which was 
disconnected from the observed time of maximum PF-06747775 plasma concentration 
(0.5 hours post dose).  There were no cardiovascular effects (blood pressure, heart rate, or 
electrocardiogram [ECG] parameters) in dogs at single doses up to 30 mg/kg.  There also 
were no effects on ECG parameters in dogs after repeat doses up to 90 mg/kg/day in the 
1-month definitive toxicity study.
1.2.2.2.7. Other Findings
Other nonadverse PF-06747775-related anatomic and clinical pathology findings in rats 
included increased inflammatory cell infiltrates (secondary to epithelial atrophy and 
subsequent inflammation) in the prostate, mesenteric lymph nodes, and connective and 
adipose tissues23in several locations at 10 mg/kg/day, decreased secretory content in the 
prostate gland with lower prostate weights and higher adrenal gland weights at 
30 mg/kg/day, lower epididymal weights in males and lower thymus weights in females at 
60 mg/kg/day without microscopic correlates.
1.2.2.3. PF-06747775 Projection of Human Pharmacokinetics
In humans, PF-06747775 is predicted to be hepatically cleared (metabolized) and thus the 
parent drug is not believed to be excreted via the bile or kidney unchanged, based on in vivo 
studies in rat and dog.  Scaling from hepatocytes and using population based physiologically-
based pharmacokinetic (PBPK) modeling (SimCYP), PF-06747775 is predicted to have a 


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geometric mean plasma clearance of 0.7 mL/min/kg, a volume of distribution of 0.78 L/kg, a 
half-life of ~11 hours, and a geometric mean oral bioavailability of 83% at doses under 
20 mg once a day.  Based on data from RRCK cells, PF-06747775 is predicted to have good 
absorption (~88%) at the predicted efficacious dose.  
PF-06747775 is indicated to be an efflux transporter substrate for both MDR1 and BCRP
using in vitro transwell evaluations, with respective efflux ratios of 20.4 and 33.9. The efflux 
transporter substrate effect is predicted to have a small effect on systemic exposure at and 
above the predicted Ceff dose of 20 mg; however, the efflux transporter substrate status may 
impede brain penetration which is evidenced by rat brain penetration studies showing little, if 
any, brain exposure compared to systemic exposure.  
PF-06747775 can potentially alter pharmacokinetics of other co-administered drugs that are 
hepatically eliminated via the CYP3A4 pathway evidenced by its ability to induce CYP3A4 
mRNA levels in cyropreserved human hepatocytes in vitro.  PF-06747775 is also thought to 
be cleared in the liver by a number of pathways: 1) CYP3A4 (62%), 2) intrinsic binding to 
glutathione, and 3) GSTM1-mediated glutathione conjugation.
1.2.2.4. PF-06747775 Nonclinical Pharmacology
PF-06747775 was studied in a variety of in vitro and in vivo model systems to determine its 
potencies at inhibiting different mutant EGFR variants, selectivity against non-target kinases, 
antitumor efficacy, pharmacokinetic/pharmacodynamic (PK/PD) relationships, and 
mechanism of action.
In recombinant enzyme and cellular assays, PF-06747775 is a highly potent and irreversible 
inhibitor against the EGFR double-mutants (L858R/T790M and del 19/T790M) and single-
mutants (L858R and del 19) and a weak inhibitor of WT EGFR.  This inhibitory potency on 
mutant targets is paralleled by subsequent inhibition of the EGFR downstream signaling axis
(eg, inhibition of phosphorylation of AKT and ERK kinases) and induction of apoptosis.  In 
xenograft mouse models, PF-06747775 demonstrates tumor growth inhibition and regression 
at well-tolerated doses in disease-relevant models driven by EGFR double- and single-
mutants.  The antitumor efficacy of PF-06747775 is dose-dependent and shows a strong 
correlation with pharmacodynamic inhibition of EGFR phosphorylation, inhibition of 
EGFR-mediated downstream signaling, and induction of apoptosis.  Using multiple in vitro 
approaches to assess non-target kinase selectivity, PF-06747775 demonstrates the potential 
for high kinase selectivity, with only 7 out of 273 (3%) tested non-target kinases showing the 
potential for inhibition by PF-06747775 at pharmacologically-relevant concentrations.  In 
order to quantitatively define plasma concentrations sufficient for efficacy (Ceff), a 
mathematical model was generated incorporating the plasma levels of PF-06747775, the
associated inhibitory effects on EGFR phosphorylation, and the antitumor efficacy in 
xenograft models.  Applying the mathematical model, the Ceff for PF-06747775 is 58 nM 
(24 ng/mL) in the H1975 L858R/T790M double-mutant model, and 119-139 nM 
(49-58 ng/mL) in the PC9 del 19 single-mutant model, when expressed as the average plasma 
concentration of unbound PF-06747775 to achieve tumor stasis.  The results from all 
xenograft models employed are consistent with tumor stasis resulting from achieving an 
average of at least 60% to 80% PD inhibition of EGFR phosphorylation over the dosing 
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1.2.3. Palbociclib
Palbociclib is a first-in-class CDK4/6 inhibitor conditionally approved in the United States 
(US) for use in combination with letrozole or fulvestrant for advanced estrogen-receptor (ER) 
positive, human epidermal growth factor receptor 2 (HER2) negative breast cancer.  By 
inhibiting CDK4/6 and subsequently downstream signaling through Rb protein that controls 
the cell cycle, palbociclib prevents actively proliferating cells from completing the cell 
division cycle, resulting in an arrest of tumor growth.  EGFR TKIs inhibit phosphorylation of 
EGFR, thereby inhibiting downstream cell signaling through the EGFR axis including AKT, 
MEK/ERK, and transcription of cell cycle related genes such as cyclin D1 and E2F target 
genes,24 resulting in the induction of apoptosis and inhibition of proliferation in EGFR-
dependent tumor cells. It is hypothesized that combination of the EGFR TKI PF-06747775 
with palbociclib in EGFR-mutant NSCLC could further impede tumor growth with increased 
efficacy over the EGFR TKI alone.  This potential increased efficacy may reflect better 
inhibition of cell cycle progression with the combination.  In addition, palbociclib may arrest 
the growth of EGFR TKI-resistant cells present or acquired and attempting to get a foot hold 
for growth in the heterogeneous tumor when the predominant EGFR-sensitive cell population 
is challenged with an EGFR TKI.
1.2.3.1. Palbociclib Nonclinical Pharmacology Data
Palbociclib nonclinical data indicate that it may be expected to have direct effect on growth 
arrest as well as potential secondary cytoreductive activity.  Single agent palbociclib has 
showed antiproliferative effects (selective G1 arrest) on Rb-positive cancer cells in vitro and 
in vivo25 where palbociclib activity was associated with reduced Rb-phosphorylation and 
decreased expression of the cell proliferation marker Ki67. 
Treatment of cultured tumor cells with palbociclib causes growth arrest that is accompanied 
by the inhibition of specific pRb phosphorylation by CDK4 or CDK6 on residues 
serine -780 and -795 of pRb.  The IC50 values for reduction of pRb phosphorylation at serine 
-780 and -795 in MDA-MB-435 breast carcinoma cells were 0.066 and 0.063 M, 
respectively.  The IC50 values for reduction of pRb phosphorylation are similar to the IC50
values of inhibition of thymidine incorporation across a range of cultured tumor and normal 
cells.
Palbociclib was tested in vitro on molecularly characterized human breast cancer cell lines.  
Results from these experiments indicate that those cell lines that are more sensitive to 
palbociclib (IC50 <150 nM) have low levels of CDKN2A (p16) and high levels of Rb1, while 
resistant cell lines show the opposite characteristics.  Sensitive cell lines in this panel 
represent mostly the luminal ER-positive subtype.26
Additional nonclinical studies were conducted with the objective to characterize the activity 
of combined PF-06747775 and palbociclib as compared to each single agent in both cell-
based and in vivo assays using models of EGFR-mutant NSCLC.  


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At the cellular level, study objectives were to address: 1) efficacy of combination versus 
single agents in long term viability assays where cell outgrowth depended on drug resistance; 
and 2) the mechanistic effects of combination versus single agent treatment using 
downstream signaling biomarker assays and cell cycle analysis.
At the in vivo level, study objectives were to address: 1) the in vivo anti-tumor efficacy of 
the combination compared to each single agent; and 2) the effect on body weight and any 
apparent clinical observations from combination versus single agent treatment in the in vivo 
efficacy studies as an indicator of safety.
In vitro and in vivo assessment of the combination of PF-06747775 and palbociclib showed 
increased efficacy over PF-06747775 alone in NSCLC models representing the first-line 
EGFRm and second-line T790M-resistant patient populations.  Mechanistic studies suggest 
the combination effect predominantly relies on the addition of the pro-apoptotic effect of 
PF-06747775 plus the anti-proliferative effect of both agents.  These studies support clinical 
testing of the PF-06747775 palbociclib combination for increased clinical benefit in 
EGFR-mutant NSCLC.27
1.2.3.2. Palbociclib Nonclinical Pharmacokinetic Data
In nonclinical species (rat, dog, and monkey), palbociclib exhibits low to moderate plasma 
clearance, large volume of distribution, and moderate oral bioavailability ranging from 23% 
to 56%.  Plasma protein binding of palbociclib is moderate in mouse, rat, rabbit, dog, and 
human plasma.  Radioequivalents were widely distributed to most rat tissues and fluids 
following an oral dose of [14C]palbociclib, with radioactivity levels consistently greater than 
those observed in blood.  In vitro, palbociclib is primarily metabolized by cytochrome P450 
(CYP)3A and sulfotransferase (SULT) 2A1 enzymes.  The major primary metabolic 
pathways for [14C]palbociclib in rats and humans involved sulfonation and oxidation.  In rats 
and dogs, [14C]palbociclib was mainly eliminated via the feces; the high fecal elimination 
occurred via biliary excretion in rats.  Palbociclib and its oxidative metabolite, PF-05089326, 
demonstrated little or no inhibition of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or 
CYP2D6 enzyme activities and thus, showed low potential for CYP-mediated PK drug 
interactions.  However, palbociclib and PF-05089326 caused time-dependent inhibition of 
CYP3A midazolam 1’-hydroxylase and testosterone 6β-hydroxylase activities and may have 
the potential for PK drug interactions with compounds for which CYP3A-mediated 
metabolism constitutes the primary mechanism of clearance.  Palbociclib did not cause 
induction of CYP1A2, CYP2B6, CYP2C8, or CYP3A4 mRNA expression and/or enzyme 
activity in vitro in human hepatocytes; thus, the potential for palbociclib to induce these 
enzymes is considered to be low at clinically relevant concentrations.  The potential for 
palbociclib to inhibit UGT enzymes (UGT1A1, UGT1A4, UGT1A6, UGT1A9, and 
UGT2B7) was assessed and the likelihood of drug-drug interaction (DDI) at clinically 
relevant concentrations is considered low.  In vitro, inhibition of efflux transporters 
P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), hepatic uptake transporters 
(OATP1B1 and OATP1B3), hepatic efflux transporter (BSEP) and renal transporters (OAT1, 
OAT3 and OCT2) by palbociclib were assessed and determined to be unlikely at clinically 
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1.2.3.3. Palbociclib Human Pharmacokinetic Data
The PK of palbociclib is explained in detail in the palbociclib Investigator’s Brochure (IB).67
Palbociclib was shown to achieve steady-state concentrations following 8 days of once-daily 
(QD) dosing. The elimination half-life (t1/2) ranges from 23.2 to 28.8 hours with a median 
time of maximum concentration (Tmax) between 4 and 8 hours post-dose. Metabolism is the 
major route of elimination of palbociclib; excretion of unchanged [14C] palbociclib in the 
feces and urine was 2.3% and 6.9% of dose, respectively. When single oral doses of 
midazolam were co-administered with multiple doses of palbociclib, weak time-dependent 
CYP3A4/5 inhibition mediated by palbociclib was observed.  In vitro studies indicate that 
palbociclib is a substrate of CYP3A4.  Based on data following coadministration of 
itraconazole and rifampin, the concurrent administration of strong CYP3A inhibitors and 
inducers with palbociclib should be avoided.
Given the shared metabolic pathway, namely CYP3A4, of PF-06747775 and palbociclib, the 
observed impact of palbociclib on the exposure of a sensitive CYP3A4 substrate 
(midazolam), and the current lack of clinical data on the ability of PF-06747775 to inhibit or 
induce the CYP3A4 enzyme, the impact of concomitant administration of each drug upon the 
exposure of the other is currently unknown. Serial PK data will be collected for each drug 
following multiple dosing.
1.2.3.4. Palbociclib Clinical Data
Palbociclib has been explored in multiple clinical trials in a variety of malignancies, as single 
agent and in combination therapy.
Two Phase 1 trials evaluated single agent administration of palbociclib to patients with 
Rb-positive cancers.  One of these trials determined that the DLT was neutropenia and the 
maximum tolerated dose (MTD) was 125 mg once daily when administered for 21 of 28 days 
(3 weeks on/1 week off schedule).28,  The most common non-hematologic adverse events 
(AEs) included fatigue, nausea, and diarrhea.  The mean half-life of palbociclib was 
26.9 hours.  Patients were selected for Rb-positive cancers, based on immunohistochemistry 
(IHC) stain, defined as positive if staining intensity was 1+ or greater above background.  
Stable disease for ≥4 cycles (16 weeks) occurred in 27% of evaluable patients and in a 
number of tumor types (liposarcoma, testicular, renal, ovarian, breast, appendiceal, 
peritoneal, melanoma, thymoma and lung).  Another Phase I trial of palbociclib using an 
alternative dosing plan (21 day cycles; 2 weeks on/1 week off schedule) observed a similar 
likelihood of disease control in a variety of tumor types.29  These studies demonstrate that 
palbociclib has substantial activity in Rb-positive tumors.
A randomized Phase 2 trial was initiated to determine the overall safety and efficacy of 
palbociclib (125 mg) and letrozole (2.5 mg) versus letrozole in post-menopausal women with 
ER+ HER2-negative advanced breast cancer.30 The objective response rate (ORR) was 45% 
for those women who received palbociclib plus letrozole versus 31% for those who received 
letrozole (statistically significant).  Importantly, the median progression-free survival (PFS)
was significantly different (26.2 versus 7.5 months) favoring the combination arm.  The most 
common adverse drug reactions of any grade reported in patients in the palbociclib plus 


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letrozole arm were neutropenia, leukopenia, fatigue, anemia, upper respiratory infection, 
nausea, stomatitis, alopecia, diarrhea, thrombocytopenia, decreased appetite, vomiting, 
asthenia, peripheral neuropathy, and epistaxis.  The most frequently reported serious adverse 
drug reaction in patients receiving palbociclib plus letrozole was diarrhea (2.4%).
Overall, neutropenia of any grade was reported in 62 (74.7%) patients in the combination 
arm, with Grade 3 neutropenia being reported in 40 (48.2%) patients, and Grade 4 
neutropenia being reported in 5 (6.0%) patients.
In the combination arm, 56.6% of patients had a maximum grade of Grade 3 neutropenia and 
4.8% of patients had a maximum grade of Grade 4 neutropenia based on laboratory data.  
The median time to first episode of neutropenia was 15 days for any grade, Grade ≥2, and
Grade 4 neutropenia, and 28 days for Grade ≥3 neutropenia in the palbociclib plus letrozole
arm.  Median duration of Grade 3 or 4 neutropenia was 7 days. Most episodes of Grade ≥3
neutropenia were managed by dose reduction and/or dose delay or temporary discontinuation 
and did not require permanent discontinuation of study treatment or addition of supportive 
therapy.  Grade 3-4 fatigue/asthenia, vomiting, diarrhea and peripheral neuropathy rates were 
6%, 0%, 4% and 0% respectively.
Based on these data, the US Food and Drug Administration (FDA) approved palobociclib for 
the treatment of hormone receptor (HR)-positive, HER2-negative advanced or metastatic 
breast cancer in combination with: 

Letrozole as initial endocrine based therapy in postmenopausal women, or 

Fulvestrant in women with disease progression following endocrine therapy. 
The indication in combination with letrozole is approved under accelerated approval based 
on PFS. Continued approval for this indication may be contingent upon verification and 
description of clinical benefit in a confirmatory trial.
Clinical data for single agent palbociclib in NSCLC, not selected for EGFRm, has 
demonstrated modest activity only.66
Additional information for palbocicib may be found in the single reference safety document 
(SRSD), which for this study is the Palbociclib Investigator’s Brochure.67  
1.2.4. Avelumab
Avelumab (MSB0010718C) is a fully human monoclonal antibody (mAb) of the 
immunoglobulin (Ig) G1 isotype.
Programmed death ligand-1 (PD-L1) is expressed by a variety of human tumors, both by the 
tumor cells, as well as by the immune cells that are present in the tumor microenvironment.31  
High levels of PD-L1 expression have been found to be associated with disease progression, 
increased metastases, poor response to treatment, and decreased survival in a number of 
human cancers.31  Importantly, anti-PD-L1 blockade has demonstrated therapeutic efficacy in 
a variety of murine tumor models as monotherapy and has shown synergistic effect in the 
combination therapy setting.32,33,34,35,36,37,38


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Avelumab selectively binds to PD-L1 and competitively blocks its interaction with 
programmed cell death protein-1 (PD-1).   Compared with anti-PD-1 antibodies that target 
T-cells, avelumab targets tumor cells, and therefore is expected to have fewer side effects, 
including a lower risk of autoimmune-related safety issues, as blockade of PD-L1 leaves the 
programmed death ligand 2 (PD-L2)/PD-1 pathway intact to promote peripheral 
self-tolerance.39,40
1.2.4.1. Avelumab Nonclincial Data
1.2.4.1.1. Nonclinical Pharmacology
The nonclinical pharmacology studies have shown that avelumab functionally enhances 
T cell activation in vitro and significantly inhibits the growth of PD-L1 expressing tumors in 
vivo.
Avelumab binds to human PD-L1 with a high affinity of 0.7 nM and not to any other B7 
family proteins, and competitively blocks the interaction of PD-L1 with PD-1. The in vitro 
study results have shown that by binding to PD-L1, avelumab effectively enhances T cell 
activation as measured by interleukin (IL)-2 or interferon-gamma (IFN-) production. In 
addition, as a fully human IgG1 antibody, avelumab has the potential to trigger the antibody-
dependent cell-mediated cytotoxicity (ADCC) against target cells expressing PD-L1.
As a monotherapy, avelumab has demonstrated anti-tumor activity against murine MC38 
colon carcinoma tumors that are characterized by a high level of PD-L1 expression. A dose-
dependent trend was observed, and 400 μg per dose (20 mg/kg, approximately) was 
identified as the optimally effective dose when given every third day for 3 total doses.
The in vivo anti-tumor effects were found to be primarily mediated by CD8+ T cells as 
evidenced by the observation that in vivo depletion of this cell type completely abrogated the 
anti-tumor efficacy of avelumab. The contribution of ADCC as a potential mechanism of 
anti-tumor activity was further demonstrated in vivo using a deglycosylated version of 
avelumab to abrogate fragment crystalline (Fc) receptor binding or via the systemic depletion 
of natural killer (NK) cells. In both settings, loss of in vivo ADCC potential significantly 
reduced the anti-tumor activity.
The combination of avelumab with commonly used cancer treatments, such as cytotoxic 
agents and radiation therapy, resulted in an improved anti-tumor activity. Chemotherapy 
with combination therapy (with folinic acid, 5-fluorouracil, and oxaliplatin [FOLFOX], and 
radiation therapy showed the better tumor growth inhibition. In particular, radiation therapy 
was found to be a highly synergistic combination with avelumab capable of causing complete 
regression of established tumors probably through generating anti-tumor immune memory.
Various immunomonitoring assays were incorporated into the in vivo studies. Treatment 
with avelumab resulted in a consistent increase in the percentage of CD8+PD-1+ T cells and 
an increased frequency of CD8+ T cells with an effector memory (TEM) phenotype as 
determined by flow cytometry. Furthermore, these changes correlated with the anti-tumor 
effect. Increases in tumor antigen-specific T cell responses, as measured by enzyme-linked 


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immunosorbent spot and pentamer immunoassays, were evident following treatment with 
avelumab and these responses were enhanced when combined with FOLFOX or radiation. 
Hence, increases in CD8+PD-1+ T cells, CD8+ TEM cells, and antigen-specific T cell 
responses, may be leveraged as PD biomarkers with translational relevance to the clinical 
setting.
1.2.4.1.2. Nonclinical Pharmacokinetics and Metabolism
As expected for a mAb binding to a cellular target, avelumab demonstrated pronounced non-
linear PK characteristics in mice and monkeys in single dose studies at doses below 
20 mg/kg, suggesting a combination of first order catabolic clearance and saturable target-
mediated clearance. Toxicokinetic data from repeated dose toxicity studies in mice, rats, and 
monkeys indicated that the PK of avelumab was linear within the dose range of 20 to 
140 mg/kg, suggesting that the target mediated clearance could be saturated when higher 
doses than 20 mg/kg are administered. Similar terminal half-lives (t1/2) of approximately 
60 to 70 hours were observed in toxicity studies in mice and monkeys.
A PK/PD study in C57BL/6 mice was used to correlate receptor occupancy data of avelumab 
in blood with drug concentrations. A plasma concentration of 58.5 μg/mL was calculated as 
required for 95% target occupancy in this model.
Avelumab is immunogenic in mice, rats, and monkeys with a lower incidence of anti-drug 
antibodies (ADAs) at higher doses. The latter is probably due to interference of free 
avelumab with the immunogenicity assay (drug interference). In animals, the generated 
ADAs seem to have the potential to increase the clearance of the avelumab. As the fully 
human avelumab represents a foreign protein to the immune system of animals, the observed 
immunogenicity of avelumab in rodents and non-human primates is not deemed predictive 
for an immune response to avelumab in humans.
1.2.4.1.3. Nonclinical Toxicology
The toxicological profile of avelumab was evaluated in repeat-dose toxicity studies of 
4-week duration with once weekly Iv bolus injection/infusion of avelumab in mice, rats, and 
cynomolgus monkeys. A repeat-dose toxicity study with intermittent once weekly Iv 
infusion of avelumab over 13 weeks followed by an 8-week recovery period in cynomolgus 
monkeys was also conducted. In addition, in vitro cytokine release assays (CRA) in human 
and cynomolgus monkey whole blood and peripheral blood mononuclear cells (PBMCs) 
followed by an optimized CRA in phytohemagglutinin (PHA) pre-stimulated PBMCs from 
16 human volunteers was completed. Tissue cross reactivity (TCR) studies in normal human 
and cynomolgus monkey tissues have also been was performed.
On the basis of the binding affinity data, the cynomolgus monkey and the mouse were 
selected as relevant species for the nonclinical safety testing of avelumab. Due to severe 
hypersensitivity reactions after repeated administration of avelumab in mice and the low 
binding affinity in rats, rodent species are not considered appropriate for nonclinical safety 
testing of avelumab and therefore, a single species approach (cynomolgus monkey only) is 
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In cynomolgus monkeys neither in the pilot 4-week Iv repeat-dose toxicity study nor in the 
pivotal 13-week study, clinical signs of hypersensitivity have been seen after repeated 
treatment with avelumab at dose levels of 20, 60, and 140 mg/kg, respectively. For the pilot 
4-week study as well as for the pivotal 13-week Iv repeat-dose toxicity study, a no observed 
adverse effect level (NOAEL) of 140 mg/kg for systemic toxicity was established.
Initial CRA in human and cynomolgus monkey whole blood and PBMCs revealed no clear-
cut evidence for release of pro-inflammatory cytokines. However, a subsequent, optimized 
CRA demonstrated evidence of potential cytokine release in PHA pre-stimulated PBMCs.
1.2.4.2. Avelumab Human Pharmacokinetics
Avelumab PK and dose proportionality following the first 1-hour infusion have been 
characterized in 77 Caucasian patients treated in the dose escalation and expansion cohorts of 
Trial EMR 100070-001 by standard non-compartmental analysis.  This analysis revealed that 
the exposure parameters of maximum concentration (Cmax) and area under the concentration-
time curve to the end of the dosing period (AUCτ) increased in a dose proportionate fashion 
for the 10 and 20 mg/kg doses. The half-life of avelumab tended to increase with dose, likely 
due to target mediated disposition at lower doses (1 and 3 mg/kg), but terminal half-life of 
10 mg/kg (102 ±28 hours) and 20 mg/kg (120 ± 42 hours) doses were similar, taking into 
account the PK variability.  This likely indicates target mediated elimination does not 
increase at these two doses and target occupancy is very high.
Target occupancy on peripheral blood CD3+ T-cells was investigated in human blood in 
vitro by flow cytometry after spiking of whole blood samples from 8 healthy volunteers with 
avelumab over a concentration range of 0.003-10 g/mL.  Fifty percent (50%) receptor 
occupancy was observed at a drug concentration of 0.122 g/mL ± 0.042 g/mL with a 
plateau indicating at least 95% receptor occupancy reached in all blood samples at 1 g/mL.
PK profiles obtained during the dose escalation phase of Trial EMR 100070-001 were 
utilized to investigate whether this concentration of at least 1 μg/mL was achieved 
throughout the dosing interval. The median ± standard deviation trough concentration 
(Ctrough) at the end of the first cycle after administration of the 10 mg/kg dose is
21 ± 12 μg/mL (n=283). This median Ctrough increases during the subsequent cycles to
25 ± 16 μg/mL (second cycle) (n=269), 27 ± 17 μg/mL (third cycle) (n=202), and remains 
between 27 and 36 μg/mL during the subsequent cycles (n=55–171).
1.2.4.3. Avelumab Clinical Experience
Avelumab is being developed jointly by Pfizer and Merck KGaA/EMD Serono, and is being 
studied in a wide variety of adult cancers, such as non-small cell lung cancer, gastric cancer, 
Merkel cell carcinoma, renal cell carcinoma, ovarian cancer, urothelial cancer, and 
Hodgkin’s Lymphoma, as single agent or in combination with chemotherapy, tyrosine kinase 
inhibitors, or other immune-modulating agents.  


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As of 05 November 2015, more than 1300 patients have been treated with avelumab. The 
largest trial is study EMR100070-001, a Phase 1, open-label, multiple-ascending dose 
clinical study aimed to investigate the safety, tolerability, PK, biological activity, and clinical 
activity of avelumab in patients with metastatic or locally advanced solid tumors.  Study 
EMR100070-001 consists of 2 parts, a dose-escalation phase and a dose-expansion phase, 
which is performed in selected tumor indications.  Avelumab is administered intravenously 
(IV) at the assigned dose level as a 1-hour infusion once every 2 weeks (Q2W).  The 
following dose levels have been investigated: 1.0 mg/kg, 3.0 mg/kg, 10.0 mg/kg, and 
20.0 mg/kg.
As of 05 November 2015, 53 patients were treated in the dose-escalation phase of study 
EMR 100070-001, with 4, 13, 15, and 21 patients treated with avelumab doses of 1, 3, 10, 
and 20 mg/kg, respectively.  None of the patients treated with doses up to 10 mg/kg 
experienced DLT, and the 10 mg/kg dose of avelumab was thus considered a safe and 
well-tolerated dose for further investigation in the tumor type specific expansion cohorts.  
One DLT (a Grade 3 immune-related adverse event characterized by increased creatine 
kinase, myositis, and myocarditis) was observed in 1 patient at the dose of 20 mg/kg.
As of 05 November 2015, 1300 patients have been enrolled in the tumor type specific 
expansion cohorts of study EMR 100070-001 and treated with the recommended dose of 
10 mg/kg avelumab Q2W. A summary of the safety data for the pooled expansion cohort is 
provided here. 
Treatment-emergent adverse events (TEAEs) were observed in 1200 (92.3%) patients, with 
the most frequent (≥10%) being fatigue (27.4%), nausea (21.2%), infusion related reaction 
(16.2%), diarrhea (15.8%),  constipation (15.7%), decreased appetite (14.9%), vomiting 
(14.5%), weight decreased (12.2%), abdominal pain (12.0%), anemia (11.9%), cough 
(11.7%), dyspnea (11.4%), pyrexia (11.4%), and chills (10.5%).
Treatment-related TEAEs were observed in 813 (62.5%) patients, and the most frequent 
(≥5%) were fatigue (16.3%), infusion-related reaction (16.1%), nausea (8.3%), chills (7.8%), 
diarrhea (6.1%), and pyrexia (5.5%). 
A total of 124 patients (9.5%) experienced Grade ≥ 3 treatment-related TEAEs, with gamma-
glutamyltransferase (GGT) increased and infusion-related reaction (IRR, 0.7% each), fatigue 
and lipase increased (0.6% each), anemia (0.5%), dyspnea (0.5%), aspartate aminotransferase 
(AST) increased (0.4%), autoimmune hepatitis and pneumonitis (0.3% each) being the most 
frequent.
A total of 509 of 1300 patients (39.2%) had at least 1 serious TEAE. Treatment-related 
serious TEAEs were reported in 71 (5.5%) patients, with the most frequent being 
infusion-related reaction (0.8%), pneumonitis (0.6%), pyrexia and dyspnea (0.4% each), and 
autoimmune hepatitis, asthenia, blood creatinine phosphokinase (CPK) increased, abdominal 
pain, colitis, diarrhea, vomiting, hyponatremia, adrenal insufficiency, and non-cardiac chest 
pain (0.2% each).  


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There were 466 deaths (35.8%) reported in the pooled expansion cohort.  The majority of 
deaths were due to progressive disease (360 patients, 27.7%). There were 33 (2.5%) deaths 
attributed to TEAEs not related to trial treatment, and 5 deaths (0.4%) in which a related 
TEAE was considered the primary reason of the death by the investigator:  pneumonitis 
radiation induced and dyspnea (1 case), acute liver failure associated with autoimmune 
hepatitis (1 case), respiratory distress and sepsis (1 case), autoimmune hepatitis with hepatic 
failure and fatigue (1 case), and pneumonitis (1 case). The cause of death was marked as 
“other” or “unknown” in 13 (1.0%) and 55 (4.2%) of cases, respectively.
A total of 175 patients (13.5%) discontinued avelumab treatment due to TEAEs, including 
79 patients (6.1%) discontinuing because of treatment related TEAEs. The most frequent 
related TEAEs leading to treatment discontinuation were infusion related reaction (IRR, 
1.9%), GGT increased (0.4%), blood CPK increased, AST increased, lipase increased, 
alanine aminotransferase (ALT) increased, colitis, myositis, arthralgia, fatigue, autoimmune 
hepatitis, and dyspnea (0.2% each).
Potential Immune-related Adverse Events (irAEs): a total of 149 patients (11.5%) 
experienced potential irAEs (based on a list of predefined Preferred Terms without further 
clinical evaluation of individual cases) which were considered treatment-related in 
99 patients (7.6%) based on investigator’s causality assessment.  The most frequent 
treatment-related potential irAEs were hypothyroidism (3.5%), pneumonitis (1.0%), 
hyperthyroidism (0.5%), adrenal insufficiency and dry eye (0.4% each), autoimmune 
hepatitis and colitis (0.3% each), and myositis (0.2%). The majority of potential irAEs were 
Grade 1 or Grade 2 in severity, with 20 (1.5%) being related irAEs of Grade ≥3 severity. A 
total of 15 patients (1.2%) had treatment-related potential irAEs leading to treatment 
discontinuation. There were no delayed related irAEs identified with onset after the on-
treatment period.
Infusion-Related Reactions: a total of 215 patients (16.5%) experienced at least 1 episode of 
IRR. Most of the events were of Grade 1 or Grade 2 severity. IRRs of Grade 3 severity 
occurred in 6 patients (0.5%), while 3 patients (0.2%) experienced Grade 4 IRRs. No there 
was no Grade 5 events of IRR reported. Most of the IRRs occurred after the first (11.5%) or 
second (3.7%) infusion. In 23 patients (1.8%), treatment was discontinued because of an 
IRR.
Immunogenicity of Avelumab in Humans: Based on the Phase 1/1b Trial EMR 100070-001, 
the incidence of ADAs was relatively low, with 1 out of 39 patients (2.6%) in the dose 
escalation cohorts and 10 out of 338 patients (2.9%) in a NSCLC expansion cohort.  In 8 of 
these 10 patients, a positive signal was observed at a single time point and a decrease in 
avelumab serum exposure was observed in the 2 patients with multiple positive samples.  
From these 11 positive patients, 2 patients had symptoms on the day of the infusion 
compatible with an immune reaction (chills and fever, nausea and vomiting) and, therefore, 
these AEs could be ADA related.  For the other 9 ADA-positive patients, no such AEs were 
recorded.
Complete information for avelumab may be found in the SRSD, which for this study is the 
avelumab IB.41


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1.2.5. Rationale for Evaluating PF-06747775 as Single Agent or in Combination with 
Palbociclib or Avelumab in Patients with EGFRm NSCLC
Activating mutations in EGFR confer constitutive activity providing the oncogenic drive in 
EGFRm NSCLC.  First and 2nd generation EGFR TKIs are effective drugs in this setting, but 
are constrained by DLTs attributed to inhibition of WT EGFR and by drug resistance caused, 
in the majority of cases, via a T790M secondary mutation in EGFR.  Third generation EGFR 
TKIs, such as osimertinib (AZD9291), with activity against EGFR with activating and 
T790M mutations, but sparing WT EGFR, have been developed and are showing promising 
efficacy and safety profiles in preliminary clinical results.  In late 2015, osimertinib was 
conditionally approved by the  Food and Drug Administration in the US and by the European 
Medicine Agency in the European Union (EU) in February 2016 for use in advanced NSCLC 
in patients with EGFR containing the T790M mutation.  However, the duration of response 
(DOR) to 3rd generation agents is also expected to be limited by tumor heterogeneity and 
intrinsic and acquired resistance, as recently published evidence has begun to corroborate in 
describing patients who become resistant to the 3rd generation agents osimertinib.42,43  A next 
step in the evolution of EGFRm NSCLC treatment strategies is the combination of EGFR 
TKIs with additional agents that can potentially provide better response rates, increased 
magnitude of response, and longer DOR via potentiated inhibition of growth and viability for 
EGFR TKI-sensitive cells, and/or activity against EGFR TKI-insensitive cells that are 
selected or arise to become resistant disease.  Such a strategy may be favored by employing 
an EGFR TKI that provides the maximal inhibitory pressure on the EGFR mutants.  
Additionally, the availability of several different 3rd generation agents provides options as
drug-drug interactions and overlapping toxicities may rule out specific combination partners.
It is hypothesized that combination treatment with palbociclib and PF-06747775 in patients 
with EGFR-mutant NSCLC could further impede tumor growth with increased efficacy over 
treatment with PF-06747775 alone.  This potential increased efficacy may reflect better 
inhibition of cell cycle progression with the combination.  In addition, palbociclib may arrest 
the growth of EGFR TKI-resistant cells present or acquired and attempting to get a foot hold 
for growth in the heterogeneous tumor when the predominant EGFR-sensitive cell population 
is challenged with an EGFR TKI.
Separately, recent evidence has shown that tumors require suppression of the host immune 
system for continued growth and spread.
The development of agents targeting the interaction of PD-1 and its ligands has shown 
promise in the treatment of various cancers including NSCLC.44  Substantial clinical activity 
was observed with anti-PD1 antibodies nivolumab and pembrolizumab, with an objective 
response rate of 15% and 20%, respectively, and long duration of response in unselected 
heavily pretreated NSCLC patients.45,46  Similarly impressive activity was observed in the 
first-line setting, demonstrating objective response rates of 30% and 26% for nivolumab and 
pembrolizumab, respectively.47,48  Anti-PD-L1 antibodies have also been studied in pre-
treated unselected NSCLC, demonstrating response rates of 16% to 23% for MEDI-4736 and 
MPDL3280a, respectively.49,50  Of note, some of these studies reported objective responses in 
EGFR-mutant patients, but estimation of response rate was difficult due to small size of this 
subgroup.49 Activity was observed in both PD-L1-positive and PD-L1-negative patients with 
a trend towards higher response rates in PD-L1-positive patients.44


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Although immune checkpoint inhibitors, including avelumab, are demonstrating promising 
activity in a variety of tumor types, there continues to be a need for new therapies.  Tumor-
directed therapies such as chemotherapy and targeted agents improve tumor antigenicity by 
inducing cell death, providing the basis for potential synergy with immune checkpoint 
inhibitors.51,52
Recent studies in genetically-engineered mouse models demonstrate that EGFR mutations 
promote tumorigenesis not only by stimulating tumor cell proliferation, but also by 
suppressing antitumor immunity, in part by upregulating PD-1 on tumor-infiltrating T cells 
through a non-cell-autonomous mechanism.63,64 Consistent with these observations, in a 
retrospective cohort of human NSCLC tumor samples, the frequency of PD-L1 
overexpression was significantly elevated in EGFRm compared to EGFR WT tumors.
Erlotinib and gefitinib demonstrated higher response rates, time to progression and overall 
survival in PD-L1 positive tumors compared to PD-L1 negative tumors.68 Taken together, 
these findings suggest that the immunosuppressive tumor microenvironment mediated by the 
PD-1/PD-L1 axis plays a potentially important role in the pathogenesis of EGFR mutant 
tumors, providing a rationale to combine PF-06747775 with avelumab in this setting.
Single-agent activity of immune checkpoint inhibitors has been observed in EGFR-mutant 
NSCLC patients.45  A study of the combination of nivolumab and erlotinib in 21 patients 
(20 previously treated with EGFR TKI; 1 TKI-naïve) demonstrated an ORR of 19% and 
24 week PFS rate of 47%. Among the patients with acquired erlotinib resistance, 
3/20 patients achieved a partial response (PR, 15%) with 9/20 patients (45%) with stable 
disease (SD). The patient who was TKI-naïve also achieved a durable PR. Safety profile of 
the combination was reported as manageable. Nineteen percent (19%) of patients 
discontinued treatment due to adverse events. Grade 3/4 treatment-related AEs occurred in 
5/21 patients (24%) and included diarrhea, increased ALT and increased AST.61
These initial promising preclinical and clinical findings provided the rationale for testing the 
combination of an EGFR TKI plus an anti-PD-1/-L1 agent in patients with advanced EGFRm 
NSCLC.  In addition to erlotinib plus nivolumab as mentioned above, several additional 
clinical trials have been planned or initiated including gefitinib plus durvalumab 
(ClinicalTrials.gov identifier NCT02088112), erlotinib plus atezolizumab (NCT02013219), 
afatinib plus pembrolizumab (NCT02364609), and EGF816 plus nivolumab 
(NCT02323126).
In contrast to the initial positive supporting data as summarized above, other results 
addressing the potential for EGFR TKI combinations with anti-PD-1/-L1 agents have been 
less supportive.  Regarding single agent activity of anti-PD-1/-L1 agents in patients with 
advanced NSCLC, some studies have found lower ORR and shorter PFS in patients with 
EGFRm tumors compared to EGFR WT tumors.53,54 Evidence across different tumor types 
suggests a higher overall mutational burden leading to increased potential for neo-
antigenicity shows a correlation with higher response rates to anti-PD-1/-L1 agents,55 and 
that smoker status correlates with higher mutational burden.56  As EGFRm NSCLC is known 
to correlate with non-smoker status, and the overall mutation burden is less in EGFRm versus 
EGFR WT tumors, this has been proposed as a rationale to explain the lower response rates.


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Current evidence suggests even stronger correlates with anti-PD-1/-L1 response are tumor 
expression of PD-L1 and the presence of CD8-positive tumor infiltrating lymphocytes 
(TILs), which together are considered necessary for a response to anti-PD-1/-L1 agents.  
These key biomarkers, while clearly linked to the mechanism of action of PD-1 pathway 
immune checkpoint inhibitors, still lack robust standardized assays to facilitate their use for 
selecting patients and predicting response.  With this limitation noted, results on the presence 
of these biomarkers in EGFRm NSCLC biopsies are also mixed.  As mentioned above, some 
studies showed increased frequency of PD-L1 overexpression in EGFRm versus EGFR WT 
NSCLC tumors.  The opposite has been observed in other studies, for example, no 
enrichment was found for PD-L1 expression in EGFRm NSCLC biopsies.56  In a recent and 
thorough study that examined various parameters of anti-PD-1/L1 in EGFRm NSCLC,53 only 
a subset of EGFRm NSCLC biopsies were found to express PD-L1 or show presence of 
CD8-positive TILs, and only rarely did these tumors contain both.  This was found to be the 
case in biopsies taken prior to EGFR TKI exposure, as well as in biopsies taken at the time of 
acquired resistance.  The authors suggest the lack of these mechanistic biomarkers could 
explain the low response rate to PD-1/-L1 agents they observed in their accompanying meta-
analysis of clinical trials.  However more work is needed to resolve current sources of 
variability in detection of these key biomarkers including the use of different anti-PD-L1 
antibodies and assay methodologies, different scoring cut-offs, attention to type of specimen 
used, and intra-tumoral heterogeneity.  Meanwhile it is important to acknowledge that not all 
studies provide strong supporting evidence for anti-PD-1/L1 agents in EGFRm NSCLC, as 
discussed in a recent mini-review.57
Tagrisso® (osimertinib) is a third generation EGFR TKI with a similar activity profile to 
PF-06747775, along with numerous differences between the compounds.  Tagrisso combined 
with the anti-PD-L1 durvalumab was tested in patients with advanced EGFRm NSCLC in 
the Phase 1b TATTON study and the Phase 3 CAURAL study.  While promising tumor 
responses were seen with the combination, it was too early to tell if the combination response 
was any different from single agent Tagrisso, and both studies revealed an increased 
incidence of interstitial lung disease (ILD).58,59  The TATTON study preliminary results 
indicated a 38% rate of ILD including 5 cases of Grade 3/4 in severity.59  Enrollment was 
suspended and both trials were put on hold in order to further assess the risk associated with 
the combination.  It is not known currently what causes increased risk of ILD but causality 
due to the interaction of Tagrisso and durvalumab cannot be ruled out.
Tagrisso has been approved for single agent use and carries a warning and precaution on the 
label for ILD/pneumonitis, occurring in 3.3% of patients.60  In clinical testing of 
PF-06747775, to date no ILD/pneumonitis AEs have been observed.   
Compared with anti-PD-1 antibodies that target T cells, avelumab is an anti-PD-L1 antibody 
that targets tumor cells.  Avelumab is expected to have fewer side effects, including a lower 
risk of autoimmune related safety issues, as blockade of PD-L1 leaves the PD-L2/PD-1 
pathway intact to promote peripheral self tolerance.  The anti-PD-1 antibodies 
pembrolizumab and nivolumab do carry a low risk of immune-related (ir) pneumonitis, with 
overall incidence of <3%.  Hence the combination of PF-06747775 plus avelumab in patients 
with EGFRm NSCLC has the potential to differentiate from other EGFR TKI / anti-PD-1/-L1 
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The clinical efficacy of avelumab in NSCLC is based on data from the unselected NSCLC 
expansion cohort in the ongoing Phase 1 trial EMR 100070-001 using a data cutoff date of 
15 January 2015, 13 weeks after the start of avelumab treatment of the last patient in this 
expansion cohort (a total of 184 treated patients).  This group of NSCLC patients presented 
with a median age of 65 years with Stage IIIB or IV NSCLC that had progressed after at least 
1 line of platinum-containing doublet chemotherapy for locally advanced or metastatic 
disease.  The Eastern Cooperative Oncology Group (ECOG) performance status (PS) was 
0 in 30% of patients and 1 in 70% of the patients.  The histologies treated were 
adenocarcinoma (62%), squamous cell carcinoma (29%), or other (9%).  These patients 
received avelumab 10 mg/kg Q2W.  Promising activity has been seen among patients with 
NSCLC that has progressed after platinum-based chemotherapy when using avelumab.  The 
median duration of treatment was 12.2 weeks (range 2.0-64.0).  As of the date of data cutoff, 
41 of the 184 patients remained on treatment.  The ORR for the NSCLC expansion cohort 
was 13.6% (95% CI: 9.0 -19.4) including confirmed and unconfirmed responses.  One patient 
(0.5%) had a complete response (CR) while 24 patients had confirmed and unconfirmed PR 
(13.0%).  The disease control rate (DCR), patients with confirmed and unconfirmed CR, PR, 
and SD, was 50.5%.  The median PFS in the NSCLC expansion cohort was 11.6 weeks (95% 
CI: 8.4 – 13.7) with the proportion of patients alive and progression-free at 24 weeks and 
48 weeks equal to 26.2% (95% CI: 19.9 – 33.0) and 18.1% (95% CI: 12.0 – 25.2), 
respectively.  The median overall survival (OS) in the NSCLC expansion cohort was 
8.4 months (95% CI: 7.3 – 10.7) with 37.0% of patients alive at 12 months (95% 
CI: 27.1-46.9) in this heavily pretreated group of patients.  The toxicity profile of avelumab 
was noted to be in line with other immune checkpoint inhibitors of PD-1 and PD-L1 
In summary, based on promising activity of immune checkpoint inhibitors including 
avelumab in NSCLC, and the preclinical rationale for the combination with PF-06747775 in 
EGFR-mutant NSCLC, the proposed Phase 1/2 study will assess the safety and efficacy of 
the PF-06747775-avelumab combination in first-line treatment of EGFRm NSCLC.
1.2.6. Rationale for Selection of the Starting Doses
1.2.6.1. PF-06747775
1.2.6.1.1. Single Agent
Definitive 1-month toxicity studies in rats and dogs identified epithelial atrophy as the 
primary toxicity in multiple organs in both species (Section 1.2.2.2 Nonclinical Safety Data).  
Dog was identified as the more sensitive species based on an increased severity of these 
findings at similar unbound concentrations.  Although a HNSTD was not identified in this 
definitive toxicity study in dogs, based on the lack of adverse body weight change at 
15 mg/kg/day, the monitorable and reversible nature of the findings, as well as the thorough 
clinical characterization of the toxicity profile (ie, inhibition of wild type EGFR), the low 
dose (15 mg/kg/day) was used in lieu of the HNSTD to calculate a human starting dose.  
Using the International Conference on Harmonization (ICH) S9 Guideline (ie, 1/6 the 
HNSTD in non-rodents) and interspecies scaling via direct body surface area, a dose of 
81 mg was calculated to be an appropriate human starting dose. However, single dose 
studies performed in dogs comparing fasted and fed states at 90 mg/kg and 15 mg/kg 
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conditions. In light of these data, a lower (approximately 3-fold) human starting dose of 25 
mg PF-06747775 was selected.  This dose (25 mg) was modeled in the fed state with hepatic 
clearance mechanisms identified as 62% CYP3A4 and 38% GSTM1 and is predicted to yield 
an unbound average concentration (Cav) of 118 nM (49 ng/mL), unbound Cmax of 171 nM 
(71 ng/mL) and unbound AUC24 of 2832 nM•h (1177 ng•h/mL).  This dose is predicted to 
provide reasonably safe but pharmacologically active human exposure with expected safety 
margins of 2.2x and 10x based on mean unbound Cav and Cmax, respectively.  The geometric 
mean plasma fraction unbound (fu) for rat is 0.224, 0.753 for dog, and 0.266 for human.  
Based on PK/PD modeling and assuming biomarker (pEGFR) inhibition IC50 and mutant 
EGFR enzyme turnover rates acquired from nonclinical in vitro and in vivo studies, tumor 
stasis is associated with average inhibition of pEGFR within the dosing interval of 
approximately 70 -80%. The unbound efficacious concentration range (Ceff) for single agent 
PF-06747775, defined as the steady state concentration required to achieve static tumor load, 
was determined by PK/PD modeling. Both estimated human and observed mouse exposures 
of PF-06747775 were used, thus providing a range of Ceff estimates. The Ceff range is 
projected to range from 56 (human exposure) to 139 (mouse exposure) nM. The resulting 
predicted PF-06747775 human dose range for tumor stasis is 9-22 mg per day.  This range is
below the proposed starting dose of PF-06747775.
1.2.6.1.2. PF-06747775 Single Agent Recommended Phase 2 Dose
In the Phase 1 dose escalation portion of this study, there were no DLTs up to the maximum 
dose tested (600 mg daily), but the longer term tolerability of the higher doses were limited 
by persistent EGFR-WT driven toxicities (Grades 1 and 2 skin toxicities and diarrhea).  
Therefore, a recommended Phase 2 Dose (RP2D) of 200 mg once daily was selected which 
provided good tolerability and clinical activity (a high rate of objective responses).
A new tablet formulation with a change to one of the excipients to improve the stability will 
be introduced at RP2D in Phase 1b/2 cohorts (Cohorts 1, 2, and 3).  Subsequently, patients 
from the Phase 1 cohorts who continue on treatment will convert to taking the new tablet 
after the initial tablet supply is exhausted.
In the event that PK of the new tablet were to differ to an extent that would cause clinical 
safety or efficacy concerns, the dose may be adjusted accordingly to account for the 
difference in systemic exposure in subsequent patients or cohorts.
1.2.6.1.3. Combination with Other Anti-Cancer Agents
The starting dose, which is the RP2D for PF-06747775 is 200 mg PO continuous dosing in 
21-day cycles (Cohort 1 and Cohort 2) and 28-day cycles (Cohort 3).
1.2.6.2. Palbociclib
Palbociclib has been studied as a single agent in a Phase 1 dose-finding study (Study 
A5481001) in patients with solid tumors or lymphomas with doses ranging from 25 to 
150 mg QD administered for 3 weeks followed by 1 week off treatment (Schedule 3/1) and 
100 to 225 mg QD administered for 2 weeks followed by 1 week off treatment 


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(Schedule 2/1).  The Schedule 3/1 was used in the subsequent breast cancer studies, and this
is the FDA-approved dosing schedule in breast cancer, but current studies are ongoing 
evaluating a continuous dosing schedule to potentially better inhibit retinoblastoma (RB)
phosphorylation. The current study will evaluate the safety and efficacy of palbociclib given 
on a continual dosing regimen in combination with PF-06747775 in patients with EGFRm 
NSCLC.
Cumulative clinical data suggest that a significant number of patients treated with palbociclib  
on the FDA approved dosing regimen experience dose interruptions and delays due to 
neutropenia without any apparent increase in febrile neutropenia compared to placebo. In 
addition, preclinical studies suggest that palbociclib exerts an antiproliferative effect on 
cancer cells that is released when the drug is discontinued.67  These data suggest that a better 
therapeutic index may be obtained by maintaining continuous exposure using a lower but still 
biologically relevant dose of palbociclib. Simulated trough and absolute neutrophil profiles 
based on actual and modelled data indicate that a 100 mg continuous daily dose will be 
associated with an absolute neutrophil count (ANC) >1000 and greater systemic exposure to 
drug compared with the FDA-approved dosing schedule of 125 mg for 3 out of 4 weeks.  A 
dose of 100 mg continuous daily dosing is currently being evaluated in clinical trials and 
emerging data appears to support its tolerability.
Lower concentrations of palbociclib simulating clinical dose reduction were tested in 
combination with PF-06747775 in combination efficacy experiments in vitro.27  The 
increased efficacy observed from the combination was the same using a fixed concentration 
of PF-06747775 at 600 nM (approximates clinical exposure of 200 mg QD) plus palbociclib 
at either 100 nM, 75 nM, or 50 nM, indicating combination efficacy is maintained at lower 
concentrations of palbociclib, down to approximately one-half of the approved dose.  In vivo 
combination efficacy experiments gave similar results.  A clear and substantial increase in 
tumor growth inhibition in vivo was observed for the combination as compared to 
PF-06747775 alone.  The combination efficacy was equally impressive using a palbociclib 
dose equivalent to the approved dose, and using a palbociclib dose equivalent to one-third of 
the approved dose.27
Neutropenia is the most frequently reported adverse event across all clinical studies of 
palbociclib. In general, neutropenia is reversible, non-cumulative, and managed by dose 
interruptions, cycle delays, and dose reductions.  Population PK/PD analysis has 
demonstrated that higher exposure of palbociclib is associated with lower neutrophil counts.  
Through model-based simulation, the average neutrophil count time profiles at different dose 
levels of palbociclib revealed a dose-response relationship and the shape of neutrophil profile 
was significantly driven by dosing schedule.  The total exposure per cycle with 100 mg QD 
on continual dosing regimen (Dose Level 1 in Cohort 2A) is expected to be lower than that 
with 125 mg QD on Schedule 3/1.  In addition, the predicted average nadir of neutrophil 
count with 100 mg QD on CDD regimen was shown to be higher than that with 125 mg QD 
on Schedule 3/1, suggesting lower risk of developing Grade 3 or 4 neutropenia.   


