Clinical trial NCT02179918
Conditions: Advanced Solid Tumors
Keywords: Advanced Solid Tumors
Sponsor: Pfizer
Start date: 2014-08-01; Completion date: 2017-02-01
Enrollment: 23 participants; Allocation: ; Intervention model: 

Brief summary:
This is a safety, pharmacokinetic and pharmacodynamic study designed to estimate the maximum tolerated dose (MTD), and determine the Recommended Phase 2 Dose (RP2D) of PF-05082566, a 4-1BB agonist monoclonal antibody (mAb), in combination with MK-3475, a PD-1 inhibitor in patients with solid tumors.

Detailed description:

Arms: arm 1: PF-05082566 +MK-3475
Interventions: intervention 1: PF-05082566 intervention 2: MK-3475
Intervention descriptions: intervention 1: Starting dose of 0.45 mg/kg q3wks IV, dose escalation intervention 2: 2 mg/kg q3wks, IV

Protocol documents:
Prot_000.pdf: 
PF-05082566
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Final Protocol Amendment 2, 08 July 2014
Page 1
A PHASE 1B STUDY OF THE 4-1BB AGONIST PF-05082566 IN COMBINATION 
WITH THE PD-1 INHIBITOR MK-3475 IN PATIENTS WITH ADVANCED SOLID 
TUMORS 
Compound:
PF-05082566
MK-3475
US IND Number:
109,154
Protocol Number:
B1641003
Phase:
1b


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Document History
Document
Version Date
Summary of Changes
Amendment 2
08-July-2014
Protocol Summary: Study Treatments

Deleted additional information concerning 
calculation of starting dose.
Section 5: Study Treatments

Section 5.2: Patient Compliance
This section was removed per FDA request 
to remove the language in this section, as 
the language in this section is redundant 
with language in revised Section 5.2.2 and 
there is no specific guidance for drugs 
administered intravenously.
Amendment 1
17 June 2014
The following are changes that were requested 
by the FDA:

Protocol Summary: Study Treatments:

Section was updated to reflect change in 
the dose range to be explored and in the 
starting dose (now 0.45 mk/kg).  
Deleted information concerning 
calculation of starting dose.

Protocol Summary: Dose escalation 
Criteria:

Table 1 was updated to reflect a starting 
dose (Dose Level 1, DL1) of 0.45 mg/kg 
and a -1 Dose Level (DL-1) of 0.20 
mg/kg.  The rest of the table was 
updated accordingly, deleting text 
concerning determination of starting 
dose.

Starting Dose Selection Strategy:

In Section 1.3, the starting dose was 
updated to reflect a starting dose of 0.45
mg/kg q3wks.

Schedule of Activities:

Additional information added to 
Footnote 24 (previously 25) stating that 
in addition to the timepoints specified, 


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blood for cytokine assays may be drawn 
when clinically indicated.

Additional timepoint ( Cycle 6 Day 1 
pre-dose) for collection added to 
Footnote 22.

Additional column added to SOA for 
Cycle 6, Day 1.

Additional timepoints (End of infusion) 
for collection added to Footnotes 22, 23, 
and 24.

Additional information added to 
footnote 32 further defining parameters 
of when a patient is considered 
withdrawn from the study.

Study Design:

In Section 3.1 information was added on 
how drug/drug interactions in this study 
will be monitored.

In Section 3.1.1, the starting dose was 
updated to reflect a starting dose of 0.45
mg/kg q3wks.

Section 3.3 DLT Definition, Grade 4 
aspartate aminotransferase (AST) and 
alanine aminotransferase (ALT) were 
added as dose-limiting toxicities. 

Patient Selection:

In Section 4.1 Inclusion Criteria, 
Criterion 1 now reads as follows: 
Histological or cytological diagnosis of 
advanced/metastatic solid tumor 
malignancy which has progressed on 
standard therapy or for which no 
standard therapy is available. 

Study Treatments:

In Section 5.3.4 (changed from Section 
5.4.4) Treatment After Initial Evidence 
of Radiologic Progression, the text in 
the first paragraph and second paragraph 
was changed to provide consistency in 
the decision process to continue or 


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discontinue therapy after disease 
progression is observed.  

In Section 5.3.4 (changed from Section 
5.4.4) Treatment After Initial Evidence 
of Radiologic Progression, text was 
added to last paragraph requiring re-
consent of patients upon continuing 
treatment after confirmed progressive 
disease.