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1.2.6.3. Avelumab
In this study, a dose of 10 mg/kg avelumab administered as a 1-hour IV infusion every Q2W 
will be administered in combination with PF-06747775.  Avelumab 10 mg/kg IV Q2W is the 
recommended dosing regimen and has been administered to a total of 1300 patients in the 
ongoing dose-expansion phase of Study EMR 100070-001.  See Section 1.2.4.3 for a 
summary of avelumab clinical experience to date.  
1.2.7. Rationale for Drug-Drug and Food-Drug Interaction Sub-Studies
In vitro, PF-06747775 appears to be predominately cleared through oxidative metabolism 
and cysteine conjugation, with primary and secondary gluthathione (GSH) conjugation
occurring in nonclinical species.  Investigations of human cytochrome P450 metabolism
using rCYP enzymes (rCYP1A2, rCYP2B6, rCYP2C8, rCYP2C9, rCYP2C19, rCYP2D6, 
rCYP3A4, and rCYP3A5) and human hepatocytes with a CYP3A4 specific chemical 
inhibitor were conducted with PF-06747775. PF-06747775 was stable in all rCYP 
incubations except those containing rCYP3A4, with minimal metabolism (~1%) observed in 
rCYP3A5.  Due to the low observed clearance in standard human hepatocyte and human 
liver microsome incubations, the CYP3A4 contribution was determined using a human 
hepatocyte relay assay with and without CYP3cide, a CYP3A4 specific inhibitor.  These data 
suggest that CYP3A4 accounts for ~60% of the hepatic metabolism of PF-06747775.  
PF-06747775 had very little reactivity in buffer fortified with GSH and was stable in all 
rGST incubations except those containing GST M1-1 (human hepatic GST).
Initial evaluation of the in vivo metabolism of PF-06747775 was conducted by profiling 
pooled plasma, bile, and urine samples from bile duct cannulated rats after single oral 
administration of PF-06747775. The plasma circulating metabolites observed were 
consistent with cysteine conjugation of PF-06747775, hydroxylation on the imidazole of 
PF-06747775, and secondary glucuronidation or cysteine conjugation of hydroxylated 
PF-06747775.  Metabolites detected in rat bile or urine were consistent with the plasma 
circulating metabolites as well as demethylation of PF-06747775 and the increased formation 
of secondary conjugative metabolites (ie, detection of N-acetyl cysteine versions of 
hydroxylated metabolites).  Hydroxylation on the pyrazole of PF-06747775 was not detected 
in any of the in vivo matrices even though it was determined to be a major metabolite in rat 
hepatocytes (as well as in monkey and human hepatocytes).  However, it is possible that the 
hydroxylated pyrazole metabolite was formed in vivo and subsequently rapidly metabolized 
into some of the secondary conjugative metabolites observed.
Based on the cumulative in vitro DDI data (direct inhibition, metabolism-dependent 
inhibition, and induction), PF-06747775 has the potential to cause PK drug interactions with 
compounds for which CYP1A2, CYP2B6, CYP2C8, and/or CYP3A4/5-mediated 
metabolism constitutes the primary mechanism of clearance. However, in vitro time 
dependent inhibition and induction kinetic parameters indicate a low probability of impact to
the exposure of CYP1A2, CYP2B6, and CYP2C8 substrates in humans based on the project 
total Cmax exposure at, or well above (X5) the projected efficacious dose.  In vitro data also
indicates a low probability of PF-06747775 to cause CYP3A4 time dependent inhibition in 
humans, but based on the induction of CYP3A4 mRNA, PF-06747775 has the potential to 
impact CYP3A4 substrates.


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To further investigate the DDI potential of PF-06747775 human PK prediction, SimCYP
(version 13.1) simulations of DDI were conducted with PF-06747775 as either a perpetrator 
or as a victim.  SimCYPsimulations were performed to assess the net effect of steady state 
PK of PF-06747775 on the human PK of a single dose of midazolam (5 mg). At a projected 
human efficacious dose of 20 mg QD of PF-06747775, the AUC and Cmax of midazolam 
decreased by 27% and 23%, respectively. Due to the potential solubility limited absorption 
of PF-06747775 in the crystalline form and the limitation of SimCYP(version 13.1) to 
model fed state for the inhibitor, increasing the dose of PF-06747775 to 80 mg decreased the 
AUC and Cmax of midazolam by 39% and 33%, respectively.  The change in AUC and Cmax
of midazolam indicate a net effect of induction.
An early evaluation of the potential drug-drug interactions described above will identify the 
effect of concomitant medications in PF-06747775 exposure and the impact of 
PF-06747775 on other drugs, which will help to provide the appropriate directions for 
concomitant medication restrictions with the ultimate goal of an optimal 
PF-06747775 exposure.
Administration of a drug product with food may change the bioavailability (BA) by various 
means, including: delay in gastric emptying, stimulation of bile flow, changes in 
gastrointestinal pH, increase of splanchnic blood flow, changes in luminal metabolism of the 
studied drug, physical or chemical food interactions with the drug product, etc.17  The 
solubility and permeability of PF-06747775 suggests that at high doses it is a class II drug
according to the biopharmaceutics classification system (BCS), and for this type of 
compound, food effects are most likely to occur as a result of a combination of factors that 
influence the in vivo drug dissolution and absorption.  Similarly, antacid medication may 
considerably alter PF-06747775 exposure.  An early evaluation of food and antacid effect on 
PF-06747775 exposure will allow an effective and optimal dose administration to patients.
1.3. Safety Considerations in the Clinical Trial
1.3.1. Benefit-Risk Assessment for PF-06747775 Single Agent
As detailed below and in Section 1.2.2.2, the toxicities observed in the nonclinical safety 
studies are all known EGFR WT mediated effects (with evidence of secondary effects from 
mucosal surface compromise).  Since these are class effects, Investigators are very familiar 
with them and their clinical management.  PF-06747775 is anticipated to have a wider 
margin of safety against EGFR WT activation than prior generation compounds of the EGFR 
TKI class, so it is predicted that it will have less EGFR WT mediated toxicity for patients 
than agents to which they have already been exposed.  Nevertheless, specific management 
guidelines will also be incorporated in the clinical trial and emphasized with Investigators.  
PF-06747775-related gastrointestinal findings were observed in rats and dogs.  Body weight 
loss was significant in the 14-day exploratory toxicity study in rats and the 1-month 
definitive toxicity study in dogs at doses 100 mg/kg/day and 60 mg/kg/day, respectively, 
resulting in unscheduled euthanasia.  Body weight losses were accompanied by transient and 
generalized observations including hunched posture, rough haircoat, anogenital staining, 
decreased skin turgor, and soft feces in rats, and abnormal feces (soft, mucoid, watery, and/or 


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red-tinged), decreased food consumption, decreased activity, and sporadic emesis in dogs.  
At 100 mg/kg/day in rats there was epithelial (esophagus) and/or mucosal (glandular and/or 
nonglandular stomach, duodenum, ileum, cecum and/or colon) atrophy.  Stomach 
erosions/ulcers were seen at the highest dose in both the 14-day and 1-month toxicity studies 
in rats; this finding was partially recovered after 1 month.  At 90 mg/kg/day in dogs there 
were tongue and esophageal findings (erosions/ulcers) that might have interfered with eating, 
and at ≥60 mg/kg/day there was multi-segment, intestinal crypt dilatation coupled with mild 
mucosal atrophy and/or erosions.  In the 14-day study in dogs, minimal atrophy of the 
intestinal mucosa was only seen at the 120 mg/kg/day dose.  Following a 1-month recovery 
phase, all findings fully reversed except non-adverse epithelial atrophy of the cecum at 
30 mg/kg/day in rats which was only partially recovered.  Based on the observations 
above, patients with existing significant gastrointestinal disease will be excluded from this 
study.  Proscriptive guidelines on early intervention for mucositis and diarrhea 
management are part of the investigational plan and will be emphasized with Investigators as 
noted above.  
Skin-related clinical observations and microscopic findings were present in rats and dogs, 
although the presentation and location of findings were slightly different between species.  In 
the 14-day exploratory study in rats, there was microscopic epidermal atrophy at 
100 mg/kg/day.  In the 1-month study in rats, skin hair granulomas, which corresponded to 
the in-life observations of swollen lip or muzzle and skin lesions at 60 mg/kg/day, and 
granulomatous inflammation in the Harderian gland at 30 mg/kg/day were due to foreign
body reactions from epithelial atrophy (ie, atrophic hair follicle epithelium and Harderian 
gland acinar epithelium).  In male dogs at ≥15 mg/kg/day and female dogs at 90 mg/kg/day, 
PF-06747775-related macroscopic skin findings consisted of abnormal color and thickened 
skin, and wound/scar/crust of the fore- and hindpaws, eyelid, ear, and/or scrotum leading to 
unscheduled euthanasia.  Microscopically the principal features were minimal to moderate 
erosions/ulcers with crust formation and/or bacterial colonization, often associated with 
minimal to mild chronic active inflammation in the subjacent dermis and subcutis.  
Following a 1-month recovery phase, all findings reversed except for mononuclear cell 
infiltrates in the Harderian gland and adnexa atrophy of the skin at 60 mg/kg/day in rats.  
Proscriptive guidelines on early intervention for skin toxicity management are part of the 
investigational plan and will be emphasized with investigators as noted above.  
Multiple clinical ocular observations involving the eye were seen in rats and dogs and 
generally correlated with minimal to marked atrophy of the corneal epithelium in rats at 
30 mg/kg/day and in dogs at 15 mg/kg/day in studies up to 1-month in duration.  These 
clinical observations included multifocal corneal opacities, rough corneal surface, and 
partially closed eyelids in rats and dogs, as well as conjunctival hyperemia, corneal edema 
with mucus/discharge, excessive lacrimation, constricted pupil/miosis, sclera congestion, and 
eye lid swelling in dogs, all of which contributed to unscheduled euthanasia at doses 
60 mg/kg/day. At the end of the recovery phase, the previous finding of corneal opacities in 
rats and dogs had resolved; however, corneal neovascularization (a further progression of the 
corneal findings) had developed in one rat at 60 mg/kg/day.  The applicability of these 
nonclinical findings to human clinical trials is limited.  Although EGFR TKIs are known to 
cause ocular findings clinically, the most common adverse ocular effect for patients on 


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EGFR inhibitors is dysfunctional tear syndrome; clinical cases of epithelial defects and/or 
corneal abrasions are rare.18 Nevertheless, Investigators will be reminded to attend to any 
ocular symptoms and management guidelines for ocular events are included in the trial. 
In the kidney at ≥100 mg/kg/day in rats, there was PF-06747775-related tubular basophilia.  
At 500 mg/kg/day there was papillary necrosis and dilatation of tubules.  Tubular basophilia 
and tubular dilatation were both bilateral and were associated with macroscopic observations 
of abnormal kidney color (mottled) in 1/5 rats at 500 mg/kg/day.  The kidney findings were 
associated with increases in BUN and/or creatinine.  There were no kidney findings in dogs 
in studies up to 1-month in duration. BUN and creatinine will be routinely monitored in the 
study at every cycle.
Cardiovascular effects of PF-06747775 were rat-specific minimal increases in blood pressure 
(20 mg/kg).  There were no observed direct effects in ECG parameters in dogs after single or 
repeat-dosing up to 90 mg/kg/day.  ECGs will be closely monitored on the study and QTc 
evaluation performed.
There were no effects on the liver after repeated dosing of PF-06747775 in nonclinical 
toxicity studies in rats and dogs up to 1-month in duration.  Liver function tests (LFTs) will 
be monitored closely with testing at each cycle start.
The SRSD for PF-06747775 is the PF-06747775 IB.
Complete information for esomeprazole, sildenafil, rifampin and itraconazole may be found 
in their corresponding package inserts.
1.3.2. Benefit-Risk Assessment Combinations with Palbociclib (Cohort 2) and 
Avelumab (Cohort 3)
PF-06747775 has proven efficacy in the Phase 1 portion of this trial with sustained (longest
is 12 months and ongoing) objective responses in patients with EGFRm NSCLC who had 
progressed on prior EGFR TKI therapy.  The toxicity profile for single-agent PF-06747775 at 
the RP2D appears tolerable for a prolonged duration of therapy, and no DLTs were observed 
at doses 3x higher. Preclinical studies combining PF-06747775 with palbociclib suggest 
significant improvement in tumor regrowth kinetics relative to PF-06747775 alone that may 
translate to improved PFS in clinical evaluation.  Such an improvement in PFS with a 
manageable toxicity profile would represent an improved benefit-risk balance of 
PF-06747775 and palbociclib for patients with resistant EGFRm NSCLC, over treatment 
with PF-06747775 alone or any other currently available therapy. 
Similarly, the combination of PF-06747775 with an immune checkpoint inhibitor such as 
avelumab has the potential to provide significantly improved clinical efficacy than either 
agent alone with manageable toxicities, and thus represents a reasonable benefit-risk for
clinical evaluation.


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2. STUDY OBJECTIVES AND ENDPOINTS
This study has separate primary and secondary objectives and endpoints for the Phase 1 and 
each of the subsequent sections of the study.
2.1. Objectives
2.1.1. Phase 1
2.1.1.1. Primary Objective

To evaluate safety and tolerability at increasing dose levels of PF-06747775 as a 
single agent in order to estimate the MTD and recommended phase 2 dose RP2D in 
patients with advanced EGFRm NSCLC (del 19 or L858R, with or without T790M)
following 1 prior line of therapy, which must have included an approved EGFR 
TKI.
2.1.1.2. Secondary Objectives

To evaluate the overall safety profile of PF-06747775;

To characterize the effects of single-agent PF-06747775 on QTc intervals;

To characterize single dose and steady state PK profiles of single-agent 
PF-06747775;

To evaluate the effect of PF-06747775 at steady state on the exposure of a single dose 
of sildenafil, a CYP3A4 probe;

To characterize the effect of food on the exposure of PF-06747775 at the RP2D;

To characterize the effect of esomeprazole, a proton pump inhibitor, on the exposure 
of PF-06747775 at the RP2D;

To characterize the effect of itraconazole, a strong CYP3A4 inhibitor on the exposure 
of PF-06747775 at the RP2D;

To characterize the effect of rifampin, a strong CYP3A4 inducer on the exposure of 
PF-06747775 at the RP2D;

To assess in plasma the presence/absence of EGFR mutations;

To evaluate the anti-tumor activity of PF-06747775 in both T790M-positive and 
T790M-negative NSCLC tumors;

To evaluate tumor tissue biomarkers including, but not limited to, EGFR mutation by 
next generation sequencing.


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2.1.2. Phase 1b/2
2.1.2.1. Primary Objectives
2.1.2.1.1. Cohort 1 – PF-06747775 Single-Agent in Patients with Previously Untreated 
EGFRm NSCLC
•
To assess the anti-tumor activity (ORR) of PF-06747775 single agent in patients with 
EGFRm NSCLC (del 19 or L858R, with or without T790M).
2.1.2.1.2. Cohort 2A – PF-06747775 Plus Palbociclib: Dose Finding
•
To evaluate safety and tolerability and determine the RP2D of PF-06747775 plus 
palbociclib in patients with EGFRm NSCLC with a secondary T790M mutation (del 
19 and T790M or L858R and T790M).
2.1.2.1.3. Cohort 2B – PF-06747775 Plus Palbociclib vs PF-06747775 Single Agent 
(Randomized)
•
To assess the PFS of PF-06747775 plus palbociclib versus PF-06747775 single agent 
in patients with EGFRm NSCLC with a secondary T790M mutation (del 19 and 
T790M or L858R and T790M).
2.1.2.1.4. Cohort 3 –PF-06747775 Plus Avelumab: Dose Finding
•
To evaluate safety and tolerability and establish the RP2D of PF-06747775 plus 
avelumab in patients with EGFRm NSCLC with a secondary T790M mutation (del 19 
and T790M or L858 R and T790M).
2.1.2.2. Secondary Objectives
•
To assess duration of response (DOR), and OS probability at 24 months (all Cohorts);
•
To assess PFS (Cohort 1, Cohort 2A, and Cohort 3);
•
To further characterize the AE profile of PF-06747775 when given as a single agent 
(Cohort 1 and Cohort 2B) and in combination with palbociclib (Cohort 2A and 2B) 
and avelumab (Cohort 3);
•
To further characterize PF-06747775 PK when given as a single agent (Cohort 1 and 
Cohort 2B) and in combination with palbociclib (Cohort 2A and 2B) and avelumab 
(Cohort 3);
•
To characterize the PK of palbociclib in combination with PF-06747775 (Cohort 2A 
and 2B);
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•
To characterize the PK of avelumab in combination with PF-06747775 (Cohort 3);
•
To further explore the effects of PF-06747775 on QTc intervals when given as a 
single agent (Cohort 1 and Cohort 2B) and in combination with palbociclib (Cohort
2A and 2B) and avelumab (Cohort 3);
•
To assess in tumor and plasma the presence/absence of EGFR mutations (All 
Cohorts);
•
To assess the immunogenicity of avelumab when given in combination with 
PF-06747775 (Cohort 3).
 
 
 
 
 
 
 
2.1.3. Japanese Patient-Only Lead In Cohort
•
To evaluate the safety and tolerability of PF 06747775 in Japanese patients (RP2D 
tolerability cohort).
•
To characterize single dose and steady state PK profiles of single agent PF-06747775 
in Japanese patients (RP2D tolerability cohort and PK cohort).
CCI


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2.2. Endpoints
2.2.1. Phase 1
2.2.1.1. Primary Endpoint(s)

Cycle 1 DLT.
2.2.1.2. Secondary Endpoints

Overall safety profile of PF-06747775 characterized by type, incidence, severity, 
seriousness, and relationship to study therapy of AE (National Cancer Institute [NCI] 
Common Terminology Criteria for Adverse Events [CTCAE] v4.03);

Laboratory abnormalities;

QT and RR for QTc effects of PF-06747775 when given as a single agent;

Plasma AUCinf, Cmax, t1/2, CL/F, and Vz/F of PF-06747775 as a single agent after 
single dose;

Ctrough, AUCtau, CL/F, observed accumulation ratio (Rac), and steady state 
accumulation ration (Rss) of PF-06747775 as a single agent after multiple doses;

Plasma AUCinf, Cmax, and CL/F of sildenafil alone and in combination with steady 
state plasma concentrations of PF-06747775;

Plasma AUCtau and Cmax of PF-06747775 at the RP2D under fed and overnight fasted 
conditions;

Plasma AUCtau and Cmax of PF-06747775 at the RP2D alone and after esomeprazole 
treatment;

Plasma AUCtau and Cmax of PF-06747775 at the RP2D alone and after itraconazole 
treatment;

Plasma AUCtau and Cmax of PF-06747775 at the RP2D alone and after rifampin 
treatment;

EGFR mutations in tumor and plasma;

Objective tumor response (OR), confirmed and unconfirmed, per Response 
Evaluation Criteria in Solid Tumors (RECIST) v1.1 for those patients with 
measurable disease.


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2.2.2. Phase 1b/2
2.2.2.1. Primary Endpoints
2.2.2.1.1. Cohort 1 - PF-06747775 Single-Agent in Patients with Previously Untreated 
EGFRm NSCLC

Confirmed OR, per RECISTv 1.1.
2.2.2.1.2. Cohort 2A - PF-06747775 Plus Palbociclib: Dose Finding

Cycle 2 DLT.
2.2.2.1.3. Cohort 2B - PF-06747775 Plus Palbociclib vs PF-06747775 Alone 
(Randomized)

PFS.
2.2.2.1.4. Cohort 3 - PF-06747775 Plus Avelumab: Dose Finding

Cycle 1 DLT.
2.2.2.2. Secondary Endpoints

PFS (Cohorts 1, 2A, 3);

ORR (Cohorts 2A, 2B, 3);

DOR (All Cohorts);

OS probability at 24 months (All Cohorts);

Overall safety profile characterized by type, incidence, severity, seriousness, and 
relationship to study therapy of AE (NCI CTCAE v4.03); laboratory abnormalities 
(All Cohorts);

PK parameters of PF-06747775 following single and multiple doses as data permit 
when given as a single agent (Cohort 1 and Cohort 2B single-agent patients);

PK parameters of PF-06747775 following multiple doses as data permit when given 
in combination with palbociclib and avelumab (Cohorts 2 and 3);

PK parameters of palbociclib and avelumab when given in combination with 
PF-06747775, as data permit (Cohorts 2 and 3);

QT and RR for QTc effects of PF-06747775 when given as a single agent (Cohort 1) 
and in combination with palbociclib (Cohort 2A and 2B) and avelumab (Cohort 3);

EGFR mutations in tumor and plasma (All Cohorts);


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•
Avelumab serum ADA (neutralizing antibodies) (Cohort 3).
 
 
 
 
2.2.3. Endpoint for Japanese Patient-Only Lead In Cohort
•
Cycle 1 DLT (RP2D tolerability cohort);
•
Overall safety profile of PF-06747775 characterized by type, incidence, severity, 
seriousness, and relationship to study therapy of AE (National Cancer Institute [NCI] 
Common Terminology Criteria for Adverse Events [CTCAE] v4.03);
•
Laboratory abnormalities;
•
PK parameters of PF-06747775 following single and multiple doses as data permit 
when given as a single agent (RP2D tolerability cohort and PK cohort).
3. STUDY DESIGN
3.1. Study Overview
This is a Phase 1/2 study of PF-06747775 as a single agent and in combination with other 
cancer treatments in patients with advanced EGFRm NSCLC.  The overall clinical study 
consists of a Phase 1 single agent dose-escalation and expansion part to determine the RP2D 
of PF-06747775 single agent in patients with previously-treated EGFRm NSCLC followed 
by sequential evaluations of PF-06747775 at the RP2D in 3 different clinical scenarios as 
detailed below:  
•
Cohort 1: Phase 2 evaluation of PF-06747775 as a single agent in previously 
untreated patients with advanced EGFRm NSCLC;
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
Cohort 2: Phase 1b single arm evaluation of PF-06747775 in combination with 
palbociclib (Cohort 2A) followed by Phase 2 randomized evaluation of PF-06747775 
in combination with palbociclib vs PF-06747775 single agent (Cohort 2B) in 
previously-treated patients with EGFRm NSCLC with a secondary T790M mutation 
(del 19 and T790M or L858R and T790M); and   

Cohort 3: Phase 1b evaluation of PF-06747775 in combination with avelumab for 
previously-treated patients with EGFRm NSCLC with a secondary T790M mutation 
(del 19 and T790M or L858R and T790M).
Cohorts 2A and 3 will determine the RP2D of PF-06747775 in combination with either 
palbociclib or avelumab, respectively, based on safety and tolerability.  Patients will be 
treated at dose level 1 (DL1) of the combination as noted in Table 14 (Cohort 2A) and
Table 17 (Cohort 3). If the initial doses tested are tolerated, that will be the combination 
dose selected.  Determination of the RP2D will be performed using the mTPI design as 
described in Section 3.1.3.1 (Cohort 2A) and Section 3.1.4 (Cohort 3).  
For Cohort 2A, after determination of the RP2D for the PF-06747775 and palbociclib 
combination, a randomized evaluation of the combination vs PF-06747775 single agent 
(2:1 ratio) will be initiated (Cohort 2B).  For Cohort 3, after determination of the RP2D for 
the PF-06747775 and avelumab combination, the dose level will be expanded to enroll an 
overall total of approximately 20 patients to further explore the safety, PK, and antitumor 
activity of the combination.


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Figure 2.
Study B7971001 Study Schema*
* Approximate enrollment totals indicated.
EGFRm = epidermal growth factor receptor mutant; NSCLC = non-small cell lung cancer; PK = 
pharmacokinetic; RP2D = Recommended Phase 2 Dose
This study will include a Japanese patient lead in cohort (LIC) to evaluate the safety, 
tolerability and PK of PF-06747775 in Japanese patients with advanced EGFRm NSCLC.
(See Section 3.1.5, Appendix 8) not pictured above.
The status of the EGFR mutations will be determined in all patients using tumor or plasma 
samples obtained at study entry. Patients providing tumor samples will be enrolled based on 
a local EGFR mutation test that includes the QIAGEN Therascreen EGFR RGQ PCR Kit, 
Roche cobas® EGFR mutation kit, or a Sponsor-approved laboratory developed test that is 
validated in a Clinical Laboratory Improvement Amendments (CLIA) laboratory.  Patients 
providing plasma samples will be enrolled based on a local EGFR mutation test that includes 
the QIAGEN Therascreen EGFR Plasma RGQ kit, Roche cobas® EGFR mutation test v2 


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(US-IVD), Sysmex Inostic’s OncoBEAMTM EGFR test, or a Sponsor-approved laboratory 
developed test that is validated in a CLIA laboratory, which will then be retrospectively 
confirmed by a validated cell free DNA (cfDNA) test as determined by the Sponsor.  All 
patients — ie, in both Phase 1 and Phase 2 parts of the study — will have their tumor EGFR 
mutation status confirmed by the central lab test using FDA approved QIAGEN Therascreen 
EGFR RGQ PCR kit (tumor-based) or a validated cfDNA test as determined by the Sponsor 
(plasma-based).  The tissue samples may also be tested retrospectively using the Thermo 
Fisher Scientific Oncomine Next Generation Sequencing (NGS) cancer panel, which detects 
exon 19 deletions, exon 20 insertions, T790M mutations, and exon 21 (L858R) substitution 
mutations.
Study design details specific to Phase 1 are provided in Section 3.1.1.  Study design details 
specific to Cohorts 1, 2, and 3 are provided in Section 3.1.2, Section 3.1.3, and Section 3.1.4, 
respectively.
All patients (regardless of Phase or Cohort) will be allowed to continue therapy until disease 
progression or intolerable toxicity, withdrawal of consent, termination of the study by the 
Sponsor, or death.  Treatment continuation beyond objective disease progression is 
acceptable if the Investigator deems the patient to have ongoing clinical benefit.  Treatment 
with PF-06747775 alone is also permitted if the combination is intolerable, but no patients 
may continue on trial on palbociclib or avelumab as single agents. Antitumor activity will be 
determined based on Investigator assessment.  Individual patients’ imaging will be 
prospectively collected for potential follow-up assessment by Blinded Independent Central 
Review (BICR).  
For all patients who have a RECIST response, confirmation of the response is required at 
least 4 weeks after initial assessment of response.
3.1.1. Phase 1
The Phase 1 part of this study is an open label, multi-center, multiple dose, non-randomized, 
safety, PK, PD, and dose escalation study of PF-06747775 as a single agent in patients with 
advanced EGFRm NSCLC (del 19 or L858R, +/- T790M).  PF-06747775 will be
administered in successive cohorts as a single agent in 21-day cycles.  The dose-escalation 
portion of Phase 1 includes a single dose lead-in period to assess single dose PK of 
PF-06747775, followed by continuous once daily dosing in a 21-day cycle. The Continual 
Reassessment Method (CRM)19 will be used to guide the dose assignment and estimate the 
MTD based on cumulative data on DLTs in the first cycle.  
The target probability of DLT at the MTD will be 30%. The MTD will be the highest dose 
with 30% of patients experiencing a DLT for a 10 patient cohort. Approximately 
36 patients will be treated during the dose escalation part of the study. An MTD expansion 
of up to 10 additional patients for the determination of the RP2D will be undertaken to better 
define the safety and provide enhanced early efficacy information.  


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Phase 1 will also include a series of PK sub-studies:
1. A sildenafil sub-study (PF-06747775 will be the CYP3A4 inducer/inhibitor and 
sildenafil the CYP3A4 substrate).
2. A food-drug and a CYP3A4 drug-drug interaction PK sub-study (CYP3A4 induction 
interaction with rifampin).
3. An antacid-drug and a CYP3A4 drug-drug interaction PK sub-study 
(CYP3A4 inhibition interaction with itraconazole).
The sildenafil sub-study will be performed in the RP2D expansion cohort.  RP2D may 
coincide with the MTD or could be lower than MTD as other factors might be taken into 
consideration when deciding the RP2D. In any case, the assessment of the potential 
CYP3A4 inhibitory effect of PF-06747775 at a dose that might be greater than the RP2D will 
not impact the estimation of the CYP3A4 inhibitory effect of PF-06747775, on the contrary,
it will show the maximum inhibitory effect that can be achieved at the RP2D.  The dose
selected for further development will undergo a series of sub-studies at the selected
recommended RP2D to fully characterize the impact of food, antacid and 
CYP3A4 inhibitors/inducers (see Section 3.5). 
Approximately 70 patients are expected to be enrolled in the Phase 1 part of the study.  
Approximately 36 patients will be enrolled into the dose escalation of the Phase 1 portion, 
depending on toxicity observed.  At the MTD, up to an additional 10 patients will be enrolled
to confirm the RP2D and participate in the sildenafil sub-study.  Additional patients 
(approximately 24) will be enrolled at the RP2D to complete the drug-drug interaction (DDI), 
food and antacid effects studies.  The sequencing of these studies relative to other portions of 
this protocol may be adjusted.  
3.1.1.1. Starting Dose
The Phase 1 study will evaluate single-agent PF-06747775 PO (tablets) with continuous daily 
dosing in 21 day cycles.  The starting dose for PF-06747775 will be 25 mg PO daily.
3.1.1.2. Dose Escalation Criteria
In Phase 1, dose escalation and de-escalation of PF-06747775 will follow the CRM 
approach.
The goal of the Phase 1 portion of the study is to determine the dose of PF-06747775 that is 
the closest to, but not higher than, a 30% probability of a DLT (ie, a target DLT rate of 0.30).  
Each dose level cohort will initially include at least 3 patients evaluable for toxicity within 
the first cycle. The first three patients (ie, the first cohort) will be treated at 25 mg, and the 
following dose level explored will be 50 mg.
To assign the dose level for each subsequent patient, the probability of DLT is estimated to a 
target rate of 30%.  This estimate is achieved for each level taking into account all the 
collected toxicity data from all treated patients up to that time and the prior expectations of 


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toxicity. Based on the observed toxicity profile, CRM permits dose-level skipping during 
dose escalation. However, in order to prevent overly aggressive dose escalation, for every 
escalation the maximum allowed dose level skipped will be limited to one dose level.  No 
restriction is applied for dose de-escalation.
The probabilities of DLT are estimated based on a Bayesian statistical model with prior 
distribution to learn about the overall dose-toxicity relationship. Patients’ DLT data will be 
reported to the study statistician who will update the dose-toxicity model before the next dose
cohort level is enrolled. Details on the CRM approach are provided in Section 9 and the 
Statistical Analysis Plan.
Patients who discontinue treatment before completing Cycle 1 (ie, the DLT evaluation time 
window) or receive less than 15 of the planned 21 PF-06747775 doses for reasons other than 
treatment-related toxicity (eg, missed appointments, misplaced investigational product
supplies, development of coexisting medical condition rendering the patient unable to 
swallow medication, development of rapidly progressing disease) will be replaced for DLT 
evaluation but will remain in the overall safety and efficacy analyses.
Dose escalation stops if:

Maximum sample size of 36 patients has been reached; or 

10 evaluable patients have been treated at the estimated MTD; or 

All doses appear to be overly toxic and the MTD cannot be determined in the current 
trial setting.
To avoid overly rapid escalation and to retain the efficiency of dose administration when 
enrollment is fast, the following restrictions will be applied: 

For each dose level, patients will be enrolled in cohorts of minimum 3 patients 
(unless 2 DLTs are observed in the first 2 patients tested at that dose level).  The first 
two patients may enroll together, but the next patient(s) will enroll at least 1 week 
later.  The timing of patient enrollment may be further evaluated as safety and PK 
data become available.

Enrollment for the next cohort of patients will open when patients on the current dose 
cohort have completed the pre-specified DLT observation period or experienced a 
DLT.

Enrollment in dose level cohorts lower than the highest tested dose level cohort may 
occur before the completion of the pre-specified DLT observation period.
Dose level skipping in escalation to untested doses will be limited to only one level 
(k k+2).  In particular, at least three patients should have been treated for at least one cycle 
at dose level k before escalation to dose level k+2.


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Dose escalation recommendation by the CRM algorithm may be overruled (but frequency 
should be minimized) by the sponsor if the nature of the existing data causes safety concern. 
Further exploration of doses lower than those recommended by the CRM model may be 
evaluated based on the totality of the safety data. 
In case the DLT rate at the initial dose level of 25 mg QD exceeds 30%, the dose level of 
20 mg QD will be tested.
3.1.1.3. Dose Levels to be Tested
The possible dose levels for evaluation of PF-06747775 during Phase 1 are shown in
Table 13. 
Dose escalation will continue as outlined in Table 13 until an MTD is defined, or the 
maximum dose to be tested is reached.  If DL-2 is not tolerated based on the criteria defined 
in Section 3.2, then the study will not continue. 
See Section 5.4.3 for more details regarding administration of investigational products.
In addition to the dose levels listed in Table 13, intermediate dose levels may be tested 
dependent upon tolerability, AE profile and other emerging data over the course of the study
after discussion between the Investigators and the sponsor.
Table 13.
Dose Levels for PF-06747775
Dose Level
PF-06747775 (mg/day)
-2
10
-1
20
1 (Starting Dose)
25
2
50
3
100
4
150
5
200
6
275
7
350
8
450
9
600
The proposed doses, schedule(s), and PK time points may be reconsidered and amended 
during the study based on the emerging safety and PK data. 
Intra-patient dose escalation may be permitted if the following conditions are satisfied: 

Cycle 1 was completed without any DLTs.

The first 3 evaluable patients at the next higher dose level have completed 
Cycle 1 with PF-06747775 without experiencing a DLT.


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
The decision to increase the dose has been approved by discussion with both the 
Investigator and the Sponsor.  A patient whose dose has been escalated will not 
contribute to the assessment of the number of DLTs at the escalated dose level.

Intermediate dose levels will be permitted if agreed to between the Investigators and 
the Sponsor (ie, dose levels that are below the doses tested in the cohorts used for 
DLT assessments, but at a dose that was not itself tested, eg, 275/d was tested, but an 
individual patient on intra-patient dose escalation only increases to 200 mg/d).
3.1.2. Cohort 1: Phase 2 Evaluation of PF-06747775 Single Agent in Previously 
Untreated Advanced EGFRm NSCLC
Upon determination of the RP2D of single-agent PF-06747775, Cohort 1 will be initiated.  
Cohort 1 of the study is an open-label, multi-center, single-arm Phase 2 evaluation of 
PF-06747775 single agent at RP2D in previously untreated patients with advanced EGFRm 
(del 19 or L858R, with or without T790M) NSCLC. 
3.1.3. Cohort 2: Phase 1b/2 Evaluation of PF-06747775 Plus Palbociclib 
Cohort 2 will be initiated upon completion of the antacid effect and itraconozole DDI PK 
sub-study.  Cohort 2 of the study consists of a Phase 1b single-arm evaluation of the safety, 
PK, and PD of the RP2D of PF-06747775 in combination with palbociclib (Cohort 2A) 
followed by a Phase 2 randomized evaluation of antitumor activity and safety of the 
combination vs PF-06747775 single agent (Cohort 2B) in patients with previously-treated 
advanced EGFRm NSCLC (del 19 and T790M or L858R and T790M).  
3.1.3.1. Cohort 2A
Cohort 2A will evaluate PF-06747775 200 mg PO daily in combination with palbociclib 
continuous daily dosing in 21 day cycles to determine the RP2D. The starting dose (DL1) 
for palbociclib will be 100 mg PO daily. 
Dose finding will follow the mTPI method with adjustments using DLT rate, using the 
dosing regimen of PF-06747775 and palbociclib as shown in Table 14.  
Table 14.
PF-06747775 and Palbociclib Dose Levels
Dose Level
PF-06747775 (mg/day)
Palbociclib (mg/day)
DL-2
200
50
DL-1
200
75
DL1 (Starting Dose Level)
200
100
These are some of the possible dose finding scenarios based on the tolerability of the starting 
dose, DL1. DL-1 will be explored only if the design recommends de-escalation from DL1. 
DL-2 will be explored only if the design recommends de-escalation at DL-1. The proposed 
doses, schedule(s) and PK time points for Cohort 2 may be altered during the study based on 
the emerging safety and PK data from this study or other emerging data. 


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There are several potential dose-finding sequences for PF-06747775 and palbociclib. The 
specific sequence to be followed depends upon the number of patients enrolled in the study 
and the number of DLTs observed at each specific DL combination. Some possible 
sequences are listed below in Table 15.
Table 15.
Some Possible Dose Finding Sequences
Possible sequences starting at Dose Level 1 (DL1)
DL1 
DL1 DL-1
DL1DL-1DL-2
Dosing will begin at DL1 and may possibly be de-escalated to DL-1 according to Table 16. 
The patients who are enrolled in DL1 will be monitored for 2 cycles for DLTs. If permitted 
by mTPI, this dose level will be expanded in cohorts of 3 patients to a total of 6 patients. If 
at any point mTPI requires a de-escalation, the next patients will be enrolled at a lower dose 
level according to Table 16. In this case, DL-1 may start. Dose re-escalation will be allowed 
as long as the current dose level has not been determined to have exceeded the target 
probability of toxicity.
The re-escalation/de-escalation rules will follow the mTPI method (Section 9.2.1.1). Briefly, 
the mTPI method relies upon a statistical probability algorithm, calculated using all patients 
treated in prior and current cohorts at the same DL to determine whether future cohorts 
should involve dose re-escalation, no change in dose, or dose de-escalation. The detailed 
dose-finding rules based on the mTPI are illustrated in Table 16.
Table 16.
Dose Escalation/De-Escalation Decision Algorithm
DLTs at 
current dose 
level
Number of patients per dose level (cumulative)
1
2
3
4
5
6
7
8
9
10
0
E
E
E
E
E
E
E
E
E
E
1
D
S
S
S
S
E
E
E
E
E
2
DU
D
S
S
S
S
S
E
E
3
DU
DU
D
D
S
S
S
E
4
DU
DU
DU
DU
DU
DU
DU
E= escalate or if current dose level is DL1 stay on DL1; S= stay at current dose; D= de-escalate; DU = de-
escalate and dose is unacceptable due to toxicity
As an example, if the total number of patients treated at DL1 is 3, then the following dosing 
rules are to be applied:

0 - 1 DLT remain at the same DL (DL1);

2 DLTs de-escalate to DL-1 and allow for possible re-escalation back to DL1;

3 DLTs de-escalate to DL-1 as DL1 is intolerable.


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Rules for dose finding using the mTPI method include the following:

The target enrollment cohort size is 3-4 patients.

The next cohort will be enrolled, if necessary, when all patients evaluable for DLT at 
the current dose cohort have been evaluated for the 2 cycles, or when more than 
1 patient in a cohort experiences a DLT, whichever comes first. The next cohort will 
receive the DL as assigned if a dose modification is required.

If a patient does not receive at least 70% of the first 2 cycles of PF-06747775 or 
palbociclib within the DLT observation period (42 days) for reasons other than 
investigational product-related toxicity, another patient will be enrolled to replace that 
patient at the current dose level.

Phase 1b is completed when at least 6 DLT-evaluable patients (see Section 9.1) have 
been  treated at a dose level confirmed to be safe.
3.1.3.2. Cohort 2B
Phase 2 Cohort 2B will be initiated once the RP2D of the PF-06747775 and palbociclib 
combination is determined. Approximately 39 patients with previously-treated advanced 
EGFRm NSCLC (del 19 and T790M or L858R and T790M) will be randomized in a 2:1 ratio 
to receive either the PF-06747775 plus palbocicib combination or PF-06747775 single agent.  
Patients will be treated continuously on a 21 day cycle with both agents and evaluated per the 
Schedule of Activities (SOA).  
Approximately 49 patients will be enrolled to test in Cohort 2 (up to 10 patients in Cohort 2A 
and 39 patients [26 PF-06747775 plus palbociclib and 13 PF-06747775 single agent] in 
Cohort 2B).  
3.1.4. Cohort 3: Phase 1b Evaluation of PF-06747775 Plus Avelumab
Cohort 3 will be initiated upon completion of enrollment to Cohort 2.  Cohort 3 of the study 
consists of a Phase 1b single-arm evaluation of the safety, PK and PD to determine the RP2D 
of PF-06747775 in combination with avelumab 10 mg/kg Q2W in patients with previously-
treated with advanced EGFRm NSCLC (del 19 and T790M or L858R and T790M).  
The starting dose levels (DL1) for the Cohort 3 combination are PF-06747775 200 mg PO 
daily and avelumab 10 mg/kg IV Q2W in 4 week cycles.
Dose finding will follow the mTPI design (see Section 9.2.1.2), using the dosing regimen of 
PF-06747775 and avelumab as shown in Table 17.
Table 17.
PF-06747775 and Avelumab Dose Levels
Dose Level
PF-06747775
(mg/day)
Avelumab
(mg/kg) Q2W
DL-1
150
10
DL1 (Starting Dose Level)
200 
10


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Dosing will begin at DL1 and may possibly be de-escalated to DL-1 according to Table 16.  
DL-1 will be explored only if the design recommends de-escalation at DL1. The proposed 
doses, schedule(s) and PK time points for Cohort 3 may be reconsidered and altered during 
the study based on the emerging safety and pharmacokinetic data from this study and other 
emerging data. 
Dose finding sequences and dose finding decision rules based on mTPI will be similar as 
stated in Section 3.1.3 with a few exceptions:

The patients who are enrolled in DL1 will be monitored for 1 cycle (28 days) for 
DLTs;

If a patient does not receive at least 70% of the first 4 weeks doses of PF-6747775 or
does not receive at least 2 infusions of avelumab within the DLT observation period
(1 cycle = 28 days) for reasons other than investigational product-related toxicity,
another patient will be enrolled to replace that patient at the current dose level.
Once RP2D of PF-06747775 in combination with avelumab is determined, the Dose 
Expansion Phase will continue to enroll patients until approximately 20 patients in total have 
been treated to further assess the safety, PK, PD, and antitumor activity of the combination.
3.1.5. Japanese Patient-Only Lead In Cohort
This study will include a Japanese patient lead in cohort (LIC) to evaluate the safety, 
tolerability and PK of PF-06747775 in Japanese patients with advanced EGFRm NSCLC at 
RP2D (PF-06747775 200 mg) when given as a single agent. This Japanese LIC will consists 
of 2 cohorts; RP2D tolerability cohort and PK cohort. The RP2D tolerability cohort will be 
enrolled first. Up to 3 patients will be enrolled and treated at RP2D. If no DLT is observed, 
no additional patients will be enrolled in this cohort. If a DLT is observed in 1 of the initial 3 
treated patients, then 3 additional patients will be enrolled and treated. Following 1 cycle 
(21 days) of treatment, a safety review will be performed by Japanese investigators and the 
Sponsor to determine whether the emerging data from this cohort would support inclusion of 
patients at Japanese sites in Phase 2 (Cohort 1) and Phase 1b/2 (Cohort 2A, 2B and 3). After 
tolerability in Japanese patients has been confirmed in the RP2D tolerability cohort, an 
additional PK cohort will be initiated. In the second PK cohort, 3 patients will be enrolled 
and they will receive 100 mg single dose followed by once daily continuous dosing at the 
RP2D. In both cohorts, blood samples will be collected for PK assessment (See Appendix 8).
3.2. DLT Definitions
Severity of adverse events will be graded according to CTCAE version 4.03.  For the purpose 
of dose escalation, any of the following adverse events occurring in the first cycle of
treatment (21 days) which are attributable to PF-06747775 will be classified as DLTs. 


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3.2.1. Phase 1 PF-06747775 Single Agent

Hematologic: 

Grade 4 neutropenia lasting >7 days;

Febrile neutropenia (defined as neutropenia Grade ≥3 [absolute neutrophil count, 
ANC, <1000 cells/mm3] and a body temperature ≥38.5°C) requiring antibiotic or 
antifungal treatment;

Grade 3 thrombocytopenia with bleeding;

Grade 4 thrombocytopenia.

Non-hematologic:

Grade 3 toxicities, except the 3 cases specified below:
1. those that have not been maximally treated (eg, nausea, vomiting);
2. rash (including all subtypes), mucositis, diarrhea;
3. Laboratory abnormalities not requiring dose modifications as indicated in 
Table 18.

Grade 4 rash, mucositis, or diarrhea; all of which must be maximally treated (see AE 
Management guidelines, Appendix 3) and persist at Grade 4 to be a DLT.

Failure to receive at least 15 of the planned 21 doses (70%) of PF-06747775 due to 
toxicities attributable to PF-06747775 that were all maximally treated.
In an asymptomatic patient, Grade 3 QTcF prolongation (QTc >500 msec) will first require 
repeat testing, re-evaluation by a qualified person, and correction of reversible causes such as 
electrolyte abnormalities or hypoxia for confirmation.  If, after correction of any reversible 
causes, the Grade 3 QTcF prolongation persists, then the event should be considered a DLT. 
3.2.2. Phase 1b Cohort 2
In addition to the definitions described for the evaluation of PF-06747775 single agent above
(Section 3.2.1), the following AEs occurring during the 42-day DLT period (ie, Cycles 1 and 
2) that are attributable to one, the other, or both compounds in the combination of 
PF-06747775 plus palbociclib will be classified as DLTs:

Any treatment-related, maximally treated AE that causes a palbociclib treatment 
delay of greater than 10 consecutive days;


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
Any treatment-related AE, except for neutropenia, that is maximally treated but still
causes omission of at least 12 of the 42 doses within the 2 cycles used for DLT 
determination of the combination (ie, either drug to be held).
3.2.3. Phase 1b Cohort 3
In addition to the definitions described for the evaluation of PF-06747775 single agent above 
(Section 3.2.1), the following AEs occurring during the first 28 day cycle that are attributable 
to one, the other or both compounds in the combination of PF-06747775 plus avelumab will 
be classified as DLTs:

Hematologic: 

Grade 4 thrombocytopenia >7 days.

Grade 4 anemia.

Non-hematologic:

Grade 3 toxicities, except the 5 cases specified below:
Transient (≤6 hours) Grade 3 flu like symptoms or fever, which is controlled 
with medical management;
Transient (≤24 hours) Grade 3 fatigue, local reactions, or headache that 
resolves to Grade ≤1;
Any Grade ≥3 amylase or lipase abnormality that is not associated with 
symptoms or clinical manifestations of pancreatitis;
Tumor flare phenomenon defined as local pain, irritation, or rash localized at 
sites of known or suspected tumor;
Single laboratory values out of normal range that are unlikely related to trial 
treatment according to the Investigator, do not have any clinical correlate, and 
resolve to Grade ≤1 within 7 days with adequate medical management.
3.3. Phase 1 MTD Definition
The MTD is defined as the highest dose with a DLT rate 30% from the CRM model 
estimate (see Section 9.2).
A patient is evaluable for the MTD determination according to the definition in the Protocol 
(MTD Evaluable) Analysis Set defined in Section 9.3.


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3.4. Recommended Phase 2 Dose (RP2D) Definition
The RP2D is the dose chosen for further study based on Phase 1/1b study results.  If the 
MTD proves to be clinically feasible for long term administration in a reasonable number of 
patients, such dose usually becomes the RP2D.  Further experience with the MTD may result 
in a RP2D dose lower than the MTD.
3.5. Phase 1 Drug Interaction Sub-Studies
Several drug interactions sub-studies will be conducted at the PF-06747775 RP2D once it is 
identified.  A food effect sub-study (drug-food interaction), and several drug-drug interaction 
sub-studies will be performed in approximately 24 patients. The potential effect on the PK of 
PF-06747775 by a high-fat, high-calorie meal, a proton pump inhibitor, a CYP3A4 inhibitor, 
and a CYP3A4 inducer will be investigated. In these sub-studies, PF-06747775 will be 
considered the CYP3A4 substrate and the proton pump inhibitor, CYP3A4 inhibitor, and 
CYP3A4 inducer will be the interacting drugs.
In addition to these sub-studies at the PF-06747775 RP2D, an additional drug-drug 
interaction sub-study will be performed in the MTD expansion cohort where 
PF-06747775 will be the CYP3A4 inhibitor and sildenafil, a CYP3A4 probe, will be the 
CYP3A4 substrate.
3.5.1. Sildenafil Sub-Study
A drug-drug interaction sub-study with sildenafil, a CYP3A4 probe, as a CYP3A4 substrate
and PF-06747775 as a CYP3A4 inhibitor will be conducted in the MTD expansion cohort of 
Phase 1 part of the study.  The main purpose of this sub-study is to appropriately estimate the 
potential CYP3A4 inhibitory ability of PF-06747775. 
A single 25 mg dose of sildenafil will be given in the morning at approximately the same 
time on Day -8 of the lead-in period and on Day 11 of Cycle 1, following an overnight fast of 
at least 10 hours. On Day 11 of Cycle 1, PF-06747775 will be given together with sildenafil
following an overnight fast of at least 10 hours. Food and liquids other than water are
allowed 2 hours after dose.  PF-06747775 dose will be given in the morning at approximately 
the same time once daily in 21 day cycles, with a breakfast of 200-300 calories.  Only on 
Day 11 of Cycle 1 will PF-06747775 be administered following an overnight fast of at least
10 hours (overnight fasting is not required on other study days). Pharmacokinetic sampling 
times are described in the Schedule of Activities (Table 3). 
3.5.2. Food Effect and Rifampin DDI Sub-Study
This PK sub-study will be a randomized, multiple dose, 2 sequence, three period crossover 
study.  Approximately twelve (12) patients will each receive a daily dose of PF-06747775 at 
the RP2D and serial PK collections will be performed under 3 different conditions or 
treatments (A-fasted, B-fed and C-with rifampin), with treatments in Period 1 and 
Period 2 assigned in random order and Period 3 as a fixed sequence.  A minimum of 
12 patients (PK evaluable) are required for this study.  Patients who withdraw may be
replaced at the discretion of the sponsor.


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For patients who participate in this sub-study, the effect of a high-fat, high-calorie breakfast 
and co-administration with a strong CYP3A4 inducer (rifampin) on PF-06747775
pharmacokinetics will be studied.  Each patient will serve as his/her own control in which the 
PF-06747775 at the RP2D will be given in the morning at approximately the same time once 
a day in 21 day cycles.
Sequence Group
PF-06747775
(C1 D1-7)
Period 
1
(C1 D8)
Period 2
(C1 D9)
Rifampin+PF-06747775
(C1 D10-20)
Period 3
(C1 D21)
Sequence 1 (N=6)
A
B
C
Sequence 2 (N=6)
B
A
C
Serial blood sampling to determine plasma concentrations of PF-06747775 will be performed 
pre-dose and up to 24 hours post dose in each period (see Table 4 of the SOA).
Sequence 1: 6 patients will be tested under fasted (Day 8 of Cycle 1) followed by fed 
(Day 9 of Cycle 1) conditions. A fixed sequence with rifampin treatment will happen after 
the fasted/fed portion has been completed.
Sequence 2: 6 patients will be tested under fed (Day 8 of Cycle 1) followed by fasted
(Day 9 of Cycle 1) conditions.  A fixed sequence with rifampin treatment will happen after 
the fed/fasted portion has been completed.

Fasted Treatment: Following an overnight fast of at least 10 hours, patients should 
be administered PF-06747775 at the RP2D with 240 mL (8 ounces) of water.  No 
food or liquids other than water are allowed for at least 4 hours post dose.  Water is 
allowed as desired except for one hour before and after drug administration. 

Fed Treatment: Following an overnight fast of at least 10 hours, patients should start 
the recommended high-fat (approximately 50% of total caloric content of the meal), 
high-calorie (approximately 800-1000 calories with 150, 250, and 500-600 calories 
from protein, carbohydrate and fat, respectively) breakfast 30 minutes prior to 
administration of PF-06747775.  Breakfast will be consumed over a 25 minute period 
with PF-06747775 at the RP2D administered 5 minutes after completion of the meal.  
PF-06747775 should be administered with 240 mL (8 ounces) of water.  No food or 
liquids other than water are allowed for at least 4 hours post dose.  Water is allowed 
as desired except for one hour before and after drug administration.  

An example test meal would be two eggs fried in butter, two strips of bacon 
(may be replaced with ham and cheese of similar caloric content), two slices 
of toast with butter, four ounces of hash brown potatoes and eight ounces of 
whole-fat milk.  Substitutions to this test meal can be made after discussion 
with the sponsor, as long as the meal provides a similar amount of calories 
from protein, carbohydrate, and fat and has comparable meal volume and 
viscosity (if substitutions are made, the contents of the meal will be 
documented by a dietitian or designate to confirm it matches the Food and 
Drug Administration (FDA) requirements for protein, carbohydrate and fat 


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described above).  However, it is understood that some patients may not be 
able to consume the entire meal.  Study staff should record the percent of the 
test meal breakfast and the time it takes to be consumed.

Rifampin + PF-06747775 Treatment: On Days 10 to 20 of Cycle 1, besides the 
daily dose of PF-06747775 at the RP2D, 600 mg of rifampin will be given to patients 
at approximately the same time once daily in the morning 2 hours prior to breakfast.  
The pharmaceutical forms should be swallowed whole.  The pharmaceutical forms 
should not be chewed, crushed, or split.  On the morning of Day 21 of Cycle 1, 
following an overnight fast of at least 10 hours, patients should be dosed with 600 mg 
dose of rifampin + PF-06747775 at the RP2D. PF-06747775 should be taken by the 
patient with 240 mL (8 ounces) of water.  No food or liquids other than water are
allowed for at least 4 hours post dose.  Water is allowed as desired except for 1 hour 
before and after drug administration.
The Days for treatment A, B and C may be modified based on the PK profile observed during 
the lead-in period in the earlier portions of the study.
This PK sub-study may be completed after 1 or both of the combination studies (Cohorts 2 
and 3) are completed.
3.5.3. Antacid Effect and Itraconazole DDI Sub-Study
This PK sub-study will be a randomized, multiple dose, 1 sequence, 3 period study.  
Approximately twelve (12) patients will each receive a daily dose of PF-06747775 and serial 
PK collections will be performed under 3 different conditions or treatments (A - fasted, B -
with esomeprazole, and C - with itraconazole), with treatments assigned in a fixed sequence.  
A washout period of 3 days prior to dosing itraconazole is required to restore the pH of the 
stomach (C1 D14 - 16).  During this washout period, PF-06747775 will be given daily in the 
morning, with a breakfast of 200-300 calories.  Food and liquids other than water are allowed 
2 hours after dose. A minimum of 12 patients (PK evaluable) are required for this study.  
Patients who withdraw may be replaced at the discretion of the sponsor.
For patients who participate in this sub-study, the effect of co-administration of an antacid 
(the proton pump inhibitor esomeprazole) or a strong CYP3A4 inhibitor (itraconazole) on 
PF-06747775 pharmacokinetics will be studied.  Each patient will serve as his/her own 
control in which the PF-06747775 at the RP2D will be given in the morning at approximately 
the same time once a day in 21 day cycles.


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Sequence 
Group
PF-06747775
(C1 D1-7)
Period 1
(C1 D8)
PF-06747775 +
Esomeprazole
(C1 D9-12)
Period 2
(C1 D13)
C1 D14-16
PF-06747775
+ itraconazole
(C1 D17-20)
Period 3
(C1 D21)
Sequence 1
(N=12)
A
B
Washout for 
esomeprazole 
effect. PF-
06747775 will be 
given once a day 
with breakfast.
C
Serial blood sampling to determine plasma concentrations of PF-06747775 will be performed 
pre-dose and up to 24 hours post dose in each period (see Table 5 of the SOA).

PF-06747775 Alone: Patients should receive PF-06747775 at the RP2D with 240 mL 
(8 ounces) of water and a breakfast of 200-300 calories.  No food or liquids other than 
water are allowed for at least 2 hours post dose. 

PF-06747775 + Esomeprazole: On Days 9 to 12 of Cycle 1, besides the daily dose of 
PF-06747775 at the RP2D, 40 mg of esomeprazole once a day will be given to 
patients 2 hours prior to breakfast and PF-06747775 dose.  Pharmaceutical forms 
should be swallowed whole.  The pharmaceutical forms should not be chewed, 
crushed, or split.  In the morning of Day 13 of Cycle 1, patients should take a 40 mg 
dose of esomeprazole and 2 hours post esomeprazole dose, patients should be dosed 
with PF-06747775 and 240 mL (8 ounces) of water and a breakfast of 
200-300 calories.  No food or liquids other than water are allowed for at least 2 hours 
post dose of PF-06747775. 

PF-06747775 + Itraconazole Treatment: On Days 17 to 20 of Cycle 1, 
PF-06747775 at the RP2D should be dosed together with 200 mg of itraconazole at 
approximately the same time once daily with a breakfast of 200-300 calories.  
Pharmaceutical forms should be swallowed whole.  The pharmaceutical forms should 
not be chewed, crushed, or split.  In the morning of Day 21 of Cycle 1, patients 
should be administered itraconazole.  Three hours after itraconazole administration,  
patients should receive PF-06747775 at the RP2D with 240 mL (8 ounces) of water
and a breakfast of 200-300 calories.  No food or liquids other than water are allowed 
for at least 2 hours post dose of PF-06747775.  
The days for treatment A, B, and C may be modified based on the PK profile observed 
during the lead-in period in the earlier portions of the study.  The dose of PF-06747775 used 
in the itraconazole portion of this sub-study may also be modified in order to avoid increased 
PF-06747775 exposure in patients at RP2D due to potent CYP3A4 inhibition by itraconazole 
and/or if the results of the 4-β-hydroxycholesterol and cholesterol analysis suggest significant 
CYP3A4 inhibition by PF-06747775. After the sub-study is complete, all patients will 
continue on PF-06747775 treatment at the RP2D.


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4. PATIENT SELECTION
This study can fulfill its objectives only if appropriate patients are enrolled.  The following 
eligibility criteria are designed to select patients for whom protocol treatment is considered 
appropriate.  All relevant medical and non-medical conditions should be taken into 
consideration when deciding whether this protocol is suitable for a particular patient.
4.1. Inclusion Criteria
Patient eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before patients are included in the study.
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. Evidence of a personally signed and dated informed consent document indicating that 
the patient has been informed of all pertinent aspects of the study.
2. Evidence of histologically or cytologically confirmed diagnosis of locally advanced 
or metastatic EGFRm (del 19 or L858R) NSCLC:
a.
As detected by local EGFR mutation test that includes QIAGEN therascreen 
EGFR RGQ PCR kit, Roche cobas® EGFR Mutation Test or a sponsor-approved 
laboratory developed test that is validated in a CLIA laboratory (with tissue 
submitted for central laboratory confirmation via FDA approved QIAGEN 
therascreen RGQ PCR kit).
b. T790M disease as follows: 
Phase 1
If a repeat biopsy was performed on the tumor following prior EGFR TKI 
therapy, then T790M positive disease must be present.  Patients of unknown 
T790M status following EGFR TKI progression (ie, no post-EGFR TKI 
progression biopsy was performed) are eligible.
In the PK sub-studies involving food/antacid and CYP3A4 effects, patients with 
EGFRm (del 19 or L858R) with any T790M status are eligible to enroll.
Studies at RP2D
Cohort 1: Patients may have de novo T790M mutation, but it is not required.
Cohort 2 and Cohort 3: Patients must have EGRFm (del 19 AND T790M or 
L858R AND T790M) NSCLC tumors as detected by local EGFR mutation test 
that includes QIAGEN Therascreen EGFR RGQ PCR kit, Roche cobas® EGFR 
Mutation Test or a sponsor-approved laboratory developed test that is validated in 
a CLIA laboratory, which will then be retrospectively confirmed by the central 


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validated Thermo Fisher Scientific Oncomine Next Generation Sequencing 
(NGS) cancer panel test. Patients will also be enrolled if they solely test positive 
for EGFR mutations (del 19 AND T790M or L858R AND T790M) in plasma 
alone (no tissue diagnosis of T790M is required) detected by local EGFR 
mutation test that includes QIAGEN Therascreen EGFR Plasma RGQ kit, Roche 
cobas® EGFR mutation test v2 (US-IVD) or Sysmex Inostic’s OncoBEAMTM
EGFR test or a sponsor-approved laboratory developed test that is validated in a 
CLIA laboratory, which will then be retrospectively confirmed by a validated 
cfDNA test as determined by the Sponsor.
c.
Prior treatment for EGFRm NSCLC as follows:
Phase 1
Has progressed after at least 1 prior line of therapy including and EGFR TKI.  
Patients may have also received other lines of therapy before or after the EGFR 
TKI.
Studies at RP2D
Cohort 1: no prior treatment for locally advanced or metastatic EGFRm NSCLC.
Cohorts 2 and 3: must have had disease progression on treatment with an 
approved 1st or 2nd generation EGFR TKI.  Patients who have been treated with a 
3rd generation EGFR TKI are ineligible for this study.  Patients may have had 
multiple lines of therapy; however, the last therapy prior to study treatment must 
have been an approved EGFR TKI and received within 6 weeks prior to study 
registration.
3. Patients must have at least one measurable lesion as defined by RECIST version 1.1
that has not been previously irradiated.
4. Tumor tissue available. Requesting formalin fixed paraffin embedded (FFPE) block 
or 15 unstained sections (5 micron). If a lesser amount of tissue is available, contact 
the sponsor. If archival tissue is not available and de novo biopsy is taken, submit the 
newer tissue sample.
5. Patients must be willing to participate in additional PK studies as required (cohort 
dependent); patient will be informed of which PK studies are required prior to 
consenting for study participation.
6. Age 18 years (or other age above 18 years of age if required by local regulation).
7. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) must be 0 or 
1. 


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8. Adequate Bone Marrow Function, including:

Absolute neutrophil count (ANC) 1,500/mm3 or 1.5 x 109/L;

Platelets 100,000/mm3 or 100 x 109/L;

Hemoglobin 9 g/dL.
9. Adequate Renal Function, including:

Serum creatinine 1.5 x upper limit of normal (ULN) or estimated creatinine 
clearance 50 mL/min as calculated using the method standard for the institution. 
10. Adequate Liver Function, including:

Total serum bilirubin 1.5 x ULN unless the patient has documented Gilbert 
syndrome;

Aspartate and alanine transaminase (AST & ALT) ≤2.5 x ULN; ≤5.0 x ULN if 
there is liver involvement secondary to tumor; 

Alkaline phosphatase 2.5 x ULN (5 x ULN in case of bone metastasis). 
11. Resolved acute effects of any prior therapy to baseline severity or CTCAE 
Grade 1 except for adverse events (AEs) not constituting a safety risk by 
investigator judgement.
12. Serum or urine pregnancy test (for females of childbearing potential) negative at 
screening and within 72 hours prior to the patient receiving the investigational 
product.
13. Male and female patients of childbearing potential and at risk for pregnancy must 
agree to use two highly effective methods of contraception throughout the study and 
for at  least 90 days (at least 180 days if required by local regulation) after the last 
dose of assigned treatment.  Female patients who are not of childbearing potential (ie, 
meet at least one of the following criteria):

Have undergone a documented hysterectomy and/or bilateral oophorectomy;

Have medically confirmed ovarian failure; or 

Achieved postmenopausal status, defined as follows: cessation of regular menses 
for at least 12 consecutive months with no alternative pathological or 
physiological cause; status may be confirmed by having a serum follicle 
stimulating hormone (FSH) level within the laboratory’s reference range for 
postmenopausal women.


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14. Patients who are willing and able to comply with scheduled visits, treatment plans, 
laboratory tests and other procedures. 
4.2. Exclusion Criteria
Patients presenting with any of the following will not be included in the study:
For All Phases/Cohorts
1. Previously diagnosed brain metastases, unless the patient has completed the 
treatment that is clinically indicated, if any, and has recovered from the acute effects 
of any treatment that was delivered prior to study registration, have discontinued 
corticosteroid treatment for these metastases prior to registration, and are 
neurologically stable.
2. Major surgery within 2 weeks prior to registration.
3. Radiation therapy, excluding stereotactic radiosurgery (SRS), within 1 week prior to
registration. 
4. Systemic anti-cancer therapy within 2 weeks or 5 half-lives (whichever is longer) of 
registration excluding EGFR TKIs. Patients on EGFR TKIs must discontinue the 
agent for a minimum of:

2 days prior to registration for erlotinib or afatinib, or 3 days for gefitinib if they 
will be part of the lead-in single dose PF-06747775 PK study (Phase 1 Dose 
Escalation Single and Multiple dose PK and ECG Assessments; Phase 1 
Sildenafil at MTD; and Phase 1b/2 First-Line Single Agent). Please contact the 
Sponsor for direction for any other EGFR TKI.

5 half-lives or 5 days (whichever is longer) prior to registration if they will be 
starting on continuous PF-06747775 dosing directly (Phase 1 PK sub-studies at 
RP2D; Phase 1b/2 Combination with Palbociclib; Phase 1b Combination with 
Avelumab).
5. Prior irradiation to >25% of the bone marrow (Appendix 1).
6. Persisting NCI CTCAE v4.03 Grade >1 toxicity related to prior therapy; however 
alopecia grade 2 is acceptable.
7. QTc >480 msec (based on the mean value of the triplicate ECGs), family or personal 
history of long or short QT syndrome, Brugada syndrome or known history of QTc 
prolongation, or Torsade de Pointes (TdP) (Appendix 5).
8. Uncontrolled electrolyte disorders that can confound the effects of a QTc prolonging 
drug (eg, hypocalcemia, hypokalemia, hypomagnesemia).
9. Prior treatment with a T790M targeted compound (3rd generation EGFR TKI).


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10. 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.
11. Any of the following in the previous 6 months: myocardial infarction, severe/unstable 
angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, 
cerebrovascular accident, stroke, transient ischemic attack or symptomatic pulmonary 
embolism, hypertension that cannot be controlled by medications (>150/100 mmHg 
despite optimal medical therapy), second degree or third degree atrioventricular (AV)
block (unless paced), or any AV block with PR >220 msec.  
12. History of extensive, disseminated, bilateral or presence of Grade 3 or 4 interstitial 
fibrosis or interstitial lung disease including a history of pneumonitis, hypersensitivity 
pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative bronchiolitis 
and pulmonary fibrosis.  Patients with a history of prior radiation pneumonitis are not 
excluded.
13. Participation in other clinical studies within 2 weeks before registration and/or during 
study participation.
14. 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.
15. Patients who are investigational site staff members directly involved in the conduct of 
the study and their family members, site staff members otherwise supervised by the 
investigator, or patients who are Pfizer employees directly involved in the conduct of 
the study.
16. Active inflammatory gastrointestinal disease, chronic diarrhea, known diverticular 
disease or previous gastric resection or lap-band.  
17. Diagnosis of any other malignancy within 5 years prior to randomization, except for 
superficial esophageal cancer (TIS or T1a) fully resected by endoscopy, prostate
cancer (Gleason score ≤6) either curatively treated or deemed to not require 
treatment, ductal in situ carcinoma of the breast that has completed curative 
treatment, adequately treated basal cell or squamous cell skin cancer, or carcinoma in 
situ of the cervix or bladder.
18. Patients with gastroesophageal reflux disease under treatment are allowed, but those 
treated with a proton pump inhibitor (PPI) will need to be switched to a H2 receptor 
antagonist with staggered dosing (twice daily [BID], 2 hours after PF-06747775 and 
10 hours before the following PF-06747775 dose).


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19. For the PK sub-studies, patients who have had a gastrectomy or have dietary or other 
restrictions that preclude at least a 10 hour overnight fast (water permitted) or 
consumption of the high-fat, high-calorie meal, will not be eligible to participate.
20. Current use or anticipated need for food, herbal supplements or drugs that are known 
strong CYP3A4 inhibitors, including their administration within 10-days prior to the 
first PF-06747775 dose (ie, strong CYP3A4 inhibitors include but are not limited to: 
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, and conivaptan.20
21. Current use or anticipated need for drugs or herbal supplements that are known strong 
CYP3A4 inducers, including their administration within 10-days prior to the first 
PF-06747775 dose (strong CYP3A4 inducers include but are not limited to:
phenobarbital, rifampin, phenytoin, carbamazepine, rifabutin, rifapentin, clevidipine, 
St. John’s Wort).20
22. Concurrent use of drugs that are CYP3A4 substrates with narrow therapeutic indices, 
such as but not limited to: astemizole, terfenadine, cisapride, pimozide, quinidine, 
tacrolimus, cyclosporine, sirolimus, (alfentanil and fentanyl, excluding transdermal 
patch) or ergot alkaloids (ergotamine, dihydroergotamine)20 is not permitted.
23. Concurrent use of drugs that are strong P-glycoprotein (P-gp) inhibitors (such as but 
not limited to: dronedarone, erythromycin, indinavir, indinavir/ritonavir, itraconazole, 
ketoconazole, lapatinib, lopinavir/ritonavir, quinidine, rifampin, ritonavir, valspodar, 
verapamil, vorapaxar). Patients must avoid the use of drugs that are known strong 
P-gp inhibitors for the duration of the study.
24. Breastfeeding female patients (including patients who intend to interrupt 
breastfeeding)
Additional Exclusion Criteria For Cohort 2 (PF-06747775 Plus Palbociclib)
1. Prior treatment with a CDK 4/6 inhibitor.
2. In addition to the restricted concomitant strong CYP3A4 inhibitors listed above for 
PF-06747775, current use (within 10 days of initial dosing of palbociclib) or 
anticipated need for moderate to strong CYP3A4 inhibitors (ie, atazanavir, 
boceprevir, delavirdine, diltiazem, erythromycin, suboxone, telaprevir, and 
verapamil).
3. In addition to the restricted concomitant strong CYP3A4 inducers listed above for 
PF-06747775, current use (within 10 days of initial dosing of palbociclib) or 
anticipated need for moderate to strong CYP3A4 inducers (ie, felbamate, nevirapine,
and primidone).


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4. Any known or suspected contraindications to or hypersensitivity to palbociclib.
Additional Exclusion Criteria For Cohort 3 (PF-06747775 Plus Avelumab)
1. Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or 
anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA 4) antibody (including 
ipilimumab, tremelimumab or any other antibody or drug specifically targeting T-cell 
co-stimulation or immune checkpoint pathways).
2. Active autoimmune disease that might deteriorate when receiving an 
immunostimulatory agent.  Patients with diabetes type I, vitiligo, psoriasis, or hypo-
or hyperthyroid disease not requiring immunosuppressive treatment are eligible.
3. Use of immunosuppressive medication at time of randomization, except the 
following:
a.
Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular 
injection);
b. Systemic corticosteroids at physiologic doses ≤10 mg/day of prednisone or 
equivalent;
c.
Steroids as premedication for hypersensitivity reactions (eg, computed 
tomography [CT] scan premedication). 
4. Prior organ transplantation including allogenic stem-cell transplantation.
5. Diagnosis of prior immunodeficiency or known HIV or AIDS-related illness.
6. HBV or HCV infection at screening (positive HBV surface antigen or HCV RNA 
[ribonucleic acid] if anti-HCV antibody screening test positive).
7. Vaccination within 4 weeks prior to randomization except for administration of 
inactivated vaccines.
4.3. Lifestyle Guidelines
4.3.1. Dietary Restrictions
PF-06747775 and palbociclib are to be taken with a breakfast of 200-300 calories with 
240 mL (8 ounces) of water at approximately the same time each morning.  Food and liquids 
other than water are allowed 2 hours after dose.  Patients must be instructed to avoid 
ingesting grapefruit, grapefruit juice, or grapefruit-containing products and grapefruit related 
citrus fruits (eg, Seville oranges, pomelos) while taking PF-06747775 and palbociclib.  For 
PK sub-studies, administration instructions may vary (see Section 3.5.1, Section 3.5.2, 
Section 3.5.3, and Section 5.4.4.1).
There are no specific dietary restrictions for avelumab administration.


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4.3.2. Contraception
In this study, patients of childbearing potential will receive PF-06747775 as single agent or 
in combination with either palbociclib or avelumab, compounds for which the teratogenic 
risks is currently unknown.  Two (2) methods of highly effective contraception must be used 
throughout the study and continued for at least 90 days after the last dose.  The investigator
or his/her designee, in consultation with the patient, will confirm the patient has selected two 
appropriate methods of contraception for the individual patient and his female partner from 
the list of permitted contraception methods (see below) and will confirm the patient has been 
instructed in their consistent and correct use.  Patients need to affirm that they meet at least 
2 of the selected methods of contraception.  The Investigator or his/her designee will discuss 
with the patient the need to use highly effective contraception consistently and correctly
according to the Schedule of Activities (SOA) and document such conversation in the 
patient’s chart.  In addition, the Investigator or his/her designee will instruct the patient to 
call immediately if a selected contraception method is discontinued or if pregnancy is known 
or suspected. 
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:

Established use of oral, inserted, injected* or implanted* hormonal methods of 
contraception is allowed provided the patient plans to remain on the same treatment 
throughout the entire study and has been using that hormonal contraceptive for an 
adequate period of time to ensure effectiveness.

Correctly placed copper-containing intrauterine device (IUD).

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.

Male sterilization with absence of sperm in the post vasectomy ejaculate.

Bilateral tubal ligation or bilateral salpingectomy or bilateral tubal occlusive 
procedure (provided that occlusion has been confirmed in accordance with the 
device’s label).

*Not commercially available in Japan.
All sexually active male patients 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.


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4.3.3. Sun Exposure
Patients will be advised to report any reaction to sun exposed skin.  In addition, special 
precautions should be taken to limit any potential photo irritation effect, by minimizing the 
patients’ exposure to light including high intensity ultraviolet B light (UVB) sources such as 
tanning beds, tanning booths and sunlamps.  Patients should be encouraged to apply liberal 
amounts of sunscreen/sunblock daily and avoid sunbathing/suntanning or other excessive sun 
exposure.  Patients should also be encouraged to wear protective clothing to limit sun 
exposure.
4.3.4. Smoking
Patients will be reminded that smoking should cease throughout the study period. 
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 team SharePoint site/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 help desk 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 help desk number can also be used by investigational 
staff if they are seeking advice on medical questions or problems; however, it should only be 
used 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 help desk 
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.
5. STUDY TREATMENTS
5.1. Screen Failures
Patients who completed the informed consent process but do NOT meet all eligibility criteria 
and therefore are NOT randomized to either treatment arm will be considered as screen 
failures.  Please see Section 4.1 and 4.2 for detailed inclusion and exclusion criteria.
Clinical sites must provide the following information using the appropriate CRFs for all 
screening failures: screening number, demographic data as well as the final patient summary 
including the reason for screening failure.


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5.2. Allocation to Treatment
In Phase 1, dose level allocation will be performed by the Sponsor after patients have given 
their written informed consent and have completed the necessary baseline assessments. The
site staff will fax or email a complete Registration Form to the designated Sponsor study 
team member.  Registration will be within 2 days prior to the Day -8 single dose lead-in as 
appropriate.  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 and fax or email to the site.
No patient shall receive investigational product until the Investigator or designee has 
received the following information in writing from the Sponsor:

confirmation of the patient’s 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.
Following dose escalation, study patients for Cohorts 1, 2, and 3 will be enrolled by the 
Sponsor after patients have provided written informed consent and have completed the 
necessary baseline assessments. Starting doses for those in Cohort 2A will be assigned as 
well.
For Cohort 2B , patients will be enrolled in a 2:1 ratio to either PF-06747775 in combination 
with palbociclib or PF-06747775 single agent. Enrollment and randomization will be  
according to a computer generated pseudo-random code.  Randomization numbers will be 
assigned by a central web-based randomized system operated by Pfizer, Inc.
Allocation of patients to treatment groups will proceed through the use of an Interactive 
Response Technology (IRT) system  The site personnel (study coordinator or specified 
designee) will be required to enter or select information including, but not limited to, the 
user’s identification (ID) and password, protocol number, the patient number and date of 
birth of the patient.  The site personnel will then be provided with a randomization number 
and date of dispensable unit (DU) or container number when drug is being supplied via the 
IRT.  The IRT system will provide a confirmation report containing the patient number and 
DU or container number assigned.  The confirmation report must be stored in the site’s files. 
There is a 24 hour a day, 365 days a year IRT helpdesk available for any questions or issues.  
The study specific IRT reference manual will provide the contact information and further 
details on the use do the IRT.
Note:  the IRT is the source of the patient number.  The IRT system will provide the patient 
number at the end of the first IRT patient transaction. 


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5.3. Patient Compliance
Patients will be required to return all unused study medication as well as the patient diary at 
the beginning of each cycle for drug accountability.  Drug accountability will be performed 
on Day 1 of every cycle prior to dispensing drug supply for the next cycle. The number of 
units returned by the patient at the end of the cycle will be counted, documented and 
recorded.  A patient dosing diary will be supplied and instructions on completing it will be 
given to patients at the beginning of each dosing cycle.
5.4. Drug Supplies 
The investigational products used in the course of this trial are PF-06747775, palbociclib,
and avelumab.
5.4.1. Dosage Form(s) and Packaging
5.4.1.1. PF-06747775
PF-06747775 will be supplied by the Sponsor for oral administration in, 25 mg, 50 mg and/or
100 mg tablets.  Available tablet strengths will be described in the Investigational Product 
(IP) manual. All tablets will be supplied in HDPE (High Density Polyethylene) bottles and 
labeled according to local regulatory requirements.  Tablets will have different sizes and 
shapes according to different strengths.  Tablet count will be appropriate for the dosing 
regimen and treatment period. 
5.4.1.2. Palbociclib
Palbociclib will be supplied by the Sponsor as capsules 25 mg, 75 mg, and 100 mg 
equivalents of palbociclib free base.  The Sponsor will supply the oral drug formulation to 
sites in HDPE bottles and labeled according to local regulatory requirements.  The capsules 
can be differentiated by their size and color.  Labeling will occur according to local 
regulatory requirements.  Capsule count will be appropriate for the dosing regimen and 
treatment period.
5.4.1.3. Avelumab
Avelumab is a sterile, clear, and colorless solution intended for IV administration.  It is 
presented at a concentration of 20 mg/mL with a nominal volume of 10 mL in glass vials 
closed with a rubber stopper and sealed with an aluminum polypropylene flip-off seal.  Each 
vial is intended for single-use only.
5.4.1.4. Concomitant Agents Used in Phase 1 PK Sub-Studies
Sildenafil (25 mg PO once daily), esomeprazole (40 mg PO once daily), itraconazole 
(200 mg PO once daily), and rifampin (600 mg PO once daily) will each be supplied to the 
appropriate PK cohort patients by the site personnel for oral administration.  Commercial 
form strength and count will be appropriate for the dosing regimen and treatment period. 


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5.4.2. 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 
all investigational agents and drugs used in this study, including but not limited to: 
PF-06747775, sildenafil, palbocicilib, and avelumab.
5.4.2.1. PF-06747775 and Palbociclib 
The patient number should be recorded on the bottle label for PF-06747775 and palbociclib
in the spaces provided by the site personnel at the time of assignment to patient.  Site 
personnel must ensure that patients clearly understand the directions of self medication.  
Patients should be given a sufficient supply to last until their next study visit.  Unused drug 
and/or empty bottles should be returned to the site at the next study visit.  Returned, unused 
medication MUST NOT be re-dispensed to the patient. 
Both PF- 06747775 and palbociclib are agents that must be handled and administered with 
care.  Patients should be instructed to keep their medication in the bottles provided and not to 
transfer it to any other containers.   
For palbociclib, due to possible unknown hazards associated with topical and environmental 
exposure to experimental agents, capsules must not be opened and/or emptied into any 
vehicle for oral ingestion; capsules must be swallowed intact.
5.4.2.2. Avelumab
Avelumab is a sterile, clear, and colorless solution intended for IV administration.  Avelumab 
is formulated as a 20 mg/mL solution and will be supplied by the sponsor in single-use glass 
vials, stoppered with a rubber septum and sealed with an aluminum polypropylene flip-off 
seal.
Packaging and labeling will be in accordance with applicable local regulatory requirements 
and applicable Good Manufacturing Practices (GMP) guidelines.  Avelumab will be packed 
in boxes each containing one vial.  The information on the trial drug will be in accordance 
with approved submission documents. 
Avelumab will be shipped in transport cool containers (2C to 8C) with temperature 
monitoring devices.
5.4.3. Administration
5.4.3.1. PF-06747775
PF-06747775 will be provided in bottles containing, 25 mg, 50 mg and/or 100 mg tablets
appropriate to the dose level the patient will receive.  Each bottle will contain enough 
medication for 21 days (Phase 1 and Cohort 2) or 28 days (Cohort 3) of dosing, plus an 
additional amount to cover potential delays in visiting the site.  Site personnel must ensure 
that patients clearly understand the directions for self-medication.  Site personnel should call 
each patient to confirm compliance within a few days of each cycle where a new dose is 


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given (eg, Cycle 1 and any cycle where a patient has changed doses). Site personnel should 
also contact each patient prior to visits in which the patient has pre-dose assessments such as 
PK blood samples that require the patient avoids taking PF-06747775 at home prior to the 
clinic visit.  Patients should be given sufficient supply to last until their next study visit. 
PF-06747775 will be dispensed at the beginning of each treatment cycle 
(or as otherwise indicated).  Patients should be instructed to keep their medication in the 
bottles provided and not transfer it to any other container. 
Patients are to take PF-06747775 by mouth (PO). Patients will swallow the study medication 
whole, and will not manipulate or chew the medication prior to swallowing. 
PF-06747775 is to be self-administered on an outpatient basis, except on visit days that 
include PK sampling (ie, pre-dose or serial PK collection) or visits in which the patient is 
administered avelumab on site (Cohort 3).  On these visit days, study treatments should be 
taken in clinic after any pre-dose assessments are completed. 
PF-06747775 will be administered once daily (QD) on a continuous basis at approximately 
the same time each day, with the exception of the single dose lead-in period for those patients 
participating in the Phase 1 dose escalation cohort or first line single-agent cohort (Cohort 1).
PF-06747775 is to be taken with a breakfast of 200-300 calories with 240 mL (8 ounces) of
water.  Food and liquids other than water are allowed 2 hours after dose. For PK sub-studies,
administration instructions may vary (see Section 3.5.1, 3.5.2, 3.5.3 and Section 5.4.4.1). 
Following completion of PK sub-study (if applicable), patients will continue on once daily 
dosing of PF-06747775 as described above.
Alternate administration may be explored based upon emerging PK or AE data. For the 
purposes of this study and DLT assessments, a cycle is defined as 21 days for Phase 1 and 
Cohort 1 and Cohort 2 and as 28 days for Cohort 3, regardless of missed doses or dose 
delays. Once the RP2D has been determined, in the event that observed PF-06747775 
plasma exposure with the new tablet formulation differs in relation to the exposure observed 
at RP2D with the initial tablet formulation to the extent that would cause clinical safety or 
efficacy concerns, the RP2D may be adjusted accordingly to account for the difference in 
systemic exposure for any subsequent patients or cohorts.  Patients should be instructed to 
take their medication at approximately the same time each day and to not take more than the 
prescribed dose at any time. 
If a patient misses a day of treatment, they 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, they must be instructed NOT to “make it up,” 
but to resume subsequent doses the next day as prescribed. 
If a patient inadvertently takes 1 extra dose during a day, the patient should NOT take the 
next dose of PF-06747775.


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5.4.3.2. Palbociclib
Palbociclib is to be self-administered with food on an outpatient basis, except on visit days 
that include PK sampling (ie, pre-dose or serial PK collection).  Palbociclib will be taken 
concomitantly with PF-06747775 with a breakfast of 200-300 calories with 240 mL 
(8 ounces) of water. Food and liquids other than water are allowed 2 hours after dose.
Patients should be instructed to swallow one palbociclib capsule daily, whole, and not to 
chew them prior to swallowing. No capsule should be ingested if it is broken, cracked, or 
otherwise not intact.
Patients who miss a day’s dose entirely must be instructed NOT to “make it up” the next day.
Patients who vomit any time after taking a dose must be instructed NOT to “make it up,” and 
to resume treatment the next day as prescribed.
Patients who inadvertently take 1 extra dose during a day must be instructed to skip the next 
day’s dose of palbociclib. 
Due to possible unknown hazards associated with topical and environmental exposure to 
experimental agents, capsules must not be opened and/or emptied into any vehicle for oral 
ingestion; capsules must be swallowed intact.
5.4.3.3. Avelumab
Avelumab will be administered over 1 hour by IV infusion. The IP Manual for this protocol 
contains specific instructions for avelumab dose calculation, reconstitution, preparation of the 
infusion fluid, and administration. In order to mitigate avelumab infusion related reactions, a 
premedication regimen of 25 to 50 mg IV or oral equivalent diphenhydramine and 650 mg 
IV or oral equivalent acetaminophen/paracetamol (as per local practice) is mandatory 
approximately 30 to 60 minutes prior to each dose of avelumab.  This may be modified based 
on local treatment standards and guidelines, as appropriate.  On days in which patients 
receive avelumab, pre-dose PK should be drawn, followed by the premedication regimen 
described above, followed then by PF-06747775 dosing in clinic along with a breakfast of 
200-300 calories, and then immediately followed by the start of avelumab infusion.
Patients will be observed in the clinic for at least 2 hours after each infusion of avelumab. If, 
following the 4th dose of avelumab, no infusion-related reactions are observed, no further 
premedication will be required for subsequent administrations and patients will require only 
1 hour of observation following the infusion.  
5.4.3.4. Concomitant Agents Used in Phase 1 PK Sub-Studies
Sildenafil, esomeprazole, itraconazole, and rifampin will be dispensed using commercially 
available strengths and commercial sources to the appropriate PK cohort patients.  Site 
personnel must ensure that patients clearly understand the directions for self-medication for 
those PK cohorts that require self dosing at home.  Patients should be given sufficient supply 
as required to complete the PK studies. 


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The study medication should be dispensed at each visit per the schedule of treatment.  
Dispensing will be performed by a qualified staff member in bottles (or blister cards, as 
appropriate) provided, in quantities appropriate for the study visit schedule.  The 
patient/caregiver should be instructed to maintain the product in the bottle (or blister cards, as 
appropriate) provided throughout the course of dosing and return the bottle (or blister cards, 
as appropriate) to the site at the next study visit. 
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 
the investigational products.

Sildenafil will be taken in the morning with water following at least a 10 hour 
overnight fast as indicated in Table 3.

Esomeprazole will be taken in the morning 2 hours prior to breakfast, with water, as 
indicated in Table 5.  

Itraconazole will be taken with food, except on the day of serial PK assessments 
where it should be taken while fasting, as indicated in Table 5.

Rifampin will be taken in the morning 2 hours prior to breakfast, with water, as 
indicated in Table 4.
5.4.4. Food Requirements
5.4.4.1. Food Requirements for PF-06747775 (Except for the Food Effect Cohort)
PF-06747775 will be administered every day (QD) with 240 mL (8 ounces) of water and a 
breakfast of 200-300 calories.  No food or liquids other than water will be consumed for 
2 hours following each dose.  The  requirement to take with a limited amount of food may be 
removed (via a letter to the investigators) if the data from the food effect study indicate that 
there is no significant food effect on the bioavailability of PF-06747775. Patients should not 
take PF-06747775 with grapefruit juice or grapefruit/grapefruit related citrus fruits (eg, 
Seville oranges, pomelos). For PK sub-studies, administration and food and water restrictions
may vary (see Section 3.5.1, 3.5.2, 3.5.3, and Section 5.4.4.1).
5.4.4.2. Requirements for PF-06747775 for the Phase 1 Food Effect Cohort
Please refer to Section 3.5.2. 
5.4.4.3. Requirements for PF-06747775 Plus Palbociclib (Cohort 2)
PF-06747775 will be administered every day just as described above with water and a small 
breakfast.  Palbociclib will be taken at the same time as the investigational product, along 
with water and breakfast, as palbociclib must be taken with food.  Patients should not take 
PF-06747775 and palbociclib with grapefruit juice or grapefruit/grapefruit related citrus 
fruits (eg, Seville oranges, pomelos).


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5.4.5. Recommended Dose Modifications
5.4.5.1. PF-06747775
Every effort should be made to administer PF-06747775 on the planned dose and schedule.
In the event of significant toxicity related to PF-06747775, 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.
PF-06747775 dose modifications may occur in 3 ways:

Within a cycle: dosing interruption until adequate recovery and dose reduction, if 
required, during a given treatment cycle; 

Between cycles: next cycle administration may be delayed due to persisting toxicity 
when a new cycle is due to start;

In the next cycle: dose reduction may be required in a subsequent cycle based on 
toxicity experienced in the previous cycle. 
5.4.5.1.1. Dosing Interruptions
Patients experiencing Grade 3 or 4 potentially PF-06747775-related toxicity or intolerable 
Grade 2 toxicity despite maximal supportive care should have PF-06747775 treatment 
interrupted.  For Grade 3 toxicities (see Appendix 3 for management guidelines) that are well 
characterized EGFR TKI toxicities, (diarrhea, mucositis, rash) the decision to hold 
PF-06747775  is at the discretion of the Investigator and is not mandated.  Appropriate 
follow up assessments should be done until adequate recovery occurs as assessed by the 
investigator.  Criteria required before treatment can resume are described Section 5.4.5.1.2.
PF-06747775 doses may be held as needed until toxicity resolution to a tolerated level (eg, 
baseline or a tolerable Grade 2 or 3, depending on the specific event.  See Table 18 for 
details).  Depending on when the AE resolved, a PF-06747775 interruption may lead to the 
patient missing all subsequent planned doses within that same cycle or even to delay the 
initiation of the subsequent cycle. 
If the AE that led to the PF-06747775 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 PF-06747775 dose reduction at the time of treatment resumption 
should be based on the criteria defined in Section 5.4.5.1.3, unless expressly agreed 
otherwise following discussion between the Investigator and the Sponsor. If a dose reduction 
is applied in the same cycle, the patient may need to return to the clinic to receive new drug 
supply.


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In the event of a PF-06747775 treatment interruption lasting >2 weeks, treatment resumption 
will be decided in consultation with the Sponsor and prior agreement from the Sponsor must 
be documented.
5.4.5.1.2. Dose Delays
Re-treatment following PF-06747775 treatment interruption for treatment related toxicity or 
at the start of any new cycle may not occur until all of the following parameters have been 
met:

ANC 1,000/mm3.

Platelets count 50,000/mm3.

Non-hematologic toxicities have returned to baseline or Grade 2 severity,
whichever is greater.
If a PF-06747775 treatment delay results from worsening of hematologic or biochemical 
parameters, the frequency of relevant blood tests should be increased as clinically indicated.
If these conditions are met within 2 weeks of treatment interruption or cycle delay, 
PF-06747775 may be resumed.  Refer to Dose Reductions Section for AEs requiring 
PF-06747775 dose reduction at the time of PF-06747775 treatment resumption. 
If these conditions are not met, PF-06747775 treatment resumption may be delayed up to a 
maximum of 3 weeks.  If these parameters have not been met after 3 weeks of dosing
interruption, then permanent discontinuation of treatment with PF-06747775 should be 
considered.  PF-06747775 treatment resumption for patients recovering from 
PF-06747775 -related toxicity after 3 weeks of treatment interruption or cycle delay may be 
considered only if the patient is deemed to be deriving obvious clinical benefit per the 
Investigator’s best medical judgment and needs to be agreed between the Investigator and the 
Sponsor.
5.4.5.1.3. Dose Reductions
Following dosing interruption or cycle delay due to toxicity, the PF-06747775 dose may need 
to be reduced when treatment is resumed.
Dose reduction of PF-06747775 by 1 and, if needed, 2 dose levels will be allowed depending 
on the type and severity of toxicity encountered.  Patients requiring more than 2 dose 
reductions of PF-06747775 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. 
Once the PF-06747775 dose has been reduced for a given patient, the patient should remain 
on the new dose for at least 2 cycles before considering re-escalation.  Dose re-escalation 
may be undertaken thereafter at the Investigator’s discretion by no more than 1 dose level per 
2 cycles back to the previously obtained highest dose level.


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Patients experiencing a DLT during Phase 1 or Cohorts 2A or 3 may resume dosing at the 
next lower dose level (if applicable) once adequate recovery is achieved.  No dose reductions 
are planned for patients experiencing toxicities other than those listed as DLTs.  However, 
Investigators should always manage their patients according to their medical judgment based 
on the particular clinical circumstances and patients experiencing recurrent and intolerable 
Grade 2 toxicity may resume dosing at the next lower PF-06747775 or palbociclib dose level 
once recovery to Grade 1 or baseline is achieved. 
Recommended PF-06747775 dose reductions are described in Table 18.


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Table 18.
PF-06747775 Dose Modifications for Drug-Related Toxicity
Toxicity
Grade 1
Grade 2
Grade 3
Grade 4
Non-hematologic 
Continue at the 
same dose level.
Continue at the 
same dose level. 
Withhold dose until 
toxicity is grade 
2 or has returned 
to baseline, 
whichever is higher, 
then resume 
treatment at the 
same dose level or 
reduce the dose by 
1 level at the 
discretion of the 
investigator.a
If the event is a lab 
value change only, 
evaluation of the 
underlying AE and 
patient will guide 
dose modifications 
and DLT 
considerations.
If the Grade 3 event 
is a typical EGFR 
TKI toxicity and 
tolerable (eg, rash) 
dosing may 
continue at the 
discretion of the 
investigator.b
Withhold dose until 
toxicity is grade 2, 
or has returned to 
baseline, whichever 
is higher, then 
reduce the dose by 
1 level and resume 
treatment, or 
discontinue at the 
discretion of the 
investigator.a
Hematologic
Continue at the 
same dose level.
Continue at the 
same dose level.
Withhold dose until 
toxicity is grade 2, 
or has returned to 
baseline, then 
resume treatment at 
the same dose 
level.b
Withhold dose until 
toxicity is grade 2, 
or has returned to 
baseline, then 
reduce the dose by 
1 level and resume 
treatment.b
a.
Nausea, vomiting or diarrhea must persist at Grade 3 or 4 despite maximal medical therapy to require dose 
modification.
b.
Cycle will not be extended to cover for the missing doses.
5.4.5.2. Palbociclib
Recommendations for palbociclib dose modifications are listed in Table 19. Modifications 
from these guidelines should only occur after discussion between the Investigator and the 
Sponsor. Appropriate follow up assessments should be performed until the Investigator has 
determined the patient has adequately recovered.  


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Table 19.
Recommended Dose Modifications for Adverse Events Associated with 
Palbociclib 
Toxicity (NCI CTCAE version 4.03)
Proposed Action for Palbociclib
Hematologic
Neutropenia and/or thrombocytopenia
See Table 20
Grade 3 Neutropenia + Fever ≥38.5ºC 
and/or infection
Withhold until fever resolves and ANC ≥1000; resume at next lower dose level
Cardiovascular
QTc prolongation
See Table 21
Gastrointestinal 
Mucositis, Grade 3
Withhold until symptoms resolve to Grade ≤ 1; resume at the same or next 
lower dose level at the discretion of the investigator.
Mucositis, Grade 4
Permanently discontinue if symptoms uncontrollable by supportive care
Nausea, Vomiting, or Diarrhea Grade 3 
Withhold dose until toxicity is Grade ≤2 or has returned to baseline, whichever 
is higher, then resume treatment at the same dose level or reduce the dose by 1 
level at the discretion of the investigator.  Must persist at Grade 3 despite 
maximal medical therapy to require dose modification
Nausea, Vomiting, or Diarrhea Grade 4
Withhold dose until toxicity is Grade ≤2, or has returned to baseline, 
whichever is higher, then reduce the dose by 1 level and resume treatment, or 
discontinue at the discretion of the investigator.  Must persist at Grade 4 
despite maximal medical therapy to require dose modification
Hepatic
AST and/or ALT >10 - ≤20 x ULN
Withhold until recovery to ≤ Grade 1or baseline, then resume at next lower 
dose level or discontinue
ALT, Grade 2 with bilirubin > 2x ULN
Withhold until recovery to ≤ Grade 1or baseline.  Resume at next lower dose 
level or discontinue
Infection
Sepsis (with or without neutropenia)
Withhold until resolution and ANC ≥1000; resume at next lower dose level
Lung
Uncomplicated Pulmonary Embolism 
(Grade 3)
Withhold until recovery; then resume at same or next lower dose level or 
discontinue as per investigator judgment
Pulmonary Embolism(a) (Grade 4)
Withhold until recovery; then resume at same or next lower dose level or 
discontinue as per investigator judgment
Immune System
Hypersensitivity reactions Grade 3 or 
4(b)
Withhold until symptoms resolve, then resume at the same dose level
Other 
Any other Grade 3 non-hematologic 
toxicity 
Withhold until Grade 1 or Grade 2 (if not considered a safety risk); resume at 
the next lower dose
Abbreviations: ANC=Absolute Neutrophil Count
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 investigational product administration and 
aggressive symptomatic therapy.
5.4.5.2.1. Dose Modifications for Hematologic Toxicities
The below table presents guidelines for palbociclib dose modifications for patients who 
experience hematologic toxicities. 