In Section 5.3.6 (changed from Section 
5.4.6) Dose Delays, the platelet count 
was changed to 75,000/L; non-
hematologic toxicity language was 
corrected to read Grade ≤ 2 if not 
considered a safety risk for the patient.

In Sections 5.3.6, Tables 8, 9, and 10, 
and Section 5.3.7.3 (changed from 
5.4.7.3) the period for resumption of 
treatment of study drugs was changed 
from 12 to 9 weeks.

In Section 5.3.7 (changed from 5.4.7) 
Dose reductions, Table 7 was updated to 
reflect the -1 dose of 0.20 mg/kg.

In Section 5.3.7.2 (changed from 
5.4.7.2) Supportive Care Guidelines, 
text was added to provide guidance on 
dose reductions of the study drugs after 
immune-related events. 

Assessments:

In Section 7.2.1 PK for PF-05082566, 
an additional timepoint was added (End 
of infusion and Cycle 6 Day 1 pre-dose).

In Section 7.2.2 PK for MK-3475, two 
additional timepoints were added (End 
of infusion).

 
 

Also added that for all patients: 
Cytokine analyses, in addition to the 
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timepoints specified above, may be 
performed whenever clinically 
indicated. 

Data Analysis/Statistical Methods:

In Section 9.1. Analysis Sets: revised 
the definition of the DLT Evaluable Set. 
Added the ECG/QTc Analysis Set.

In Section 9.2. Statistical Methods for 
Dose Allocation: TITE CRM, updated 
doses to reflect the 0.20 mg/kg dose and 
updated prior assumption.

In Section 9.4. Efficacy Analysis: 
Added time to response description.

In Section 9.5.1.1 additional information 
on how drug/drug interactions in this 
study will be monitored.

Other Non-FDA Changes:

IND # 

Changed from 121, 729 to 109, 154.

Schedule of Activities:

 
 

Study Design:

The protocol title was changed to Phase 
1b from Phase 1 to be consistent with 
the Phase 1b designation on the title 
page and throughout the protocol

Study Treatments 

In Section 5.3 (changed from Section 
5.4) Administration, the following text 
was added to the first paragraph: 
Patients will be observed in the clinic 
for at least 2 hours after each infusion 
of study drug.

Administrative Changes:

Administrative changes were made to 
enhance the readability of the protocol 
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and clarify inconsistencies.

References:

Added one additional reference for the 
use of TITE-CRM modeling.
Original protocol
17 April 2014
Not applicable (NA)
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
4-1BB
TNFRSF9, CD137, ILA
4-1BBL
4-1BB Ligand, TNFSF9
ACTH
Andrenocorticotropic hormone
ADA
Anti -drug antibody
ADCC
Antibody-dependent cellular cytotoxicity
AE
Adverse Event
ALT
Alanine amino transferase
ANOVA
Analysis of variance
APC
Antigen presenting cell
AST
Aspartate aminotransferase
AUC
Area under the concentration vs time curve
AUC0-168
area-under-the-curve from time zero to 168 hours
AUC0-672
area-under-the-curve from time zero to 672 hours
AUC0-last
area-under-the-curve from time zero to last measurable concentration
BUN
Blood urea nitrogen 
CCR7
Chemokine (C-C motif) receptor 7; CD197
CD3
Cluster of differentiation 3
CD4
Cluster of differentiation 4
CD8
Cluster of differentiation 8
CD16
Cluster of differentiation 16, FCRIIIa and FCRIIIb
CD20
Cluster of differentiation 20
CD25
Cluster of differentiation 25, alpha chain of the IL-2 receptor
CD40
Cluster of differentiation 40, TNFRSF5
CD45
Cluster of differentiation 45, Protein tyrosine phosphatase, receptor type C (PTPRC),  leukocyte 
common antigen
CD45RA
CD45 (PTPRC) RA isoform
CD45RO
CD45 (PTPRC) RO isoform
CD56
Cluster of differentiation 56; neural cell adhesion molecule
CD134
Cluster of differentiation 134, TNFRSF4, OX-40
CD137
Cluster of differentiation 137, TNFRSF9,  4-1BB,  ILA
Cave
Estimated average serum concentration
Cmax
Maximum observed serum concentration 
CNS 
Central Nervous System
COPD
Chronic Obstructive Pulmonary Disease
CRP
C reactive protein
CT
Computed Tomography
CTCAE
Common technical criteria for adverse events
CXCR6
Chemokine (C-X-C motif) receptor 6; CD186
DC
Dendritic cell
DLT
Dose limiting toxicity
DNA
Deoxyribonucleic acid
EC10
Concentration required to achieve 10% of the maximal response
ECD
Extracellular domain
ECG
Electrocardiogram
ECHO
Echocardiogram