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Table 20.
Recommended Dose Modifications for Neutropenia and/or 
Thrombocytopenia
Cycle Day
Absolute 
Neutrophil 
Count (ANC)
(cells/mm3)
Platelet 
count
(cells/mm3)
Proposed Action for Palbociclib
Day 1 (cycle 
start)
<1000
OR
<100,000
Delay dose until recovery (ANC1000 AND platelet count 
100,000
5.4.5.2.2. Dose Modifications for QTc Prolongation 
Patients experiencing QTc prolongation (QTc 501 msec on at least two separate ECGs) 
should have their palbociclib treatment interrupted/delayed. 
In the event of QTc prolongation, possible alternative reversible causes such as serum 
electrolytes abnormalities, or usage of concomitant medications with the potential to prolong 
the QTc interval should be evaluated. 
If such reversible causes are identified, then they should be corrected accordingly 
(ie, correction of electrolyte abnormalities with supplements to within normal limits and/or 
discontinuation (if possible) of concomitant medications known to prolong the QT interval). 
Recommended dose modifications in the event of QTc prolongation are provided in the 
following table.
Table 21.
Palbociclib Dose Modifications in the Event of QTc Prolongation
Toxicity (NCI CTCAE Grade, Version 4.03)
Grade 2 QTc prolongation
Grade 3 QTc prolongation
Grade 4 QTc 
prolongation
Reversible 
cause 
identified 
Treat reversible cause 
Initiate more frequent ECG monitoring 
according to investigator’s best 
medical judgment until QTc480 msec 
Continue at the same dose level
Treat reversible cause 
Withhold treatment until QTc<501 msec 
Resume treatment at the same dose level.
Monitor ECG more frequently as per 
investigator’s best medical judgment until 
QTc480 msec.  
Permanently 
discontinue
No reversible 
cause 
identified
Initiate more frequent ECG monitoring 
according to investigator’s best 
medical judgment until QTc480 msec 
Continue at the same dose level
Withhold treatment until QTc<501 msec 
Monitor ECG more frequently as per 
investigator’s best medical judgment until 
QTc480 msec. Resume treatment at the next 
lower dose level
Permanently 
discontinue


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1. If the QTc remains above 480 msec more than 2 cycles or if Grade 2 QTc 
prolongation recurs in the absence of other alternative causes or despite correction of 
alternative causes, then dose adjustment and/or discontinuation should be considered 
in consultation with a cardiologist and the Sponsor, taking into account the emerging 
safety data from palbociclib trials and the investigator’s best medical judgment.
2. If the Grade 3 QTc prolongation occurs again after one DL reduction, further dose 
adjustment and/or discontinuation should be discussed with the Sponsor in 
consultation with a cardiologist, taking into consideration the emerging safety data 
from palbociclib trials and the investigator’s best medical judgment.
5.4.5.3. Avelumab
5.4.5.3.1. Special Precautions for Avelumab Administration
As with all monoclonal antibody therapies, there is a risk of allergic reactions including 
anaphylactic shock.  Avelumab should be administered in a setting that allows for immediate 
access to an intensive care unit or equivalent environment and administration of therapy for 
anaphylaxis, such as the ability to implement immediate resuscitation measures.  Steroids 
(dexamethasone 10 mg), epinephrine (1:1,000 dilution), allergy medications (IV 
antihistamines), bronchodilators, or equivalents, and oxygen should be available for 
immediate access.
In order to mitigate avelumab infusion-related reactions, a premedication regimen of 25 to 
50 mg IV or oral equivalent diphenhydramine and 650 mg IV or oral equivalent 
acetaminophen/paracetamol (as per local practice) is mandatory approximately 30 to 
60 minutes prior to each dose of avelumab.  This may be modified based on local treatment 
standards and guidelines, as appropriate. 
Patients will be observed in the clinic for at least 2 hours after each infusion of avelumab. If, 
following the 4th dose of avelumab, no infusion-related reactions are observed, no further 
premedication will be required for subsequent administrations and patients will require only 
1 hour of observation following the infusion.  
Infusion of avelumab will be stopped in case of Grade ≥2 infusion-related, allergic, or 
anaphylactic reactions.  If an infusion/allergic reaction occurs, the patient must be treated 
according to the best available medical practice.  Patients should be instructed to report any 
delayed reactions to the Investigator immediately. 
Treatment recommendations for the management of infusion related reactions, severe 
hypersensitivity reactions, and tumor lysis syndrome are outlined in Section 5.4.5.3.3, 
Section 5.4.5.3.4, and Section 5.4.5.3.5, respectively. 
Investigators should also monitor patients closely for potential irAEs, which may become 
manifest at the earliest weeks of treatment.  Immune-related AEs include pneumonitis, 
colitis, hepatitis, endocrinopathies including thyroid disorders (hyperthyroidism, 
hypothyroidism, thyroiditis), adrenal insufficiency, rash, nephritis and other immune-
mediated reactions including eye disorders (uveitis, iritis), myositis, and myocarditis.  
Treatment recommendations for the management of irAEs are outlined in Section 5.4.5.3.5.


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5.4.5.3.2. Management of Avelumab Infusion Related Reactions
Since avelumab is administered IV, infusion related reactions may occur (with symptoms 
such as fever, chills, rigors, diaphoresis, and headache).  Treatment of the infusion related 
reaction and modifications of avelumab infusion are mainly dependent upon severity, as 
indicated in Table 22.
Table 22.
Treatment Modification for Symptoms of Avelumab Infusion-Related 
Reactions
NCI CTCAE Grade 
Treatment Modification for Avelumab
Grade 1 – mild
Mild transient reaction; infusion interruption not 
indicated; intervention not indicated.
Decrease the avelumab infusion rate by 50% and 
monitor closely for any worsening.
The total infusion time for avelumab should not 
exceed 120 minutes.
Grade 2 – moderate
Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment (eg, 
antihistamines, NSAIDs, narcotics, IV fluids); 
prophylactic medications indicated for 24 hours.
Stop avelumab infusion.
Resume infusion at 50% of previous rate as soon 
as infusion-related reaction has resolved or 
decreased to at least Grade 1 in severity, and 
monitor closely for any recurrence or worsening.
Grade 3 or Grade 4 – severe or life-threatening
Grade 3: Prolonged (eg, not rapidly responsive to 
symptomatic medication and/or brief interruption of 
infusion); recurrence of symptoms following initial 
improvement; hospitalization indicated for clinical 
sequelae.
Grade 4: Life-threatening consequences; urgent 
intervention indicated.
Stop the avelumab infusion immediately and 
disconnect bag infusion tubing from the patient.
Avelumab treatment must be permanently 
discontinued.
IV=intravenous, NCI-CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Event, 
NSAIDs=nonsteroidal anti-inflammatory drugs.
Once the avelumab infusion rate has been decreased by 50% due to an infusion related 
reaction, it must remain so for all subsequent infusions.  The total infusion time for avelumab 
should not exceed 120 minutes (2 hours).
Additional Modifications for Patients with Grade 2 Infusion Related Reactions
In the event of a Grade 2 infusion related reaction that does not improve or worsens after 
implementation of the modifications indicated in Table 7 (including reducing the infusion 
rate by 50%), the Investigator may consider treatment with corticosteroids, and the infusion 
should not be resumed for that cycle.  At the next cycle, the Investigator may consider the 
addition of H2 blocker antihistamines (eg, famotidine or ranitidine), meperidine, or ibuprofen 
to the mandatory premedication.  Prophylactic steroids are NOT permitted.


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5.4.5.3.3. Management of Avelumab Related Severe Hypersensitivity Reactions and Flu 
like Symptoms
As with all monoclonal antibody therapies, avelumab can induce flu like symptoms and 
hypersensitivity reactions, including impaired airway, decreased oxygen saturation (<92%), 
confusion, lethargy, hypotension, pale/clammy skin, and cyanosis.
Avelumab should be administered in a setting that allows for immediate access to an 
intensive care unit or equivalent environment, if required.  Patient should be placed on 
monitor immediately and epinephrine injection and dexamethasone infusion should be 
available for immediate access.
For prophylaxis of flu like symptoms, 25 mg indomethacin or comparable non-steroidal anti-
inflammatory drug (NSAID) dose (eg, ibuprofen 600 mg, naproxen sodium 500 mg) may be 
administered at Investigator discretion 2 hours before and 8 hours after the start of each dose 
of avelumab IV infusion.  Alternative treatments for fever (eg, paracetamol or ibuprofen) and 
rigors (eg, meperidine) may be given to patients at the discretion of the Investigator.
5.4.5.3.4. Management of Tumor Lysis Syndrome
Avelumab can induce antibody directed cellular cytotoxicity (ADCC) in preclinical models, 
so there is a potential risk of tumor lysis syndrome (TLS).  Should this occur, patients should 
be treated as per local guidelines and the management algorithm (Figure 3) published by 
Howard et al.65


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Figure 3.
Assessment and Initial Management of Tumor Lysis Syndrome
Measure serum potassium, phosphorus, calcium, creatinine, uric acid, and urine output
No TLS at diagnosis
Assess cancer mass
Laboratory TLS
≥2 abnormal laboratory
test values
No symptoms
Small or resected
localized tumor
Medium-size 
cancer mass
Large cancer mass
Bulky tumor or organ 
infiltration
Bone marrow replaced
with cancer
Assess cell-lysis potential
Assess cell-lysis potential
Low
High
Medium or
unknown
Low
High
Medium or
unknown
Negligible Risk
of Clinical TLS
No prophylaxis
No monitoring
Low Risk or
of Clinical TLS
Intravenous fluids
Allopurinol
Daily laboratory tests
High Risk of
Clinical TLS
Intravenous fluids
Rasburicase
Cardiac monitoring
Laboratory tests every
6-8 hr 
Established
Clinical TLS
Intravenous fluids
Rasburicase
Cardiac monitoring
Intensive care unit
Laboratory tests every
4-6 hr 
High Risk of
Clinical TLS
Intravenous fluids
Allopurinol or ras-
buricase
Inpatient monitoring
Laboratory tests every
8-12 hr 
Assess patient
presentation
Preexisting nephropathy
Dehydration
Hypotension
Nephrotoxin exposure
No
Yes
Clinical TLS
Acute kidney injury
Symptomatic hypo-
calcemia
Dysrhythmia


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5.4.5.3.5. Management of Avelumab Immune Related Adverse Events
Since inhibition of PD-L1 stimulates the immune system, irAEs may occur.  Treatment of 
irAEs is mainly dependent upon severity (NCI CTCAE grade v4.03):

Grade 1 to 2: treat symptomatically or with moderate dose steroids, more frequent 
monitoring;

Grade 1 to 2 (persistent): manage similar to Grade 3 to 4 AE;

Grade 3 to 4: treat with high dose corticosteroids.
Treatment of irAEs should follow guidelines set forth in the following table.
Table 23.
Management of Avelumab Immune-Related Adverse Events 
Gastrointestinal irAEs
Severity  of Diarrhea / Colitis
(NCI CTCAE v4.03)
Management
Follow-up
Grade 1
Diarrhea: <4 stools/day over 
baseline;
Colitis: asymptomatic 

Continue avelumab therapy

Symptomatic treatment (eg, 
loperamide)
Close monitoring for worsening 
symptoms
Educate patient to report worsening 
immediately
If worsens:
Treat as Grade 2 or 3/4 
Grade 2
Diarrhea: 4 to 6 stools per day over 
baseline; IV fluids indicated <24 
hours; not interfering with 
activities of daily living (ADL)
Colitis: abdominal pain; blood in 
stool 

Delay avelumab therapy

Symptomatic treatment
If improves to Grade 1: 
Resume avelumab therapy
If persists >5-7 days or recur:
0.5 to 1.0 mg/kg/day 
methylprednisolone or equivalent 
When symptoms improve to Grade 1, 
taper steroids over at least 1 month, 
consider prophylactic antibiotics for 
opportunistic infections, and resume 
avelumab therapy per protocol.
If worsens or persists >3 to 5 days with 
oral steroids:
Treat as Grade 3 to 4
Grade 3 to 4
Diarrhea (Grade 3): ≥7 stools per 
day over baseline; incontinence; IV 
fluids ≥24 hrs; interfering with 
ADL
Colitis (Grade 3): severe 
abdominal pain, medical 
intervention indicated, peritoneal 
signs
Grade 4: life-threatening, 
perforation

Discontinue avelumab therapy per 
protocol

1.0 to 2.0 mg/kg/day 
methlyprednisolone IV or  
equivalent

Add prophylactic antibiotics for 
opportunistic infections 

Consider lower endoscopy
If improves: 
Continue steroids until Grade 1, then 
taper over at least 1 month
If persists >3 to 5 days, or recurs after 
improvement:
Add infliximab 5 mg/kg (if no 
contraindication); Note: infliximab 
should not be used in cases of 
perforation or sepsis


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Table 23.
Management of Avelumab Immune-Related Adverse Events 
Dermatological irAEs
Severity of Rash
(NCI-CTCAE v4.03)
Management
Follow-up
Grade 1 to 2 
Covering ≤ 30% body surface area 
Symptomatic therapy (eg, 
antihistamines, topical steroids) 
Continue avelumab therapy
If persists >1 to 2 weeks or recurs: 
Consider skin biopsy 
Delay avelumab therapy
Consider 0.5 to 1.0 mg/kg/day 
methylprednisolone IV or oral 
equivalent.  Once improving, taper 
steroids over at least 1 month, 
consider prophylactic antibiotics for 
opportunistic infections, and resume 
therapy
If worsens: 
Treat as Grade 3 to 4 
Grade 3
Covering >30% body surface area 
Delay avelumab therapy
Consider skin biopsy 
Dermatology consult 
1.0 to 2.0 mg/kg/day 
methylprednisolone IV or IV 
equivalent 
If improves to Grade 1: 
Taper steroids over at least 1 month 
and add prophylactic antibiotics for 
opportunistic infections 
Resume avelumab therapy
If Grade ≥3 toxicity recurs: 
Discontinue avelumab
Grade 4
Life-threatening consequences
Discontinue avelumab therapy.
Consider skin biopsy,
Dermatology consult.
1.0 to 2.0 mg/kg day 
methylprednisolone IV or equivalent
If improves to Grade 1:  
Taper steroids over at least 1 month 
and add prophylactic antibiotics for 
opportunistic infections. 
Pulmonary AEs
Grade of Pneumonitis
(NCI-CTCAE v4.03)
Management
Follow-up
Grade 1
Radiographic changes only 
Consider delay of avelumab therapy 
Monitor for symptoms every 2 to 3 
days 
Consider Pulmonary and Infectious 
Disease consults 
Re-image at least every 3 weeks
If worsens: 
Treat as Grade 2 or Grade 3 to 4 
Grade 2
Mild to moderate new symptoms
Delay avelumab therapy
Pulmonary and Infectious Disease 
consults
Monitor symptoms daily, consider 
hospitalization 
1.0 mg/kg/day methyl-prednisolone 
IV or oral equivalent 
Consider bronchoscopy, lung biopsy 
Re-image every 1 to 3 days 
If improves: 
When symptoms return to near 
baseline, taper steroids over at least 
1 month and then resume avelumab
therapy and consider prophylactic 
antibiotics
If not improving after 2 weeks or 
worsening: 
Treat as Grade 3 to 4 


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Table 23.
Management of Avelumab Immune-Related Adverse Events 
Grade 3 to 4
Severe new symptoms; New / 
worsening hypoxia; life-threatening 
Discontinue avelumab therapy
Hospitalize 
Pulmonary and Infectious Disease 
consults
2 to 4 mg/kg/day 
methylprednisolone IV or IV 
equivalent 
Add prophylactic antibiotics for 
opportunistic infections 
Consider bronchoscopy, lung 
biopsy 
If improves to baseline: 
Taper steroids over at least 6 weeks 
If not improving after 48 hours or 
worsening: 
Add additional immunosuppression 
(eg, infliximab, cyclophosphamide, 
intravenous immunoglobulin, or 
mycophenolate mofetil) 
Hepatic irAEs
Liver Function Tests (LFT) 
Increase
(NCI-CTCAE v4.03)
Management
Follow-up
Grade 1
Grade 1 AST or ALT > ULN to 3.0 
x ULN and/or Total bilirubin 
> ULN to 1.5 x ULN 
Continue avelumab therapy
Continue liver function monitoring 
If worsens: 
Treat as Grade 2 or 3 to 4 
Grade 2
AST or ALT >3.0 to ≤5 x ULN 
and/or total bilirubin >1.5 to
≤3 x ULN 
Delay avelumab therapy
Increase frequency of monitoring to 
every 3 days.
Permanently discontinue 
investigational product therapy if 
AST/ALT >3X ULN with 
concurrent elevation if total 
bilirubin >2X ULN without another 
obvious cause.  
If returns to baseline: 
Resume routine monitoring, resume 
v therapy
If elevations persist >5 to 7 days or 
worsen : 
0.5 to 1 mg/kg/day 
methylprednisolone or oral 
equivalent and when LFT returns to 
Grade 1 or baseline, taper steroids 
over at least 1 month, consider 
prophylactic antibiotics for 
opportunistic infections, and resume 
avelumab therapy
Grade 3 to 4
AST or ALT >5 x ULN and /or 
total bilirubin >3 x ULN 
Discontinue avelumab therapy 
Increase frequency of monitoring to 
every 1 to 2 days 
1.0 to 2.0 mg/kg/day 
methylprednisolone IV or IV 
equivalent
Add prophylactic antibiotics for 
opportunistic infections 
Consult gastroenterologist
Consider obtaining MRI/CT scan of 
liver and liver biopsy if clinically 
warranted
If returns to Grade 2: 
Taper steroids over at least 1 month 
If does not improve in >3 to 5 days, 
worsens or rebounds: 
Add mycophenolate mofetil 1 gram 
(g) twice daily 
If no response within an additional 3 
to 5 days, consider other 
immunosuppressants per local 
guidelines 


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Table 23.
Management of Avelumab Immune-Related Adverse Events 
Endocrine irAEs
Endocrine Disorder
Management
Follow-up
Asymptomatic thyroid stimulating 
hormone (TSH) abnormality 
Continue avelumab therapy  
If TSH <0.5 x LLN, or TSH > 2 x ULN, or consistently out of range in 2 
subsequent measurements: include free T4 at subsequent cycles as clinically 
indicated; consider endocrinology consult 
Symptomatic endocrinopathy 
Evaluate endocrine function 
Consider pituitary scan 
Symptomatic with abnormal lab / 
pituitary scan: 
Delay avelumab therapy
1.0 to 2.0 mg/kg/day 
methylprednisolone IV or by mouth 
equivalent 
Initiate appropriate hormone 
therapy 
No abnormal lab / pituitary MRI 
scan but symptoms persist: Repeat 
labs in 1 to 3 weeks / MRI in 1 
month 
If improves (with or without 
hormone replacement): 
Taper steroids over at least 
1 month and consider prophylactic 
antibiotics for opportunistic 
infections 
Resume avelumab therapy 
Patients with adrenal insufficiency 
may need to continue steroids with 
mineralocorticoid component 
Suspicion of adrenal crisis (eg, 
severe dehydration, hypotension, 
shock out of proportion to current 
illness) 
Delay avelumab therapy 
Rule out sepsis 
Stress dose of IV steroids with mineralocorticoid activity 
IV fluids 
Consult endocrinologist 
If adrenal crisis ruled out, then treat as above for symptomatic 
endocrinopathy
Patients with adrenal insufficiency may need to continue steroids with a 
mineralcorticoid component.
Avelumab therapy may be discontinued based on clinical judgment.
ADL=activities of daily living, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
irAE=immune-related adverse event, IV=intravenous, LLN=lower limit of normal, MRI=magnetic resonance 
imaging, NCI-CTCAE=National Cancer Institute-Common Terminology Criteria for Adverse Events, 
NSAIDs=nonsteroidal anti-inflammatory drugs, T4=thyroxine, TSH=thyroid-stimulating hormone, ULN=upper 
limit of normal.
5.5. Investigational Drug Storage 
The investigator, or an approved representative, eg, pharmacist will ensure that all 
investigational products, including any comparative agents 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 must be stored in its original container and in accordance with the 
drug label. 
Storage conditions stated in the single reference safety document (SRSD), the investigator 
brochure, will be superseded by the storage conditions stated on the label. 


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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 study.  Even for 
continuous monitoring systems, a log or site procedure which ensures active daily evaluation 
for excursions should be documented.  The operation of the temperature monitoring device 
and storage unit (for example, refrigerator), as applicable, must be regularly inspected to 
ensure it is maintained in working order. 
Any excursions from the product label storage conditions must be reported upon discovery.  
The site must actively pursue options for returning the product to labeled storage conditions, 
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.  
Specific details regarding information the site should report for each excursion will be 
provided to the site. 
Site staff will instruct patients on the storage requirements for take home medications.
The Investigational Product Manual must be referenced for any additional guidance on 
storage conditions and actions to be taken when conditions are outside the specified range
and will have details for each of the investigational products.
5.6. Drug Accountability 
The investigator’s site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the drug supplies.  The Sponsor or designee will provide guidance on the 
destruction of unused investigational product (eg, at the site).
5.7. Concomitant Treatment(s)
Medications or vaccinations specifically prohibited in the Exclusion Criteria are also not
allowed during the active treatment period.
Concomitant treatment considered necessary for the patient’s wellbeing 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 will be 
recorded on the CRF. 
5.7.1. Considerations Specific to PF-06747775
Pre-clinical data suggests that PF-06747775 could be a CYP3A4 time-dependent inhibitor, 
and a CYP3A4, CYP1A2 and glutathione S-transferase isoform M1 (GST-M1) substrate.  All 
concomitant treatments must be reviewed during Cycle 1 prior to serial PK collections.


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Based on the preclinical data of PF-06747775, the use of CYP3A4 substrates with Narrow 
Therapeutic Index (NTI) and strong CYP3A4 inducers or inhibitors are prohibited (see
Section 4.2).  However, the following concomitant medications should be discussed with the 
sponsor:
Because inhibition of CYP3A4 isoenzymes may increase PF-06747775 exposure leading to a 
potential increases in toxicities, caution should be warranted with co-administration of 
moderate CYP3A4 inhibitors (Moderate CYP3A4 inhibitors are but not limited to: 
erythromycin, verapamil, atazanavir, fluconazole, darunavir, diltiazem, delavirdine, 
aprepitant, imatinib, tofisopam, ciprofloxacin, cimetidine).20  Concomitant use of 
PF-06747775 and a CYP3A4 substrate may increase the exposure of the CYP3A4 substrate.  
Therefore, caution should be warranted with co-administration of PF-06747775 with drugs 
that are not NTI but are mainly metabolized via CYP3A4.
Concomitant use of PF-06747775 and proton pump inhibitors (PPIs) may significantly 
decrease the exposure of PF-06747775.  Therefore, PPIs are prohibited. Patients with 
gastroesophageal reflux disease under treatment are allowed, but treatment with a PPI will 
need to be switched to a H2 receptor antagonist with staggered dose (BID, 2 hours after 
PF-06747775 and 10 hours before the following PF-06747775 dose).  The restriction on PPIs 
may be removed (via a letter to the investigators) based on the emerging data from the 
Phase 1 PK sub-study with esomeprazole.
5.7.1.1. PF-06747775 in Combination with Palbociclib (Cohort 2A and 2B)
All concomitant treatment restrictions listed in the Exclusion Criteria for palbociclib 
(Section 4.2) also pertain to the combination with palbociclib. Clinical data suggest 
palbociclib is a weak time-dependent inhibitor of CYP3A4/5, and clinical exposure of 
palbociclib was impacted by strong CYP3A4 inhibitors and inducers. Therefore the use of 
CYP3A4 substrates with Narrow Therapeutic Index (NTI) and strong CYP3A4 inducers or 
inhibitors are still prohibited in patients receiving this combination. The solubility of 
palbociclib free base is pH-dependent and therefore concomitant administration of agents 
which increase gastric pH can alter the solubility and absorption of palbociclib free base 
formulations. As described above, patients on PPIs will need to be switched to a H2 receptor 
antagonist with staggered dose (BID, 2 hours after PF-06747775 + palbociclib and 10 hours 
before the following PF-06747775 + palbociclib dose).  
Dexamethasone use is not recommended with palbociclib.  Alternative steroid choices are 
suggested.  A patient requiring systemic dexamethasone treatment should be discussed with 
the Sponsor.  Topical use of dexamethasone is permitted.
Further clinical experience with palbociclib and concomitant treatments is explained in detail 
in the palbociclib IB.67


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5.7.1.2. PF-06747775 in Combination with Avelumab (Cohort 3)
All concomitant treatment restrictions listed in the Exclusion Criteria for avelumab 
(Section 4.2) above for single-agent PF-06747775 also pertain to the combination with 
avelumab. In addition, patients are prohibited from receiving the following therapies during 
treatment with avelumab:   

Immunotherapy, immunosuppressive drugs [unless otherwise indicated for the 
treatment of irAEs (Section 5.4.5.3.5)], or other experimental pharmaceutical 
products (ie, chemotherapy or systemic corticosteroids except for short-term 
treatment of allergic reactions or for the treatment of irAEs) (Section 5.7.6 contains 
further details regarding use of corticosteroids);

Any vaccine therapies for the prevention of infectious disease except for inactive 
vaccines;

Herbal remedies with immunostimulating properties (eg, mistletoe extract) or known 
to potentially interfere with major organ function (eg, hypericin);

Acetaminophen use should be restricted to no more than 2 g/day.
Further clinical experience with avelumab and concomitant treatments is explained in detail 
in the avelumab IB.67
5.7.2. Other Anti-tumor/Anti-cancer or Experimental Drugs
No additional systemic anti-tumor treatment will be permitted while patients are receiving 
study therapy. 
Palliative radiotherapy on study is permitted for the treatment of painful lesions providing 
that the lesions were known at the time of study entry, have not increased in size more than 
20% and are not target lesions, and the investigator clearly indicates that the need for
palliative radiotherapy is not indicative of disease progression.  If a patient has progressed, 
and it has been documented as such for study purposes, but the patient remains on 
investigational product for clinical benefit, they may also receive palliative radiotherapy for a 
painful lesion or single site progression.  In view of the current lack of data about the 
interaction of PF-06747775 with radiotherapy, PF-06747775 treatment should be interrupted 
during palliative radiotherapy, stopping 2 days before and resuming treatment after recovery 
to baseline.
In view of the current lack of data about the interaction of palbociclib with radiotherapy, 
palbociclib treatment should be interrupted during palliative radiotherapy, stopping 1 day 
before and resuming treatment 1 week after.  


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5.7.3. 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. 
Patients who are receiving bisphosphonates may continue while on therapy but initiation of 
bisphosphonate therapy after registration will be considered progression of disease unless 
otherwise agreed by the investigator in consultation with the sponsor.
For prevention of dry skin, patients should begin a regimen of moisturizers prior (ideal) or 
with start of dosing, and use appropriate measures to prevent excessive sun exposure.
Treatment of acneiform rash may include topical steroids, topical antibiotics, and oral 
antibiotics. 
Mucositis can be treated with antibiotic-free oral rinse; chlorhexidine should be avoided.
Primary prophylactic use of granulocyte-colony stimulating factors (G-CSFs) is not 
permitted, but they may be used to treat treatment-emergent neutropenia as indicated by 
ASCO guidelines or local regulations.  If neutropenic complications are observed in a cycle 
in which primary prophylaxis with colony stimulating factors (CSFs) was not received, 
secondary prophylaxis may be given at the discretion of the investigator, but only if dose 
delay is not considered a reasonable alternative.  For the safety evaluation cohort, G-CSFs 
should not be used in Cycles 1 and 2, as this may interfere with the evaluation of the cohort.
5.7.4. Anti-Diarrheal and Anti-Emetic Therapy
See Appendix 3 for AE management guidelines.
For diarrhea, patients should begin therapy with loperamide at first evidence of increased 
frequency of bowel movement with adjustment in dose or prescription of alternative 
medication when necessary.  The potential need for increased oral hydration (including 
electrolyte-containing fluids) should also be evaluated early. 
Other measures may be utilized per the investigator judgment or emerging data-driven 
guidelines where these are available. 
5.7.5. 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 prohibited in the 
Concomitant Treatment(s) section. 
5.7.6. Corticosteroids 
Chronic, systemic corticosteroid use for palliative or supportive purpose is not permitted.  
Symptomatic treatment on an individual basis may be considered upon discussion and prior 
agreement with sponsor. Acute emergency administration, topical applications, inhaled 
sprays, eye drops or local injections of corticosteroids are allowed.  


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5.7.6.1. Cohort 2A and 2B (PF-06747775 Plus Palbociclib): 
In addition to recommendations in Section 5.7.6 above, use of dexamethasone is not 
recommended with palbociclib.  Alternative steroid choices are suggested.  A patient 
requiring systemic dexamethasone treatment should be discussed with the Sponsor.  Topical 
use of dexamethasone is permitted.
Chronic immunosuppressive therapies should be avoided, including systemic corticosteroids. 
Short course of oral steroids or inhaled/topical steroids are allowed.
5.7.6.2. Cohort 3 (PF-06747775 Plus Avelumab): 
With all immunotherapies intended to augment cell-mediated immunity, there is a risk that 
concomitant immunosuppressives such as steroids will counteract the intended benefit. 
However, studies with anti-CTLA4 compounds indicate that short-term use of steroids may 
be employed without compromising clinical outcomes. Therefore, in addition to 
recommendations in Section 5.7.6 above, the use of steroids in this cohort (Cohort 3) is 
restricted as follows:

Therapeutic use: for the treatment of infusion-related reactions and short-term 
treatment of irAEs is permitted according to the modalities indicated in Table 23;

Physiologic use: replacement for adrenal insufficiency at doses equivalent to 10 mg 
prednisone daily is acceptable;

Prophylactic use, eg, for the prevention of acute infusion-related reactions is 
prohibited.
There are no prohibited therapies during the Post-Treatment Follow-up Phase.
5.7.7. Surgery 
Caution is advised on theoretical grounds for any surgical procedures during the study.  The 
appropriate interval of time between surgery and PF-06747775 required to minimize the risk 
of impaired wound healing and bleeding has not been determined.  Stopping PF-06747775 is 
recommended at least 2 days prior to surgery.  Postoperatively, the decision to reinitiate
PF-06747775 treatment should be based on a clinical assessment of satisfactory wound 
healing and recovery from surgery.
Caution is advised on theoretical grounds for any non-cancer related surgical procedures 
during the study.  The appropriate interval of time between surgery and administration of any 
of the investigational products required to minimize the risk of impaired wound healing and 
bleeding has not been determined.  Based on the available pharmacokinetic data, stopping 
palbociclib is recommended at least 7 days prior to elective surgery.  Stopping 
PF-06747775 is recommended at least 2 days prior to surgery.  Postoperatively, the decision 
to reinitiate investigational treatment(s) should be based on a clinical assessment of 
satisfactory wound healing and recovery from surgery.


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6. STUDY PROCEDURES 
All patients must sign an informed consent document prior to undergoing any study-specific 
procedures (unless considered standard of care).
6.1. Screening
See SOA and Assessments section. 
To establish eligibility patients must have the following (see SOA):

General Medical History with focus on active and pertinent clinical history (signs and 
symptoms experienced within 14 days of registration).  Full cardiac and respiratory 
history must be obtained.

Tumor History - oncology history (including smoking status), prior systemic therapy 
regimen and dates of administration as well as reason for discontinuation), symptoms 
from prior EGFR TKI therapy if applicable, history of concomitant medications, and 
information on prior anticancer treatments.

Physical Examination – at a minimum must include pulmonary, cardiac, abdominal 
and skin exams.  A basic neurologic exam is also a minimum requirement for patients 
with known disease involvement of the neurologic system.

Tumor Tissue sample – patients will provide a sample of their tumor prior to 
beginning any study therapy.  

In Phase 1, the sample can be from archival sampling, but if no stored sample 
is available, then a new biopsy is required for enrollment. For enrollment in 
the Phase 1 portion, patients must have confirmed del 19 or L858R disease by 
a biopsy after progression of prior EGFR TKI therapy and T790M status is 
known, it must be T790M positive in the dose finding and MTD expansion 
parts of the Phase 1 study.  Enrollment will be based on local EGFR mutation 
testing that includes QIAGEN Therascreen EGFR RGQ PCR kit, Roche 
cobas® EGFR Mutation Test or a Sponsor-approved laboratory developed test 
that is validated in a CLIA laboratory.  

In the Phase 1b/2 portions of the study, patients enrolled in Cohort 1 must 
have either del 19 or L858R mutations and may have de novo T790M 
mutations, but T790M is not required. Patients enrolled in Cohorts 2a, 2b and 
3, must be confirmed T790M+, with either del 19 or L858R (del 19 and 
T790M or L858R and T790M).  Acceptable local testing methods include 
QIAGEN Therascreen EGFR RGQ PCR kit, Roche cobas® EGFR Mutation 
Test or a Sponsor-approved laboratory developed test that is validated in a 
CLIA laboratory. Patients will also be enrolled if they solely test positive for 
EGFR mutations (del 19 AND T790M or L858R AND T790M) in plasma 
alone (no tissue diagnosis of T790M is required) detected by local EGFR 


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mutation test that includes QIAGEN Therascreen EGFR Plasma RGQ kit, 
Roche cobas® EGFR mutation test v2 (US-IVD) or Sysmex Inostic’s 
OncoBEAMTM EGFR test or a sponsor-approved laboratory developed test 
that is validated in a CLIA laboratory. EGFR mutation status will be 
confirmed by retrospective central lab testing on the submitted specimen.  
Central confirmation will use the FDA approved QIAGEN Therascreen EGFR 
RGQ PCR kit (tumor) or a validated cfDNA test as determined by the Sponsor 
(plasma). The tissue samples may also be tested retrospectively using Thermo 
Fisher Scientific Oncomine Next Generation Sequencing (NGS) cancer test 
panel. 

A mandatory archived formalin-fixed, paraffin-embedded (FFPE) tumor tissue block 
must be provided that is of sufficient size to allow, if possible, for sectioning of fifteen 
(15) 5-micron tissue sections. If an FFPE tumor tissue block cannot be provided, sites 
should try to provide fifteen (15) unstained slides each containing a 5-micron tissue 
section cut serially from the same FFPE block. If archived FFPE tissue is not available, a 
de novo (ie, fresh) tumor sample must be obtained in accord with local institutional 
practice for tumor biopsies. Archived or de novo tumor tissue from cytologic sampling 
(eg, fine needle aspiration, including FFPE cell pellet material), is not adequate and
should not be submitted. Acquisition of the mandatory tumor tissue and submission to 
the Sponsor-designated Central Laboratory (see Study Manual) can be completed outside 
the 28-day screening window, but is required for enrollment.  
In the case of discrepant results, the central lab test will be considered definitive and the 
patient, while eligible to continue on study, may need to be replaced in the statistical 
analyses.  
6.2. Study Period
For treatment period procedures, including follow up, see SOA and Assessments section.
6.3. Patient Withdrawal
Patients may withdraw from treatment at any time at their own request, or they may be 
withdrawn at the discretion of the investigator or sponsor for safety or behavioral reasons, or 
the inability of the patient to comply with the protocol-required schedule of study visits or 
procedures at a given study site.  Treatment continuation beyond objective disease 
progression may be considered on a case-by-case basis if the investigator deems the patient 
to have ongoing clinical benefit. 
Reasons for withdrawal of study treatment may include:

Disease progression;

Global deterioration of health status requiring discontinuation;

Unacceptable toxicity;


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
Pregnancy;

Significant protocol violation;

Lost to follow-up;

Patient refusal of further treatment;

Study terminated by Sponsor;

Death.

Reasons for withdrawal from study follow-up may include:

Completed study follow-up;

Study terminated by Sponsor;

Lost to follow-up;

Refusal of further follow-up for survival.
If a patient is to continue on investigational treatment despite objective progression, the 
following must be confirmed and documented appropriately:

Patients must still meet initial selection criteria of ECOG performance status 0 - 1 and 
adequate hematologic, renal, hepatic and coagulation function.

Patients must not show rapid tumor progression or symptomatic progression that 
requires urgent medical intervention (eg, CNS metastasis, respiratory failure due to 
tumor compression, spinal cord compression).
Also, at the time of disease progression, patients eligible to continue on investigational 
treatment must sign an additional informed consent form that clearly specifies that treatment 
with the investigational drug beyond initial evidence of tumor progression is not the standard 
of care, outline the potential risks of continuing such treatment, and list alternative treatment 
options, including FDA-approved or locally-approved therapy for the population.
If a patient does not return for a scheduled visit, every effort should be made to contact the 
patient.  All such efforts and outcomes should 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 
for a final visit and return any unused investigational product, if applicable, and follow-up 
with the patient regarding any unresolved AEs.


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If the patient refuses further visits, the patient should continue to be followed for survival 
(Phase 1b/2; for 24 months following last subject first visit [LSFV]) unless the patient 
withdraws consent for disclosure of future information or for further contact.  In this case, no 
further study specific evaluations should be performed, and no additional data should be 
collected.  The Sponsor may retain and continue to use any data collected before such 
withdrawal of consent.
7. ASSESSMENTS
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances, outside of the control of the investigator which 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.
Patients participating in any of the Phase 1 PK sub-studies, including the sildenafil sub-study 
(MTD expansion cohort), the food effect/rifampin DDI sub-study, or the antacid 
effect/itraconazole DDI sub-study, will continue to complete study assessments as outlined in 
Table 1 (Phase 1 Schedule of Activities), upon completion of the Cycle 1 sub-study portion
with the exceptions noted on the relevant SOA footnotes.
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.
A full physical examination, including an examination of all major body systems (including 
general appearance, head, ears, eyes, nose, mouth, throat, neck, thyroid, lungs, heart, breasts, 
abdomen, and musculoskeletal), height (at Screening only), weight, blood pressure, and pulse 
rate, which may be performed by a physician, registered nurse, or other qualified health care 
provider, will be required at Screening.  Symptom-directed physical examinations, blood 
pressure, and pulse rate assessments will be performed at all other timepoints.
7.1.1. Pregnancy Testing
For female patients of childbearing potential, who do not fit the definition of “female patients 
who are not of childbearing potential” in inclusion criterion 13, 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 therapy-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 of the first day of the menstrual period before the patient may receive the 
investigational product. Pregnancy tests will also be routinely repeated at every cycle during 


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the active treatment period, at the end of study therapy, and additionally whenever 
1 menstrual cycle is missed or when potential pregnancy is otherwise suspected.  In the case 
of a positive confirmed pregnancy, the patient will be withdrawn from the study medication 
and will be withdrawn from the study.  Additional pregnancy tests may also be undertaken if 
requested by IRB/ECs or if required by local regulations.
Qualitative urine pregnancy tests must be sensitive to at least 25 mIU/mL.  Qualitative urine 
point-of-service pregnancy tests are to be conducted with the test kit in accord with 
instructions provided in its package insert and will be performed on 2 occasions prior to 
starting study therapy-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.  Pregnancy tests will also be
routinely repeated at every cycle during the active treatment period, at the end of study 
therapy and additionally whenever 1 menstrual cycle is missed or when potential pregnancy 
is otherwise suspected.  Patients who have missed a menstrual period or who show an 
indeterminate or positive result on the qualitative point-of-service urine test may not further 
progress in the study until pregnancy is ruled out using further diagnostic testing 
(eg, a negative quantitative serum pregnancy test conducted at a certified laboratory).  In the 
case of a positive confirmed pregnancy, the patient will be withdrawn from study medication 
and from the study.  Additional pregnancy tests may also be undertaken if requested by 
IRB/ECs or if required by local regulations.
7.1.2. Contraception Check
Male patients who are able to father children, and female patients who are of childbearing 
potential will need to affirm that they meet the criteria for correct use of 2 of the selected 
methods of contraception.  The investigator or his or her designee will discuss with the 
patient the need to use 2 highly-effective contraception methods consistently and correctly, 
and document such conversation in the patient’s chart.  In addition, the investigator or his or 
her designee will instruction the patient to call immediately if one or both selected 
contraception methods are discontinued, or if pregnancy is known or suspected in the patient 
or the patient’s partner.
7.1.3. 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) seriousness, and relatedness.
Adverse events that occur during the study, including baseline signs and symptoms, will be 
recorded on the adverse events CRF page.


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7.1.4. Laboratory Safety Assessment
Hematology and blood chemistry will be drawn at the time points described in the Schedule 
of Activities and analyzed at local laboratories.  
Hematology
Chemistry
Coagulation
Urinalysis
Pregnancy Test
Hemoglobin
ALT
PT or INR
Urine dipstick for urine 
protein: If positive and 
if clinically indicated
collect 24-hr and 
microscopic (Reflex 
Testing)
For female patients of 
childbearing 
potential,  serum or 
urine (to be specified 
in the protocol)
Platelets
AST
PTT
WBC
Alk Phos
Absolute Neutrophils
Sodium
Absolute Lymphocytes
Potassium
Absolute Monocytes
Magnesium
Urine dipstick for urine 
blood: If positive collect 
a microscopic (Reflex 
Testing)
Absolute Eosinophils
Chloride
Absolute Basophils
Total Calcium
Total Bilirubin***
BUN or Urea
Creatinine
Uric Acid
Glucose 
Albumin
Phosphorous or 
Phosphate
*** For Hy's law potential cases, in addition to repeating AST and ALT, laboratory tests should include 
albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, gamma-glutamyl transferase, prothrombin 
time (PT)/INR, and alkaline phosphatase. 
In addition, for patients participating in Cohort 3 of the study, thyroid function tests 
consisting of Free T4, thyroid stimulating hormone (TSH), and adrenocorticotropic hormone 
(ACTH) will be performed at the time points outlined in the respective SOA (Table 11).  
7.1.5. Vital Signs and Physical Examination
Patients will have a physical exam to include weight, vital signs, assessment of ECOG PS
and height.  Height will be measured at the first patient study assessment only.  Vital signs
will be collected as per SOA.
7.1.6. 12-Lead ECG
Electrocardiogram (ECG): Triplicate 12-lead (with a 10-second rhythm strip) tracing will be 
used for all ECGs.  The ECG data that will be summarized in the clinical study report will be 
centrally read by an independent laboratory.  However, for patient safety, the ECG reading at 
the clinical site will drive any clinically required intervention. 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 and relevant PK and ECG assessment tables),
3 consecutive ECGs will be performed at approximately 2 minutes apart to determine the 
mean QTcF interval. If the mean QTcF is prolonged >500 msec, ie, CTC AE Grade ≥3), 
then the ECGs should be re-evaluated by a qualified person at the site for confirmation as 
soon as the finding is made, including verification that the machine reading is accurate.  If 
manual reading verifies a QTcF of >500 msec, immediate correction for reversible causes 
(including electrolyte abnormalities, hypoxia and concomitant medications for drugs with the 


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potential to prolong the QTcF interval) should be performed.  In addition, repeat ECGs 
should be immediately performed hourly for at least 3 hours until the QTcF interval falls 
below 500 msec.  If QTcF interval reverts to less than 500 msec, and in the judgment of the 
investigator(s) and sponsor is determined to be due to cause(s) other than investigational 
product, treatment may be continued with regular ECG monitoring.  If in that timeframe the 
QTcF intervals rise above 500 msec the investigational product will be held until the QTcF 
interval decreases to <500 msec.  Patients will then re-start the investigational product at the 
next lowest dose level.  If the QTcF interval has still not decreased to <500 msec after 
2-weeks, or if at any time a patient has a QTcF interval >515 msec or becomes symptomatic, 
the patient will be removed from the study.  Additional triplicate ECGs may be performed as 
clinically indicated.
Prior to concluding that an episode of QTcF prolongation 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 a specialist.
If the patient experiences a cardiac or neurologic AE (specifically syncope, dizziness, 
seizures, or stroke), an ECG (triplicate) should be obtained at the time of the event. 
When matched with PK sampling (see Table 2, Table 10, and Table 12), 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). ECG assessments pre-dose should happen prior to breakfast.
7.2. Pharmacokinetics Assessments
7.2.1. Blood for PK analysis of PF-06747775 and Sildenafil
Blood samples (4 mL whole blood in K2EDTA tubes) will be collected for PK analysis of 
PF-06747775 and sildenafil as outlined in the SOA (Table 2 to Table 12).  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 AEs and the date and time 
documented in the CRF.
Where noted in the SOA, blood samples for PF-06747775 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. 
Blood samples for sildenafil will be collected only in the MTD expansion cohort on 
Day -8 of lead-in period and on Day 11 of Cycle 1 (see Table 3).
Blood samples for PK analysis of PF-06747775 will be collected in the Phase 1 (following 
both single and multiple doses of PF-06747775) and in Phase 1b/2 (following single and/or
multiple doses of PF-06747775) portions of the study (see Table 2 to Table 12) for detailed 
information).  PK tools will be provided to the clinical sites summarizing the different PK 
assessments.


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Patients participating in any of the Phase 1 PK sub-studies, including the sildenafil sub-study 
(MTD expansion cohort), the food effect/rifampin DDI sub-study, or the antacid 
effect/itraconazole DDI sub-study, will complete PK assessments as outlined in the SOA 
(See Table 3, Table 4, or Table 5). Upon completion of the sub-study portion, no additional 
scheduled PK or 4-β-hydroxycholesterol/cholesterol assessments are required, and patients 
will continue to complete all other study assessments as outlined in Table 1 (Phase 1 
Schedule of Activities) with the exceptions noted on the relevant SOA footnotes.
All efforts will be made to obtain the pharmacokinetic samples at the scheduled nominal time 
relative to dosing.  The exact time of the sample collection will always be noted on the CRF, 
as this information will be used in the pharmacokinetic analysis.  However, samples obtained 
within 30% of the nominal time (eg within 18 minutes of a 60 minute sample) will be 
considered protocol compliant, with the actual time of the sample collection noted on the 
CRF. Pre-dose PK samples should be collected within 1 hour of dosing. If a scheduled blood 
sample collection cannot be completed for any reason, the missed sample time may be 
re-scheduled with agreement of clinical investigators, patient and sponsor. All samples, 
regardless of protocol compliance, which contain actual time of collection will be used by the 
sponsor in pharmacokinetic analyses.
PK samples will be assayed for all the analytes using a validated analytical method in 
compliance with Pfizer standard operating procedures.  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 pharmacokinetics of the investigational product, samples 
may be used for potential qualitative and/or quantitative metabolite analyses and/or
evaluation of the bioanalytical methods for PF-06747775 and their metabolites. The results 
of such analyses may be included in the clinical report.
7.2.2. Blood for 4-β-Hydroxycholesterol and Cholesterol Analysis
Three (3) mL of blood will be collected in lithium heparin tubes for the analysis of 
4-β-hydroxycholesterol and cholesterol as outlined in the SOA for Phase 1 (Table 2, Table 3, 
Table 4, or Table 5).
Patients participating in any of the Phase 1 PK sub-studies, will complete 
4-β-hydroxycholesterol/ cholesterol assessments as outlined in the SOA (See Table 3, 
Table 4, or Table 5). Upon completion of the sub-study portion, no additional scheduled PK
or 4-β-hydroxycholesterol/cholesterol assessments are required, and patients will continue to 
complete all other study assessments as outlined in the SOA (Table 1).
Samples will be assayed for all the analytes using a validated analytical method in 
compliance with Pfizer standard operating procedures.  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 pharmacokinetics of the investigational product, samples 
may be used for potential qualitative and/or quantitative metabolite analyses and/or 
evaluation of the bioanalytical methods for 4-β-hydroxycholesterol and cholesterol and their 
metabolites. The results of such analyses may be included in the clinical report.


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7.2.3. Blood for Metabolite Profiling of PF-06747775
Metabolite profiling will be conducted in the RP2D expansion cohort for all patients.  The 
remaining plasma collected for PF-06747775 PK analysis will be used for metabolite 
profiling.
Once the metabolite profiling samples have been analyzed and the report completed, the 
samples will be disposed.
7.2.4. Blood for PK Analysis of Palbociclib
Blood samples (4 mL in K2EDTA tubes) will be collected following multiple doses for PK 
analysis of palbociclib along with PF-06747775 as outlined in the SOAs (Table 9 and
Table 10).  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 AEs and the date and time 
documented in the CRF.
Where noted in the SOA, blood samples for palbociclib 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. PK tools will be provided to 
the clinical sites summarizing the different PK assessments.
PK samples will be assayed for all the analytes using a validated analytical method in 
compliance with Pfizer standard operating procedures.  Details regarding the collection, 
processing, storage and shipping of the blood samples will be provided in the study manual.
7.2.5. Blood for PK Analysis of Avelumab
Blood samples (3.5 mL in Serum Separator Tubes [SST]) will be collected following single 
and multiple doses for PK analysis of avelumab as outlined in the SOA (Table 12).  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 AEs and the date and time 
documented in the CRF.
Where noted in the SOA, blood samples for avelumab 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. PK tools will be provided to 
the clinical sites summarizing the different PK assessments.  On days when both a PK sample 
and avelumab infusion are performed, the PK sample is to be drawn from the arm opposite 
(contralateral) from that arm which is receiving the avelumab infusion.
PK samples will be assayed for all the analytes using a validated analytical method in 
compliance with Pfizer standard operating procedures.  Details regarding the collection, 
processing, storage and shipping of the blood samples will be provided in the study manual.


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7.2.6.1. Shipment of Genotyping Samples
The shipment address and assay lab contact information will be provided to the investigator 
site prior to initiation of the study.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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7.5. 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.
The same imaging technique used to characterize each identified and reported lesion at 
baseline will be employed in the following tumor assessments.
Anti-tumor activity will be assessed through radiological tumor assessments conducted at 
baseline, during treatment as specified in the Schedule of Activities, whenever disease 
progression is suspected (eg, symptomatic deterioration), and at the time of withdrawal from 
treatment (if not done in the previous 6 weeks).
Measurable Disease per RECIST v1.1 is required for patients in both the Phase 1 and Phase 
1b/2 portions of the study.  Assessment of response will be made using RECIST version 1.1.  
(Appendix 4).  Responses must be confirmed per RECIST v1.1 guidelines.  Patients in 
Cohort 3 will also have their responses assessed by irRECIST (Appendix 6).
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All patients’ files and radiologic images must be available for source verification and for 
potential peer review. In addition, radiologic images will be collected at the time of 
acquiring the images for potential central review at a later date.
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
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7.6.2. 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;
 
 
Patients need not provide additional biospecimens for the uses described in this section; the 
biospecimens specified in the Markers of Drug Response section 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. 
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8. ADVERSE EVENT REPORTING
8.1. Adverse Events
All observed or volunteered AEs regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
sections. 
For all AEs, the investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as an SAE
requiring immediate notification to Pfizer or its designated representative.  For all AEs, 
sufficient information should be obtained by the investigator to determine the causality of the 
AE.  The investigator is required to assess causality.  Follow-up by the investigator may be 
required until the event or its sequelae resolve or stabilize at a level acceptable to the 
investigator, and Pfizer concurs with that assessment.
As part of ongoing safety reviews conducted by the sponsor, any nonserious 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 the 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 nonserious AEs ends 
at the time the new treatment is started.  Death must be reported if it occurs during the SAE
reporting period after the last dose of investigational product, irrespective of any intervening 
treatment.
8.3. Definition of an Adverse Event
An AE is any untoward medical occurrence in a clinical investigation patient administered a 
product or medical device; the event need not necessarily have a causal relationship with the 
treatment or usage.  Examples of AEs include but are not limited to:

Abnormal test findings;


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
Clinically significant symptoms and signs;

Changes in physical examination findings;

Hypersensitivity;

Drug abuse;

Drug dependency.
Additionally, they may include the signs or symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasations;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure.
Worsening of signs and symptoms of the malignancy under study should be reported as AEs
in the appropriate section of the CRF.  Disease progression assessed by measurement of 
malignant lesions on radiographs or other methods should not be reported as AEs.
8.4. Medication Errors
Medication errors may result, in this study, from the administration or consumption of the 
wrong product, by the wrong patient, at the wrong time, or at the wrong dosage strength.
Such medication errors occurring to a study participant are to be captured on the medication 
error CRF which is a specific version of the AE page, and on the SAE form when 
appropriate.  In the event of medication dosing error, the sponsor should be notified 
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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 AE(s) are captured on an AE CRF page.
8.5. Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be reported as 
an AE are as follows: 

Test result is associated with accompanying symptoms; and/or

Test result requires additional diagnostic testing or medical/surgical intervention;
and/or

Test result leads to a change in study dosing (outside of the protocol stipulated dose 
adjustments) 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.


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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 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.
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 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);


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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 
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).


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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;

Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual patient;

Admission exclusively for the administration of blood products.
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as AEs.  However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE.  For example, an acute appendicitis 
that begins during the AE reporting period should be reported as the AE, and the resulting 
appendectomy should be recorded as treatment of the AE.
8.8. Severity Assessment
GRADE
Clinical Description of Severity
0
No Change from normal or reference range (This grade is not included in the 
Version 4.03 CTCAE document but may be used in certain circumstances.)
1
MILD adverse event
2
MODERATE adverse event
3
SEVERE adverse event
4
LIFE-THREATENING consequences; urgent intervention indicated
5
DEATH RELATED TO adverse event
Note the distinction between the severity and the seriousness of an AE. A severe event is not 
necessarily an SAE. For example headache may be severe (interferes significantly with the 
patient’s usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs listed above.


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8.9. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
nonserious); the investigator must record the causal relationship in the CRF, as appropriate, 
and report such an assessment in accordance with the SAE reporting requirements if 
applicable.  An investigator’s causality assessment is the determination of whether there 
exists a reasonable possibility that the investigational product caused or contributed to an 
AE; generally the facts (evidence) or arguments to suggest a causal relationship should be 
provided.  If the investigator does not know whether or not the investigational product caused 
the event, then the event will be handled as “related to investigational product” for reporting 
purposes, as defined by the sponsor (see 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).
3. A male patient 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 a EDP supplemental 
form, regardless of whether an SAE has occurred.  In addition, the investigator must submit 
information regarding environmental exposure to a Pfizer product in a pregnant woman (eg, a 
patient reports that she is pregnant and has been exposed to a cytotoxic product by inhalation 
or spillage) using the EDP supplemental form.  This must be done irrespective of whether an 
AE has occurred and within 24 hours of awareness of the exposure.  The information 
submitted should include the anticipated date of delivery (see below for information related 
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Follow-up is conducted to obtain general information on the pregnancy and its outcome for
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer of the outcome as a follow-up 
to the initial EDP supplemental form. In the case of a live birth, the structural integrity of the 
neonate can be assessed at the time of birth.  In the event of a termination, the reason(s) for
the termination should be specified and, if clinically possible, the structural integrity of the 
terminated fetus should be assessed by gross visual inspection (unless 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 adverse event.
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 Patient Withdrawal)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted earlier, and recorded on the appropriate AE CRF 
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When a patient withdraws because of a SAE, the SAE must be reported in accordance with 
the reporting requirements defined below.
8.13. Eliciting Adverse Event Information
The investigator is to report all directly observed AEs and all AEs spontaneously reported by 
the study patient.  In addition, each study patient will be questioned about AEs.
8.14. Reporting Requirements
Each AE is to be assessed to determine if it meets the criteria for SAEs.  If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate.
8.14.1. Serious Adverse Event Reporting Requirements
If an SAE occurs, Pfizer is to be notified within 24 hours of investigator awareness of the 
event.  In particular, if the SAE is fatal or life-threatening, notification to Pfizer must be 
made immediately, irrespective of the extent of available AE information.  This time frame 
also applies to additional new information (follow-up) on previously forwarded SAE reports 
as well as to the initial and follow-up reporting of EDP, exposure via breastfeeding and 
occupational exposure cases. 
In the rare event that the investigator does not become aware of the occurrence of an SAE 
immediately (eg, if an outpatient study patient initially seeks treatment elsewhere), the 
investigator is to report the event within 24 hours after learning of it and document the time 
of his or her first awareness of the AE.
For all SAEs, the investigator is obligated to pursue and provide information to Pfizer in 
accordance with the time frames for reporting specified above.  In addition, an investigator 
may be requested by Pfizer to obtain specific additional follow-up information in an 
expedited fashion.  This information collected for SAEs is more detailed than that captured 
on the AE CRF.  In general, this will include a description of the AE in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality.  Information on other possible causes of the event, such as concomitant 
medications, vaccines, and/or illnesses, must be provided.  In the case of a patient death, a 
summary of available autopsy findings must be submitted as soon as possible to Pfizer or its 
designated representative. 
8.14.2. Non-Serious Adverse Event Reporting Requirements
All AEs will be reported on the AE page(s) of the CRF.  It should be noted that the form for 
collection of SAE information is not the same as the AE CRF.  Where the same data are 
collected, the forms must be completed in a consistent manner.  For example, the same AE
term should be used on both forms.  AEs should be reported using concise medical 
terminology on the CRFs as well as on the form for collection of SAE information.


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8.14.3. Sponsor’s Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in a statistical analysis plan (SAP), which will be maintained by the
sponsor.  This document may modify the plans outlined in the protocol; however, any major 
modifications of the primary endpoint definition and/or its analysis will also be reflected in a 
protocol amendment.
9.1. Analysis Sets 
9.1.1. Safety Analysis Set
The safety analysis set includes all enrolled patients who receive at least one dose of study 
treatment.  For Cohort 2B, patients will be classified according to the treatment assigned at 
randomization unless the incorrect treatment(s) are received throughout the dosing period in 
which case patients will be classified according to the first treatment received.  The safety 
analysis set will be the primary population for evaluating treatment 
administration/compliance and safety.
9.1.2. Full Analysis Set
The full analysis set includes all enrolled patients.  For Cohort 2B, the full analysis set will 
include all patients who are randomized.  Patients will be classified according to the 
treatment assigned at randomization. The full analysis set will be the primary population for 
evaluating all efficacy endpoints and patient characteristics.
9.1.3. Per Protocol Analysis Set (Phase 1 and Cohorts 2A and 3)
For Phase 1/1b, the per protocol analysis set (evaluable for MTD/dose selection) includes
patients who are eligible, receive study treatment and who either experience a DLT during 
the first cycle of PF-06747775 or PF-06747775 plus avelumab or the first 2 cycles of 
PF-06747775 plus palbociclib, or complete the DLT observation period. Patients with major 
treatment deviations during the DLT observation period other than treatment related toxicity
are not evaluable for the MTD/dose selection assessment and will be replaced as needed to 
permit MTD/dose selection estimation. 
9.1.4. Pharmacokinetic Analysis Sets
The PK concentration population is defined as all treated patients who have at least one 
concentration in at least 1 treatment period.
The PK parameter analysis population is defined as all treated patients who have sufficient 
information to estimate at least 1 of the PK parameters of interest.


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9.1.5. Response Evaluable Analysis Set
The response evaluable analysis set will include all patients who received at least one dose of 
study medication, have measurable disease and adequate baseline assessment, and at least 
1 post-baseline assessment during the study.  For Cohort 2B, all randomized patients will be 
used.  In the Phase 1b/2 portion of the study, patients enrolled in Cohort 1 must have either 
del 19 or L858R mutations and may have de novo T790M mutations, but T790M is not 
required. Patients enrolled in Cohorts 2a, 2b and 3, must have T790M-positive NSCLC to be 
evaluable for response rate determination for the decision rules used in the study. Patients 
enrolled into Cohort 1 of the Phase1b/2 portion of the study are not required to have T790M-
positive NSCLC.  
 
 
9.2. Statistical Methods and Properties
9.2.1. Statistical Methods for Dose Escalation/De-Escalation
9.2.1.1. Continual Reassessment Method (Phase 1)
Many alternative designs have been proposed to the standard 3+3 design for Phase I dose 
escalation studies that improve its accuracy, efficiency and statistical validity. 
The Phase 1 portion of this study employs a CRM approach to estimate the MTD.  The CRM 
algorithm utilizes the Bayesian methodology to continuously learn about the dose-toxicity 
relationship after each cohort’s DLT data becomes available. The underlying model 
assumption is that DLT rate at each dose can be expressed as Pr (DLT|dose x) =f(x, β), where 
f is a monotonically increasing function in dose x and β is an unknown parameter with prior 
distribution placed on it at the beginning of the trial. The first two cohorts patients will be 
assigned to 25 mg/QD and 50 mg/QD respectively if the DLT data warrants dose escalation.  
After the DLT data of the 25 mg/QD and 50 mg/QD cohorts becomes available (~3 wks), the 
prior distribution of β is updated based on their DLT responses and becomes a posterior 
distribution.  The current estimate of MTD is calculated and the next cohort’s dose 
assignment is chosen as the dose closest to this estimated MTD but not exceeding it. This 
process is continued until 1 of the stopping rules below is triggered. 
•
Maximum sample size of 36 patients has been reached; or
•
10 evaluable patients have been treated at the estimated MTD; or 
•
All doses appear to be overly toxic and the MTD cannot be determined in the current 
trial setting.
CCI


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The above described CRM algorithm constantly incorporates additional information about 
dose-DLT relationship learned from the data via modeling and that is reflected on the 
projected MTD.  By design, such dose allocation procedure will eventually cluster dose 
assignments around the dose yielding a DLT rate closest to but no more than 30%.
Once one of the aforementioned conditions for stopping the CRM is met, the dose identified 
as MTD will be evaluated together with information gathered from PK analyses and the 
overall safety profile in order to determine the RP2D.  The dose(s) likely to be considered the 
RP2D will be expanded to 10 patients if not already tested within the CRM context in order 
to confirm the RP2D.
Extensive simulation results assessing the CRM properties can be found in O’Quigley et all 
(1990).19
9.2.1.2. Modified Toxicity Probability Interval (mTPI) (Phase 1b)
The mTPI design62 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 = 0.30).  If the 
toxicity rate of the currently used dose level is far smaller than pT, the mTPI will recommend 
escalating the dose level; if it is close to target probability (pT), the mTPI will recommend 
continuing at the current dose; if it is far greater than pT, the mTPI will recommend de-
escalating the dose level. These rules are conceptually similar to those used by the 3+3 
design, except the decisions of an mTPI design are based on posterior probabilities calculated 
under a coherent probability model. 
Being a model-based design, mTPI automatically and appropriately tailors dose-escalation 
and de-escalation decisions for different studies with different toxicity parameters. More 
importantly, all the dose-escalation decisions for a given study can be pre-calculated under 
the mTPI design and presented in a two-way table (Appendix 7). Thus, compared to other 
advanced model-based designs published in the literature, the mTPI design is logistically less 
complicated and easier to implement. 
Decision rules are based on calculating unit probability mass (UPM) of 3 dosing intervals 
corresponding to under, proper, and over dosing in terms of toxicity. Specifically, the 
underdosing interval is defined as (0; pT-e1), the overdosing interval (pT+e2, 1), and the 
proper-dosing interval (pT- e1, pT+ e2), where e1 and e2 are small fractions. Based on the 
expected safety profile of PF-06459988 as a single-agent, e1 is selected as 0.05, and e2 is 
selected as 0.03. Therefore, the target interval for the DLT rate is (0.25, 0.33).
The 3 dosing intervals are associated with 3 different dose-escalation decisions. The 
underdosing interval corresponds to a dose escalation (E), over-dosing corresponds to a dose 
de-escalation (D), and proper-dosing corresponds to remaining at the current dose (S). Given 
a dosing interval and a probability distribution, UPM of that dosing interval is defined as the 
probability of a patient belonging to that dosing interval divided by the length of the dosing 
interval. The mTPI design calculates the UPMs for the 3 dosing intervals, and the one with 
the largest UPM informs the corresponding dose-finding decision, which is the dose level to 


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be used for future patients. For example, if the under-dosing interval has the largest UPM, 
the decision will be to escalate, and the next cohort of patients will be treated at the next 
higher dose level. Ji et al.62 have demonstrated that the decision based on UPM is optimal in 
that it minimizes a posterior expected loss (ie, minimizes the chance of making a wrong 
dosing decision). 
The dose-finding portion of the study uses a modified version of the mTPI design that 
maximizes the number of evaluable patients treated at each dose to 6 patients. Dose finding 
is complete  when at least 6 evaluable patients have been treated at the highest dose with 
DLT rate 33%. In case de-escalation is required from the initial starting DL1, it is 
estimated that up to approximately 10-12 DLT-evaluable patients will need to be enrolled to
estimate the MTD for the PF-06747775 plus palbociclib combination. For the PF-06747775 
plus avelumab combination, up to approximately 10 – 12 patients may be enrolled.
9.3. Sample Size Determination
9.3.1. Phase 1 Sample Size
Due to the dynamic nature of the Bayesian allocation procedure, the sample size of CRM 
approach cannot be determined in advance.  The maximum sample size is set as 36 for dose 
escalation cohorts.
In Phase 1 portion of the study, patients will participate in a dose escalation phase aimed at 
estimating the MTD.  The sample size for this portion of the study will vary depending on the 
number of DLTs observed.  It is expected that about 36 patients will be required. 
In addition to dose escalation, additional patients (approximately 24) will be enrolled with 
the aim of evaluating the DDI, food and antacid effects studies at RP2D prior to initiating the 
Phase 1b/2 portion. 
The planned sample size for the MTD expansion cohort is 10 evaluable patients.  An 
evaluable patient will have both a baseline and on-treatment tumor assessment.  This 
expansion cohort will also be used to conduct the sildenafil sub-study. 
9.3.2. Phase 1b/2 Sample Size
The sample size planned for Phase 2 Cohort 1 is about 20 patients to provide preliminary 
information on efficacy, safety, and PK endpoints in previously untreated patients with 
advanced EGFRm NSCLC. With 20 patients the maximum width of the exact 2-sided 90% 
confidence interval for ORR will be ≤0.396. 
The sample size planned for the Phase 1b (Cohort 2A and Cohort 3) dose finding part arises 
from logistic feasibility and is not entirely driven by statistical considerations.  Due to the 
dynamic nature of the dose allocation procedure and unknown safety profile of the 
combination, the sample size of the interval design cannot be determined in advance.  It is 
expected that approximately 10 DLT evaluable patients will be required for each of the dose 
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After dose selection determined for Cohort 3, the Dose Expansion Phase will continue to 
enroll patients until approximately 20 patients in total have been treated to further assess the 
safety, PK, PD, and antitumor activity of the combination.
Phase 2 (Cohort 2B), the planned sample is about 39 patients. These patients will be 
randomized with a 2:1 ratio for the combination of PF-06747775 and palbociclib vs 
PF-06747775 single agent. The primary objective is to estimate the hazard ratio (HR) and its 
corresponding confidence interval for PFS.  For a target sample size of 39 patients 
randomized in ratio of 2:1 and 26 events, the approximate width of the 2-sided 90% CI for 
the logHR for PFS will be 1.37 which corresponds to the upper bound being approximately 
3.93 times the lower bound on the HR scale.
9.4. Efficacy Analysis
9.4.1. Phase 1
In the Phase 1 portion of the study anti-tumor activity is a secondary objective.
Tumor response will be presented in the form of patient data listings that include, but are not 
limited to, tumor type, starting dose, tumor response at each visit, and best overall response.
9.4.2. Phase 1b/2
In the Phase 1b/2 portion of the study efficacy is the primary objective.  Objective Response 
Rate (ORR) is calculated as the proportion of patients with a confirmed complete response 
(CR) or partial response (PR) relative to the total number of response evaluable patients or 
for Cohort relative to all randomized patients.  Patients who die, progress, or drop out for any
reason after enrollment/randomization prior to responding will be included in the analysis as 
nonresponders. An exact 2-sided 90% CI for objective response rate will be presented for 
each group and treatment arm. In addition for Cohort 2B, the 2-sided 90% confidence 
interval for the difference in objective response rates will be provided.
Duration of response will be calculated for patients with an objective response.  Duration of
PR or CR is the time from start date (date of first documentation of PR or CR) to date of first
documentation of objective progression or death.  The median duration of response from the 
Kaplan-Meier curve and corresponding 2-sided 90% confidence interval will be computed.
Progression Free Survival (PFS) is defined as the time from the date of cycle 1 day 1 (first 
dose) to the date that objective progressive disease is documented or death due to any cause, 
whichever occurs first.  PFS will be characterized in terms of the median, and the probability 
of remaining progression-free at 6 months (based on Kaplan-Meier estimates).  Approximate 
90% confidence intervals corresponding to these estimates will also be computed. 
Patients last known 1) to be alive 2) not to have started new (non-protocol) anti-cancer 
treatment and 3) to be progression-free, and who have a baseline and at least one on-study 
disease assessment, are censored at the date of the last objective disease assessment that 
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Patients with inadequate baseline disease assessment are censored at the date of first dose.  
Patients with no on-study disease assessments are censored at the date of first dose unless 
death occurred prior to the second planned assessment (in which case the death is an event). 
Patients starting new anti-cancer treatment prior to progression are censored at the date of 
last objective disease assessment documenting no progression prior to the new treatment. 
Patients who had an unacceptably long interval between tumor assessments (2 or more 
missed assessments) will be censored at the date of last objective disease assessment 
documenting no progression prior to the long interval, regardless of the objective response 
status at the tumor assessment following the long interval. 
Survival is defined as the time from the date of first dose to the date of death.  The 
probability of being alive at 24 months (based on Kaplan-Meier estimates) will be estimated.  
To calculate the confidence interval for 24 months survival probability, a 2-sided 90% 
confidence interval for the log (-log (2-year survival probability)) will be calculated based on 
a normal approximation and then back transformed.
In Cohort 2B randomized part, PFS, duration of response, and OS at 24 months will be 
presented by using the Kaplan-Meier method and the start date will be the date of 
randomization for PFS and OS.  For these endpoints, median event time and a 2-sided 90% 
confidence interval for the median for each treatment arm will be provided using the 
Brookmeyer-Crowley method. An exact 2-sided 90% CI for objective response rate will be 
presented for each group and treatment arm  as well as the 2-sided 90% confidence interval 
for the difference in ORR.
Additional details will be provided in the Statistical Analysis Plan.
9.5. Analysis of Other Endpoints
9.5.1. Analysis of Pharmacokinetics
9.5.1.1. Single Dose and Steady State PF-06747775 PK Analysis
For Phase 1 and all groups in Phase 1b/2, plasma pharmacokinetic parameters including the 
maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), and 
area under the plasma concentration versus time curve (AUCinf, AUCtau) for 
PF-06747775 will be estimated using non-compartmental analysis.  Area under the plasma 
concentration versus time curve to the last quantifiable concentration (AUClast), terminal 
elimination half-life (t1/2), oral plasma clearance (CL/F), apparent volume of distribution 
(Vz/F), observed accumulation ratio (Rac) and steady state accumulation ratio (Rss) will be 
also estimated.  The single dose and steady state PK parameters will be summarized
descriptively by dose, cycle and day.  The PK parameters for the food-drug and drug-drug 
interaction studies will be summarized descriptively by sub-study and treatment.


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The single dose and steady state PF-06747775 concentrations will be summarized 
descriptively (n, mean, SD, coefficient of variation (CV), median, minimum, maximum, 
geometric mean and its associated CV) by dose, cycle, day, and nominal time.  Individual 
patient and median profiles of the concentration-time data will be plotted by dose, cycle, and 
day (single dose and steady state) using nominal times.  Median profiles will be presented on 
both linear-linear and log-linear scales.  
For the food-drug and drug-drug interaction studies, PF-06747775 and sildenafil (when 
appropriate) concentrations will be summarized descriptively (n, mean, SD, coefficient of 
variation (CV), median, minimum, maximum, geometric mean and its associated CV) by 
treatment and nominal time.  Individual patient and median profiles of the concentration-time 
data will be plotted by treatment using nominal times.  Median profiles will be presented on 
both linear-linear and log-linear scales. 
Dose normalized AUC for the single dose (AUCinf) and steady state (AUCtau), AUClast and 
Cmax will be plotted against dose (using a logarithmic scale) by cycle and day.  These plots 
will include individual patient values and the geometric means for each dose.  These plots 
will be used to help understand the relationship between the PK parameters and dose.
Trough concentrations from steady state assessments in Phase 1 and 1b/2 will be plotted for 
each dose using a box-whisker plot by cycle and day within cycle in order to assess the 
attainment of steady state.  
9.5.1.2. Effect of Food on PF-06747775 Pharmacokinetics
PF-06747775 at the RP2D will be evaluated for the effect that a high-fat, high-calorie meal 
may have on PF-06747775 exposure. 
Natural log transformed area under the curve (AUCtau) and Cmax values will be analyzed 
using a mixed effects model with sequence, period/visit and treatment (fed, fasted) as fixed 
effects and patient within sequence as a random effect to estimate the effect of food on 
PF-06747775 PK.  Estimates of the adjusted mean differences (fed-fasted) and corresponding 
90% confidence intervals will be obtained from the model.  The adjusted mean differences 
and 90% confidence intervals for the differences will be exponentiated to provide estimates 
of the ratios of adjusted geometric means (fed/fasted) and 90% confidence intervals for the 
ratios.  
9.5.1.3. Sildenafil Sub-Study: MTD Expansion Cohort
The main purpose of this sub-study is to appropriately estimate the potential 
CYP3A4 inhibitory ability of PF-06747775.
Natural log transformed area under the curve (AUCinf) and Cmax values will be analyzed 
using a mixed effects model with treatment as fixed effects and patient as random effect to 
estimate the effect PF-06747775 on sildenafil exposure.  Estimates of the adjusted mean 
differences (with and without PF-06747775) and corresponding 90% confidence intervals 
will be obtained from the model.  The adjusted mean differences and 90% confidence 


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intervals for the differences will be exponentiated to provide estimates of the ratios of 
adjusted geometric means (with/without PF-06747775) and 90% confidence intervals for the 
ratios.
 
 
 
 
 
 
 
 
 
9.5.1.5. PF-06747775-Esomeprazole Drug-Drug Interaction Study
PF-06747775 at the RP2D will be evaluated for the effect that an acid reducing agent, 
esomeprazole, a proton pump inhibitor, may have on PF-06747775 exposure. 
Natural log transformed area under the curve (AUCtau) and Cmax values will be analyzed 
using a mixed effects model with treatment as a fixed effects and patient as a random effect 
to estimate the effect of esomeprazole on PF-06747775 PK.  Estimates of the adjusted mean 
differences (with and without esomeprazole [PF-06747775 alone]) and corresponding 90% 
confidence intervals will be obtained from the model.  The adjusted mean differences and 
90% confidence intervals for the differences will be exponentiated to provide estimates of the 
ratios of adjusted geometric means (with/without esomeprazole) and 90% confidence 
intervals for the ratios. 
9.5.1.6. PF-06747775-Itraconazole Drug-Drug Interaction Study
PF-06747775 at the RP2D will be evaluated for the effect that a strong CYP3A4 inhibitor, 
itraconazole, may have on PF-06747775 exposure. 
Natural log transformed area under the curve (AUCtau) and Cmax values will be analyzed 
using a mixed effects model with treatment as fixed effects and patient as a random effect to 
estimate the effect itraconazole on PF-06747775 PK.  Estimates of the adjusted mean 
differences (with and without itraconazole [PF-06747775 alone]) and corresponding 90% 
confidence intervals will be obtained from the model.  The adjusted mean differences and 
90% confidence intervals for the differences will be exponentiated to provide estimates of the 
ratios of adjusted geometric means (with/without itraconazole) and 90% confidence intervals 
for the ratios.
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9.5.1.7. Palbociclib PK Analysis
Cohort 2A and 2B: For palbociclib, plasma pharmacokinetic parameters including the
minimum plasma concentration (Ctrough), maximum observed plasma concentration (Cmax), 
time to maximum plasma concentration (Tmax), and area under the plasma concentration 
versus time curve (AUClast, AUCtau) will be estimated as data permit using non-
compartmental analysis.  The steady state PK parameters will be summarized descriptively 
by dose, cycle, and day.
The steady state palbociclib concentrations will be summarized descriptively (n, mean, SD, 
coefficient of variation (CV), median, minimum, maximum, geometric mean and its 
associated CV) by dose, cycle, day, and nominal time.
The trough concentrations for palbociclib will be plotted for each dose using a box-whisker 
plot by cycle and day within cycle in order to assess the attainment of steady state.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
CCI
CCI
CCI
CCI


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9.6. Safety Analysis
Summaries and analyses of safety parameters will include all patients in the Safety Analysis 
Set.
All patients who receive any study treatment will be included in the final summaries and 
listings of safety data.  Summaries of AEs and other safety parameters will be provided as 
appropriate.
Frequencies of patients experiencing at least 1 AE will be displayed by system organ class 
(SOC) and preferred term according to MedDRA terminology.  Detailed information 
collected for each AE will include: a description of the event; duration; whether the AE was 
serious; intensity (severity) of event; relationship to investigational product; action taken; and 
clinical outcome.  Intensity (severity) of the AEs will be graded according to the NCI 
CTCAE version 4.0.  Emphasis in the analysis will be placed on AEs classified as treatment 
emergent.
Summary tables will present the number of patients observed with AEs and corresponding 
percentages.  The denominator used to calculate incidence percentages consists of patients 
receiving at least 1 dose of study medication.  Within each table, the AEs will be categorized 
by MedDRA SOC and preferred term. Additional subcategories will be based on event 
intensity and relationship to investigational product.
Individual patient listings will be prepared for all AE data.  Summary tables for extent of 
exposure to study medication will also be provided.
9.6.1. Analysis of Phase 1 and Phase 1b Primary Endpoint
Dose Limiting Toxicity (DLT) is the primary endpoint of the dose escalation/ dose finding
component of the following groups: Phase 1, Phase 1b Cohort 2A, and Phase 1b Cohort 3.  
The occurrence of DLTs observed in these dosing cohorts will be used to estimate the MTD 
and select the RP2D as described in the Study Design Section.  Adverse Events constituting 
DLTs will be listed by dose level.
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9.6.2. Analysis of Secondary Safety Endpoints
The Safety Analysis Set will be used for all secondary safety evaluations. Summaries of AEs
and other safety parameters will be presented separately for each group. For Cohort 2B 
randomized part, summary will be presented by treatment arm.
9.6.2.1. 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 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).
9.6.2.2. 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 lab 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. 
9.6.2.3. ECG
The analysis of ECG results will be based on patients in the safety analysis set with baseline 
and on-treatment ECG data. Baseline will be defined as the ECG measurement performed 
prior to dosing (Cycle 1 Day 1).
ECG measurements (an average of the triplicate measurements) will be used for the 
statistical analysis and all data presentations.  Any data obtained from ECGs repeated for 
safety reasons after the nominal time-points will not be averaged along with the preceding 
triplicates.  Interval measurements from repeated ECGs will be included in the outlier 
analysis (categorical analysis) as individual values obtained at unscheduled time points.
QT intervals will be corrected for heart rate (QTc) using standard correction factors [ie, 
Fridericia’s (default correction), Bazett’s, and possibly a study specific factor, as appropriate].  
Data will be summarized and listed for QT, HR, RR, PR, QRS, QTcF (and other correction 
factors, eg,  QTcB as appropriate), by dose.  Individual QT` (all evaluated corrections) 
intervals will be listed by treatment, 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 value and 
changes from baseline in corrected QT after treatment by treatment, dose and time point.  For 
each patient, the maximum change from baseline will be calculated as well as the maximum 
post-baseline value across time-points.  Categorical analysis will be conducted for the 
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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.
9.7. Data Safety Monitoring Committee
An external Data Safety Monitoring Committee will not be established for the study. For the 
purpose of this protocol, Pfizer procedures for periodic safety review will be applied by an 
internal safety review committee with medical and statistical expertise 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;

Surveillance for nonserious AEs and lab abnormalities in an ongoing manner, and 
DLT evaluations at the end of Cycle 1; 

Discussions between the investigators and the sponsor of AEs and laboratory tests 
abnormalities observed at each dose level in an ongoing manner at regular 
teleconferences and/or meetings to determine the safety profile and decide if further 
patient enrollment is appropriate.
10. QUALITY CONTROL AND QUALITY ASSURANCE
During study conduct, Pfizer or its agent will conduct periodic monitoring visits 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.
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.
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.


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


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


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The investigator must ensure that each study patient, is fully informed about the nature and 
objectives of the study and possible risks associated with participation. 
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each patient before any study specific activity, excluding standard of care, is 
performed.  The investigator will retain the original of each patient's signed consent 
document.
12.4. Patient Recruitment
Advertisements approved by ethics committees and investigator databases may be used as 
recruitment procedures.
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 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 Other Participating Countries 
End of trial in all other participating countries is defined as last subject last visit (LSLV). 
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, drug safety problems, or at the discretion of Pfizer.  In 
addition, Pfizer retains the right to discontinue development of PF-06747775 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 4 weeks.  As directed by Pfizer, all study 
materials must be collected and all CRFs completed to the greatest extent possible.


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15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations. 
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies conducted in patients that evaluate the safety and/or efficacy of a Pfizer 
product, regardless of the geographical location in which the study is conducted.  US Basic 
Results are submitted for posting within 1 year of the primary completion date for studies in 
adult populations or within 6 months of the primary completion date for studies in pediatric 
populations.
Primary completion date is defined as the date that the final patient was examined or received 
an intervention for the purposes of final collection of data for the primary outcome, whether 
the clinical study concluded according to the 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 has no objection to publication by an investigator of any information collected or 
generated by the investigator, whether or not the results are favorable to the investigational 
drug. 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 before it is submitted or otherwise disclosed.


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The investigator will provide manuscripts, abstracts, or the full text of any other intended 
disclosure (poster presentation, invited speaker or guest lecturer presentation, etc.) to Pfizer 
at least 30 days before they are submitted for publication or otherwise disclosed. If any 
patent action is required to protect intellectual property rights, the investigator agrees to delay 
the disclosure for a period not to exceed an additional 60 days.
The investigator will, on request, remove any previously undisclosed confidential 
information (other than the study results themselves) before disclosure.
If the study is part of a multicentre study, the investigator agrees that the first publication is 
to be a joint publication covering all centers. 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.


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Strome S, Sho M, Akahori T, et al. B7-H1 blockade augments adoptive T-cell 
immunotherapy for squamous cell carcinoma. Cancer Res 2003;63:6501-5. 
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Zhang L, Gajewski TF, Kline J. PD-1/PD-L1 interactions inhibit antitumor immune 
responses in a murine acute myeloid leukemia model. Blood 2009;114:1545-52. 
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Latchman Y, Wood CR, Chernova T, et al. PD-L1 is a second ligand for PD-1 and 
inhibits T cell activation. Nat Immunol 2001;2(3):261-8.

Michot JM, Bigenwald C, Champiat S, et al.  Immune-related adverse events with 
immune checkpoint blockade:  a comprehensive review.  Eur J Cancer 2016;54:139-
148.

Avelumab. Investigator Brochure, Version 5. 05 February 2016.

Piotrowska Z, Niederst MJ, Karlovich CA, et al. Heterogeneity Underlies the 
Emergence of EGFRT790 Wild-Type Clones Following Treatment of T790M-Positive 
Cancers with a Third-Generation EGFR Inhibitor. Cancer Discov 2015; 5(7):713-22.

Thress KS, Paweletz CP, Felip E, et al. Acquired EGFR C797S mutation mediates 
resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M. Nat Med 
2015; 21(6):560-2.

Gettinger SN and Herbst R. B7-H1/PD-1 blockade therapy in non-small cell lung 
cancer: current status and future direction. Cancer J. 2014 Jul-Aug;20(4):281-9.

Brahmer JR, Horn L, Gandhi L, et al. Nivolumab (anti–PD-1, BMS- 936558, ONO-
4538) in patients (pts) with advanced non–small-cell lung cancer. Presented at the 
ASCO Meeting 2014. Chicago, IL. Abstract 8112.

Garon EB, Leighl NB, Rizvi NA, et al. Safety and clinical activity of MK-3475 in 
previously treated patients (pts) with non–small cell lung cancer (NSCLC). Presented at 
the ASCO Meeting 2014 abstract 8020).

Gettinger SN, Shepherd FA, Antonia SA, et al. First-line nivolumab (anti-PD-1; BMS-
936558; ONO-4538) monotherapy in advanced NSCLC: safety, efficacy, and 
correlation of outcomes with PD-L1 status. J Clin Oncol. 2014; 32:5s (abstr. 8024).

Rizvi NA, Garon EB, Patnaik A, et al. Safety and clinical activity of MK-3475 as initial 
therapy in patients with advanced non–small cell lung cancer (NSCLC). J Clin Oncol 
32:5s, 2014 (suppl; abstr 8007).


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Brahmer JB, Rizvi NA, Lutzky J, et al. Clinical activity and biomarkers of MEDI4736, 
an anti–PD-L1 antibody, in patients with NSCLC. J Clin Oncol 32:5s, 2014 (suppl; 
abstr 8021).

Horn L, Herbst R, Spiegel D et al. An analysis of the relationship of clinical activity to 
baseline EGFR status, PD-L1 expression and prior treatment history in patients with 
non–small cell lung cancer (NSCLC) following PD-L1 blockade with MPDL3280A 
(anti-PDL1). Presented at the IASLC 14thWorld Conference on Lung Cancer; July 
2012; Amsterdam, the Netherlands.

Zhou C, Wu Y-L, Chen C, et al. Erlotinib versus chemotherapy as first-line treatment 
for patients with advanced EGFR mutation-positive non-small-cell lung cancer 
(OPTIMAL,CTONG-0802): a multicenter, open-label, randomised, phase 3 study. 
Lancet Oncol. 2011; 12: 735-42.

Zitvogel L. et al (2013) Mechanism of Action of Conventional and Targeted 
Anticancer Therapies: Reinstating Immunosurveillance Immunity 39:74.

Gainor JF, Shaw AT, Sequist LV, Fu X, Azzoli CG, Piotrowska Z, et al.  EGFR 
Mutations and ALK Rearrangements Are Associated with Low Response Rates to PD-1 
Pathway Blockade in Non-Small Cell Lung Cancer (NSCLC): A Retrospective 
Analysis.   Clin Cancer Res. 2016 May 25.

Herbst RS, Baas P, Kim DW, Felip E, Pérez-Gracia JL, Han JY, et al.  Pembrolizumab 
versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung 
cancer (KEYNOTE-010): a randomised controlled trial.  Lancet. 2016 Apr 
9;387(10027):1540-50.

Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, et al..  Cancer 
immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-
small cell lung cancer.  Science. 2015 Apr 3;348(6230):124-8.

Govindan R, Ding L, Griffith M, Subramanian J, Dees ND, Kanchi KL, et al.  Genomic 
landscape of non-small cell lung cancer in smokers and never-smokers.  Cell. 2012 Sep 
14;150(6):1121-34.
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Gettinger S, Politi K.  PD-1 axis inhibitors in EGFR and ALK Driven Lung Cancer: 
Lost cause?  Clin Cancer Res. 2016 Jul 28.
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AstraZeneca halts NSCLC trials of AZD9291 and durvalumab.  Oct 12, 2015. 
http://www.thepharmaletter.com/article/astrazeneca-halts-nsclc-trials-of-azd9291-and-
durvalumab.


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M. Ahn M, Yang J, Yu H, Saka H, Ramalingam S, Goto K, et al. Osimertinib combined 
with durvalumab in EGFR-mutant non-small cell lung cancer: Results from the 
TATTON phase Ib trial.  Abstract 1360, presented at the European Lung Cancer 
Congress Annual Meeting 2016.

TAGRISSO - U.S. Food and Drug Administration 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/208065s000lbl.pdf.

Rizvi NA, Chow LQM, Borghaei H, et al. Safety and response with nivolumab (anti-
PD-1; BMS-936558, ONO-4538) plus erlotinib in patients (pts) with epidermal growth 
factor receptor mutant (EGFR MT) advanced NSCLC. J Clin Oncol. 2014; 32: 5s (abstr. 
8022).
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Ji Y, Lui P, Li Y, et al. A modified toxicity probability interval method for dose-
findingtrials. Clin Trials. 2010; 7: 653-63.

Akbay EA, Koyama S, Carretero J, et al. Activation of the PD-1 pathway contributes to 
immune escape in EGFR-driven tumors. Cancer Disc. 2013; 3: 1355-63.
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Chen N, Fang W, Zhou J, et al. Up-regulation of PD-L1 by EGFR activation mediate 
the immune escape in EGFR-driven NSCLC: implication for optimal immune targeted 
therapy for NSCLC patients with EGFR mutation. J Thorac Oncol. 2015; ePub. 

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2011;364(19):1844-54.

Gopalan PK, Pinder MC, Chiappori A, Ivey AM, Villegas AG, Kaye FJ, et al.  A phase 
II clinical trial of the CDK 4/6 inhibitor palbociclib (PD 0332991) in previously treated, 
advanced non-small cell lung cancer (NSCLC) patients with inactivated CDKN2A.  J 
Clin Oncol 32:5s, 2014 (suppl; abstr 8077). 

Palbociclib. Investigator Brochure, December 2015.

D’Incecco A, Andreozzi M, Ludovini V, et al. PD-1 and PD-L1 expression in 
molecularly selected non-small-cell lung cancer patients. Br J Cancer. 2015; 112: 
95-102.


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17. APPENDICES
Appendix 1. Bone Marrow Reserve in Adults (to be Used in Support of Exclusion of 
>25% Prior Irradiation of the Bone Marrow)
Adapted from R.E. ELLIS: The Distribution of Active Bone Marrow in the Adult, Phy. 
Med. Biol.  5, 255-258, 1961
Marrow Distribution of the Adult
SITE
MARROW
wt. (g)
FRACTION 
RED 
MARROW
AGE 40
RED 
MARROW
wt. (g)
AGE 40
% TOTAL
RED MARROW
CRANIUM
Head :
136.6
AND
Cranium
165.8
0.75
124.3
13.1
13.1
MANDIBLE
Mandible
16.4
0.75
12.3
Upper Limb Girdle :
86.7
HUMERI,
SCAPULAE,
2 Humerus, 
head & neck
26.5
0.75
20.0
8.3
8.3
CLAVICLES
2 Scapulae 
67.4
0.75
50.5
2 Clavicles
21.6
0.75
16.2
Sternum
39.0
0.6
23.4
2.3
Ribs : 
82.6
1 pair
10.2
All 0.4
4.1
2
12.6
5.0
3
16.0
6.4
STERNUM
4
18.6
7.4
AND
5
23.8
9.5
7.9
10.2
RIBS
6
23.6
9.4
7
25.0
10.0
8
24.0
9.6
9
21.2
8.5
10
16.0
6.4
11
11.2
4.5
12
4.6
1.8
Sacrum 
194.0
0.75
145.6
13.9
PELVIC 
BONES
2 os coxae
310.6
0.75
233.0
22.3
36.2
FEMUR
2 Femoral head 
and neck
53.0
0.75
40.0
3.8


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Marrow Distribution of the Adult (cont’d)
SITE
MARROW
wt. (g)
FRACTION RED 
MARROW
AGE 40
RED 
MARROW
wt. (g)
AGE 40
% TOTAL
RED MARROW
Vertebrae
(Cervical):
35.8
1
6.6
All 0.75
5.0
2
8.4
6.3
3
5.4
4.1
3.4
4
5.7
4.3
5
5.8
4.4
6
7.0
5.3
7
8.5
6.4
Vertebrae
(Thoracic):
147.9
1 pair
10.8
All 0.75
8.1
2
11.7
8.8
3
11.4
8.5
4
12.2
9.1
VERTEBRAE
5
13.4
10.1
14.1
28.4
6
15.3
11.5
7
16.1
12.1
8
18.5
13.9
9
19.7
14.8
10
21.2
15.9
11
21.7
16.3
12
25.0
18.8
Vertebrae
(Lumbar) :
114.1
1 pair
27.8
All 0.75
20.8
2
29.1
21.8
10.9
3
31.8
23.8
4
32.1
24.1
5
31.4
23.6
TOTAL
1497.7
1045.7
100.0
100.0


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Appendix 2. ECOG PS 
Grade ECOG
0
Fully active, able to carry on all pre-disease performance without restriction.
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, 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.


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Appendix 3. AE Management Guidelines 
In all instances, it is recommended that patients be instructed at time of starting drug therapy 
to call the Investigator/Site if no improvement in symptoms has been observed after 24 hours 
of patient taking the recommended/optimal pharmacologic treatment.
Abbreviations:
BSA: Body Surface Area.
ADL: Activities of Daily Living. 
Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
Self care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, 
taking medications and not bedridden. (definitions per CTCAEv4).
GABA: gamma-Aminobutyric Acid.
DIARRHEA

Patients should be encouraged to drink 8 to 10 large glasses of clear liquids per day 
while on study in order to maintain adequate hydration.

General dietary measures to limit impact of diarrhea could include:

Stop all lactose-containing products in patients with evidence of lactose 
intolerance;

Eat frequent small meals if experiencing increased frequency of stools;

Consider low fat regimen enriched with bananas, rice, applesauce, and toast.


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Diarrhea Management Guideline
Grade of Event
Grade 1: increase of <4 stools per day over 
baseline;
Loperamide 4 mg at the first onset of diarrhea and then 2 mg every 
2 hours until the patient is diarrhea-free for at least 12 hours.  
(During the night the patient may take 4mg of loperamide every 
4 hours).
Fluid intake of at least 2 liter (L) should be maintained to avoid 
dehydration: patients are to drink 8-10 large glasses of clear liquids.  
Consideration for maintenance of electrolyte balance would include 
electrolyte-containing drinks, broth, clear juices. 
Grade 2: increase of 4-6 stools per day 
over baseline;
Loperamide as above, or consider use of diphenoxylate 
hydrochloride and atropine sulfate formula (eg Lomotil, Diarced, 
Co-Phenotroope) at standard doses.
Fluid intake of at least 2 L should be maintained to avoid 
dehydration. 
Monitor patient closely and consider intravenous hydration. 
Grade 3: increase of 7 stools per day over 
baseline; or incontinence; or limiting self 
care ADL: or hospitalization indicated
Oral therapy with diphenoxylate hydrochloride and atropine sulfate 
formula, or tincture of opium. 
Fluid intake of at least 2 L should be maintained, intravenously if 
necessary. 
Consider use of octreotide (Sandostatin) 100-150 microgram (g) 
subcutaneously twice daily with escalation to 500 g three times 
daily.
Grade 4: life-threatening 
Maximal inpatient fluid and nutritional support, antibiotics as 
indicated in judgment of investigator for fever, leucocytosis, marked 
dehydration, etc.


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DERMATOLOGIC TOXICITY
Acneiform/Papulopustular Rash:
Acneiform/ Papulopustular Rash Management 
Guideline
Grade 1:
<10% body surface area (BSA) papules and / or 
pustules (with or without symptoms of pruritis or 
tenderness)
Topical steroids *
And
Topical antibiotic bid (clindamycin 1 - 2%,
erythromycin 1% - 2%, metronidazole 1%)
Grade 2:
10 to 30% BSA papules and / or pustules (with or 
without symptoms of pruritis or tenderness), or 
psychosocial impact, or limited instrumental ADL
Oral antibiotic for at least 4 weeks  
(doxycycline 100mg bd, minocycline 
100mg bd or oxytetracycline 500mg bd);
Stop topical antibiotic if being used
And
Topical steroids *
Grade 3:
>30% BSA papules and / or pustules (with or 
without symptoms of pruritis or tenderness); or

limiting self-care ADL: or

associated with local superinfection with oral 
antibiotics indicated
Oral antibiotic for 4 weeks 
(doxycycline 100 mg bd, minocycline 
100mg bd or oxytetracycline 500 mg bd)
If infection suspected (yellow crusts, purulent 
discharge, painful skin / nares):
switch oral antibiotic to broad spectrum/gram 
negative cover for at least 10 days
consider skin swab for bacterial culture, 
And
Topical steroids (continue)*
Consider dermatology consultation
* Moderate/Low strength steroids include: 
Triamcinolone acetonide 0.025% 
Desonide 0.05%
Alclometasone 0.05% cream
Fluticasone propionate 0.05% 
For patients intolerant or allergic to tetracycline 
antibiotics, use an antibiotic with Staphloccoccus 
coverage (eg, cephalexin, sulfamethoxazole/ 
trimethoprim)
Dry Skin/ Xerosis:
Prophylaxis against dry skin would include:

Initiation of skin moisturizing cream or ointment regimen upon establishment of 
eligibility (ie prior to first dose).  (avoid skin lotions, as they may contain alcohol);

Avoidance of excessive exposure to hot water during showering/ bathing;


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
Avoidance of household tasks involving immersion in hot water/ detergent/ solvents;

Avoidance of excessive sun exposure/ tanning.  Use sunscreen containing zinc oxide 
or titanium dioxide with SPF at least 30:  apply every two hours when exposed to sun.
Xerosis/ Dry Skin Management Guideline
Grade 1:
<10% BSA and no
associated erythema or pruritis
Over-the-counter Moisturizing cream or ointment 
to face bid 
AND
Ammonium lactate 12% (or equivalent) cream to 
body bid
Grade 2:
10 to 30% BSA and associated with erythema or 
pruritis; or
limited instrumental ADL
OTC Moisturizing cream or ointment to face bid; 
AND
Ammonium lactate 12% cream OR salicylic acid 
6% cream to body bid
Grade 3
>30% BSA and associated with pruritis; or
limiting self care ADL
OTC Moisturizing cream or ointment to face bid; 
AND
Ammonium lactate 12% cream OR salicylic acid 
6% cream to body bid 
AND
Topical steroid* to eczematous areas bid
*Moderate/Low strength steroid include:
Triamcinolone acetonide 0.025% (Aristocort A 
cream) 
Desonide 0.05% (DesOwen cream, lotion) 
Alclometasone 0.05% cream (Allocate cream)
Fluticasone propionate 0.05% 
Paronychia:
Minimization of periungual trauma and superinfection is advised:

Wearing comfortable shoes, 

trimming nails but avoiding aggressive manicuring, 

wearing gloves while cleaning (eg, household, dishes).