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ECOG
Eastern Cooperative Oncology Group
ED50
Dose required to achieve 50% of the maximal response
ELISA
Enzyme linked immunosorbent assay
ERK
Extracellular signal-regulated kinase
FACS
Fluorescent-activated cell sorting; flow cytometry
Fc
Fragment crystallizable
FL
Follicular lymphoma
GCP
Good clinical practice
GGT
Gamma-glutamyl traspeptidase 
GTD
Greatest transverse diameter
Hb
Hemoglobin
HLA
Human leukocyte antigen
ICH
International conference on harmonization
ICOS
Inducible T-cell costimulator; CD278
IEC
Independent ethics committee
IFN-
interferon-gamma
IgG2
Immunoglobulin G subclass 2
IL-1
Interleukin 1 beta
IL-2
Interleukin 2
IL-4
Interleukin 4
IL-6
Interleukin 6
IL-8
Interleukin 8
IL-10
Interleukin 10
IL-12p70
Interleukin 12 ( bioactive 75 kDa heterodimer of IL-12p40 and IL-12 p35)
IRB
Institutional Review Board
ITGB7
Integrin, beta 7
IV
Intravenous
Ki-67
Antigen identified by mAb Ki-67
LDH
Lactate dehydrogenase 
LFT
Liver function test
LOAEL
Lowest observed adverse effect level
mAb
Monoclonal antibody
MABEL
Minimal anticipated biological effect level
MCL
Mantle cell lymphoma
MUGA
Multigated acquisition
MPK
Milligrams per kilogram, mg/kg
MTD
Maximum tolerated dose
NCI
National cancer institute
NF-kB
Nuclear Factor kappa B
NHL 
Non-Hodgkin's Lymphoma
NK
Natural killer cell
NKT
Natural killer T cell
NOAEL
No observed adverse effect level
NSCLC
Non-small cell lung cancer
OBD
Optimal biological dose
ORR
Overall response rate
OS
Overall survival


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PBL
Peripheral blood leukocyte
PBMC
Peripheral blood mononuclear cells
PBS
Phosphate Buffered Saline
PFS
Progression-free survival 
PGRD
Pfizer Global Research & Development
PK
Pharmacokinetics
POM
Proof of mechanism
PR
Partial response
PT
Prothrombin time
RECIST
Response evaluation criteria in solid tumors
RNA
Ribonucleic acid
RP2D
Recommended Phase 2 Dose
SAMD
Single agent, multiple dose
SC
Subcutaneous
sCD25
Soluble CD25
sCD137
Soluble CD137 (soluble 4-1BB)
SCID
Severe combined immunodeficiency
SAE
Serious adverse event
SEM
Standard error of the mean
sFasL
Soluble Fas Ligand
SPR
Surface plasmon resonance
t1/2
Half-life
TGI
Tumor growth inhibition
TITE-CRM
Time-to-Event Continual Reassessment Method
TNF
Tumor necrosis factor
TNF
Tumor necrosis factor alpha
TNFR
Tumor necrosis factor receptor
TNFRSF
Tumor necrosis factor receptor super family
TRAF
TNFR associated factor
VCAM1
Vascular cell adhesion protein 1
TSH
Thyroid Stimulating Hormone
Vss
Volume of distribution at steady state
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PROTOCOL SUMMARY
Indication
Advanced solid tumors.
Study Rationale
PF-05082566 is a fully humanized IgG2 monoclonal antibody and promising new molecular 
entity that binds to human 4-1BB with high affinity and specificity.  MK-3475 is a potent and 
highly selective humanized monoclonal antibody (mAb) of the IgG4/kappa isotype designed 
to directly block the interaction between PD-1 (programmed death-1) and its ligands, 
PD-L1 and PD-L2.  In vitro and in vivo data demonstrated immunomodulatory activity and 
anti-tumor activity of PF-05082566 when dosed as a single agent, in combination with 
antibody-dependent cellular cytotoxicity (ADCC) inducing antibodies, and significantly 
enhanced anti-tumor activity in combination with anti-PD1 antibodies.  The safety and 
tolerability of PF-05082566 is currently being evaluated in a First-in-Patient Phase 1 study as
a single agent and in combination with rituximab (Study B1641001).  PF-05082566 has been 
well tolerated (thus far up to 2.4 mg/kg) when administered every 4-weeks (q4wks), without
adverse events (AEs) above Grade 1 severity attributed to PF-05082566, when administered 
as a single agent.  The preliminary pharmacokinetic (PK) results from the ongoing Phase 1
study suggest that exposure of PF-05082566 increases dose proportionally with a terminal 
half-life of approximately 10 days.
MK-3475, previously known as SCH 900475, is a potent and highly selective humanized 
monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the 
interaction between PD-1 and its ligands, PD-L1 and PD-L2.  MK-3475 has been studied in 
patients with advanced solid tumors.  Anti-tumor activity has been noted in advanced 
melanoma, as well as advanced non-small cell lung cancer (NSCLC) patients.  In addition, 
MK-3475 has been generally well tolerated in these patients.
While preclinical data demonstrated significant immunomodulatory activity and anti-tumor 
activity of PF-05082566 when dosed as a single agent, it is hypothesized that in some tumors 
upregulation of PD-1 on tumor-infiltrating lymphocytes, and its ligand PD-L1 on tumor cells, 
may down-modulate the activity of anti-tumor lymphocytes stimulated by an agonist 
anti-4-1BB antibody.  PD-L1 may be expressed on tumor cells as a result of activated T cells 
within the tumor producing inflammatory cytokines, such as interferon gamma (IFN-).  In 
accord with this, studies in mice suggest that activated tumor-infiltrating T lymphocytes 
(TILs) induce the expression of PD-L1, which in turn results in down modulation of the 
Tcells.  This is thought to be one mechanism for tumor cell evasion of the immune system.  
Tumor cells expressing PD-L1 may be better candidates for anti-PD-1 therapies than tumors 
that do not express PD-L1.  It is clear from the study of biopsies that many tumors do not 
contain detectable numbers of infiltrating T cells, which could account in part for lack of 
PD-L1 expression in many of these tumors.  In theory, an agonist anti-4-1BB antibody may 
activate T cells, which can traffic to tumors that would not otherwise contain these activated 
cells, where they may induce the expression of PD-L1.  Therefore, the local environment 