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Paronychia Management Guideline
Grade 1
Nail fold edema or erythema; or
disruption of the cuticle
Topical Antibiotics and vinegar soaks *
Grade 2
Localized intervention indicated; or oral intervention 
indicated (eg, antibiotic, antifungal, antiviral); or nail 
fold edema or erythema with pain; or associated with 
discharge or nail plate separation; or limiting 
instrumental ADL
Topical antibiotics and vinegar soaks*
Apply silver nitrate weekly
Grade 3
Surgical intervention,  or IV antibiotics indicated; or 
limiting self-care ADL
Topical antibiotics and vinegar soaks*
Apply silver nitrate weekly
Surgical consultation as needed
*Topical antibiotics/ vinegar soaks
Topical antibiotics: Clindamycin 1%, 
erythromycin 1%
Vinegar soaks consist of soaking fingers or toes in 
a 1:1 solution of white vinegar in water for 
15 minutes every day
For a video on how to apply silver nitrate, visit: 
http://www.youtube.com/watch?v=HF5oopqheJY
Pruritus/ Itching guidelines:
Prophylaxis against dry skin would include:

Initiation of skin moisturizing regimen prior to first dose.  Non-scented emollient skin 
cream should be used;

Avoidance of excessive exposure to hot water during showering/ bathing;

Avoidance of household tasks involving immersion in hot water/ detergent/ solvents;

Avoidance of excessive sun exposure/ tanning.  Use sunscreen containing zinc oxide 
or titatinium dioxide with SPF at least 30:  apply every two hours when sun exposure 
is anticipated.
Pruritus Management Guideline
Grade 1:
Mild or localized; or topical intervention indicated
Topical steroid moderate/ low strength (as listed 
above for acneiform rash)
or 
Topical antipruritics (pramoxine 1%, doxepin 5% 
cream) applied twice daily


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Grade 2
Intense or widespread, intermittent; skin changes from 
scratching (eg, edema, papulation, excoriations, 
lichenification, oozing/crusts); or oral intervention 
indicated; or limiting instrumental ADL
Topical steroid moderate strength
or 
Topical antipruritics (pramoxine 1%, doxepin 5% 
cream) applied twice daily
AND
Oral antihistamines 
Grade 3:
Intense or widespread,  constant; or limiting self-care
ADL or sleep; or oral corticosteroid or 
immunosuppressive therapy indicated
Oral antihistamines
AND
GABA agonists (gabapentin or pregabalin) or 
Doxepin 
Antihistamines: diphenhydramine 25-50 mg tid; 
hydroxizine 25 mg tid; fexofenadine 60 mg tid
GABA agonists (adjust if renal impairment) : 
Gabapentin 300 mg every 8 hours or Pregabalin 
50-75 mg every 8 hours
Tricyclics: Doxepin 25-50 mg every 8 hours
MUCOSITIS
Patients who have not had dental checkup within 6 months prior to start of dosing are 
encouraged to do so, especially to identify any persistent issue related to recent 
chemotherapy.  Once on treatment, patients are to consult the site health care team prior to 
undertaking any dental or oral surgery procedure to determine if it would be appropriate to 
proceed depending on presence of any ongoing mucosal inflammation/ stomatitis. 
Between scheduled visits, patient self-report of oral mucosal discomfort or of visible changes 
in appearance to oral mucosa is encouraged.  Periodic systemic examination of the oral 
cavity is required at scheduled visits and as otherwise indicated by patient self-report 
between visits.
Patients should practice good oral care including a soft-bristle toothbrush replaced frequently 
and use of bland rinses or moisturizers. 
Regular use of warm water non-medicated saline rinse is recommended if stomatitis 
develops.  Frequent sips of water during meals may assist swallowing and therefore maintain 
caloric intake and hydration in patients experiencing oral pain 
Use of chlorhexidine is to be avoided.
Topical anesthetics or systemic analgesics may be used as indicated in judgment of the 
investigator and according to local clinical practices.  Topical steroid rinses have been 
reported to be helpful in severe cases (eg, dexamethasone 0.5 mg/ 5 mL swish and 
expectorate four times daily).


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Consultation with nutritionist is to be considered if toxicity may compromise maintenance of 
adequate caloric intake.
Keratoconjunctivitis
Keratoconjunctivtis Guideline
Grade 1
Asymptomatic or mild symptoms; intervention not 
indicated
No intervention or dose modification is mandated
Grade 2
Symptomatic; topical intervention indicated; or 
limiting instrumental ADL
Patients should be examined within 72 hours. Exam 
should include slit-lamp, fundoscopic exam and 
visual acuity and other investigation required per 
investigator judgement.Preservative free artificial 
tears, ointments, and /or other therapies as clinically 
indicated.
Study Treatment: If symptom lasts 2 weeks, 
withhold treatment untilGrade 1 and then reduce 
one dose level.
Grade 3
Limiting self-care ADL
Patients should be examined within 72 hours. Exam 
should include slit-lamp, fundoscopic exam and 
visual acuity and other investigation required per 
investigator judgement. Preservative free artificial 
tears, ointments, and/or other therapies as clinically 
indicated.
Study Treatment: Drug should be withheld until 
recovers toGrade 1 and then reduce one dose level.


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Appendix 4. RECIST Version 1.1
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.
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’).
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. 


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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. 

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. 


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
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
Subjects 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 discontinuation 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
Best Overall Response
The best overall response (BOR) is the best response recorded from the start of treatment 
until disease progression.  This is derived from the sequence of objective statuses.  Objective 
statuses are not considered after objective progression is documented or after start of the first 
anticancer treatment post discontinuation of protocol treatment.  BOR for each patient will be 
derived as one of the following categories. 

Complete response (CR): At least one objective status of CR documented before 
progression.

Partial response (PR): At least one objective status of PR documented before 
progression.

Stable disease (SD): At least one objective status of stable documented at least 
6 weeks after start of treatment date and before progression but not qualifying as CR, 
PR.

Progressive Disease (PD): Objective status of progression within 12 weeks of start 
of treatment date, not qualifying as CR, PR or SD. 

Indeterminate (IND): Progression not documented within 12 weeks after start of 
treatment date and no other response category applies. 


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Appendix 5. List of Drugs Known to Predispose to Torsade de Pointes
Generic Name
Brand Name(s)
Amiodarone
Cordarone, Pacerone
Arsenic trioxide
Trisenox
Astemizole
Hismanal
Azithromycin
Zithromax
Bepridil
Vascor
Chloroquine
Aralen
Chlorpromazine
Thorazine
Cisapride
Propulsid
Citalopram
Celexa
Clarithromycin
Biaxin
Disopyramide
Norpace
Dofetilide
Tikosyn
Domperidone
Motilium
Droperidol
Inapsine
Erythromycin
Erythrocin, E.E.S. 
Flecainide
Tambocor
Halofantrine
Halfan
Haloperidol
Haldol
Ibutilide
Corvert
Levomethadyl
Orlaam
Mesoridazine
Serentil
Methadone
Dolophine, Methadose
Moxifloxacin
Avelox
Ondansetron*
Zofran
Pentamidine
Pentam, NebuPent
Pimozide
Orap
Probucol
Lorelco
Procainamide
Pronestyl, Procan
Quinidine
Cardioquin, Quinaglute
Sotalol
Betapace
Sparfloxacin
Zagam
Terfenadine
Seldane
Thioridazine
Mellaril
Vandetanib
Caprelsa
*when administered intravenously at high dose (32 mg).
Adapted from the University of Arizona Cancer Center for Education and Research on Therapeutics: "Torsades 
List: Drugs with a Risk of Torsades de Pointes," drugs that are generally accepted by the QTdrugs.org Advisory 
Board to carry a risk of Torsades de Pointes on the University of Arizona CERT website: 
http://www.crediblemeds.org/.  This list is not meant to be considered all inclusive.  See website for current list


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Appendix 7. Detailed Dose Escalation/De-Escalation Scheme for mTPI Design Based on 
30% Toxicity Rate.
DLTs at 
current dose 
level
Number of patients per dose level (cumulative)
1
2
3
4
5
6
7
8
9
10
0
E
E
E
E
E
E
E
E
E
E
1
D
S
S
S
S
E
E
E
E
E
2
DU
D
S
S
S
S
S
E
E
3
DU
DU
D
D
S
S
S
E
4
DU
DU
DU
DU
DU
DU
DU
E= escalate or if current dose level is DL1 stay on DL1; S= stay at current dose; D= de-escalate; DU = de-
escalate and dose is unacceptable due to toxicity
Escalation/De-escalation algorithms for total number of patients treated at the current dose 
level (current and previous cohorts):

With 2 patients treated at current dose level

0 DLT -> escalate

1 DLT -> remain at the same dose

2 DLTs -> de-escalate and consider current dose as intolerable

With 3 patients treated at current dose level

0 DLT -> escalate

1 DLT -> remain at the same dose

2 DLTs -> de-escalate 

3 DLTs -> de-escalate and consider current dose as intolerable

With 4 patients treated at current dose level

0 DLT -> escalate

1-2 DLTs -> remain at the same dose

3-4 DLTs -> de-escalate and consider current dose as intolerable

With 5 patients treated at current dose level

0 DLT -> escalate

1-2 DLTs -> remain at the same dose


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
3 DLTs -> de-escalate

4-5 DLTs -> de-escalate and consider current dose as intolerable

With 6 patients treated at current dose level

0-1 DLT -> escalate

2 DLTs -> remain at the same dose

3 DLTs -> de-escalate

4-6 DLTs -> de-escalate and consider current dose as intolerable

With 7 patients treated at current dose level

0-1 DLT -> escalate

2-3 DLTs -> remain at the same dose

4 DLTs -> de-escalate

5-7 DLTs -> de-escalate and consider current dose as intolerable

With 8 patients treated at current dose level

0-1 DLT -> escalate

2-3 DLTs -> remain at the same dose

4-8 DLTs -> de-escalate and consider currentdose as intolerable

With 9 patients treated at current dose level

0-2 DLT -> escalate

3 DLTs -> remain at the same dose

4-9 DLTs -> de-escalate and consider current dose as intolerable

With 10 patients treated at current dose level

0-3 DLT -> escalate (MTD if highest dose)

4-10 DLTs -> de-escalate and consider current dose as intolerable


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Appendix 8. Japanese Patient-Only Lead In Cohort
To date, there is no documented experience with PF-06747775 in Japanese patients.
Therefore, this study will include a Japanese patient lead in cohort (LIC) to evaluate the 
safety, tolerability and PK of PF-06747775 in Japanese patients with advanced EGFRm 
NSCLC. This Japanese LIC will include 2 cohorts; RP2D tolerability cohort and PK cohort.  
The PK cohort will not form part of the RP2D tolerability cohort and therefore does not need 
to have completed enrollment prior to Japanese enrollment in the other study cohorts (cohorts 
1, 2A/2B, 3).

Objective
RP2D tolerability cohort
To evaluate the safety and tolerability of PF 06747775 in Japanese patients.
PK cohort
To characterize single dose and steady state PK profiles of single agent PF-06747775 in 
Japanese patients

Study design
RP2D tolerability cohort
Initially up to 3 patients will be enrolled and treated. If a DLT [DLT definitions are same as 
Phase 1 PF-06747775 Single Agent (See Section 3.2)] is observed in 1 of the initial 3 treated 
patients, then 3 additional patients will be enrolled and treated. Patients who discontinue 
treatment before completing Cycle 1 (ie, the DLT observation period) or receive less than 15
of the planned 21 PF-06747775 doses for reasons other than treatment related toxicity (eg, 
missed appointments, misplaced study drug supplies, development of coexisting medical 
condition rendering the patient unable to swallow medication, development of rapidly 
progressing disease) will be replaced for DLT evaluation but will remain in the overall safety 
and efficacy analyses. If 33% patients experience DLT (0/3 or 1/6), then the tested dose 
would be considered tolerable in Japanese patients. If >33% patients experience DLT, then 
Japan sites will not join the other cohorts and a lower dose cohort may be explored if deemed 
necessary. Additional patients may be included for further safety and tolerability assessments 
in the LIC as appropriate. 


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DLT ≤1/6
DLT ≥2/6
RP2D tolerability cohort Schema
PK cohort
After tolerability has been confirmed in RP2D tolerability cohort, PK cohort will be initiated. 
In PK cohort, 3 patients will be enrolled and they will have 100 mg single dose followed by 
once daily multiple dose at RP2D. Both in RP2D tolerability cohort and PK cohort, blood 
samples will be collected for PK assessment. Single dose PK in 100 mg and RP2D and 
multiple dose PK at RP2D in Japanese patients will be assessed in this Japanese LIC.
Japanese LIC Patients 
(minimum 3 patients)
DLT ≤ 0/3
DLT = 1/3
DLT >1/3
Japan Will Not Join 
other cohorts
Add 3 Patients 
for 
Confirmation
Japan Will Join 
other cohorts


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Table A8-1. Japanese patient-Only LIC RP2D Tolerability Cohort Schedule of Assessments
LEAD-
IN PK
CYCLE 130
(21 days)
CYCLE 2
(21 days)
CYCLES ≥3
(21 days)
End of 
Treatment28
Follow- up29
Visit Identifier
Screening2
Day -4
Day 11
Day 8
Day 15
Day 1
Day 1
Visit Window
28 days from 
registration
1
1
1
2
2
3
+7
Informed consent3
X
Tumor history
X
Medical history
X
Physical examination
X
(X)
X
X
Baseline signs and symptoms4
X
Height
X
Weight
X
X
X
X
Vital signs5
X
X
X
X
X
X
X
X
Performance status (ECOG)6
X
X
X
X
X
X
X
X
Contraception check7
X
(X)
X
X
X
Laboratory
Hematology8
X
(X)
X
X
X
X
X
Blood Chemistry9
X
(X)
X
X
X
X
X
Coagulation10
X
(X)
X
X
X
Urinalysis11
X
(X)
X
Pregnancy test12
X
X
X
X
X
(12-lead) ECG13
X
See TableA8-2
X
Pulse Oximetry14
X
X
X
X
X
X
(up to Cycle 5)
X
Chest X ray or Chest CT15
X
Registration and Treatment
Registration16
X
PF-0674777517
X
Once daily PO continuous
Tumor assessments 
CT or MRI imaging18
X
X and every 
other cycle 
(every 
6 weeks) 
+/- 7 days
X
Other clinical assessments


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LEAD-
IN PK
CYCLE 130
(21 days)
CYCLE 2
(21 days)
CYCLES ≥3
(21 days)
End of 
Treatment28
Follow- up29
Visit Identifier
Screening2
Day -4
Day 11
Day 8
Day 15
Day 1
Day 1
Visit Window
≤28 days from 
registration
±1
±1
±1
±2
±2
±3
+7
Adverse Events19
X
X
X
X
X
X
X
Concomitant treatments and 
non-drug supportive 
interventions20
X
X
X
X
X
X
Other samplings
 
 
Pharmacokinetics22
See TableA8-2
 
 
 
 
Survival27
X
CT = computed tomography; ECG = electrocardiogram; MRI =  magnetic resonance imaging
Footnotes:
1.
Day relative to start of study treatment (Day 1).
2.
Screening: to be obtained within 28 days prior to registration.
3.
Informed Consent: must be obtained prior to undergoing any study specific procedures unless considered standard of care. After completion of Cycle 1, 
patients will be asked to sign an additional consent document for confirmation of the patient’s willingness to continue participation in this study before 
starting Cycle 2.
4.
Baseline Signs & Symptoms: patients will be asked about any signs and symptoms experienced within the past 14 days of registration.  Baseline signs and 
symptoms (including NCI CTCAE grade, if applicable) will be recorded on the Medical History case report form (CRF) page.
5.
Vital signs: vital signs include blood pressure (BP) and heart rate (HR).  Vital signs will be taken and recorded during the site clinic visit. 
6.
Performance status: use Eastern Cooperative Oncology Cohort (ECOG) – see Appendix 2.
7.
Contraception Check: Male patients who are able to father children, and female patients who are of childbearing potential will need to affirm that they 
meet the criteria for correct use of 2 of the selected methods of contraception.  The investigator or his or her designee will discuss with the patient the need to 
use 2 highly effective contraception methods consistently and correctly, and document such conversation in the patient’s chart.  In addition, the investigator 
or his or her designee will instruct the patient to call immediately if one or both selected contraception methods are discontinued, or if pregnancy is known or 
suspected in the patient or the patient’s partner.
8.
Hematology: See Section 7.1.4 for specific required tests.  No need to repeat on Cycle 1 Day 1 (C1D1) if baseline assessment performed within 7 days prior 
to that date.
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9.
Blood Chemistry: See Section 7.1.4 for specific required tests.  No need to repeat on C1D1 if baseline assessment performed within 7 days prior to that 
date.
10. Coagulation: See Section 7.1.4 for specific required tests.  No need to repeat on C1D1 if baseline assessment performed within 7 days prior to that date.
11. Urinalysis: See Section 7.1.4 for specific required tests.  Dipstick is acceptable.  Microscopic analyses if dipstick abnormal.  No need to repeat on C1D1 if 
baseline assessment performed within 7 days prior to that date.
12. Serum/Urine Pregnancy Test: For female patients of childbearing potential, ie, who do not fit the definition of “female patients who are not of childbearing 
potential” in inclusion criterion 13, a serum or urine pregnancy test, with sensitivity of at least 25 mIU/mL and assayed in a certified laboratory>, will be 
performed on two occasions prior to starting study therapy - once at the start of screening and once at the baseline visit, immediately before investigational 
product administration.  Pregnancy tests will also be routinely repeated at every cycle during the active treatment period, at the end of study therapy and 
additionally whenever one menstrual cycle is missed or when potential pregnancy is otherwise suspected.  Additional pregnancy tests may also be 
undertaken if requested by institutional review board/ethics committee (IRB/ECs) or if required by local regulations.
13. Triplicate 12-lead ECGs: At each time point, three consecutive 12-lead ECGs will be performed approximately 2 minutes apart to determine mean QTcF 
interval.  When coinciding with blood sample draws for pharmacokinetics (PK), ECG assessment should be performed prior to blood sample collection, such 
that the blood sample is collected at the nominal time (ie, the timing of the PK collections over rides the timing of the ECG collections).  ECG assessments 
pre-dose should happen prior to breakfast.  If the mean QTcF is prolonged (value of >500 msec), the ECGs should be re-evaluated by a qualified person at 
the institution for confirmation.  Additional triplicate ECGs may be performed as clinically indicated.  ECG assessments will be performed  according to the 
schedule outlined in Table A8-2.
14. Pulse Oximetry: Pulse oximetry will be performed within 14 days prior to the first dose of investigational product treatment, and during treatment as 
described in the table above.  Pulse oximetry should be repeated if clinically indicated.
15. Chest X ray or Chest CT: Chest X ray or Chest CT will be performed within 14 days prior to the first dose of study drug.  Chest X ray or CT should be 
repeated if clinically indicated and at the discretion of the investigator.  Patients who have had a CT scan including chest for the purpose of tumor 
assessment for this study will not need to be repeated at baseline.
16. Registration: Patients will be enrolled according to a computer generated pseudo-random code.  Randomization numbers will be assigned by a central 
web-based randomization system operated by Pfizer Inc. 
17. Study Treatment: The recommended Phase 2 Dose (RP2D) of PF-06747775 will be given with a breakfast of 200-300 calories in the morning every day at 
approximately the same time once daily in 21 day cycles. A single lead-in dose will be given on Day -4, and continuous daily dosing with start on Cycle 1 
Day 1. See Table A8-2 for more details.
18. CT or MRI Tumor Assessments: Baseline assessments must be within 28 days of first study treatment.  Tumor assessments will include all known or 
suspected disease sites.  Tumor response will be assessed per RECIST v1.1.  Imaging may include chest, abdomen and pelvis CT or MRI scans.  Minimally, 
chest, liver and adrenals must be imaged.  Brain scans are required at baseline and every assessment if intra-cerebral disease is present; if no intra-cerebral 
disease is found at baseline, then brain imaging is only required on study if clinically indicated.  Bone scans will be performed at baseline if clinically 
indicated and on-study as appropriate to follow disease.  For all patients with RECIST measurable disease who have a RECIST response, confirmation of the 
response is required at least 4 weeks after initial assessment of response. Tumor assessment should be repeated at the End of Treatment visit if more than 
6 weeks have passed since the last evaluation.  For patients that have discontinued the treatment period due to reasons other than disease progression: Tumor 
assessments must continue until documented progression of disease by investigator. Patients who discontinue treatment without PD should continue to have 
tumor assessments performed every 6 weeks until PD is confirmed by investigator regardless of subsequent anti-cancer treatments.


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19. Adverse Event (AE) Assessments: Adverse events should be documented and recorded at each visit using the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTC AE) version 4.0.  Patients must be followed for AEs for 28 days after the last treatment administration 
or until all drug related toxicities have resolved, whichever is later; or earlier than 28 days should the patient commence another anticancer therapy in the 
meantime.  For serious adverse events (SAEs), the active reporting period to Pfizer or its designated representative begins from the time that the patient 
provides informed consent, which is obtained prior to the patient’s participation in the study, ie, prior to undergoing any study-related procedure and/or 
receiving investigational product, through and including 28 calendar days after the last administration of the investigational product.  Serious adverse events 
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 serious adverse events that the investigator believes have at least a reasonable possibility of being related to investigational product are to be reported to 
the sponsor.
20. Concomitant Treatments: all concomitant medications and Non Drug Supportive Interventions should be recorded in the CRF.
 
 
 
 
22. PK Sampling: serial blood samples will be collected after single and multiple doses (steady state) of PF-06747775 to characterize PK behavior. See Table 
A8-2 for more detailed information. 
 
 
 
 
 
27. Survival: Will be performed every 2 months for up to 24 months after PD or new anti-cancer therapy has commenced (telephone contact is acceptable).
28. End of Treatment visit: Obtain these assessments if not completed in the last week (last 6 weeks for tumor assessments). 
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, 
vital signs, and assessment for resolution of any treatment related toxicity. Patients continuing to experience toxicity at this point following discontinuation 
of treatment will continue to be followed at least every 4 weeks until resolution or determination, in the clinical judgment of the investigator, that no further 
improvement is expected.  For patients that have discontinued the treatment period due to reasons other than disease progression: Tumor assessments will 
continue to be performed every 6 weeks during long term follow up until documented disease progression, start of a new anti-cancer treatment, death or lost 
to follow-up (whichever occurs first).  All patients will be followed for at least 24 months after initial dose of last patient treated.
30. Patients will be hospitalized at least the first 14 days on Cycle 1.
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Table A8-2.Japanese Patient-Only LIC RP2D Tolerability Cohort - PK and ECG Assessments
Visit Identifier
Lead-in
Cycle 1
Cycles 2 - 4
Day
-4
-3
-2
-1
1 (± 1)
2-10
11
(± 2)
12
1
(± 2)
Hours Post 
Dose
0a
1
2
4
6
8
24
48
72
96f 
(Pre-
Doseb)
0a
Pre-Doseb
Pre-
Doseb
1
2
4
6
8
24 (Pre-
Doseb)
Pre-Doseb
PF-
06747775 Dosec
X
X
Once daily PO continuous, with breakfast
PK blood 
samplingd
Xb
X
X
X
X
X
X
X
X
Xb
Xb
Xb
X
X
X
X
X
Xb
Xb
12-Lead ECGe
X
X
X
X
X
X
a.
0 hrs. Dose time: dose time of PF-06747775 triggers the defined post dose sample collection times.
b.
Pre-dose sample collection: before study treatment dose.
c.
PF-06747775 dose: PF-06747775 dose will be given in the morning with a breakfast of 200-300 calories, at approximately the same time once daily in 
21 day cycles starting continuous dosing on Cycle 1 Day 1. On days in which pre-dose ECG or PK assessments are conducted, dosing should occur in clinic 
with breakfast after pre-dose ECGs are completed and pre-dose PK samples are drawn. Food is allowed 2 hrs. after dose. 
d.
PK blood sampling for PF-06747775 analysis: On Day -4, 4 mL of blood in K2EDTA tubes will be collected as shown above for single dose PK analysis.  
On Day 1 of Cycle 1, (96 hr post lead-in dose) a PK sample will be taken before dose of PF-06747775 (the start of continuous daily dosing). On days 2-10, 
trough samples will be collected prior to PF-06747775 dose (pre-dose) to determine attainment of steady state. The samples will be collected every day from 
Day 2 to 5. After that, samples will be collected on every other day, ie., trough samples will be collected on Cycle 1 Days 2, 3, 4, 5, 7 and 9, until serial PK 
sampling occurs on Day 11 (± 1). On Day 11 of Cycle 1, 4 mL of blood in K2EDTA tubes will be collected as shown above for multiple dose PK analysis.  
On Day 1 of Cycles 2 - 4, 4 mL of blood in K2EDTA tubes will be collected prior to PF 06747775 dose (pre-dose) for steady state PK analysis. If, during the 
course of treatment, a patient needs to reduce the dose of PF-06747775, serial PK samples may be taken at least 1 week after starting the reduced dose using 
the same PK blood sampling schedule as outlined above for Cycle 1 Day 11 through pre-dose on Day 12.  
e.
Triplicate 12-Lead ECG: At each time point, three consecutive 12-lead ECGs will be performed approximately 2 minutes apart.  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 (ie, the timing of the PK collections over rides the timing of the ECG collections).  ECG assessments pre-dose should happen prior to breakfast.  If the 
mean QTcF is prolonged (value of >500 msec), the ECGs should be re-evaluated by a qualified person at the institution for confirmation.  Additional 
triplicate ECGs may be performed as clinically indicated.  ECG assessments will be performed at pre-dose and 2 hrs. post dose on Day -4, pre-dose and 
2 hrs. and 6 hrs. post dose on Day 11 of Cycle 1, and pre-dose on Days 1 of Cycles 2 - 4.  The 2 hrs. post dose ECG assessment is intended to target Cmax, 
this time point may be re-assessed as data emerge.
f.
If the -1 day window is utilized for the Cycle 1 Day 1 visit, then the 72 hrs. PK blood draw should occur prior to the dose of PF-06747775, which starts the 
once daily continuous dosing; in this case the 96 hrs. PK blood draw will not be completed.
Abbreviations: PK = pharmacokinetic; PO = by mouth; QTcF = QT interval corrected by Fridericia’s formula


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Table A8-3. Japanese Patient-Only LIC PK Cohort Schedule of Assessments
LEAD-IN 
PK
CYCLE 1
(21 days)
CYCLE 2
(21 days)
CYCLES ≥3
(21 days)
End of 
Treatment28
Follow- up29
Visit Identifier
Screening2
Day -7
Day 11
Day 8
Day 15
Day 1
Day 1
Visit Window
28 days from 
registration
1
1
1
2
2
3
+7
Informed consent3
X
Tumor history
X
Medical history
X
Physical examination
X
(X)
X
X
Baseline signs and symptoms4
X
Height
X
Weight
X
X
X
X
Vital signs5
X
X
X
X
X
X
X
X
Performance status (ECOG)6
X
X
X
X
X
X
X
X
Contraception check7
X
(X)
X
X
X
Laboratory
Hematology8
X
(X)
X
X
X
X
X
Blood Chemistry9
X
(X)
X
X
X
X
X
Coagulation10
X
(X)
X
X
X
Urinalysis11
X
(X)
X
Pregnancy test12
X
X
X
X
X
(12-lead) ECG13
X
See TableA8-4
X
Pulse Oximetry14
X
X
X
X
X
X
(up to Cycle 5)
X
Chest X ray or Chest CT15
X
Registration and Treatment
Registration16
X
PF-0674777518
X
Once daily PO continuous
Tumor assessments 
CT or MRI imaging18
X
X and every 
other cycle 
(every 
6 weeks) 
+/- 7 days
X
Other clinical assessments


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LEAD-IN 
PK
CYCLE 1
(21 days)
CYCLE 2
(21 days)
CYCLES ≥3
(21 days)
End of 
Treatment28
Follow- up29
Visit Identifier
Screening2
Day -7
Day 11
Day 8
Day 15
Day 1
Day 1
Visit Window
≤28 days from 
registration
±1
±1
±1
±2
±2
±3
+7
Adverse Events19
X
X
X
X
X
X
X
Concomitant treatments and 
non-drug supportive 
interventions20
X
X
X
X
X
X
Other samplings
 
 
Pharmacokinetics22
See TableA8-4
 
 
 
 
Survival27
X
CT = computed tomography; ECG = electrocardiogram; MRI =  magnetic resonance imaging
Footnotes:
1.
Day relative to start of study treatment (Day 1).
2.
Screening: to be obtained within 28 days prior to registration.
3.
Informed Consent: must be obtained prior to undergoing any study specific procedures unless considered standard of care. 
4.
Baseline Signs & Symptoms: patients will be asked about any signs and symptoms experienced within the past 14 days of registration.  Baseline signs and 
symptoms (including NCI CTCAE grade, if applicable) will be recorded on the Medical History case report form (CRF) page.
5.
Vital signs: vital signs include blood pressure (BP) and heart rate (HR).  Vital signs will be taken and recorded during the site clinic visit. 
6.
Performance status: use Eastern Cooperative Oncology Cohort (ECOG) – see Appendix 2.
7.
Contraception Check: Male patients who are able to father children, and female patients who are of childbearing potential will need to affirm that they 
meet the criteria for correct use of 2 of the selected methods of contraception.  The investigator or his or her designee will discuss with the patient the need to 
use 2 highly effective contraception methods consistently and correctly, and document such conversation in the patient’s chart.  In addition, the investigator 
or his or her designee will instruct the patient to call immediately if one or both selected contraception methods are discontinued, or if pregnancy is known or 
suspected in the patient or the patient’s partner.
8.
Hematology: See Section 7.1.4 for specific required tests.  No need to repeat on Cycle 1 Day 1 (C1D1) if baseline assessment performed within 7 days prior 
to that date.
9.
Blood Chemistry: See Section 7.1.4 for specific required tests.  No need to repeat on C1D1 if baseline assessment performed within 7 days prior to that 
date.
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10. Coagulation: See Section 7.1.4 for specific required tests.  No need to repeat on C1D1 if baseline assessment performed within 7 days prior to that date.
11. Urinalysis: See Section 7.1.4 for specific required tests.  Dipstick is acceptable.  Microscopic analyses if dipstick abnormal.  No need to repeat on C1D1 if 
baseline assessment performed within 7 days prior to that date.
12. Serum/Urine Pregnancy Test: For female patients of childbearing potential, ie, who do not fit the definition of “female patients who are not of childbearing 
potential” in inclusion criterion 13, a serum or urine pregnancy test, with sensitivity of at least 25 mIU/mL and assayed in a certified laboratory>, will be 
performed on two occasions prior to starting study therapy - once at the start of screening and once at the baseline visit, immediately before investigational 
product administration.  Pregnancy tests will also be routinely repeated at every cycle during the active treatment period, at the end of study therapy and 
additionally whenever one menstrual cycle is missed or when potential pregnancy is otherwise suspected.  Additional pregnancy tests may also be 
undertaken if requested by institutional review board/ethics committee (IRB/ECs) or if required by local regulations.
13. Triplicate 12-lead ECGs: At each time point, three consecutive 12-lead ECGs will be performed approximately 2 minutes apart to determine mean QTcF 
interval.  When coinciding with blood sample draws for pharmacokinetics (PK), ECG assessment should be performed prior to blood sample collection, such 
that the blood sample is collected at the nominal time (ie, the timing of the PK collections over rides the timing of the ECG collections).  ECG assessments 
pre-dose should happen prior to breakfast.  If the mean QTcF is prolonged (value of >500 msec), the ECGs should be re-evaluated by a qualified person at 
the institution for confirmation.  Additional triplicate ECGs may be performed as clinically indicated. ECG assessments will be performed  according to the 
schedule outlined in Table A8-4.
14. Pulse Oximetry: Pulse oximetry will be performed within 14 days prior to the first dose of investigational product treatment, and during treatment as 
described in the table above.  Pulse oximetry should be repeated if clinically indicated.
15. Chest X ray or Chest CT: Chest X ray or Chest CT will be performed within 14 days prior to the first dose of study drug.  Chest X ray or CT should be 
repeated if clinically indicated and at the discretion of the investigator.  Patients who have had a CT scan including chest for the purpose of tumor 
assessment for this study will not need to be repeated at baseline.
16. Registration: Patients will be enrolled according to a computer generated pseudo-random code.  Randomization numbers will be assigned by a central 
web-based randomization system operated by Pfizer Inc. 
17. Study Treatment: PF-06747775 will be given with a breakfast of 200-300 calories in the morning every day at approximately the same time once daily in 
21 day cycles. A single lead-in dose will be given on Day -7, and continuous daily dosing with start on Cycle 1 Day 1. See Table A8-4 for more details.
18. CT or MRI Tumor Assessments: Baseline assessments must be within 28 days of first study treatment.  Tumor assessments will include all known or 
suspected disease sites.  Tumor response will be assessed per RECIST v1.1.  Imaging may include chest, abdomen and pelvis CT or MRI scans.  Minimally, 
chest, liver and adrenals must be imaged.  Brain scans are required at baseline and every assessment if intra-cerebral disease is present; if no intra-cerebral 
disease is found at baseline, then brain imaging is only required on study if clinically indicated.  Bone scans will be performed at baseline if clinically 
indicated and on-study as appropriate to follow disease.  For all patients with RECIST measurable disease who have a RECIST response, confirmation of the 
response is required at least 4 weeks after initial assessment of response. Tumor assessment should be repeated at the End of Treatment visit if more than 
6 weeks have passed since the last evaluation.  For patients that have discontinued the treatment period due to reasons other than disease progression: Tumor 
assessments must continue until documented progression of disease by investigator. Patients who discontinue treatment without PD should continue to have 
tumor assessments performed every 6 weeks until PD is confirmed by investigator regardless of subsequent anti-cancer treatments.


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19. Adverse Event (AE) Assessments: Adverse events should be documented and recorded at each visit using the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTC AE) version 4.0.  Patients must be followed for AEs for 28 days after the last treatment administration 
or until all drug related toxicities have resolved, whichever is later; or earlier than 28 days should the patient commence another anticancer therapy in the 
meantime.  For serious adverse events (SAEs), the active reporting period to Pfizer or its designated representative begins from the time that the patient 
provides informed consent, which is obtained prior to the patient’s participation in the study, ie, prior to undergoing any study-related procedure and/or 
receiving investigational product, through and including 28 calendar days after the last administration of the investigational product.  Serious adverse events 
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 serious adverse events that the investigator believes have at least a reasonable possibility of being related to investigational product are to be reported to 
the sponsor.
20. Concomitant Treatments: all concomitant medications and Non Drug Supportive Interventions should be recorded in the CRF.
 
 
 
 
22. PK Sampling: serial blood samples will be collected after single and multiple doses (steady state) of PF-06747775 to characterize PK behavior. See Table 
A8-4 for more detailed information. 
 
 
.
 
 
 
27. Survival: Will be performed every 2 months for up to 24 months after PD or new anti-cancer therapy has commenced (telephone contact is acceptable).
28. End of Treatment visit: Obtain these assessments if not completed in the last week (last 6 weeks for tumor assessments). 
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, 
vital signs, and assessment for resolution of any treatment related toxicity. Patients continuing to experience toxicity at this point following discontinuation 
of treatment will continue to be followed at least every 4 weeks until resolution or determination, in the clinical judgment of the investigator, that no further 
improvement is expected.  For patients that have discontinued the treatment period due to reasons other than disease progression: Tumor assessments will 
continue to be performed every 6 weeks during long term follow up until documented disease progression, start of a new anti-cancer treatment, death or lost 
to follow-up (whichever occurs first).  All patients will be followed for at least 24 months after initial dose of last patient treated.
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Table A8-4. Japanese Patient-Only LIC PK Cohort - PK and ECG Assessments
Visit 
Identifi
er
Lead-in
Wash 
out
Cycle 1
Cycles 
2 - 4
Day
-7
-6
-5
-4
-3
1 (± 1)
2
8
(± 
1)
15 (± 2)
16
1
(± 2)
Hours 
Post 
Dose
0a
1
2
4
6
8
2
4
4
8
7
2
96
0a
(Pre
-
Dos
eb)
1
2
4
6
8
24
(Pr
e-
Do
seb
)
Pr
e-
D
os
eb
Pre-
Dos
eb
1
2
4
6
8
24 
(Pre-
Doseb
)
Pre-
Doseb
PF-
0674777
5 Dosec
X
(100 
mg)
X
(RP
2D)
Once daily PO continuous, with breakfast (RP2D)
PK 
blood 
samplin
gd
Xb
X
X
X
X
X
X
X
X
X
Xb
X
X
X
X
X
Xb
Xb
Xb
X
X X
X X
Xb
Xb
12-Lead 
ECGe
X
X
X
X
X
X
X
X
a.
0 hrs. Dose time: dose time of PF-06747775 triggers the defined post dose sample collection times.
b.
Pre-dose sample collection: before study treatment dose.
c.
PF-06747775 dose: PF-06747775 dose will be given in the morning with a breakfast of 200-300 calories, at approximately the same time once daily in 
21 day cycles starting continuous dosing on Cycle 1 Day 1. On Day -7, subject will take a 100 mg single dose. Starting on Day 1 in Cycle 1, a once daily 
dose of RP2D (200 mg) will be taken.
d.
PK blood sampling for PF-06747775 analysis: For PK analysis, 4 mL of blood in K2EDTA tubes will be collected as shown above. Serial PK samples will 
be collected on days -7 to -3 in lead-in, Days 1 to2 and Days 15 to 16 in Cycle 1. In addition, trough samples will be collected on Day 8 of Cycle 1. On Day 
1 of Cycles 2 - 4, 4 mL of blood in K2EDTA tubes will be collected prior to PF 06747775 dose (pre-dose) for steady state PK analysis. If during the course 
of treatment a patient needs to reduce the dose of PF-06747775, serial PK samples may be taken at least 1 week after starting the reduced dose using the 
same PK blood sampling schedule as outlined above for Cycle 1 Day 15 through pre-dose on Day 16.  
e.
Triplicate 12-Lead ECG: At each time point, three consecutive 12-lead ECGs will be performed approximately 2 minutes apart.  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 (ie, the timing of the PK collections over rides the timing of the ECG collections).  ECG assessments pre-dose should happen prior to breakfast.  If the 
mean QTcF is prolonged (value of >500 msec), the ECGs should be re-evaluated by a qualified person at the institution for confirmation.  Additional 


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triplicate ECGs may be performed as clinically indicated.  ECG assessments will be performed at pre-dose and 2 hrs. post dose on Day -7 and Day 1 in cycle 
1, pre-dose and 2 hrs. and 6 hrs. post dose on Day 11 of Cycle 1, and pre-dose on Days 1 of Cycles 2 - 4.  The 2 hrs. post dose ECG assessment is intended 
to target Cmax, this time point may be re-assessed as data emerge.
Abbreviations: PK = pharmacokinetic; PO = by mouth


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
Patient Selection for Japanese patient-Only LIC 
Inclusion and exclusion criteria are same as Phase 1 (See Section 4.1, 4.2) except for prior 
treatment with a 3rd generation EGFR TKI. Patients who are prior treatment with a 3rd 
generation EGFR TKI are not excluded in Japanese patient-Only LIC.

Safety Review Process for RP2D tolerability cohort
Following 1 cycle (21 days) of treatment, a safety review will be performed as described in 
“Data Analysis/Statistical Methods for Japanese patient-Only LIC” by Japanese investigators 
and the Sponsor to determine whether the emerging data from this cohort will support 
inclusion of patients at Japan sites in Phase 2 (Cohort 1) and Phase 1b/2 (Cohort 2A, 2B and 
3). The PK cohort data or enrollment does not need to be completed to allow this 
determination.

Data Analysis/Statistical Methods for Japanese patient-Only LIC
Japanese patients enrolled into the LIC will be analyzed separately from patients enrolled in 
the main part of the study. DLT is the primary endpoint of the analysis for the LIC, and the 
occurrence of DLTs will be used to assess safety and tolerability at the RP2D in Japanese 
patients. AEs constituting DLTs will be listed. The definition of the per protocol analysis set 
for the LIC is described in the section of study design in Appendix 8. See Section 9 for 
additional details regarding the statistical analysis.


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SAP_001.pdf: 
Protocol B7971001                                                                               Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 1
  
PROTOCOL B7971001
PHASE 1/2 OPEN-LABEL STUDY OF PF-06747775 (EPIDERMAL GROWTH 
FACTOR RECEPTOR T790M INHIBITOR) IN PATIENTS WITH ADVANCED 
EPIDERMAL GROWTH FACTOR RECEPTOR MUTANT (DEL 19 OR L858R 
T790M) NON-SMALL CELL LUNG CANCER
STATISTICAL ANALYSIS PLAN
(SAP)
Version: 
3.0
Author: 
Date:  
05 January 2017
This document contains confidential information belonging to Pfizer Inc. Except as may be 
otherwise agreed to in writing, by accepting or reviewing these materials, you agree to hold such 
information in confidence and not to disclose it to others (except where required by applicable 
law), nor to use it for unauthorized purposes. In the event of actual or suspected breach of this 
obligation, Pfizer Inc. should be promptly notified.
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Protocol B7971001                                                                             Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 2
TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................5
APPENDICES ...........................................................................................................................7
1. AMENDMENTS FROM PREVIOUS VERSION(S) ...........................................................8
2. INTRODUCTION .................................................................................................................8
2.1. Study Design .............................................................................................................8
2.1.1. Phase 1..........................................................................................................9
2.1.2. Cohort 1: Phase 2 Evaluation of PF-06747775 Single Agent in 
Previously Untreated Advanced EGFRm NSCLC...........................................10
2.1.3. Cohort 2: Phase 1b/2 Evaluation of PF-06747775 Plus Palbociclib ........10
2.1.3.1. Cohort 2A..................................................................................10
2.1.3.2. Cohort 2B ..................................................................................10
2.1.4. Cohort 3: Phase 1b Evaluation of PF-06747775 Plus Avelumab..............10
2.2. Study Objectives .....................................................................................................11
2.2.1. Phase 1........................................................................................................11
2.2.1.1. Primary Objective .....................................................................11
2.2.1.2. Secondary Objectives................................................................11
2.2.2. Phase 1b/2 ..................................................................................................12
2.2.2.1. Primary Objectives....................................................................12
2.2.2.2. Secondary Objectives................................................................12
3. INTERIM ANALYSES, FINAL ANALYSES, AND UNBLINDING...............................13
4. HYPOTHESES AND DECISION RULES.........................................................................13
4.1. Statistical Hypotheses .............................................................................................13
4.2. Statistical Decision Rules........................................................................................14
5. ANALYSIS POPULATIONS .............................................................................................14
5.1. Full Analysis Set .....................................................................................................14
5.2. Safety Analysis Set..................................................................................................14
5.3. QTc Evaluable Analysis Set....................................................................................14
5.4. QTc-PK Evaluable Analysis Set .............................................................................14
5.5. Per Protocol Analysis Set (Phase 1, and Cohorts 2A and 3)...................................14
5.6. Response Evaluable Analysis Set ...........................................................................15
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5.7. PK Analysis Sets .....................................................................................................15
5.9. Immunogenicity Analysis Set (Phase 1b Cohort 3 only) ........................................15
5.10. 4--Hydroxycholesterol and Cholesterol Analysis Set (Phase 1 only).................15
5.12. Treatment Misallocations......................................................................................15
5.13. Protocol Deviations...............................................................................................16
6. ENDPOINTS AND COVARIATES ...................................................................................16
6.1. Efficacy Endpoints ..................................................................................................16
6.2. Safety Endpoints .....................................................................................................18
6.2.1. DLT (Phase 1 only) ....................................................................................18
6.2.2. Adverse Events...........................................................................................18
6.2.3. Laboratory Abnormalities...........................................................................19
6.2.4. ECG Results................................................................................................19
6.3. PK Endpoints...........................................................................................................20
6.3.1. Phase 1 PF-06747775 PK Endpoints..........................................................20
6.3.1.1. Phase 1 Single and Multiple Dose PK (Dose Escalation).........20
6.3.1.2. Multiple Dose PK (MTD Expansion Sildenafil 
Sub-Study).........................................................................................20
6.3.1.3. Food-PF-0674777 and 
CYP3A4 Inducer-PF-06747775 Interactions ....................................21
6.3.1.4. Antacid - PF-06747775 and 
CYP3A4 Inhibitor - PF-06747775 Interactions ................................21
6.3.2. Phase 1 Sildenafil PK Endpoints................................................................21
6.3.3. Phase 1b/2 PF-06747775 PK endpoints .....................................................22
6.3.3.1. Phase 2 Single Agent PF-06747775 in Previously 
Untreated Disease (Cohort 1) ............................................................22
6.3.3.2. Phase 1b Single Arm PF-06747775 in Combination with 
Palbociclib (Cohort 2A) ....................................................................22
6.3.3.3. Phase 2 Randomized PF-06747775 in Combination with 
Palbociclib vs PF-06747775 alone (Cohort 2B)................................23
6.3.3.4. Phase 1b PF-06747775 in Combination with Avelumab 
(Cohort 3) ..........................................................................................23
6.3.4. Phase 1b/2 Palbociclib PK Endpoints.........................................................23
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6.3.4.1. Phase 1b Single Arm PF-06747775 in Combination with 
Palbociclib (Cohort 2A) ....................................................................23
6.3.4.2. Phase 2 Randomized PF-06747775 in Combination with
Palbociclib vs PF-06747775 alone (Cohort 2B)................................24
6.3.5. Phase 1b Avelumab PK Endpoints (Cohort 3) ...........................................24
6.4. Other Endpoints.......................................................................................................25
6.4.2. Endpoints for Immunogenicity Data of Avelumab (Phase 1b Cohort 
3 only)..............................................................................................................25
6.4.3. Endpoints for 4--Hydroxycholesterol and Cholesterol (Phase 
1 only)..............................................................................................................25
6.4.6. Baseline Characteristics..............................................................................26
6.4.7. Study Treatment Exposure .........................................................................26
6.4.7.1. Treatment Exposure ..................................................................26
6.4.7.2. Dose Reductions and Interruptions ...........................................27
6.4.7.3. Infusion rate reductions.............................................................27
6.5. Covariates................................................................................................................27
7. HANDLING OF MISSING VALUES ................................................................................27
7.1. Missing Dates..........................................................................................................27
7.2. Missing Efficacy Endpoint Values..........................................................................29
7.3. Pharmacokinetics ....................................................................................................29
7.4. ECG.........................................................................................................................30
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES ..........................31
8.1. Statistical Methods ..................................................................................................31
8.1.1. Statistical Methods for Dose Escalation/De-escalation..............................31
8.1.1.1. CRM (Phase 1)..........................................................................31
8.1.1.2. mTPI (Phase 1b)........................................................................31
8.1.2. Sample Size Determination ........................................................................32
8.1.2.1. Phase 1 Sample Size..................................................................32
8.1.2.2. Phase 1b/2 Sample Size.............................................................33
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8.1.3. Simulation for CRM ...................................................................................33
8.1.4. Statistical Methods for Different Types of Endpoints................................35
8.2. Statistical Analyses .................................................................................................35
8.2.1. Analysis of Efficacy Endpoints ..................................................................35
8.2.1.1. Phase 1.......................................................................................35
8.2.1.2. Phase 1b/2 .................................................................................35
8.2.2. Analysis of Safety Endpoints......................................................................37
8.2.2.1. Analysis of Primary Endpoint for Phase 1, Phase 1b 
Cohort 2A, and Cohort 3 ...................................................................37
8.2.2.2. Analysis of Secondary Safety Endpoint....................................38
8.2.3. Baseline Characteristics..............................................................................43
8.2.4. Analysis of Pharmacokinetics.....................................................................43
8.2.4.1. Population Pharmacokinetic Analysis or PK/PD Modeling .....43
8.2.4.2. PF-06747775 Single-Dose and Steady State PK Analysis........45
8.2.4.4. Sildenafil Sub-study:  MTD Expansion Cohort ........................47
8.2.4.5. Phase 2 Single Agent PF-06747775 in Previously 
Untreated Disease (Cohort 1) ............................................................48
8.2.4.6. Phase 1b Single Arm Combination with Palbociclib 
(Cohort 2A) .......................................................................................49
 
9. REFERENCES ....................................................................................................................54
LIST OF TABLES
Table 1. PF-06747775 Single Dose and Steady State Parameters...........................................20
Table 2. PF-06747775 Steady State Parameters for Food Effect/Rifampin and 
Antaaci/Itraconazole Sub-studies .........................................................................21
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Table 3. Single Dose Silenafil PK Parameters for Sildenafil Sub-study.................................22
Table 4 . PF-06747775 Steady State Parameters for Single Arm Combination with 
Palbociclib (Cohort 2A)........................................................................................23
Table 5. Steady State Parameters for Palbociclib for Single Arm Combination with 
PF-06747775 (Cohort 2A)....................................................................................24
Table 6. Probability of DLT as a Function of Dose.................................................................34
Table 7. Operating Charateristics of the CRM in Phase 1.......................................................34
Table 8. PK Parameters to be Determined for PF-06747775 ..................................................43
Table 9. PK Parameters to be Determined for Sildenafil.........................................................44
Table 10. PK Parameters to be Determined for Palbociclib....................................................45


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APPENDICES
Appendix 1. Programming Specifications for AE analyses.....................................................55
Appendix 2. STUDY SPECIFIC INFORMATION FOR EFFICACY ...................................57
Appendix 3. DETERMINATION OF EFFICACY – SOLID TUMORS................................58
Appendix 4. Detailed Dose Escalation/De-Escalation Scheme for mTPI Design Based 
on 30% Toxicity Rate ...........................................................................................63
Appendix 5. Treatment Exposure ............................................................................................65


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1. AMENDMENTS FROM PREVIOUS VERSION(S) 
This is Version 3.0. New study cohorts are incorporated in the protocol amendment 3 (dated 
Sept 20, 2016).
2. INTRODUCTION
This document describes the planned statistical analyses for Protocol B7971001.  This 
analysis plan is meant to supplement the study protocol.  In this document any text taken 
directly from the protocol is italicized. 
Any deviations from this main analysis plan will be described in the Clinical Study Report. 
2.1. Study Design
This is a Phase 1/2 study of PF-06747775 as a single agent and in combination with other 
cancer treatments in patients with advanced EGFRm non-small Cell lung cancer (NSCLC).  
The overall clinical study consists of a Phase 1 single agent dose-escalation and expansion 
part to determine the recommended Phase 2 dose (RP2D) of PF-06747775 single agent in 
patients with previously-treated EGFRm NSCLC followed by sequential evaluations of 
PF-06747775 at the RP2D in 3 different clinical scenarios as detailed below:  

Cohort 1: Phase 2 evaluation of PF-06747775 as a single agent in previously 
untreated patients with advanced EGFRm NSCLC;

Cohort 2: Phase 1b single arm evaluation of PF-06747775 in combination with 
palbociclib (Cohort 2A) followed by Phase 2 randomized evaluation of 
PF-06747775 in combination with palbociclib vs PF-06747775 single agent (Cohort 
2B) in previously-treated patients with EGFRm NSCLC with a secondary T790M 
mutation (del 19 and T790M or L858R and T790M); and 

Cohort 3: Phase 1b evaluation of PF-06747775 in combination with avelumab for 
previously-treated patients with EGFRm NSCLC with a secondary T790M mutation 
(del 19 and T790M or L858R and T790M). 
Cohorts 2A and 3 will determine the RP2D of PF-06747775 in combination with either 
palbociclib or avelumab, respectively, based on safety and tolerability.  Patients will be 
treated at dose level 1 (DL1) of the combination as noted in Table 14 of the protocol (Cohort 
2A) and Table 17 of the protocol (Cohort 3).  If the initial doses tested are tolerated, that will 
be the combination dose selected.  Determination of the RP2D will be performed using the 
mTPI design as described in Section 2.1.3.1 of the protocol (Cohort 2A) and Section 2.1.4 of 
the protocol (Cohort 3). 
For Cohort 2A, after determination of the RP2D for the PF-06747775 and palbociclib 
combination, a randomized evaluation of the combination vs PF-06747775 single agent 
(2:1 ratio) will be initiated (Cohort 2B).  For Cohort 3, after determination of the RP2D for 
the PF-06747775 and avelumab combination, the dose level will be expanded to enroll an 
overall total of approximately 20 patients to further explore the safety, PK, and antitumor 
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2.1.1.   Phase 1
The Phase 1 part of this study is an open label, multi-center, multiple dose, non-randomized, 
safety, PK, 
 and dose escalation study of PF-06747775 as a single agent in patients with 
advanced EGFRm NSCLC (del 19 or L858R, +/- T790M).  PF-06747775 will be 
administered in successive cohorts as a single agent in 21-day cycles.  The dose-escalation 
portion of Phase 1 includes a single dose lead-in period to assess single dose PK of 
PF-06747775, followed by continuous once daily dosing in a 21-day cycle.  The Continual 
Reassessment Method (CRM) will be used to guide the dose assignment and estimate the 
maximum tolerated dose (MTD) based on cumulative data on dose-limiting toxicities (DLTs)
in the first cycle. 
The target probability of dose-limiting toxicities (DLTs) at the MTD will be 30%.  The MTD
will be the highest dose with 30% of patients experiencing a DLT for a 10 patient cohort.  
Approximately 36 patients will be treated during the dose escalation part of the study.  An 
MTD expansion of up to 10 additional patients for the determination of the RP2D will be 
undertaken to better define the safety and provide enhanced early efficacy information. 
Phase 1 will also include a series of PK sub-studies:
1. A sildenafil sub-study (PF-06747775 will be the CYP3A4 inducer/inhibitor and 
sildenafil the CYP3A4 substrate).
2. A food-drug and a CYP3A4 drug-drug interaction PK sub-study (CYP3A4 induction 
interaction with rifampin).
3. An antacid-drug and a CYP3A4 drug-drug interaction PK sub-study 
(CYP3A4 inhibition interaction with itraconazole).
The sildenafil sub-study will be performed in the RP2D expansion cohort.  RP2D may 
coincide with the MTD or could be lower than MTD as other factors might be taken into 
consideration when deciding the RP2D.  In any case, the assessment of the potential 
CYP3A4 inhibitory effect of PF-06747775 at a dose that might be greater than the RP2D will 
not impact the estimation of the CYP3A4 inhibitory effect of PF- 06747775, on the contrary, 
it will show the maximum inhibitory effect that can be achieved at the RP2D.  The dose 
selected for further development will undergo a series of sub-studies at the selected 
recommended RP2D to fully characterize the impact of food, antacid and 
CYP3A4 inhibitors/inducers. 
Approximately 70 patients are expected to be enrolled in the Phase 1 part of the study.  
Approximately 36 patients will be enrolled into the dose escalation of the Phase 1 portion, 
depending on toxicity observed.  At the MTD, up to an additional 10 patients will be enrolled 
to confirm the RP2D and participate in the sildenafil sub-study.  Additional patients 
(approximately 24) will be enrolled at the RP2D to complete the drug-drug interaction 
(DDI), food and antacid effects studies.  The sequencing of these studies relative to other 
portions of this protocol may be adjusted. 
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2.1.2. Cohort 1: Phase 2 Evaluation of PF-06747775 Single Agent in Previously Untreated 
Advanced EGFRm NSCLC
Upon determination of the RP2D of single-agent PF-06747775, Cohort 1 will be initiated.  
Cohort 1 of the study is an open-label, multi-center, single-arm Phase 2 evaluation of 
PF-06747775 single agent at RP2D in previously untreated patients with advanced EGFRm 
(del 19 or L858R, with or without T790M) NSCLC. 
2.1.3. Cohort 2: Phase 1b/2 Evaluation of PF-06747775 Plus Palbociclib 
Cohort 2 will be initiated upon completion of the antacid effect and itraconozole DDI PK 
sub-study.  Cohort 2 of the study consists of a Phase 1b single-arm evaluation of the safety, 
PK, and 
of the RP2D of PF-06747775 in combination with palbociclib (Cohort 2A) 
followed by a Phase 2 randomized evaluation of antitumor activity and safety of the 
combination vs PF-06747775 single agent (Cohort 2B) in patients with previously-treated 
advanced EGFRm NSCLC (del 19 and T790M or L858R and T790M). 
2.1.3.1. Cohort 2A
Cohort 2A will evaluate PF-06747775 200 mg PO daily in combination with palbociclib
continuous daily dosing in 21 day cycles to determine the RP2D.  The starting dose (DL1) for 
palbociclib will be 100 mg PO daily. 
2.1.3.2. Cohort 2B
Phase 2 Cohort 2B will be initiated once the RP2D of the PF-06747775 and palbociclib 
combination is determined.  Approximately 39 patients with previously-treated advanced 
EGFRm NSCLC (del 19 and T790M or L858R and T790M) will be randomized in a 2:1 ratio 
to receive either the PF-06747775 plus palbocicib combination or PF-06747775 single 
agent.  Patients will be treated continuously on a 21 day cycle with both agents and 
evaluated per the Schedule of Activities (SOA). 
Approximately 49 patients will be enrolled to test in Cohort 2 (up to 10 patients in Cohort 2A 
and 39 patients [26 PF-06747775 plus palbociclib and 13 PF-06747775 single agent] in 
Cohort 2B). 
2.1.4. Cohort 3: Phase 1b Evaluation of PF-06747775 Plus Avelumab
Cohort 3 will be initiated upon completion of enrollment to Cohort 2.  Cohort 3 of the study 
consists of a Phase 1b single-arm evaluation of the safety, and PK to determine the RP2D of 
PF-06747775 in combination with avelumab 10 mg/kg Q2W in patients with 
previously-treated with advanced EGFRm NSCLC (del 19 and T790M or L858R and 
T790M). 
The starting dose levels (DL1) for the Cohort 3 combination are PF-06747775 200 mg PO 
daily and avelumab 10 mg/kg IV Q2W in 4 week cycles.
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2.2. Study Objectives
2.2.1. Phase 1
2.2.1.1. Primary Objective

To evaluate safety and tolerability at increasing dose levels of PF-06747775 as a 
single agent in order to estimate the MTD and RP2D in patients with advanced 
EGFRm NSCLC (del 19 or L858R, with or without T790M) following 1 prior line of 
therapy, which must have included an approved EGFR TKI.
2.2.1.2. Secondary Objectives

To evaluate the overall safety profile of PF-06747775;

To characterize the effects of single-agent PF-06747775 on QTc intervals;

To characterize single dose and steady state PK profiles of single-agent 
PF-06747775;

To evaluate the effect of PF-06747775 at steady state on the exposure of a single dose 
of sildenafil, a CYP3A4 probe;

To characterize the effect of food on the exposure of PF-06747775 at the RP2D;

To characterize the effect of esomeprazole, a proton pump inhibitor, on the exposure 
of PF-06747775 at the RP2D;

To characterize the effect of itraconazole, a strong CYP3A4 inhibitor on the exposure 
of PF-06747775 at the RP2D;

To characterize the effect of rifampin, a strong CYP3A4 inducer on the exposure of 
PF-06747775 at the RP2D;

To assess in plasma the presence/absence of EGFR mutations;

To evaluate the anti-tumor activity of PF-06747775 in both T790M-positive and 
T790M-negative NSCLC tumors;

To evaluate tumor tissue biomarkers including, but not limited to, EGFR mutation by 
next generation sequencing.
 
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2.2.2. Phase 1b/2
2.2.2.1. Primary Objectives
2.2.2.1.1. Cohort 1 – PF-06747775 Single-Agent in Patients with Previously Untreated 
EGFRm NSCLC

To assess the anti-tumor activity (objective response rate [ORR]) of 
PF-06747775 single agent in patients with EGFRm NSCLC (del 19 or L858R, with or 
without T790M).
2.2.2.1.2. Cohort 2A – PF-06747775 Plus Palbociclib: Dose Finding

To evaluate safety and tolerability and determine the RP2D of PF-06747775 plus 
palbociclib in patients with EGFRm NSCLC with a secondary T790M mutation (del 
19 and T790M or L858R and T790M).
2.2.2.1.3. Cohort 2B – PF-06747775 Plus Palbociclib vs PF-06747775 Single Agent 
(Randomized)

To assess the progression-free survival (PFS) of PF-06747775 plus palbociclib versus 
PF-06747775 single agent in patients with EGFRm NSCLC with a secondary T790M 
mutation (del 19 and T790M or L858R and T790M).
2.2.2.1.4. Cohort 3 –PF-06747775 Plus Avelumab: Dose Finding

To evaluate safety and tolerability and establish the RP2D of PF-06747775 plus 
avelumab in patients with EGRm NSCLC with a secondary T790M mutation (del 
19 and T790M or L858 R and T790M).
2.2.2.2. Secondary Objectives 

To assess duration of response (DOR), and overall survival (OS) probability at 
24 months (all Cohorts);

To assess PFS (Cohort 1, Cohort 2A, and Cohort 3);

To further characterize the adverse event (AE) profile of PF-06747775 when given as 
a single agent (Cohort 1 and Cohort 2B) and in combination with palbociclib (Cohort 
2A and 2B) and avelumab (Cohort 3);

To further characterize PF-06747775 PK when given as a single agent (Cohort 1 and 
Cohort 2B) and in combination with palbociclib (Cohort 2A and 2B) and avelumab 
(Cohort 3);

To characterize the PK of palbociclib in combination with PF-06747775 (Cohort 2A 
and 2B);

To characterize the PK of avelumab in combination with PF-06747775 (Cohort 3);


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
To further explore the effects of PF-06747775 on QTc intervals when given as a 
single agent (Cohort 1 and Cohort 2B) and in combination with palbociclib (Cohort 
2A and 2B) and avelumab (Cohort 3);

To assess in plasma the presence/absence of EGFR mutations (All Cohorts);

To assess tumor markers of sensitivity and/or resistance to 
PF-06747775 (All Cohorts);

To assess the immunogenicity of avelumab when given in combination with 
PF-06747775 (Cohort 3).
 
 
 
 
 
 
 
 
 
 
 
3. INTERIM ANALYSES, FINAL ANALYSES, AND UNBLINDING
This is an open label study therefore unblinding is not applicable.  There is no formal interim 
analysis planned for this study.
The final analysis for the clinical study report will be done after all patient data have been 
submitted and cleaned, unless other arrangements are agreed upon by the Sponsor.  The 
analysis will be performed at the time of official data base release.
4. HYPOTHESES AND DECISION RULES
4.1. Statistical Hypotheses
There is no formal hypothesis testing for any phases or cohorts of the study. 
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4.2. Statistical Decision Rules
Phase 1:
In Phase 1 dose finding part of the study, the doses of PF-06477775 will be assigned to each 
enrolled patient using a CRM (O’Quigley el al, 1990).  Statistical decision rules at the dose 
escalation/de-escalation stage will be discussed in detail in Section 8.1.
Phase 1b Cohort 2Aand Cohort 3:
In Cohorts 2A and 3, dose finding will follow the mTPI method (Ji Y el al, 2010) with 
adjustments using DLT rate.  Statistical decision rules at the dose escalation/de-escalation 
stage will be discussed in detail in Section 8.1.
5. ANALYSIS POPULATIONS
Patients not enrolled to the study (ie, screen only patients) will not be included in any 
analysis.
5.1. Full Analysis Set
The full analysis set includes all enrolled patients.  For Cohort 2B, the full analysis set will 
include all patients who are randomized.  Patients will be classified according to the 
treatment assigned at randomization.
5.2. Safety Analysis Set
The safety analysis set includes all enrolled patients who receive at least one dose of study 
treatment.  For Cohort 2B, patients will be classified according to the treatment assigned at 
randomization unless the incorrect treatment(s) are received throughout the dosing period in 
which case patients will be classified according to the first treatment received.
5.3. QTc Evaluable Analysis Set
QTc evaluable analysis set will include all treated subjects who had at least 1 ECG 
assessment undertaken pre-dose and 1 post dose at steady state in triplicate.
All ECGs obtained during the study will be evaluated for safety.  ECG assessments will be 
documented by principal investigator at the site and by independent review (central read).
5.4. QTc-PK Evaluable Analysis Set
QTc-PK evaluable analysis set will include all treated subjects who had at least 1 ECG 
assessment undertaken pre-dose and 1 post dose at steady state in triplicate paired with a PK 
collection sample and resulting treatment concentration.
All ECGs obtained during the study will be evaluated for safety.
5.5. Per Protocol Analysis Set (Phase 1, and Cohorts 2A and 3)
For Phase 1/1b, the per protocol analysis set (evaluable for MTD/dose selection) includes 
patients who are eligible, receive study treatment and who either experience a DLT during 


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the first cycle of PF-06747775 or PF-06747775 plus avelumab or the first 2 cycles of 
PF-06747775 plus palbociclib, or complete the DLT observation period with no DLT.  
Patients with major treatment deviations during the DLT observation period other than 
treatment related toxicity are not evaluable for the MTD/dose selection assessment and will 
be replaced as needed to permit MTD/dose selection estimation. 
5.6. Response Evaluable Analysis Set
The response evaluable analysis set will include all patients who received at least one dose 
of study medication, have measurable disease and adequate baseline assessment, and at least 
1 post-baseline assessment during the study.  For Cohort 2B, all randomized patients will be
used.  In the Phase 1b/2 portion of the study, patients must have T790M-positive NSCLC to 
be evaluable for response rate determination for the decision rules used in the study.  
Patients enrolled into Cohort 1 of the Phase1b/2 portion of the study are not required to have 
T790M-positive NSCLC. 
5.7. PK Analysis Sets
The PK concentration population is defined as all treated patients who have at least one 
concentration in at least 1 treatment period for a particular analyte (ie, PF-06747775, 
sildenafil, palbociclib, or avelumab).
The PK parameter analysis population is defined as all treated patients who have sufficient 
information to estimate at least 1 of the PK parameters of interest for a particular analyte.
 
 
5.9. Immunogenicity Analysis Set (Phase 1b Cohort 3 only)
The immunogenicity analysis set is a subset of the safety analysis set and will include 
patients who have at least one Anti-drug antibodies/neutralizing antibodies (ADA/Nab)
sample collected for avelumab.
5.10. 4--Hydroxycholesterol and Cholesterol Analysis Set (Phase 1 only)
The analysis set for the ratio of blood 4--hydroxycholesterol/cholesterol concentration will 
include patients who have both measurable 4--hydroxycholesterol and cholesterol 
concentrations from at least 1 visit or treatment period.
 
5.12. Treatment Misallocations
For Cohort 2B see Section 5.1 and 5.2.
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5.13. Protocol Deviations
All deviations will be described when they appear and relate to the statistical analyses or 
analysis populations. 
6. ENDPOINTS AND COVARIATES
6.1. Efficacy Endpoints 
Assessment of response will be made using RECIST version 1.1 (Appendix 3).  All response
statuses will be based on investigator assessment.
For the purposes of the definitions of endpoints, the term “on treatment” includes the period 
from the date of the first dose until 28 days after the last dose of each patient.
Start date for a patient is date of first treatment (if treatment start date is not available, date 
of enrollment is used) all cohorts (excluding Cohort 2B) and date of randomization for 
Cohort 2B.

Confirmed Overall response rate (ORR) is defined as complete response (CR) or 
partial response (PR) according to RECIST 1.1 that must be confirmed ≥4 weeks later.  
Patients who do not have an on-treatment radiographic tumor assessment due to early 
progression, who receive anti-tumor treatment other than the study medication prior to 
reaching a CR or PR, 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.
Each patient 
will have an objective response status (0: no ORR; 1: ORR) and ORR) will be calculated 
as the percentage of patients with a confirmed CR or PR relative to the total number of 
response evaluable patients (which is defined as all randomized patients for Cohort 2B). 

CR:  Two objective statuses of CR a minimum of four weeks apart documented 
before progression and start of new anti-cancer therapy.

PR:  Two objective statuses of PR or better (PR followed by PR or PR followed by 
CR) a minimum of four weeks apart documented before progression and start of new 
anti-cancer therapy, but not qualifying as CR.  Sequences of PR- Stable- PR are 
considered PRs as long as the two PR responses are observed at a minimum of 
4 weeks apart.

SD:  At least one objective status of stable or better documented at least 6 weeks after 
start date and before progression and the start of new anti-cancer therapy but not 
qualifying as CR or PR. 

PD:  Progression documented within 12 or 16 weeks (for Cohort 3) after start date 
and not qualifying as CR, PR or SD

Not Evaluable (NE):  All other cases.  Note that reasons for NE should be 
summarized and the following reasons could be used:
Early death (death prior to 6 weeks after start date)


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No post-baseline assessments 
All post-baseline assessments have overall response NE
New anti-cancer therapy started before first post-baseline assessment
SD too early (<6 weeks after start date)
PD too late (>12 or 16 weeks [for Cohort 3] after start date)
Special and rare cases where BOR is NE due to both early SD and late PD will be 
classified as ‘SD too early’.

All response statuses will be based on investigator assessment
In Phase 1 part of the study, both confirmed and unconfirmed OR for patients with 
measurable diseases will be assessed.

Best Overall Response (BOR) is the best response recorded from start date until disease 
progression or start of new anti-cancer therapy.  For a patient to be called having a BOR 
of Stable Disease (SD), the patient must maintain the status of stable disease for at least 
6 weeks after starting treatment as documented by a tumor assessment at or beyond this 
time point.  The definition of overall response status at each assessment follows RECIST 
v1.1.

Duration of Response (DoR) is measured in patients with an objective response from the 
time measurement criteria are first met for CR/PR (whichever occurs first) until the first 
date that progressive disease, or death (whichever occurs first) is objectively documented.  
If tumor progression data include more than 1 date, the first date will be used.  Censoring 
for DoR is identical to the censoring rules presented for Progression-Free Survival (PFS) 
below when patients have at least 1 on study disease assessment.
DoR (months) = [progression/death date – first date of OR +1]/30.4

PFS is defined as the time from the start date to the date of the first documentation of PD
or death due to any cause.  In this study antitumor activity will be assessed through 
radiological tumor assessments conducted at screening and every 6 or 8 weeks (Cohort 3) 
until documented disease progression, start of a new anti-cancer treatment, death or lost 
to follow-up.  The allowable time window for disease assessments is ±1week.  Therefore 
time without adequate assessment is defined as 12 or 16 weeks (Cohort 3) plus 2 weeks.  
Therefore PD or death within 14 or 18 weeks (Cohort 3) of the last adequate tumor 
assessment will be counted as an event according to the tumor assessment date or date of 
death, as appropriate.  For patients who do not have an adequate baseline tumor 
assessment or who do not have any post-baseline tumor assessments, censoring will 
occur on the start date unless death occurred on or before the time of the second planned 
tumor assessment (ie, on or before week 14 or 18 [Cohort 3]) in which case the death will 
be considered an event.  In addition, if a new anti-cancer therapy is started prior to an 
event, the patient will be censored on the date of the last adequate tumor assessment that 
documented no progression prior to the start of the new anti-cancer therapy.


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PFS (in months) will be calculated as (first event date – start date +1)/30.4.
An adequate post-baseline assessment is defined as an assessment where a response of CR, 
PR, SD, non-CR/non-PD, or PD can be determined.  Time points where the response is NE 
or no assessment was performed will not be used for determining the censoring date. 

Six-Month PFS is defined as the PFS probability at six months based on Kaplan-Meier 
estimate. 

Overall Survival (OS) is defined as the time from the start date to date of death due to 
any cause.  In the absence of confirmation of death (see the paragraph below for survival 
follow-up), survival time will be censored at the last date the patient was known to be 
alive. 
All patients should continue to be followed every 2 months.  It is understood that not all 
patients will be available for continued clinic visits; however, every attempt should be 
made to collect survival information (alive or dead and date of last contact or death).  
This information may be obtained by telephone interview if the patient is unable to visit 
the clinic.

Two-Year Survival is defined as the OS probability (alive, or not) at 2-years based on 
the Kaplan-Meier estimate. 
6.2. Safety Endpoints
6.2.1. DLT (Phase 1 only)
Severity of adverse events will be graded according to CTCAE v 4.03.  Adverse events 
meeting one of the definition criteria in protocol Section 3.2 occurring in the first cycle of 
treatment of PF-06747775, or PF-06747775 plus avelumab, or the first 2 cycles of 
PF-06747775 plus palbociclib, not related to progressive disease and attributable to
PF-06747775 (Cohort 1) or that are attributable to one, the other or both compounds in 
Cohort 2A (PF-06747775 plus palbociclib) and Cohort 3 (PF-06747775 plus avelumab), 
respectively, will be classified as DLTs.
DLT is the primary endpoint of the dose escalation component of the study.  The occurrence 
of DLTs observed in the dose level is used to estimate the MTD.  AEs constituting DLTs will 
be listed by dose level.
6.2.2. 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). 
Treatment Emergent Adverse Events
All deaths, regardless of cause, will be summarized from treatment start until 28 days after 
the last dose.  Non-fatal events occurring after treatment start regardless of causes, will be 
summarized up until 28 days after the last dose or until start of new anti-cancer treatment, 


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whichever is first.  Disease progression is not considered a treatment emergent adverse event 
unless the patient dies of disease within 28 days after the last dose.  Events that are 
continuations of baseline abnormalities are considered treatment emergent adverse events 
only if there is an increase in grade over baseline, or if there is an increase following a 
decrease during the study.
Treatment Related Adverse Events
Treatment emergent adverse events will be summarized with causality related to treatment as 
judged by the investigator.  Events that are continuation of baseline abnormalities are not 
considered treatment related unless there is an increase in grade, or if there is an increase 
following a decrease, and the increase is judged by the investigator to be due to treatment.
Immune-related Adverse Events (irAE) 
For Cohort 3, irAEs are identified according to a pre-specified search list of MedDRA 
preferred terms, documented in the Safety Review Plan and finalized for analysis prior to 
database lock.
Infusion-related Reactions (IRR)
For Cohort 3, IRRs are identified by 3 preferred terms (infusion related reaction, drug 
hypersensitivity, and anaphylactic reaction) occurring on the date of the infusion of avelumab
(not prior to infusion of avelumab) or the day following study drug infusion. 
6.2.3. Laboratory Abnormalities
Laboratory abnormalities are characterized by type, frequency, severity (as graded by NCI 
CTCAE v.4.03) and timing.
6.2.4. ECG Results
For Phase 1, changes in QTc (QTcB, QTcF, and/or QTcS) from baseline to Day 11 of Cycle 
1 and Day 1 of Cycles 2-4 will be used to characterize the potential effect of PF-06747775 on 
the QT interval with QTcF being the primary correction method.  The baseline for Phase 1 is 
defined as the ECGs recorded on Day -8 pre-dose. 
For Phase 1b/2, changes in QTc from baseline to Day 11 (Cohort 1) or Day 15 (Cohort 2A, 
2B, and 3) of Cycle 1 and Day 1 of Cycles 2-3 (Cohort 3) or 2-4 (Cohort 1, 2A and 2B) will 
be used to characterize the potential effect of PF-06747775 on the QT interval with QTcF 
being the primary correction method.  The baseline for Phase 1b/2 is defined as the ECGs 
recorded on Day -4 (Cohort 1) or Day 1 (Cohort 2A, 2B, and 3) pre-dose. 
All ECGs obtained during the study will be evaluated for safety.  The triplicate data will be 
averaged and all summary statistics and data presentations will use the triplicate averaged 
data.  Any data obtained from ECGs repeated for safety reasons after the nominal time points 
will not be averaged along with the preceding triplicates.  For all patients in the QTc 
evaluable analysis set, individual change in QTc (QTcB, QTcF and/or QTcS) will be 
calculated for each nominal post-baseline time point.  ECG results will be reported by 
treatment/cohort, and may also be reported by treatment dose.


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6.3. PK Endpoints
6.3.1. Phase 1 PF-06747775 PK Endpoints 
6.3.1.1. Phase 1 Single and Multiple Dose PK (Dose Escalation)
PK blood samples for the determination of plasma PF-06747775 concentrations will be 
collected at the times specified in the protocol schedule of activities.  PK parameters for 
PF-06747775 will be determined from the plasma concentration-time data using standard 
noncompartmental methods and be reported by dose. 
PF-06747775 PK parameters for the analysis of single dose and steady state PK are listed in
Table 1.  Single dose parameters will be assessed on Day - 8 of the lead in period and steady 
state parameters will be assessed on Day 11 of Cycle 1.  Steady state Ctrough will also be 
assessed as the pre-dose concentration on Day 1 of Cycle 2-4.  Dose-normalized parameters 
may be reported together for all dose levels.
Table 1. PF-06747775 Single Dose and Steady State Parameters
Parameter
State
Analysis Scale
Summary
AUClast
sd
ln
D
AUCinf
*
sd
ln
D
AUC24
sd
ln
D
AUCtau
ss
ln
D
Cmax
sd, ss
ln
D
Tmax
sd, ss
R
D
t½*
sd
R
D
Ctrough
ss
ln
D
CL/F*
sd, ss
ln
D
Vz/F*
sd, ss
ln
D
Rac
ss
ln
D
Rss
*
ss
ln
D
AUClast(dn)
sd
ln
D
AUCinf(dn)*
sd
ln
D
AUC24(dn)
sd
ln
D
AUCtau(dn)
ss
ln
D
Cmax(dn)
sd, ss
ln
D
Ctrough(dn)
ss
ln
D
sd=single dose; ss=steady state; ln=natural-log transformed; R=raw (untransformed); D=displayed with 
descriptive statistics; *=if data permits; dn=dose-normalized.
6.3.1.2. Multiple Dose PK (MTD Expansion Sildenafil Sub-Study)
PF-06747775 steady state PK parameters for the sildenafil sub-study are listed in Table 
1 (excluding Rac and Rss) and will be assessed only on Day 11 of Cycle 1.  On Day-8 patients 
received a single dose of sildenafil followed by continuous daily dosing of 
PF-06747775 starting on Day 1.  On Day 11, patients receive another single dose of 
sildenafil along with PF-06747775 (steady state) under fasting conditions. 


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If more than one dose level of PF-06747775 was used for patients in the sub-study, steady 
state parameters will also be reported by dose, and dose-normalized steady-state parameters 
will also be reported.
6.3.1.3. Food-PF-0674777 and CYP3A4 Inducer-PF-06747775 Interactions
PF-06747775 PK parameters for the food effect and rifampin sub-study are listed in Table 
2 and will be reported by treatment.  For the food effect and rifampin sub-study, steady-state 
PF-06747775 PK parameters will be assessed on Days 8, 9, and 21 of Cycle 1.  Days 8 and 
9 are PF-06747775 administered alone under fasted or fed conditions according to the 
randomization schedule; Day 21 is PF-06747775 with rifampin. 
6.3.1.4. Antacid - PF-06747775 and CYP3A4 Inhibitor - PF-06747775 Interactions
PF-06747775 PK parameters for the antacid effect and itraconazole sub-study are listed in 
Table 2 and will be reported by treatment.  For the antacid and itraconazole sub-study, 
steady-state PF-06747775 PK parameters will be assessed on Days 8, 13, and 21 of Cycle 1.  
Day 8 is PF-06747775 alone, Day 13 is PF-06747775 with esomeprazole, and Day 21 is 
PF-06747775 with itraconazole.  To prevent toxicity, during treatment with itraconazole the 
dose of concomitant PF-06747775 will be reduced, and relevant steady-state 
PF-06747775 PK exposure parameters will be dose-normalized for comparison to the 
reference treatment of PF-06747775 alone, or for any comparison across the 3 treatments in 
this sub-study.
Note the Days for these sub-studies may be modified based on the PK profile observed 
during the lead-in period in the earlier portions of the study.
Table 2. PF-06747775 Steady State Parameters for Food Effect/Rifampin and 
Antaaci/Itraconazole Sub-studies
Parameter
Analysis Scale
Plasma PF-06747775
AUCtau
ln
A, D
Cmax
ln
A, D
Tmax
R
D
AUCtau(dn)*
ln
A, D
Cmax(dn)*
ln
A, D
ln=natural-log transformed; R=raw (untransformed); D=displayed with descriptive statistics; A=analyzed 
using statistical model; dn=dose-normalized; *=dose-normalized parameters will be used for itraconazole 
effect comparison to reference treatment of PF-06747775 alone in the antacid/itraconazole sub-study.
6.3.2. Phase 1 Sildenafil PK Endpoints  
PK blood samples for the determination of plasma sildenafil concentrations will be collected 
at the times specified in the protocol schedule of activities for the MTD expansion sildenafil 
sub-study. 
PK parameters for sildenafil will be determined from the plasma concentration-time data 
using standard noncompartmental methods (Table 3) Single dose parameters will be assessed 
on Day -8 for sildenafil alone, and on Day 11 of Cycle 1 for sildenafil with PF-06747775. 


Protocol B7971001                                                                             Statistical Analysis Plan
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If more than one dose level of PF-06747775 was used for patients in the MTD expansion 
sildenafil sub-study, sildenafil PK parameters may also be reported by dose of 
PF-06747775 assigned.
Table 3. Single Dose Silenafil PK Parameters for Sildenafil Sub-study
Parameter
Analysis Scale
Plasma Sildenafil 
AUClast
ln
D
AUCinf
*
ln
A, D
Cmax
ln
A, D
Tmax
R
D
t½*
R
D
CL/F*
ln
D
ln=natural-log transformed; R=raw (untransformed); D=displayed with descriptive statistics; A=analyzed using 
statistical model; *=if data permits.
6.3.3. Phase 1b/2 PF-06747775 PK endpoints  
6.3.3.1. Phase 2 Single Agent PF-06747775 in Previously Untreated Disease (Cohort 1)
PK blood samples for the determination of plasma PF-06747775 concentrations will be 
collected at the times specified in the protocol schedule of activities.  PK parameters for 
PF-06747775 will be determined from the plasma concentration-time data using standard 
noncompartmental methods. 
PF-06747775 PK parameters for the analysis of single dose and steady state PK are listed in 
Table 1 (excluding the dose-normalized parameters).  Single dose parameters will be 
assessed on Day -4 of the lead in period and steady state parameters will be assessed on Day 
11 of Cycle 1.  Steady state Ctrough will also be assessed as the pre-dose concentration on Day 
1 of Cycle 2-4.
6.3.3.2. Phase 1b Single Arm PF-06747775 in Combination with Palbociclib (Cohort 
2A)
PK blood samples for the determination of plasma PF-06747775 concentrations in 
combination with palbociclib will be collected at the times specified in the protocol schedule 
of activities.  PK parameters for PF-06747775 will be determined from the plasma 
concentration-time data using standard noncompartmental methods. 
PF-06747775 PK parameters for the analysis of steady state PK when given concomitantly 
with palbociclib are listed in Table 4 and will be assessed on Day 15 of Cycle 1.  Steady state 
Ctrough will also be assessed as the pre-dose concentration on Day 1 of Cycle 2-4, and both 
Ctrough (the pre-dose concentration) and the concentration at 2 hours post-dose (approximate 
Cmax) will be assessed on Day 15 of Cycle 2. 
If more than one dose level of palbociclib was used in this dose-finding cohort, 
PF-06747775 PK parameters may also be reported by dose of palbociclib assigned.
All patients in this cohort will receive PF-06747775 and therefore they are eligible to meet 
the requirements of the PF-06747775 PK analysis set and have PF-06747775 PK reported.


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Table 4 . PF-06747775 Steady State Parameters for Single Arm Combination with 
Palbociclib (Cohort 2A)
Parameter
Analysis Scale
Plasma PF-06747775
AUCtau
ln
D
Cmax
ln
D
Tmax
R
D
Ctrough
ln
D
ln=natural-log transformed; R=raw (untransformed); D=displayed with descriptive statistics.
6.3.3.3. Phase 2 Randomized PF-06747775 in Combination with Palbociclib vs 
PF-06747775 alone (Cohort 2B)
PF-06747775 steady state Ctrough (pre-dose concentration) and the concentration at 2 hours 
post-dose (approximate Cmax) when given concomitantly with palbociclib will be assessed on 
Day 15 of Cycle 1 and on Day 1 of Cycle 2-4.
All patients in this cohort will receive PF-06747775 and therefore they are eligible to meet 
the requirements of the PF-06747775 PK analysis set and have PF-067775 PK reported.
6.3.3.4. Phase 1b PF-06747775 in Combination with Avelumab (Cohort 3)
PF-06747775 steady state Ctrough (pre-dose concentration) when given concomitantly with 
avelumab will be assessed on Day 15 of Cycle 1 and on Day 1 of Cycle 2-3.
If more than one dose level of PF-06747775 was used in this cohort, Ctrough will be reported 
by dose level, and dose-normalized PF-06747775 Ctrough may also be reported.
6.3.4. Phase 1b/2 Palbociclib PK Endpoints
PK blood samples for the determination of plasma palbociclib concentrations will be 
collected as specified in the schedule of activities and PK parameters for palbociclib will be 
determined using standard noncompartmental methods.
6.3.4.1. Phase 1b Single Arm PF-06747775 in Combination with Palbociclib (Cohort 
2A)
Palbociclib PK parameters for the analysis of steady state PK when given concomitantly with 
PF-06747775 are listed in Table 5 and will be assessed on Day 15 of Cycle 1.  Steady state 
Ctrough (pre-dose concentration) will also be assessed on Day 1 of Cycle 2-4 and on Day 15 of 
Cycle 2. 
If more than one dose level of palbociclib was used in this dose-finding cohort, palbociclib 
PK parameters will be reported by dose level, and dose-normalized PK parameters for 
palbociclib will be reported.
All patients in this cohort will receive palbociclib along with PF-06747775, and therefore 
they are eligible to meet the requirements of the palbociclib PK analysis set and have 
palbociclib PK reported.


Protocol B7971001                                                                             Statistical Analysis Plan
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Table 5. Steady State Parameters for Palbociclib for Single Arm Combination with 
PF-06747775 (Cohort 2A)
Parameter
Analysis Scale
Plasma Palbociclib 
AUCtau*
ln
D
AUClast
ln
D
Cmax
ln
D
Tmax
R
D
Ctrough
ln
D
AUCtau(dn)*
ln
D
AUClast(dn)
ln
D
Cmax(dn)
ln
D
Ctrough(dn)
ln
D
ln=natural-log transformed; R=raw (untransformed); D=displayed with descriptive 
statistics; *=if data permits; dn=dose-normalized.  AUClast for palbociclib following 
multiple doses will be reported since AUCtau may not be estimable given the PK 
sampling times utilized in the combination study.
6.3.4.2. Phase 2 Randomized PF-06747775 in Combination with Palbociclib vs 
PF-06747775 alone (Cohort 2B)
Palbociclib steady state Ctrough (pre-dose concentration) will be assessed on Day 15 of Cycle 
1 and on Day 1 of Cycle 2-4.
Only the patients randomized to receive palbociclib along with PF-06747775 will be eligible 
for the PK analysis set for palbociclib and have palbociclib PK reported.
6.3.5. Phase 1b Avelumab PK Endpoints (Cohort 3)
PK blood samples for the determination of serum avelumab concentrations will be collected 
as specified in the schedule of activities.
PK parameters for avelumab during Cycle 1 include pre-dose concentration (Ctrough) and end 
of infusion peak concentration (Cmax) and will be assessed on Day 1 and Day 15 of Cycle 1.  
Multiple dose (steady state) parameters will be assessed on Day 1 of Cycle 2 (Ctrough and 
Cmax) and on Day 1 of Cycle 3 (Ctrough only).  After Cycle 3, Ctrough will be assessed every 
3 cycles thereafter.
Avelumab PK parameters (pre-dose and end of infusion [EOI] serum concentration) may also 
be reported by presence and/or magnitude (titer) of avelumab ADA/nAb.
If more than one dose level of PF-06747775 was used for patients in this cohort, avelumab 
PK parameters/serum concentrations may also be reported by dose of PF-06747775 assigned.


Protocol B7971001                                                                             Statistical Analysis Plan
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6.4. Other Endpoints
 
 
 
6.4.2. Endpoints for Immunogenicity Data of Avelumab (Phase 1b Cohort 3 only)
Blood samples for the determination of serum anti-drug antibody (ADA) and neutralizing 
antibody (Nab) levels for avelumab will be collected as specified in the schedule of activities. 
ADA/ Nab data will be listed and summarized, with the percentage of patients with positive 
ADA and neutralizing antibodies.  For patients with positive ADA, the magnitude (titer), 
time of onset, and duration of ADA response will also be described, if data permit.
6.4.3. Endpoints for 4--Hydroxycholesterol and Cholesterol (Phase 1 only)
Blood samples for the determination 4--hydroxycholesterol and cholesterol concentrations 
will be collected as specified in the schedule of activities, and the molar ratio of 
4--hydroxycholesterol: cholesterol will be reported by patient and visit, according to 
treatment/cohort and dose.  The ratio may also be reported in individuals as change in ratio 
over time compared to baseline or first sample collected. 
 
 
 
 
 
 
 
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6.4.6. Baseline Characteristics
The following baseline characteristics will be presented: age, sex, race, height, weight, 
performance status, primary diagnosis, time from initial diagnosis to first dose, stage of 
disease, number of prior systemic therapies, number of prior surgeries, prior radiotherapy 
(yes/no), and involved disease sites.
6.4.7. Study Treatment Exposure 
6.4.7.1. Treatment Exposure 
The summary of treatment exposure and compliance for PF-06747775 or palbociclib will 
include the following information:

Duration (weeks)

Cumulative dose (mg) 

Dose intensity (mg/week)
The summary of treatment exposure and compliance for avelumab will include the following 
information:

Duration (weeks)

Total number of infusions received

Cumulative dose (mg/kg)

Dose intensity (mg/kg/cycle)

Relative dose intensity (%)
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Detailed algorithm will be presented in Appendix 5.
6.4.7.2. Dose Reductions and Interruptions
Dose reduction is as a day when the actual dose taken is less than the initial prescribed dose 
for any reason with the exception that a day with total dose administered of 0mg is not 
considered a dose reduction.  Number of patients with at least one dose reduction as well as a 
breakdown of dose reductions (1 / 2 / 3 / ≥4) will be summarized by treatment /cohort. 
A dose interruptions/missed dose is defined as a planned dosing day with 0 mg total dose 
administered.  Number of patients with at least one dose interruption as well as a breakdown 
of interruptions (1 / 2 / 3 / ≥4) will be summarized by treatment /cohort. 
6.4.7.3. Infusion rate reductions
For Cohort 3, the frequency (number and percentage) of patients with at least one infusion 
rate reduction of 50% or more as well as the frequency of patients with 1, 2, or ≥3 infusion 
rate reductions of 50% or more will be summarized by treatment.
6.5. Covariates
None.
7. HANDLING OF MISSING VALUES
7.1. Missing Dates
Missing or Partial Death Dates
It is recommended that the database be designed to mandate a complete death date.  If there 
is a record for death, but the date is missing or is partial, it will be imputed based on the last 
contact date ().

If the entire date is missing, the death date will be imputed as the day after the date of 
last contact.

If the day or both day and month is missing, the death date will be imputed to the 
maximum of the full (non-imputed) day after the date of last contact and the 
following: 

1st day of the month and year of death, if day of death is missing OR

January 1st of the year of death, if both the day and month of death are 
missing.
Date of Last Dose of Study Drug
No imputation will be done for first dose date.  Date of last dose of study drug, if unknown or 
partially unknown, will be imputed as follows:

If the last date of study drug is completely missing and there is no End of Treatment 
eCRF page and no death date, the patient should be considered to be ongoing and use 


Protocol B7971001                                                                             Statistical Analysis Plan
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the cutoff date for the analysis as the last dosing date.  Note:  teams should confirm 
that the patient is actively receiving dose at the time of the data cutoff.

If the last date of study drug is completely or partially missing and there is EITHER 
an End of Treatment eCRF page OR a death date available (within the data cutoff 
date), then impute this date as the last dose date:
= 31DECYYYY, if only Year is available and Year < Year of min (EOT date, death 
date) 
= Last day of the month, if both Year and Month are available and Year = Year of 
min (EOT date, death date) and Month < Month of min (EOT date, death date)
= min (EOT date, death date), for all other cases.
Date of Start of New Anti-cancer Therapy
Incomplete dates for start date of new anti-cancer therapy will be imputed as follows and will 
be used for determining censoring dates for efficacy analyses. 

The end date of new anti-cancer therapy will be included in the imputations for start 
date of new anti-cancer therapy.  If the end date of new anti-cancer therapy is

completely missing then it will be ignored in the imputations below

partially missing with only year (YYYY) available then the imputations below 
will consider 31DECYYYY as the end date of the new anti-cancer therapy

partially missing with only month and year available then the imputations 
below will consider the last day of the month for MMMYYYY as the end date 
of the new anti-cancer therapy

For patients who have not discontinued study treatment at the analysis cutoff date, 
last dose of study treatment is set to the analysis cutoff date is the imputations below 

If the start date of new anti-cancer therapy is completely or partially missing then the 
imputed start date of new anti-cancer therapy is:
= 31DECYYYY, if only Year is available and Year < Year of min [max(PD date + 1, 
last dose of study treatment + 1), end date of new anti-cancer therapy] 
= Last day of the month, if both Year and Month are available and 
Year = Year of min [max(PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy] 
Month < Month of min [max(PD date + 1 day, last dose of study treatment + 
1 day), end date of new anti-cancer therapy]
= min [max(PD date + 1, last dose of study treatment + 1), end date of new 
anti-cancer therapy], for all other cases.


Protocol B7971001                                                                             Statistical Analysis Plan
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Other Missing or Partial Dates
In compliance with Pfizer standards, imputation methods generally apply to partial dates as 
follows:

If the day of the month is missing for a start date used in a calculation, the 1st of the 
month will be used to replace the missing date. 

If both the day and month are missing, the first day of the year is used. 

For stop dates, the last day of the month, or last day of the year is used if the day or 
day and month are missing, respectively. 
These rules are used unless the calculations result in negative time durations (eg, date of 
resolution cannot be prior to date of onset).  In these cases, the resolution and onset dates will 
be the same and the duration will be set to 1 day. 
7.2. Missing Efficacy Endpoint Values
For all efficacy analyses no values will be imputed for missing data, except as specified in
Section 6. For ORR, patients with no post-baseline tumor evaluations due to early 
progression will be counted as non-responders. 
7.3. Pharmacokinetics
Concentrations Below the Limit of Quantification
For all calculations, figures and estimation of individual pharmacokinetic parameters, all 
concentrations assayed as below the level of quantification (BLQ) will be set to zero.  In 
log-linear plots these values would not be represented. The BLQ values will be excluded 
from calculations of geometric means and their confidence intervals.  A statement similar to 
“All values reported as BLQ have been replaced with zero” should be included as a footnote 
to the appropriate tables and figures.
Deviations, Missing Concentrations and Anomalous Values
In summary tables and plots of median profiles, statistics will be calculated.  Concentrations 
will be set to missing if one of the following cases is true:

A concentration has been reported as ND (ie, not done) or NS (ie, no sample);

A deviation in sampling time is of sufficient concern or a concentration has been 
flagged as anomalous by the clinical pharmacologist.
Note that summary statistics will not be presented at a particular time point if more than 50% 
of the data are missing. For analysis of pharmacokinetic concentrations, no values will be 
imputed for missing data.


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For steady state PK assessment, if a pre-dose PK sample (0 hr or 24 hr) was missed, taken 
erroneously after dosing, or the reported concentration appears anomalous, the plasma 
concentration reported for the other pre-dose PK sample (24 hr or 0 hr) from that visit, if 
available, will be imputed to replace the missing or erroneous pre-dose concentration.  This 
will be done only if deemed appropriate by the PK analyst or clinical pharmacologist in order 
to allow for steady state PK evaluation. 
Pharmacokinetic Parameters
Whether actual or nominal PK sampling time will be used for the derivation of PK 
parameters will be determined by the results of interim PK analyses. 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 be calculated by setting NC values to missing; and statistics 
will not be presented for a particular treatment if more than 50% of the data are NC.  For 
statistical analyses (ie, analysis of variance), 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 a
deviation from the assigned dose level or interruption of daily dosing so that steady-state 
cannot be assumed), this will be footnoted in summary tables and will not be included in the 
calculation of summary statistics or statistical analyses.
7.4. ECG
For analyses using the QTc analysis set, no values will be imputed for missing data except 
for averaging of triplicate measurements.  If one or two of the triplicate measurements for an 
ECG parameter are missed, the average of the remaining two measurements or the single 
measurement can be used in the analyses.  If all triplicate measurements are missing at a time 
point for an ECG parameter, no values will be imputed for this time point and no analyses 
related to this time point will be performed.
 
 
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Protocol B7971001                                                                             Statistical Analysis Plan
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8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES
8.1. Statistical Methods 
8.1.1. Statistical Methods for Dose Escalation/De-escalation
8.1.1.1. CRM (Phase 1)
The Phase 1 portion of this study employs a CRM approach to estimate the MTD.  The CRM 
algorithm utilizes the Bayesian methodology to continuously learn about the dose-toxicity 
relationship after each cohort’s DLT data becomes available.  The underlying model 
assumption is that DLT rate at each dose can be expressed as Pr (DLT|dose x) =f(x, ), 
where f is a monotonically increasing function in dose x and is an unknown parameter with 
prior distribution placed on it at the beginning of the trial.  The first two cohorts patients will 
be assigned to 25 mg/QD and 50 mg/QD respectively if the DLT data warrants dose 
escalation.  After the DLT data of the 25 mg/QD and 50 mg/QD cohorts becomes available 
(~3 wks), the prior distribution of is updated based on their DLT responses and becomes a 
posterior distribution.  The current estimate of MTD is calculated and the next cohort’s dose 
assignment is chosen as the dose closest to this estimated MTD but not exceeding it.  This 
process is continued until 1 of the stopping rules below is triggered. 

Maximum sample size of 36 patients has been reached; or

10 evaluable patients have been treated at the estimated MTD; or 

All doses appear to be overly toxic and the MTD cannot be determined in 
the current trial setting.
The above described CRM algorithm constantly incorporates additional information about 
dose-DLT relationship learned from the data via modeling and that is reflected on the 
projected MTD.  By design, such dose allocation procedure will eventually cluster dose 
assignments around the dose yielding a DLT rate closest to but no more than 30%.
Once one of the aforementioned conditions for stopping the CRM is met, the dose identified 
as MTD will be evaluated together with information gathered from PK analyses and the 
overall safety profile in order to determine the RP2D.  The dose(s) likely to be considered the 
RP2D will be expanded to 10 patients if not already tested within the CRM context in order 
to confirm the RP2D.
Extensive simulation results assessing the CRM properties can be found in O’Quigley et all 
(1990).
8.1.1.2. mTPI (Phase 1b)
The mTPI design 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 = 0.30).  If the 
toxicity rate of the currently used dose level is far smaller than pT, the mTPI will recommend 
escalating the dose level; if it is close to target probability (pT), the mTPI will recommend 
continuing at the current dose; if it is far greater than pT, the mTPI will recommend 


Protocol B7971001                                                                             Statistical Analysis Plan
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de-escalating the dose level.  These rules are conceptually similar to those used by the 
3+3 design, except the decisions of an mTPI design are based on posterior probabilities 
calculated under a coherent probability model. 
Being a model-based design, mTPI automatically and appropriately tailors dose-escalation 
and de-escalation decisions for different studies with different toxicity parameters.  More 
importantly, all the dose-escalation decisions for a given study can be pre-calculated under 
the mTPI design and presented in a two-way table (see Appendix 4).  Thus, compared to 
other advanced model-based designs published in the literature, the mTPI design is 
logistically less complicated and easier to implement. 
Decision rules are based on calculating unit probability mass (UPM) of 3 dosing intervals 
corresponding to under, proper, and over dosing in terms of toxicity.  Specifically, the 
underdosing interval is defined as (0; pT-e1), the overdosing interval (pT+e2, 1), and the 
proper-dosing interval (pT- e1, pT+ e2), where e1 and e2 are small fractions.  Based on the 
expected safety profile of PF-06459988 as a single-agent, e1 is selected as 0.05, and e2 is 
selected as 0.03.  Therefore, the target interval for the DLT rate is (0.25, 0.33).
The 3 dosing intervals are associated with 3 different dose-escalation decisions.  The 
underdosing interval corresponds to a dose escalation (E), over-dosing corresponds to a 
dose de-escalation (D), and proper-dosing corresponds to remaining at the current dose (S).  
Given a dosing interval and a probability distribution, UPM of that dosing interval is defined 
as the probability of a patient belonging to that dosing interval divided by the length of the 
dosing interval.  The mTPI design calculates the UPMs for the 3 dosing intervals, and the 
one with the largest UPM informs the corresponding dose-finding decision, which is the dose 
level to be used for future patients.  For example, if the under-dosing interval has the largest 
UPM, the decision will be to escalate, and the next cohort of patients will be treated at the 
next higher dose level. Ji et al. have demonstrated that the decision based on UPM is optimal 
in that it minimizes a posterior expected loss (ie, minimizes the chance of making a wrong 
dosing decision). 
The dose-finding portion of the study uses a modified version of the mTPI design that 
maximizes the number of evaluable patients treated at each dose to 6 patients.  Dose finding 
is complete when at least 6 evaluable patients have been treated at the highest dose with DLT 
rate 33%.  In case de-escalation is required from the initial starting DL1, it is estimated 
that up to approximately 10-12 DLT-evaluable patients will need to be enrolled to estimate 
the MTD for the PF-06747775 plus palbociclib combination.  For the PF-06747775 plus 
avelumab combination, up to approximately 10 – 12 patients may be enrolled.
8.1.2. Sample Size Determination
8.1.2.1. Phase 1 Sample Size
Due to the dynamic nature of the Bayesian allocation procedure, the sample size of CRM 
approach cannot be determined in advance.  The maximum sample size is set as 36 for dose 
escalation cohorts.