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within tumors that do not respond to anti-PD-1 therapies or anti-4-1BB single agent therapies 
may be converted to an immune responsive environment by combining an anti-PD-1
antagonist antibody with an anti-4-1BB agonist antibody.  In support of this concept, an 
agonist anti-4-1BB antibody in combination with an anti-PD-1 antagonist antibody showed 
significantly improved anti-tumor activity compared with either single agent in multiple 
mouse models.  In addition, safety data in mice indicated that the addition of an 
anti-PD-1 antibody did not add to the toxicity of an anti-4-1BB agonist antibody. 
STUDY OBJECTIVES AND ENDPOINTS
Objectives
Primary Objectives

To estimate the Maximum Tolerated Dose (MTD) and select the Recommended 
Phase 2 Dose (RP2D) for the combination of PF-05082566 with MK-3475 in patients 
with advanced solid cancer.
Secondary Objectives

To evaluate the overall safety profile; 

To characterize the pharmacokinetics of PF-05082566 and MK-3475 given in 
combination following IV administration;

To evaluate the immunogenicity of PF-05082566 and MK-3475 when given in 
combination;

To assess the anti-tumor effect of PF-05082466 in combination with MK-3475 (by 
RECIST criteria);

Expansion Cohorts Only: To characterize the mechanism of sensitivity and/or 
resistance to PF-05082566 in combination with MK-3475 in tumor tissue.

 

 
 
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Endpoints
Primary Endpoint

First 2 cycles Dose-Limiting Toxicity (DLT) of PF-05082566 in combination with 
MK-3475.
Secondary Endpoints

Adverse events as characterized by type, frequency, severity (as graded by NCI
CTCAE v.4.03), timing, seriousness and relationship to study therapy 
PF-05082566 in combination with MK-3475;

Laboratory abnormalities as characterized by type, frequency, severity (as graded by 
NCI CTCAE v.4.03); 

Vital signs, weight, Eastern Cooperative Oncology Group (ECOG) Performance 
Status;

PK parameters of PF-05082566 and MK-3475, including but not limited to Cmax,
Ctrough, Tmax, AUC0-last,, AUC0-, CL and Vd (as data permits);

Anti-Drug Antibody levels for PF-05082566 and MK-3475;

Objective tumor response by Response Evaluation Criteria in Solid Tumors 
(RECIST) v1.1;

Time-to-response (expansion cohorts only);

Duration of response (expansion cohorts only);  

Progression–free survival (expansion cohorts only);

Expansion Cohorts Only: Paired de-novo tumor biopsy collection at sequential time 
points for analysis of exploratory mechanistic biomarkers such as IHC assessment of 
tumor-infiltrating lymphocytes, quantitation of T cell receptor sequences, and gene 
expression.