Protocol B7971001                                                                             Statistical Analysis Plan
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In Phase 1 portion of the study, patients will participate in a dose escalation phase aimed at 
estimating the MTD.  The sample size for this portion of the study will vary depending on the 
number of DLTs observed.  It is expected that about 36 patients will be required. 
In addition to dose escalation, additional patients (approximately 24) will be enrolled with 
the aim of evaluating the DDI, food and antacid effects studies at RP2D prior to initiating 
the Phase 1b/2 portion. 
The planned sample size for the MTD expansion cohort is 10 evaluable patients.  An 
evaluable patient will have both a baseline and on-treatment tumor assessment.  This 
expansion cohort will also be used to conduct the sildenafil sub-study. 
8.1.2.2. Phase 1b/2 Sample Size
The sample size planned for Phase 2 Cohort 1 is about 20 patients to provide preliminary 
information on efficacy, safety, and PK endpoints in previously untreated patients with 
advanced EGFRm NSCLC.  With 20 patients the maximum width of the exact 2-sided 90% 
confidence interval for ORR will be ≤0.396. 
The sample size planned for the Phase 1b (Cohort 2A and Cohort 3) dose finding part arises 
from logistic feasibility and is not entirely driven by statistical considerations.  Due to the 
dynamic nature of the dose allocation procedure and unknown safety profile of the 
combination, the sample size of the interval design cannot be determined in advance.  It is 
expected that approximately 10 DLT evaluable patients will be required for each of the dose 
finding cohorts. 
After dose selection determined for Cohort 3, the Dose Expansion Phase will continue to 
enroll patients until approximately 20 patients in total have been treated to further assess the 
safety, PK, 
 of the combination.  Phase 2 (Cohort 2B), the planned 
sample is about 39 patients. These patients will be randomized with a 2:1 ratio for the 
combination of PF-06747775 and palbociclib vs PF-06747775 single agent. The primary 
objective is to estimate the hazard ratio (HR) and its corresponding confidence interval for 
PFS.  For a target sample size of 39 patients randomized in ratio of 2:1 and 26 events, the 
approximate width of the 2-sided 90% CI for the logHR for PFS will be 1.37 which 
corresponds to the upper bound being approximately 3.93 times the lower bound on the HR 
scale. 
8.1.3. Simulation for CRM
Several simulations were performed to fine-tune the CRM performance and to study 
operating characteristics of the chosen “best” CRM design.  Below is a brief description of 
the simulation setup and key findings.  Competing designs were evaluated against 6 different 
plausible scenarios of dose-toxicity profile varying in steepness of dose-DLT curve and 
location of the true MTD within the studied dose range.  These scenarios are summarized in
Table 6.
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Protocol B7971001                                                                             Statistical Analysis Plan
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Table 6. Probability of DLT as a Function of Dose
Dose-Toxicity Curve Scenario
Dose
Sc. 1:
MTD=
50-flat
Sc. 2:
MTD=
50-steep
Sc. 3:
MTD=
150-flat
Sc. 4:
MTD=
150-steep
Sc. 5:
MTD=
600-flat
Sc. 6:
MTD=
600-steep
25    mg/QD
0.25
0.25
0.10
0.10
0.05
0
50    mg/QD
0.30
0.30
0.20
0.20
0.07
0
100 mg/QD
0.40
0.60
0.25
0.25
0.10
0
150 mg/QD
0.50
0.80
0.30
0.30
0.12
0
200 mg/QD
0.60
0.85
0.40
0.60
0.15
0
275 mg/QD
0.70
0.9
0.50
0.80
0.17
0
350 mg/QD
0.80
0.92
0.60
0.90
0.20
0
450 mg/QD
0.90
0.95
0.80
0.98
0.22
0.10
600 mg/QD
0.98
0.98
0.98
0.98
0.25
0.30
For each of the competing designs (ie, CRM design variant), the following operating 
characteristics were assessed, by scenario, to further quantify the trade-off between precision 
of MTD estimation and design cost:

Probability to select MTD.

Design cost:
Average Sample Size;
Average Number of DLTs;
Average Proportion of DLTs.
These operating characteristics are summarized in Table 7 for the final design selected based 
on 1000 trials simulated. 
Table 7. Operating Charateristics of the CRM in Phase 1
MTD Dose Selection Decision (Probability, %)
Scenarios
25
mg/Q
D
50
mg/Q
D
100
mg/QD
150
mg/Q
D
200
mg/Q
D
275
mg/Q
D
350
mg/Q
D
450
mg/Q
D
600
mg/Q
D
Average 
Size
Averag
e Num 
DLTs
Average 
DLTs (%)
MTD 
50 flat
26.09
30.8
9.32
1.14
0.1
0.03
0.04
0
0
15.7
5.03
38.8
MTD
50 steep
33.25
34.97
1.12
0
0
0
0
0
0
14.9
4.8
38.8
MTD 
150 flat
10.36
29.07
24.38
12.78
5.85
4.36
3.41
0.42
0.09
24.4
6.3
27.1
MTD 
150 stee
p
10.2
29.59
34.74
13.15
2.22
0.54
0.09
0
0
23.5
6.1
27.2
MTD
600 flat
0.97
2.85
3.31
1.98
2.11
4.17
6.83
11.33
65.48
34.3
5.4
16.2
MTD 
600 stee
p
0
0
0
0
0
0.02
0.12
0.36
99.5
36
3.8
10.5


Protocol B7971001                                                                             Statistical Analysis Plan
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8.1.4. Statistical Methods for Different Types of Endpoints
Standard summary statistics will be used for description of different types of variables: 
 

Time-to-event: Kaplan-Meier estimate of survivor function, median time to event, 
Brookmeyer-Crowley confidence interval for median time to event, probability of 
event by a particular time point, log(−log) method with back transformation for 
confidence interval of estimated probability of event by a given time point;

Categorical: count and percentage of each category, confidence interval of the 
percentage based on normal approximation (unless specified otherwise).
Summaries of efficacy, PK 
 endpoints will be provided for dose level in Phase 1 and 
by treatment arm in all other cohorts.  Summaries of other endpoints (demographics, safety, 
study conduct, etc.) will be provided for dose level in Phase 1 unless stated otherwise and by 
treatment arm in all other cohorts.
Listings for derived data in summaries will be provided.  Listings of raw data will be 
provided as well.
8.2. Statistical Analyses
Data will be presented by Phase and Cohort within each Phase separately.  Refer to Section 
5 for definitions of analysis sets.
8.2.1. Analysis of Efficacy Endpoints
8.2.1.1. Phase 1
Analysis Set: Safety
In the Phase 1 portion of the study anti-tumor activity is a secondary objective.
Tumor response will be presented in the form of patient data listings that include, but are not 
limited to, tumor type, starting dose, tumor response at each visit, and best overall response.
8.2.1.2. Phase 1b/2       
8.2.1.2.1. Primary Analysis of Efficacy
8.2.1.2.1.1. Cohort 1 – PF-06747775 Single-Agent in Patients with Previously Untreated 
EGFRm NSCLC
Primary analyses in Phase 2 Cohort 1 portion of study is based on objective response rate 
(ORR) which is calculated as the proportion of patients with a confirmed complete 
response(CR) or partial response (PR) relative to the total number of response evaluable 
patients using the Response Evaluable Analysis Set.  A Clopper- Pearson exact 2-sided 90% 
CI for objective response rate will be presented.
C
C
I
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Protocol B7971001                                                                             Statistical Analysis Plan
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A table summarizing objective response will include the number of patients and percentage
of patients for CR, PR, SD, PD, IND, and objective response (CR+PR), the 90% CI for the 
objective response rate.  Categories of symptomatic deterioration (per the case report form 
for end of treatment subject summary) and early death (ie, death prior to the second on-study 
assessment) may be presented in the table.
A waterfall plot will be presented for maximum percent change in tumor size (sum of 
diameters) from baseline, with best overall response identified.
Sensitivity analysis for ORR will be performed based on safety analyses set.
8.2.1.2.1.2. Cohort 2B – PF-06747775 Plus Palbociclib vs PF-06747775 Alone 
(Randomized)
The primary endpoint of PFS will be analysed and displayed graphically for each arm 
separately using the Kaplan-Meier method on the Full Analysis Set.  The hazard ratio and its 
2-sided 90% CI will be estimated.  The median event time and 2-sided 90% CI using the 
Brookmeyer-Crowley method will be provided for each arm separately.  Estimated 
probability of remaining progression-free at 6 months and its 2-sided 90% CI, using log-log 
transformation and back-transformation will be provided for each arm as well.
8.2.1.2.2. Secondary Analysis of Efficacy  
Analysis Set: Safety Analysis Set unless specified otherwise
8.2.1.2.2.1. Phase 1
In the Phase 1 portion of the study anti-tumor activity is a secondary objective.
Tumor response will be presented in the form of patient data listings that include, but are not 
limited to, tumor type, starting dose, tumor response at each visit, and best overall response 
using Safety Analysis Set.
8.2.1.2.2.2. Phase 2 Cohort 1
DOR in responding patients will be characterized in terms of the median based on 
Kaplan - Meier estimates) among all responding patients.  Their 90% confidence interval will 
also be computed. 
PFS in the Safety Analysis Set will be characterized in terms of the median and 2-sided 90% 
confidence interval and the estimated probability of remaining progression-free at 6 months 
(based on Kaplan- Meier estimates), a 2-sided 90% confidence interval for the 
log(-log(6-month PFS probability)) will be calculated based on a normal approximation and 
then back transformed.
OS in the Safety Analysis set will be characterized in terms of the median and 2-sided 90% 
confidence interval and the estimated probability of being alive at 24 months (based on 
Kaplan-Meier estimates), a 2-sided 90% confidence interval for the log(-log(2-year survival 
probability)) will be calculated based on a normal approximation and then back transformed.


Protocol B7971001                                                                             Statistical Analysis Plan
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8.2.1.2.2.3. Phase 2 Cohort 2A 
In the Cohort 2A portion of the study anti-tumor activity is a secondary objective.
Tumor response will be presented in the form of patient data listings that include, but are not 
limited to, tumor type, starting dose, tumor response at each visit, best overall response, PFS, 
and OS, using Safety Analysis Set.
8.2.1.2.2.4. Phase 2 Cohort 2B
The point estimate and 90% Clopper- Pearson exact 2-sided CI of the proportion of patients 
with ORR will be summarized by treatment arm using the Response Evaluable Analysis Set.  
A Pearson χ2 test will be used to compare ORR between the two treatment arms.  The point 
estimate and the 2-sided 90% confidence interval for the difference in ORR will be 
presented.
DOR in responding patients and OS in the Full Analysis Set will be analysed and displayed 
graphically for each treatment arm using the Kaplan-Meier method and the median and 
2-sided 90% confidence interval will be provided for each endpoint as well as the hazard 
ratio and 2-sided 90% confidence interval for OS.  The estimate of survival probabilities at 
24 months and its 2-sided 90% CI (using log-log transformation and back-transformation) 
will be provided for each arm separately for OS.
8.2.1.2.2.5. Phase 2 Cohort 3
The median event time and corresponding 2-sided 90% CI will be provided for PFS, DOR 
and OS in the RP2D expansion cohort for responding patients (DOR) and the Safety Analysis 
Set (PFS and OS) .  The estimated probability of remaining progression-free at 6 month and 
its 2-sided 90% CI (using log-log transformation and back-transformation) will be provided 
for PFS.  The estimate of survival probability at 24 month and 90% CI (using log-log 
transformation and back-transformation) will be provided for OS.
The point estimate and 2-sided 90% exact CI of the proportion of patients with ORR
(confirmed and unconfirmed) will be summarized using the Response Evauable and Safety 
Analysis Sets.
For DOR, the number of CR and PR patients may be small and thereby limit use of the 
Kaplan-Meier method to provide reliable estimates.  In this case, only descriptive statistics or 
listings will be provided.
 
8.2.2. Analysis of Safety Endpoints
8.2.2.1. Analysis of Primary Endpoint for Phase 1, Phase 1b Cohort 2A, and Cohort 3
Analysis set: Per Protocol
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Protocol B7971001                                                                             Statistical Analysis Plan
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Dose Limiting Toxicity (DLT) is the primary endpoint of Phase1 and Phase1b Cohort 2A and 
Cohort 3 of the study.  The occurrence of DLTs observed in the dosing cohorts is used to 
estimate the MTD as described in the protocol.  Adverse Events constituting DLTs will be 
listed per dose level.
8.2.2.2. Analysis of Secondary Safety Endpoint
Analysis: Safety
All safety reports will be separated by Phase and Cohort.  Safety data in Phase 1, Cohort 2A, 
and Cohort 3 will be reported by dose level or treatment arm, and total.  Safety data in Cohort 
2B will be reported by treatment arm.
Summary of 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 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). 
Deaths will be summarized by time period (on-treatment vs. during follow-up) and cause of 
death. Deaths that occurred within 28 days after the last dose of study medication are 
defined as on-treatment deaths. Death data will also be listed.
For all safety analyses, only descriptive methods will be used without any formal statistical 
test.
Treatment-emergent adverse events (all causality and treatment related) including:

number of patients evaluable for AEs;

total number of AEs (counting each unique preferred term across all patients);

total number of SAEs (counting each unique preferred term across all patients);

number of patients with AEs;

number of patients with SAEs;

number of patients with Grade 3 or Grade 4 AEs;

number of patients with Grade 5 AEs;

number of patients who discontinued due to AEs (per the AE CRF page);


Protocol B7971001                                                                             Statistical Analysis Plan
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Page 39

number of patients with dose decreases due to AEs (per the AE CRF page);

number of patients with dose delays due to AEs (per the AE CRF page).
The following summaries will be presented for all-causality and treatment-related treatment
emergent AEs, or treatment- emergent irAEs and IRR (Cohort 3 only) separately.
The number and percentage of patients with treatment-emergent AEs will be summarized by
MedDRA system organ class, preferred term, and maximum CTCAE grade for all cycles
combined for each dose level.  The total for all grades will be included as the last column.
The number and percentage of patients with treatment-emergent AEs will be summarized by
MedDRA preferred term and maximum CTCAE grade in descending order of frequency
(based on total frequency for all grades) for all cycles combined for each dose level.  The 
total for all grades will be included as the last column.
The number and percentage of patients with treatment-emergent SAEs will be summarized
by MedDRA system organ class, preferred term, and maximum CTCAE grade for all cycles
combined for each dose level.  The total for all grades will be included as the last column.
The number and percentage of patients with treatment-emergent AEs of Grade 3-5 will be
summarized by MedDRA preferred term and maximum CTCAE grade in descending order
of frequency (based on total frequency for all grades) for all cycles combined for each dose 
level.  The total for all grades will be included as the last column.
Laboratory Tests
The number and percentage of patients who experienced laboratory test abnormalities will be 
summarized according to worst toxicity grade observed for each lab assay.  The analyses will 
summarize laboratory tests both on the entire treatment period and by cycle (Cycle 1, 
Cycle 2, and Cycles beyond 2).  For laboratory tests without CTC grade definitions, results 
will be categorized as normal, abnormal or not done.

Hematology – Descriptive statistics will be provided for each test result and for 
change from baseline by visit. Baseline is defined as the last evaluation prior to the 
first dose of study drug. Hematology results will be graded according to the NCI 
CTCAE Version 4.03. A summary of maximum CTCAE grade as well as shift 
summary of baseline grade by maximum CTCAE grade, cycle, and dose will be 
presented. Patients who developed a grade 3 or greater toxicity will also be listed.

Biochemistry - Descriptive statistics will be provided for each parameter result and 
for change from baseline by visit. Baseline is defined as the last evaluation prior to 
the first dose of study drug.  Biochemistry results will be graded according to the NCI 
CTCAE version 4.03. A summary of maximum CTCAE grade as well as shift 
summary of baseline grade by maximum CTCAE grade, cycle, and dose will be 
presented. Patients who developed a grade 3 or greater toxicity will also be listed.

Urine - Urinalysis data will be listed for each subject.


Protocol B7971001                                                                             Statistical Analysis Plan
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
Other Laboratory Tests – Individual patient test results will be listed.
ECG
Triplicate ECGs will be performed (approximately 2 minutes apart) before vital signs or any 
type of blood draws at indicated visits per Schedule of Activities table in the protocol.  If a 
patient experiences a cardiac or neurologic AE (specifically syncope, dizziness, seizures, or 
stroke) triplicate ECGs should be obtained at the time of the event.
All ECGs obtained during the study will be evaluated for safety.  The triplicate data will be 
averaged and all summary statistics and data presentations will use the triplicate averaged 
data based on independent cardiologist central reading data.  ECG data recorded on CRF by 
principal investigator will be listed only.  Any data obtained from ECGs repeated for safety 
reasons after the nominal time points will not be averaged along with the preceding 
triplicates.
QT measurements corrected by heart rate (QTc) will be used for the data analysis and 
interpretation.  In addition to commonly used techniques including Bazzett’s (QTcB) and 
Fridericia’s (QTcF) methods, a study-specific correction method will be evaluated (QTcS) 
for the QTc evaluable patients.  QTcF is planned to be the primary analysis method for the 
secondary QT endpoint.  If QTcF cannot sufficiently correct for the heart rate, the most 
appropriate correction method that eliminates any QT vs. RR relationship may be chosen 
after reviewing the data.
Analysis of QTc
Changes in QTc (QTcB, QTcF, and/or QTcS) from baseline to steady state will be 
summarized by dose and by treatment arm (PF-06747775 alone, or in combination with 
palbociclib or avelumab), using descriptive statistics and categorical analysis by nominal 
time point.  The primary correction factor will be QTcF.  If QTcF cannot sufficiently correct 
for the heart rate, the most appropriate correction method that eliminates any QT vs. RR 
relationship may be chosen after reviewing the data. 
For Phase 1, Day 11 of Cycle 1 and Day 1 of Cycles 2-4 will be used to characterize the 
potential effect of PF-06747775 on the QT interval.  The baseline for Phase 1 is defined as 
the ECGs recorded on Day -8 pre-dose. 
For Phase 1b/2, Day 11 (Cohort 1) or Day 15 (Cohort 2A, 2B, and 3) of Cycle 1 and Day 1 of 
Cycles 2-3 (Cohort 3) or 2-4 (Cohort 1, 2A, and 2B) will be used to characterize the potential 
effect of PF-06747775 on the QT interval.  The baseline for Phase 1b/2 is defined as the 
ECGs recorded on Day -4 (Cohort 1) or Day 1 (Cohort 2A, 2B, and 3) pre-dose.
A random effect model with the nominal time point as a fixed effect and the patients as a 
random effect will be used to estimate the mean change in QTc from baseline at each 
post-baseline nominal time point by dose and by treatment.  The 2-sided 90% CI for the 
changes from baseline in QTc (equivalent to the boundaries of upper one-sided 90% 
confidence intervals) will be provided at each post-baseline nominal time point.


Protocol B7971001                                                                             Statistical Analysis Plan
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Mean QTcF change and 90% CI from baseline will be presented along with the mean and 
90% CI plasma concentrations of PF-06747775 by dose, by treatment, and by nominal time
point in a summary table. 
Summary and Categorical Analysis of ECG
For the ECGs assessments the following directions should be followed by the ECG central 
Laboratory:

Review of ECGs from a particular patient should be performed by a single 
reader.

Pre-specification of the lead for internal measurements.

Baseline and on-treatment ECGs should be based on the same lead.
All ECGs obtained during the study will be evaluated for safety.  ECGs recorded on 
Day -8 (Phase 1), Day -4 (Phase 1b/2 Cohort 1) or Day 1 (Phase 1b/2 Cohort 2A, 2B, and 3)
pre-dose will be used as baseline.  For Phase 1 the QTc baseline-adjusted on Day 11 of Cycle 
1 and Day 1 of Cycles 2-4 will be used to characterize the potential effect of PF-06747775 on 
the QT interval.  For Phase 1b/2, the QTc baseline-adjusted on Day 11 (Cohort 1) or Day 
15 (Cohort 2A, 2B, and 3) of Cycle 1 and Day 1 of Cycles 2-3 (Cohort 3) or 2-4 (Cohort 1, 
2A, and 2B) will be used to characterize the potential effect of PF-06747775 on the QT 
interval.
For Phase 1, figures of Mean Corrected Change from Baseline in QTcF Intervals vs. Time by 
Cycle 1 Day 11 and Day 1 of Cycles 2-4 will be presented.
For Phase 1b/2 Cohort 1, figures of Mean Corrected Change from Baseline in QTcF Intervals 
vs. Time by Cycle 1 Day 11 and Day 1 of Cycles 2-4 will be presented.
For Phase 1b/2 Cohort 2A and 2B, figures of Mean Corrected Change from Baseline in QTcF 
Intervals vs. Time by Cycle 1 Day 15 and Day 1 of Cycles 2-4 will be presented.
For Phase 1b/2 Cohort 3, figures of Mean Corrected Change from Baseline in QTcF Intervals 
vs. Time by Cycle 1 Day 15 and Day 1 of Cycles 2-3 will be presented.
All figures listed above may also be presented by dose of study treatment(s).
The triplicate data will be averaged and all summary statistics and data presentations will use 
the triplicate averaged data.  Any data obtained from ECGs repeated for safety reasons after 
the nominal time points will not be averaged along with the preceding triplicates.
For all patients in the safety analysis population, individual change in QTc (QTcB, QTcF, 
QTcS) will be calculated for each nominal post-baseline time point.  These individual 
changes will be summarized using descriptive statistics.


Protocol B7971001                                                                             Statistical Analysis Plan
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Page 42
For all patients in the safety analysis population, categorical analysis of the QTcF/QTcB data 
will be conducted and summarized as follows:

The number and percentage of patients with maximum increase from baseline in 
QTcF/QTcB (<30, 30- 60, and ≥60 ms).

The number and percentage of patients with maximum post-dose QTcF/QTcB 
(<450, 450-<480, 480- <500, and ≥500 ms).

PR changes from baseline ≥25% and absolute values over >200 ms.

QRS changes from baseline ≥25% and absolute values over >110 ms.

Number and percentage of individuals with abnormal ECG findings.

Number and percentage of individuals with AEs that could be associated with 
prolongation of cardiac repolarization or proarrhythmia, eg, palpitations, dizziness, 
syncope, cardiac arrhythmias, and sudden death.
The ECG analyses described above for the safety population will be repeated separately for 
the QTc evaluable population.

The following analyses will be provided for the QTcB, QTcF, QTcS, QRS, PR, 
RR-derived HR, systolic blood pressure, and diastolic blood pressure: absolute 
parameter with 2-sided 90% confidence intervals, and baseline-adjusted parameter with 
2-sided 90% confidence intervals. 

Provide categorical analyses of outliers for the QTc, QRS, PR, and RR-derived heart 
rate. For outlier thresholds use QTc>450, 480, & 500 ms, QTc increase from baseline 
>30 ms & 60 ms, QRS>110 ms, PR>200 & 220 ms, HR <50, 40, & 30 bpm and 
HR>90 bpm. 
Data will be summarized and listed for QT, HR, RR, PR, QRS, QTcF (and other correction 
factors, eg, QTcB as appropriate), by dose and by treatment.  Individual QT` (all evaluated 
corrections) intervals will be listed by time and dose.  The most appropriate correction factor 
will be selected and used for the following analyses of central tendency and outliers and used 
for the study conclusions.  Descriptive statistics (n, mean, median, standard deviation, 
minimum, and maximum) will be used to summarize the absolute corrected QT value and 
changes from baseline in corrected QT after treatment by dose, treatment, and time point.  
For each patient, the maximum change from baseline will be calculated as well as the 
maximum post-baseline value across time-points.  Categorical analysis will be conducted for 
the maximum change from baseline in corrected QT and the maximum post-baseline QT 
value. 
Shift tables by dose and by treatment/cohort will be provided for baseline vs worst on 
treatment corrected QT (one or more correction method will be used) using Maximum CTC 
AE Grade.  Shift tables will also be provided for ECG abnormality at baseline vs. on 


Protocol B7971001                                                                             Statistical Analysis Plan
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treatment (yes, no, not done: (n, %)).  Patients experiencing clinically-relevant 
morphological ECG changes will be summarized (including frequency and percentage).  
These tables may also be provided by dose, and with several treatments/cohorts and doses 
combined.  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.
8.2.3. Baseline Characteristics
Analysis Set: Full
Patient characteristics such as age, gender, height, weight, ethnicity, diagnosis, performance 
status, and medical history at study entry will be summarized in frequency tables, and 
descriptive statistics will be provided for quantitative variables.
8.2.4. Analysis of Pharmacokinetics
8.2.4.1. Population Pharmacokinetic Analysis or PK/PD Modeling
Data may be pooled with other study results and/or explored further in a standalone PK/PD 
report.
8.2.4.1.1. Derivation of Pharmacokinetic Parameters Prior to Analysis
Pharmacokinetic parameters for PF-06747775 will be derived from plasma 
PF-06747775 concentration-time data as described in the following table.
PF-06747775 PK parameters for either single or multiple doses from the multiple 
sub-studies/cohorts may be reported together by dose or as dose-normalized parameters, in 
addition to reporting by cohort or treatment.
Table 8. PK Parameters to be Determined for PF-06747775
Parameter
Definition
Method of Determination
AUClast
Area under the plasma 
concentration-time profile from time 
zero to the time of the last 
quantifiable concentration (Clast)
Linear/Log trapezoidal method
AUCinf
a
Area under the plasma 
concentration-time profile from time 
zero extrapolated to infinite time 
AUClast + (Clast*/kel),
where Clast* is the predicted plasma 
concentration at the last quantifiable 
time point estimated from the 
log-linear regression analysis
AUC24
Area under the plasma 
concentration-time profile from time 
zero to 24 hours
Linear/Log trapezoidal method
AUCtau
Area under the plasma 
concentration-time profile from time 
zero to time tau, the dosing interval, 
where tau = 24 hours
Linear/Log trapezoidal method
Cmax
Maximum observed plasma 
concentration 
Observed directly from data
Tmax
Time for Cmax
Observed directly from data as time 
of first occurrence


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Parameter
Definition
Method of Determination
t½
a
Terminal half-life
Loge(2)/kel,
where kel is the terminal phase rate 
constant calculated by a linear 
regression of the log-linear 
concentration-time curve.  Only those 
data points judged to describe the 
terminal log-linear decline were used 
in the regression.
Ctrough
Predose concentration during multiple 
dosing
Observed directly from data
CL/Fa
Apparent clearance
Dose / AUCinf for single dose
Dose / AUCτ for steady state
Vz/Fa
Apparent volume of distribution
Dose / (AUCinf · kel) for single dose
Dose / (AUCτ ·kel) for steady state
Rac
Observed accumulation ratio
Steady state AUCtau / Single dose 
AUC24
Rss
a
Steady state accumulation ratio
Steady state AUCtau / Single dose 
AUCinf
AUClast(dn)
Dose-normalized AUClast
AUClast / Dose
AUCinf(dn)a
Dose-normalized AUCinf
AUCinf / Dose
AUCtau(dn)
Dose-normalized AUCtau
AUCtau / Dose
AUC24(dn)
Dose-normalized AUC24
AUC24 / Dose
Cmax(dn)
Dose-normalized Cmax
Cmax / Dose
Ctrough(dn)
Dose-normalized Ctrough
Ctrough / Dose
aIf data permit
Pharmacokinetic parameters for sildenafil will be derived from plasma sildenafil 
concentration-time data as described in the following table.
Table 9. PK Parameters to be Determined for Sildenafil
Parameter
Definition
Method of Determination
AUClast
Area under the plasma 
concentration-time profile from time 
zero to the time of the last 
quantifiable concentration (Clast)
Linear/Log trapezoidal method
AUCinf
a
Area under the plasma 
concentration-time profile from time 
zero extrapolated to infinite time 
AUClast + (Clast*/kel),
where Clast* is the predicted plasma 
concentration at the last quantifiable 
time point estimated from the 
log-linear regression analysis
Cmax
Maximum observed plasma 
concentration 
Observed directly from data
Tmax
Time for Cmax
Observed directly from data as time 
of first occurrence
t½
a
Terminal half-life
Loge(2)/kel,
where kel is the terminal phase rate 
constant calculated by a linear 
regression of the log-linear 
concentration-time curve.  Only those
data points judged to describe the 
terminal log-linear decline were used 
in the regression.
CL/Fa
Apparent clearance
Dose / AUCinf
aIf data permit
Cohort 2A and 2B: Pharmacokinetic parameters for palbociclib will be derived from plasma 
palbociclib concentration-time data as described in the following table (Table 10).


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Table 10. PK Parameters to be Determined for Palbociclib
Parameter
Definition
Method of Determination
AUClast
Area under the plasma 
concentration-time profile from time 
zero to the time of the last 
quantifiable concentration (Clast)
Linear/Log trapezoidal method
AUCtau
a
Area under the plasma 
concentration-time profile from time 
zero to time tau, the dosing interval, 
where tau = 24 hours
Linear/Log trapezoidal method
Cmax
Maximum observed plasma 
concentration 
Observed directly from data
Tmax
Time for Cmax
Observed directly from data as time 
of first occurrence
Ctrough
Predose concentration during multiple 
dosing
Observed directly from data
AUClast(dn)b
Dose-normalized AUClast
AUClast / Dose
AUCtau(dn)a,b
Dose-normalized AUCtau
AUCtau / Dose
Cmax(dn)b
Dose-normalized Cmax
Cmax / Dose
Ctrough(dn)b
Dose-normalized Ctrough
Ctrough / Dose
a If data permit; b To be determined only if more than one palbociclib dose is assigned and utilized in combination 
treatment. 
For avelumab, end-of-infusion peak (Cmax) and pre-dose concentration (Ctrough) will be 
reported from serum avelumab concentration-time data.
8.2.4.2. PF-06747775 Single-Dose and Steady State PK Analysis
The single dose and steady-state PK parameters will be summarized descriptively (n, mean, 
SD, coefficient of variation (CV), median, minimum, maximum, geometric mean and its 
associated CV) by treatment/cohort, dose, cycle and day, for both Phase 1 and Phase 1b/2, as 
data permit.  This applies to the single dose and/or steady state PK collected for 
PF-06747775 in cohorts in the Phase 1 dose escalation, the Phase 1 MTD expansion 
sildenafil sub-study, and the Phase 2 single agent PF-06747775 in previously untreated 
patients (Cohort 1). 
The single dose and steady-state PF-06747775 plasma concentrations will be summarized 
descriptively (n, mean, SD, coefficient of variation (CV), median, minimum, maximum, 
geometric mean and its associated CV) by treatment/cohort, dose, cycle, day, and nominal 
time.
Dose-normalized parameters as data permit for single dose (AUCinf, AUClast, and Cmax) and 
steady-state (AUCtau and Cmax) will be plotted against dose (using a logarithmic scale) by 
cycle and day (nominal visit time).  These plots will include individual patient values and the 
geometric means for each dose.  These plots will be used to help understand the relationship 
between the PK parameters and dose.  Plots of dose-normalized parameters may also be 
presented together across multiple treatment/cohorts (ie, from Phase 1 dose escalation, DDI 
sub-study, combination with another agent, etc.).
Trough concentrations (pre-dose concentrations) will be plotted for each dose using a 
box-whisker plot by cycle and day within cycle in order to assess the attainment of 
steady-state. 


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Individual patient and median profiles of the single dose and steady-state concentration-time 
data will be plotted by treatment, dose, cycle, and day, using actual times for individual 
patients and nominal times for median profiles.  Median profiles will be presented on both 
linear-linear and log-linear scales, paged by treatment, cycle and day with all doses on the 
same plot.  Individual patient profiles will be presented on linear-linear and log-linear scales, 
paged by treatment, cycle, day, and dose with all subjects on the same plot.  Only data for 
days with intensive PK sampling will be presented in these plots (ie, days with only a single 
pre-dose PK sample will not be included).  Plots of median profiles may also be presented 
together across multiple treatments/cohorts (ie, from Phase 1 dose escalation, DDI sub-study, 
combination with another agent, etc.) either by PF-06747775 dose assigned, or using 
dose-normalized plasma concentrations.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI
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Protocol B7971001                                                                             Statistical Analysis Plan
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8.2.4.3.2. Itraconazole and Antacid Sub-Study 
The treatment selected for further development will be evaluated for the effect that an acid 
reducing agent, esomeprazole, a proton pump inhibitor, as well as a strong 
CYP3A4 inhibitor, itraconazole, may have on PF-06747775 exposure.  For the esomeprazole 
effect, natural log transformed AUCtau and Cmax values will be analyzed using a mixed effects 
model with treatment (fasted and esomeprazole) as fixed effect and patient as a random 
effect.  For the itraconazole effect natural log transformed AUCtau(dn) and Cmax(dn) values 
will be analyzed using a mixed effects model with treatment (fasted, and itraconazole) as 
fixed effect and patient as a random effect. 
Esomeprazole Drug-Drug Interaction: Estimates of the adjusted mean differences (with 
esomeprazole - fasted) and corresponding 90% confidence intervals will be obtained from the 
model.  The adjusted mean differences and 90% confidence intervals for the differences will 
be exponentiated to provide estimates of the ratios of adjusted geometric means (with 
esomeprazole/fasted) and 90% confidence intervals for the ratios. 
Itraconazole Drug-Drug Interaction:  Estimates of the adjusted mean differences (with 
itraconazole - fasted) and corresponding 90% confidence intervals will be obtained from the 
model.  The adjusted mean differences and 90% confidence intervals for the differences will 
be exponentiated to provide estimates of the ratios of adjusted geometric means (with 
itraconazole/fasted) and 90% confidence intervals for the ratios.
8.2.4.4. Sildenafil Sub-study:  MTD Expansion Cohort 
Sildenafil PK:
Sildenafil PK parameters for this sub-study will be summarized descriptively (n, mean, SD, 
coefficient of variation (CV), median, minimum, maximum, geometric mean and its 
associated CV) by treatment.  Sildenafil AUCinf and Cmax values will be plotted by treatment 
(with and without PF-06747775) using box-and-whisker plots.  Sildenafil parameter 
descriptive summary and box-and-whisker plots may also be presented by the 
PF-06747775 dose assigned.
The main purpose of this sub-study is to appropriately estimate the potential 
CYP3A4 inhibitory ability of PF-06747775.  Natural log transformed AUCinf and Cmax values 
for sildenafil will be analyzed using a mixed effects model with treatment as fixed effect and 
patient as random effect to estimate the effect of steady-state PF-06747775 on sildenafil 
exposure.  Estimates of the adjusted mean differences (with and without PF-06747775) and 
corresponding 90% confidence intervals will be obtained from the model.  The adjusted 
mean differences and 90% confidence intervals for the differences will be exponentiated to 
provide estimates of the ratios of adjusted geometric means (with/without PF-06747775) and 
90% confidence intervals for the ratios.  Estimates of mean differences and confidence 
intervals may be also reported by the PF-06747775 dose assigned.
CCI


Protocol B7971001                                                                             Statistical Analysis Plan
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Plasma sildenafil concentrations will be summarized descriptively (n, mean, SD, coefficient 
of variation (CV), median, minimum, maximum, geometric mean and its associated CV) by 
treatment and nominal time.  Sildenafil concentration summaries may also be reported by the 
PF-06747775 dose assigned.
Individual patient and median profiles of the sildenafil concentration-time data will be 
plotted by treatment, using actual times for individual patients and nominal times for median 
profiles.  Median profiles will be presented on both linear-linear and log-linear scales with 
both treatments on the same plot.  Individual patient profiles will be presented on 
linear-linear and log-linear scales, paged by treatment with all subjects on the same plot.  
Median and individual sildenafil profiles may also be presented by the PF-06747775 dose 
assigned.
PF-06747775 PK: 
PF-06747775 parameters at steady-state (assessed on Cycle 1 Day 11) will be summarized
descriptively (n, mean, SD, coefficient of variation (CV), median, minimum, maximum, 
geometric mean and its associated CV) and presented as described above in 
Section 8.2.4.2 Plasma PF-06747775 concentrations will be summarized descriptively (n, 
mean, SD, coefficient of variation (CV), median, minimum, maximum, geometric mean and 
its associated CV) by nominal time.  Individual and median concentration-time profiles may 
be presented as well. 
If more than one dose level of PF-06747775 was assigned and utilized in the MTD expansion 
sub-study, then PF-064747775 PK parameters and concentration-time plots will be presented 
by dose, and dose-normalized parameters will also be reported.  Individual and median 
concentration-time profiles may also be generated for dose-normalized plasma 
concentrations.
8.2.4.5. Phase 2 Single Agent PF-06747775 in Previously Untreated Disease (Cohort 1)
The single dose and steady-state PK parameters for PF-06747775 will be summarized 
descriptively (n, mean, SD, coefficient of variation (CV), median, minimum, maximum, 
geometric mean and its associated CV) by cycle and day, as described above in 
Section 8.2.4.2.  Single dose parameters will be assessed on Day -4 of the lead in period and 
steady-state parameters will be assessed on Day 11 of Cycle 1.  Single dose and steady-state 
plasma PF-06747775 concentrations will be summarized descriptively (n, mean, SD, 
coefficient of variation (CV), median, minimum, maximum, geometric mean and its 
associated CV) by cycle, day, and nominal time.
Individual and median concentration-time profiles following single and multiple-dose may be 
presented as well as described in Section 8.2.4.2.
Trough concentrations (pre-dose concentrations) may be plotted using a box-and-whisker 
plot by cycle and day within cycle in order to assess the attainment of steady-state. 


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8.2.4.6. Phase 1b Single Arm Combination with Palbociclib (Cohort 2A) 
PF-06747775 PK: 
PF-06747775 PK parameters at steady-state will be summarized descriptively(n, mean, SD, 
coefficient of variation (CV), median, minimum, maximum, geometric mean and its 
associated CV) by cycle and day, as described above in Steady-state parameters will be 
assessed on Day 15 of Cycle 1.  Plasma PF-06747775 concentrations will be summarized 
descriptively (n, mean, SD, coefficient of variation (CV), median, minimum, maximum, 
geometric mean and its associated CV) by cycle, day, and nominal time.
Individual and median concentration-time profiles following multiple-dose may be presented 
as described in Section 8.2.4.2.
Trough concentrations (pre-dose concentrations) will be plotted using a box-and-whisker plot 
by cycle and day within cycle in order to assess the attainment of steady-state.
If more than one dose level of palbociclib was used in this dose-finding cohort, 
PF-06747775 PK parameters, plasma concentrations, and figures may also be presented by 
dose of palbociclib assigned.  Box-and-whisker plots for PF-06747775 Cmax and AUCtau at 
each dose of palbociclib may be generated also.
Palbociclib PK:
Palbociclib steady-state PK parameters will be summarized descriptively (n, mean, SD, 
coefficient of variation (CV), median, minimum, maximum, geometric mean and its 
associated CV) by dose (if applicable), cycle, and day.  Steady-state parameters will be 
assessed on Day 15 of Cycle 1.
The steady state palbociclib concentrations will be summarized descriptively (n, mean, SD, 
coefficient of variation (CV), median, minimum, maximum, geometric mean and its 
associated CV) by dose (if applicable), cycle, day, and nominal time.
The trough concentrations (pre-dose concentrations) for palbociclib will be plotted using a 
box-and-whisker plot by cycle and day within cycle in order to assess the attainment of 
steady state.  Individual and median concentration-time profiles following multiple-dose 
(using the methods described above in Section 8.2.4.2. for PF-06747775) may be presented 
as well. 
If more than one dose level of palbociclib was used in this cohort, then palbociclib PK 
parameters, plasma concentrations, and figures may be presented by dose, and 
dose-normalized parameters may be presented as well.  Box-and-whisker plots for 
palbociclib Cmax and AUCtau or AUClast at each dose may be generated also.


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CCI
CCI


Protocol B7971001                                                                             Statistical Analysis Plan
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CCI
CCI


Protocol B7971001                                                                             Statistical Analysis Plan
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CCI
CCI
CCI


Protocol B7971001                                                                             Statistical Analysis Plan
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CCI
CCI
CCI


Protocol B7971001                                                                             Statistical Analysis Plan
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9. REFERENCES
1.
Ji Y et al. A modified toxicity probability interval method for dose-finding trials.
Clinical Trials 2010; 7:653 663.
2.
Brookmeyer R, Crowley JJ. A confidence interval for the median survival time. 
Biometrics. 38: 29-41, 1982.
3.
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer. Jan; 45(2):228-47, 
2009.
4.
Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am 
Stat Assoc. 53: 457-81, 1958.
5.
O’Quigley J, Pepe M, Fisher L: Continual reassessment method: A practical design for 
phase I clinical trials in cancer. Biometrics 46: 33-48, 1990.


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APPENDICES
Appendix 1. Programming Specifications for AE analyses
a. Time to AE onset

Definition
Time to AE onset (days) will be calculated as first AE start date – first dose date +1.  
The definition and calculations are similar for time to Grade 3/4 AE onset.
AE start date
The Date of Onset for the first occurrence of the AE based on the Log AE CRF page. 
First dose date
The date of the starting dose: Cycle 1 Day 1
b. Duration of AE

Definition
Duration of AE (days) is defined as the cumulative duration across episodes of the 
AE where duration for each episode is calculated as AE end date – AE start date
+1 excluding any overlap.  Duration of AE is defined for subjects with the AE.
AE start date
The Date of Onset based on the Log AE CRF page. 
AE end date
The Date Resolved based on the Log AE CRF page. 

Censoring
AE resolution is considered an event (censoring variable=1).  If a subject has an AE 
that was ongoing (does not have to be the last AE) at the time of analysis, the time is 
censored (censoring variable=0) at the last available on treatment visit date.  Subjects 
who die prior to resolution of the AE will be censored at the date of death.  If the date 
of death is the same as the date of the resolution of the AE, the subject will be 
censored at that date (ie, resolution will not be considered an event) only if the AE is 
the AE that resulted in death.
Date of death
Death date is based on the Notice of Death CRF page.


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
Clustered Events
For clustered events, a patient could have multiple events in the cluster which may 
overlap.  In this case, AE duration will be summed across all events in the cluster 
accounting for the overlap (ie, overlapping periods between events in the same cluster 
are not double-counted).  Lags between events in the same cluster are not included in 
the duration.
The following scenarios provide examples of the calculation for 2 events in the same 
cluster.  The extension to 3 or more events of the same cluster is similar.

TWO EVENTS OF THE SAME CLUSTER WHERE ONE EVENT COMPLETELY 
CONTAINS THE OTHER EVENT
    event 1                  [------------------------------]
           
                startdate1                     enddate1
    event 2                      [------------------------]
                                         startdate2            enddate2
   
duration = enddate1-startdate1+1

CERTAIN PORTIONS OF TWO EVENTS IN THE SAME CLUSTER OVERLAP
    event 1                  [------------------------------]
            
                 startdate1                     enddate1
    event 2                                          [------------------------]
            
                                              startdate2            enddate2
    duration = enddate2-startdate1+1

TWO EVENTS OF THE SAME CLUSTER ARE CONTIGUOUS TO EACH OTHER  
    event 1                 [------------------------------]
            
              startdate1                     enddate1
    event 2                                                           [------------------------]
            
                                                            startdate2            enddate2
duration = enddate2-startdate1+1

TWO EVENTS OF THE SAME CLUSTER ARE NON-OVERLAPPING 
    event 1                  [------------------------------]
            
                 startdate1                     enddate1
    event 2                                                                               [------------------------]
                                                                                                     startdate2         enddate2
    duration = (enddate1-startdate1+1) + (enddate2-startdate2+1)


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Appendix 2. STUDY SPECIFIC INFORMATION FOR EFFICACY

Baseline:  is defined as the last observation prior to the first dose or randomization 
(Cohort 2B) of study treatment. 

Adequate Baseline: 

Baseline tumor evaluations must be performed within 4 weeks (28 days) prior 
to the first dose of study treatment or randomization (Cohort 2B);  

Presence of target and/or non-target lesions at baseline) for solid tumors;

All lesions recorded at baseline must have an associated status recorded on the 
CRF;

Baseline lesions must be assessed with an acceptable method that includes: 
Conventional CT Scan, Spiral CT Scan, X-ray, MRI, Physical Exam, Bone 
Scan and Other. Note: If based on data review “unacceptable” methods (eg,
ultrasound, etc) are noted under “Other”, then this category will not be 
considered acceptable (on a case by case basis).

“On-treatment” period for safety: is defined as the period from the date of the first 
dose until 28 days after the last dose of each patient.

Subsequent anti-tumor treatment:  include systemic anticancer therapy (other than 
study medication), radiation and surgical resection.


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Appendix 3. DETERMINATION OF EFFICACY – SOLID TUMORS
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.

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.


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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. 
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’).
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


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
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. 

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. 


Protocol B7971001                                                                             Statistical Analysis Plan
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
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. 


Protocol B7971001                                                                             Statistical Analysis Plan
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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
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

Adapted from: Eisenhauer EA, Therasse P, Bogaerts J, et al.  New response evaluation 
criteria in solid tumours: revised RECIST guideline (version 1.1).  Eur J Cancer. 
2009 Jan; 45(2):228-47.


Protocol B7971001                                                                             Statistical Analysis Plan
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Appendix 4. Detailed Dose Escalation/De-Escalation Scheme for mTPI Design Based on 
30% Toxicity Rate
DLTs at 
current dose 
level
Number of patients per dose level (cumulative)
1
2
3
4
5
6
7
8
9
10
0
NA
NA
E
E
E
E
E
E
E
E
1
D
S
S
S
S
E
E
E
E
E
2
DU
D
S
S
S
S
S
E
E
3
DU
DU
D
D
S
S
S
E
4
DU
DU
DU
DU
DU
DU
DU
E= escalate or if current dose level is DL1 stay on DL1; S= stay at current dose; D= de-escalate; DU = 
de-escalate and dose is unacceptable due to toxicity
Escalation/De-escalation algorithms for total number of patients treated at the current dose 
level (current and previous cohorts)

With 2 patients treated at current dose level

0 DLT -> escalate

1 DLT -> remain at the same dose

2 DLTs -> de-escalate and consider current dose as intolerable

With 3 patients treated at current dose level

0 DLT -> escalate

1 DLT -> remain at the same dose

2 DLTs -> de-escalate 

3 DLTs -> de-escalate and consider current dose as intolerable

With 4 patients treated at current dose level

0 DLT -> escalate

1-2 DLTs -> remain at the same dose

3-4 DLTs -> de-escalate and consider current dose as intolerable

With 5 patients treated at current dose level

0 DLT -> escalate

1-2 DLTs -> remain at the same dose

3 DLTs -> de-escalate

4-5 DLTs -> de-escalate and consider current dose as intolerable

With 6 patients treated at current dose level


Protocol B7971001                                                                             Statistical Analysis Plan
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
0-1 DLT -> escalate

2 DLTs -> remain at the same dose

3 DLTs -> de-escalate

4-6 DLTs -> de-escalate and consider current dose as intolerable

With 7 patients treated at current dose level

0-1 DLT -> escalate

2-3 DLTs -> remain at the same dose

4 DLTs -> de-escalate

5-7 DLTs -> de-escalate and consider current dose as intolerable

With 8 patients treated at current dose level

0-1 DLT -> escalate

2-3 DLTs -> remain at the same dose

4-8 DLTs -> de-escalate and consider currentdose as intolerable

With 9 patients treated at current dose level

0-2 DLT -> escalate

3 DLTs -> remain at the same dose

4-9 DLTs -> de-escalate and consider current dose as intolerable

With 10 patients treated at current dose level

0-3 DLT -> escalate (MTD if highest dose)

4-10 DLTs -> de-escalate and consider current dose as intolerable


Protocol B7971001                                                                             Statistical Analysis Plan
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Appendix 5. Treatment Exposure 
PF-06747775 or Palbociclib:  
The dose level is calculated as actual dose administered (mg/day).  The duration of treatment 
(in weeks) during the study is defined as:
duration (weeks) = (last dose date – first dose date + 1)/7
The cumulative dose (mg) per patient in a time period is the sum of the actual dose levels that 
the patient received within that period (ie, total dose administered (mg)).  In a week if all 
doses (eg, 2×5=10 mg/day) were received the cumulative dose would be 7×10 mg.
The dose intensity (DI) and the relative dose intensity (RDI) will be calculated for each 
patient during the study.  The DI (mg/week) during the study is defined as
DI (mg/week) = [cumulative dose (mg)]/[duration (week)]
The RDI is defined as the ratio of the DI and planned dose and expressed in %
RDI (%) = 100 × [DI (mg/week]/[3xd (mg/week)]
where d is fixed at the start of treatment for a patient, which can be 7x200 for PF-06747775;
7x100, 7x75, or 7x50 for palbociclib; for PF-06747775 in Cohort 3, the denominator will 
[4 x d (mg/week)] as it will be 4 weeks per cycle.
Avelumab:
The dose level for avelumab is calculated as actual dose administered/weight (mg/kg).  The 
last available weight of the patient on or prior to the day of dosing will be used.
The duration of avelumab treatment (in weeks) during the study for a patient is defined as:
duration (weeks) = (last dose date –first dose date + 14)/7
The cumulative dose (mg/kg) of avelumab per patient in a time period is the sum of the 
actual dose levels that the patient received within that period (ie, total dose administered 
(mg) / weight (kg)).
Each cycle for avelumab is defined by a 4-week period with 1 infusion every 2 week.  The 
dose intensity (DI) and the relative dose intensity (RDI) will be calculated for each patient 
across all cycles.  The dose intensity (mg/kg/cycle) per cycle is defined as
DI (mg/kg/cycle) = Cumulative dose (mg/kg)/ [duration of therapy (in weeks)/4]
The relative dose intensity (RDI) is defined as the actual dose intensity divided by the 
planned dose per cycle and expressed in %.
RDI (%) = 100 × [DI (mg/kg/cycle)/2x10 (mg/kg/cycle)]