 
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STUDY DESIGN
This is a Phase 1b, open-label, multi-center, multiple-dose, safety, pharmacokinetic 
 
 study designed to estimate the maximum tolerated dose (MTD), and 
determine the Recommended Phase 2 Dose (RP2D) of PF-05082566 in combination with 
MK-3475 in patients with advanced solid tumors. 
Once the MTD of PF-05082566 administered in combination with MK-3475 has been 
estimated with confidence, one or more expansion cohorts of patients with selected advanced 
solid tumors will be enrolled to further study the safety, tolerability, 
 
and preliminary anti-tumor activity for PF-05082566 in combination with MK-3475 to 
support recommended Phase 2 dose (RP2D) selection, as well as to study tumor-associated 
biomarkers.  The tumor types for further study could include NSCLC and potentially other 
tumor types based on emerging data from the dose escalation phase of this study.
Antitumor activity will be assessed by radiological tumor assessments conducted at baseline, 
at 9 weeks after the first dose of study drug, and every 6 weeks thereafter, whenever disease 
progression is suspected (eg, symptomatic deterioration), and at the time of End of 
Treatment/Withdrawal (if not done in the previous 6 weeks), using RECIST version 1.1.  
Safety will be monitored at regular intervals throughout the study by means of laboratory 
tests and clinical visits.  Pharmacokinetic 
 blood endpoints will also be 
monitored in all patients. 
For all patients in dose-expansion cohorts, a de novo biopsy will be required at study entry 
followed by a second biopsy at the time of the week 9 scans (after 3 cycles of treatment).  
Optional de novo biopsies may be collected from patients in dose-escalation cohorts to 
support the assessment of disease progression.  
 
 
 
 
Study Treatments:
PF-05082566 will be administered as a 1 hour intravenous infusion q3wks in escalating 
doses and may include the following planned doses: 0.20 mg/kg, 0.45 mg/kg, 0.9 mg/kg, 
1.8 mg/kg, 3.6 mg/kg, and 5 mg/kg.  The starting dose of PF-05082566 will be set at 
0.45 mg/kg.
MK-3475 will be administered as a 30 minutes IV infusion at a dose of 2 mg/kg q3wks.  This 
MK-3475 dose was chosen based on PK, safety, and efficacy considerations (see Section 1.3
for more details).
After estimation of the MTD for the combination on the q3wk schedule, PF-05082566 may 
be co-administered along with MK-3475 to study safety and tolerability on an alternative 
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dosing schedule for both drugs.  Other study drugs doses may also be tested based on 
emerging safety and tolerability data.  The initiation of additional patient cohorts to explore 
additional dosing schedules or study drugs doses will be at the discretion of the Sponsor.
 
 
 
 
 
 
 
 
 
  Therefore, patients with RECIST defined disease progression who are 
continuing to derive clinical benefit from the study treatment will be eligible to continue 
treatment with PF-05082566 plus MK-3475 provided that the treating physician has 
determined that the benefit/risk for doing so is favorable.  The duration of treatment will be 
up to 32 cycles (approximately 24 months) in all patients.
Dose escalation and MTD estimation for the PF-05082566 plus MK-3475 combination will 
be conducted according to the following algorithm:
a.
Dose escalation and de-escalation of PF-05082566 follows the Time-to-Event 
Continual Reassessment Method (TITE-CRM) up to a maximum dose of 5.0 mg/kg
q3wk.
b. The MTD is defined as the highest combination dose with a DLT rate <25% from the 
model estimate.
c.
Dose escalation stops if: 

Maximum study sample size is reached; or

9 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. 
Treatment with study drugs will continue until completion of 32 cycles (approximately 
24 months) of treatment, disease progression (RECIST v. 1.1), patient refusal, unacceptable 
toxicity occurs, or the study is prematurely terminated by the Sponsor; whichever comes 
first.  Discontinuation from treatment may be considered at the investigator’s discretion for 
patients who have attained a confirmed CR, have been treated for at least 24 weeks on study, 
and have at least two treatments with MK-3475 and PF-05082566 beyond the date the initial 
CR was declared.  Patients who then experience radiologic disease progression will be 
eligible for re-treatment with both study drugs at the discretion of the investigator and by the 
approval of the Sponsor, if no cancer treatment was administered since the last dose of study 
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drugs, the patient meets the safety parameters listed in the Inclusion/Exclusion criteria, and 
the trial is still open.  Patients will resume therapy at the same dose and schedule at the time 
of initial discontinuation.  Patients who complete a maximum number of 32 cycles 
(approximately 24 months) on study treatment and demonstrate clinical benefit with 
manageable toxicity and are willing to continue receiving the study treatment will be given 
the opportunity to continue treatment upon agreement between investigator and sponsor.
Dose Escalation Criteria:
Based on the starting dose example above, dose escalation and de-escalation will be carried 
out according to Table 1.  
Table 1.
Dose Escalation Cohorts
Dose Escalation Cohort
PF-05082566
MK-3475
-1
0.20 mg/kg q3wks
2 mg/kg q3wks
1 (Starting Dose Level)
0.45 mg/kg q3wks
2 mg/kg q3wks
2
0.9 mg/kg q3wks
2 mg/kg q3wks
3
1.8 mg/kg q3wks
2 mg/kg q3wks
4
3.6 mg/kg q3wks
2 mg/kg q3wks
5
5 mg/kg q3wks
2 mg/kg q3wks
* q3wks: every 3 weeks


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SCHEDULE OF ACTIVITIES: 
The Schedule of Activities table provides an overview of the protocol visits and procedures.  Refer to the Assessments section of the 
protocol for detailed information on each assessment required for compliance with the protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed in the Schedule of Activities table, in order to 
conduct evaluations or assessments required to protect the wellbeing of the patient.
Table 2.
Schedule of Activities: (PF-05082566 Plus MK 3475: 21 Day Treatment Cycles)
Screening1
CYCLES 1-2
CYCLES 3-8
CYCLES>835
End of Treatment31
Follow 
up32
Protocol Activity
Within 28 days of 
registration
Day
1
Day
8
Day 15
Day 1
Day 8
Day 15
Day 1
Visit Window
() 2
() 2
() 2
() 2
() 2
() 7
Informed Consent2
X
Tumor History3
X
Medical History4
X
Physical Examination5
X
X
X
X
X
ECOG Performance Status6
X
X
X
X
X
Baseline signs and symptoms7
X
Vital signs8
X
X
X
X
X
X
X
Contraception Check
X
X
X
X
X
X
X
X
X
X
Safety Labs/Measurements
12 lead ECG9
X
X
X
X
Hematology10
X
X
X
X
X
X
X
X
X
Blood Chemistry11
X
X
X
X
X
X
X
X
X
Coagulation12
X
X
X
X
X
X
X
Urinalysis13
X
X
Pregnancy Test14
X
X
X
X
X
Hepatitis B and C tests37
X
T3, FT4 and TSH36
X
X
X
X
X
Endocrine function assessment15
X
As clinically indicated
Registration and Treatment 
Registration16
X


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Table 2.
Schedule of Activities: (PF-05082566 Plus MK 3475: 21 Day Treatment Cycles)
Screening1
CYCLES 1-2
CYCLES 3-8
CYCLES>835
End of Treatment31
Follow 
up32
Protocol Activity
Within 28 days of 
registration
Day
1
Day
8
Day 15
Day 1
Day 8
Day 15
Day 1
Administration of
PF-0508256617
X
X
X
Administration of MK-347518
X
X
X
Tumor Assessments 
CT or MRI scan19
X
To be assessed at week 9 and then every 
6 weeks
X
X
Other Clinical Assessments
AEs20
Monitored and Recorded Continuously
X
X
Review Prior/Concomitant 
Medications21
X
Monitored and Recorded Continuously


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Table 3.
Schedule of Activities: (PF-05082566 and MK 3475: Dose Escalation and Expansion): Pharmacokinetic, 
 and Pharmacogenomic Assessments
Cycles 1-2
Cycles 3-4
Cycle 5
Cycle 6
Cycle 7
Cycles >735
End of 
Treatment31 Follow up32
Assessments [() 2 days 
for Cycles 1-7 and () 7 days for 
Cycles >7] 
Day 1
Day 1
Day 1 Day 8 Day 15
Day 1
Day 1
Day 8
Day 1
Blood for PF-05082566 PK22
X
X
X
X
X
X
X
X
X
X
Blood for MK-3475 PK23
X
X
X
X
X
X
X
X
 
 
Banked biospecimen (blood)26
X
(Cycle 1)
Blood for Pharmacogenomics 
(RNA)27
X
Blood for T cell receptor 
quantitation28
X
X
X
X
Blood for 
PF-05082566 Immunogenicity 
(ADA) testing29
X
(Cycle 1)
X
(Cycle 3)
X
X
X
X
Blood for MK-3475 Immunogenicity 
(ADA) testing30
X
(Cycle 1)
X
(Cycle 3)
X
X
X
X
X
De novo tumor biopsy for biomarker 
assessment (Dose escalation)33
X (unscheduled, to be collected at discretion of investigator and sponsor)
De novo tumor biopsy for biomarker 
assessment (Expansion cohorts 
only)34
X (taken prior 
to D1 dose)
X (taken at the 
time of Cycle 3 
tumor 
assessment)
Footnotes for Schedule of Activities: 
1.
Screening: To be performed within 28 days of treatment initiation.
2.
Informed Consent: Must be obtained prior to undergoing any study specific procedure and may occur prior to the 28-day screening period.
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3.
Tumor History: To be collected within 28 days prior to registration.  Includes oncology history; information on prior regimens, including dosing and duration of 
administration plus description of best response observed. 
4.
Medical History: Include history of other diseases (active or resolved) and concomitant illnesses. 
5.
Physical Examination: Includes major body systems.  Weight for the purposes of dose calculation must be recorded at Screening and within 7 days pre-dose Day 1 of each 
cycle.  Height will be measured at baseline only. 
6.
ECOG Performance Status: ECOG performance scale is available in Appendix 2 of the protocol.
7.
Baseline signs and symptoms: Patients will be asked about any signs and symptoms experienced within the past 14 days prior to starting treatment and record on the AE 
CRF page.  During study treatment any new or worsened conditions since baseline should be reported on the AE CRF.
8.
Vital Signs: Blood pressure, and pulse rate will be recorded in a supine or seated position.
9.
Triplicate 12 Lead ECG: See Section 7.1.5 for details.  At each time point, 3 consecutive 12 lead ECGs will be performed approximately 2 minutes apart to determine mean 
QTc.  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.  ECGs will be collected as follows: a) at Screening; b) On Cycles 1-8/Day 1, at pre PF-05082566 infusion and end of MK-3475 infusion; and c) at End of 
Treatment.  If the mean QTc interval is prolonged (>500 msec), then the ECGs should be reevaluated by a qualified person at the center for confirmation.  Additional 
triplicate ECGs may be performed as clinically indicated.  While pre-dose ECG assessments will be required for all patients, post-dose ECG assessments will be required only 
for patients in dose escalation cohorts. 
10. Hematology: No need to repeat on C1D1 if baseline assessment performed within 7 days prior to that date.  To be performed weekly. If during the first 2 cycles of treatment 
a grade 4 hematologic event is evident, the hematology assessment should be repeated at least every other day to assess for events qualifying as DLT.  See Table 4 for the 
Required Laboratory Tests list.
11. Blood Chemistry: No need to repeat on C1D1 if baseline assessment performed within 7 days prior to that date.  To be performed weekly. See Table 4 for Laboratory Tests 
list.
12. Coagulation: No need to repeat on C1D1 if baseline assessment performed within 7 days prior to that date.  To be performed weekly for Cycle 1 and on Day 1 for all 
remaining cycles and at the End of Treatment visit.  See Table 4 for Laboratory Tests list.
13. Urinalysis: During the treatment period to be performed when clinically indicated.  If protein 2+ by semiquantitative method (eg, urine dipstick), protein will be quantified 
by 24 hour urine collection (see Table 4).  Urine reflex microscopy is required whenever urine multitest dipstick is positive for blood or protein. 
14. Serum/Urine Pregnancy Test: For female patients of childbearing potential, a serum or urine pregnancy test, with sensitivity of at least 25 mIU/mL, 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 study drug 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 IRB/IECs or if required by local regulations.  For Day 1 of 
each cycle, pregnancy testing is required immediately before study drug administration.  See Section 7.1.1 for contraception guidelines.
15. Endocrine function assessment (in addition to T3, FT4, and TSH):  During treatment, to be performed in cases of suspected hypoadrenalism or hypopituitarism.  See 
Table 4 for Laboratory Tests list.
16. Registration: Patient number and dose level allocation operated by Pfizer Inc.
17. Trial Treatment/PF-05082566 administration:  PF-05082566 will be administered once every 3 weeks (1 cycle = 21 days) as a 1 hour intravenous infusion.
18. Trial Treatment/MK-3475 administration:  MK-3475 will be administered once every 3 weeks as a 30 minute infusion.  MK-3475 infusion will start 30 minutes after 
completion of PF-05082566 infusion and after the post- PF-05082566 and pre-MK-3475 pharmacokinetic blood samples are drawn (See Section 5.3.6 for acceptable periods 
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19. Tumor Assessments:  Tumor assessments will include all known or suspected disease sites.  Imaging may include chest, abdomen and pelvis CT or MRI scans; brain CT or 
MRI scan, and bone scans (see Section 7.4.1).  The CT scans should be performed with contrast agents unless contraindicated for medical reasons.  The same imaging 
technique used to characterize each identified and reported lesion at baseline will be employed in the following tumor assessments.  Antitumor activity will be assessed 
through radiological tumor assessments conducted at baseline, at 9 weeks then every 6 weeks, whenever disease progression is suspected (eg, symptomatic deterioration), and 
at the time of End of Treatment (if not done in the previous 6 weeks).  Timing should follow calendar days and should not be adjusted for delays in cycle starts.  Follow-up 
bone scans are required every 15 weeks only if bone metastases are present at baseline.  Otherwise bone imaging is required only if new bone metastasis are suspected and at 
the time of confirmation of response for patients who have bone metastases.  Assessment of response will be made using RECIST version 1.1.
20. Adverse Event (AE) Assessments:  Adverse events should be documented and recorded at each visit using NCI CTCAE version 4.03.  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 90 calendar days after the last administration of the investigational products and before initiation of a new anti-cancer 
treatment.  The prolonged follow up is due to the pharmacokinetic properties of the investigational product MK-3475.  SAEs experienced by a patient after the active 
reporting period (see Section 8.2) has ended should be reported to the Sponsor if the Investigator becomes aware of them; at a minimum, all SAEs that the Investigator 
believes have at least a reasonable possibility of being related to study drug are to be reported to the Sponsor.  AEs (serious and non-serious) should be recorded on the Case 
Report Form (CRF) from the time the patient has taken at least one dose of study treatment through last patient visit (Day 28 after last dose).  If a patient begins a new 
anticancer therapy, the AE reporting period for non-serious AEs ends at the time the new treatment is started. Pregnancy or breast feeding that occur during the trial, within 
120 days of discontinuing treatment with MK-3475, or within 28 days after the cessation of study treatment if the patient begins a new anticancer therapy, whichever is 
earlier, should be reported as in Section 8.10 (Exposure During Pregnancy).
21. Concomitant Medications: All concomitant medications including supportive care drugs (eg, anti-emetic treatment and prophylaxis), and the drugs used to treat AEs or 
chronic diseases should be recorded in the CRF.
22. Blood for PF-05082566 Pharmacokinetics: Blood samples will be collected during Cycle 1-4 on (a) Day 1 at pre-dose and end of infusion; (b) During Cycle 5 on Day 1 at 
pre-dose, end of infusion, and at 2, 6, and 24 hrs after the start of infusion; (c) on Days 8 (192 hours), and 15 (360 hours) after start of infusion (See Section 7.2 for guidelines 
on timing of blood draws); (d) During Cycle 6 on Day 1 at pre-dose; (e) During Cycle 7 on Day 1 at pre-dose, end of infusion, 24 hrs after the start of infusion and on Day 8; 
and (f) Beyond Cycle 7, PK samples will be collected at pre-dose, for every 2 cycles up to Cycle 12, every 4 cycles thereafter, and at the End of Treatment visit.  For patients 
in expansion cohorts, same PK schedule will be followed for at least 10 patients in total from all expansion cohorts.  For other patients (all expansion cohorts), predose 
samples on Day 1 will be collected for Cycles 1, 3, 5, 6 (Section 7.2.1) and 7.  Beyond Cycle 7, PK samples will be collected at pre-dose, for every 2 cycles up to Cycle 12, 
and every 4 cycles thereafter.  Timing of sampling may be modified based on emerging PK data.  For patients discontinuing from the study, a PK sample should be collected 
at the End of Treatment assessment.
23. Blood for MK-3475 Pharmacokinetics: Blood samples will be collected (a) During Cycle 1- 4 on Day 1 at pre-dose and end of infusion; (b) During Cycle 5 on Day 1 at 
pre-dose; and end of infusion(c) During Cycle 7 on Day 1 at pre-dose,  end of infusion, 24 hrs, and on Day 8 (192 hrs) after start of infusion (See Section 7.2 for guidelines on 
timing of blood draws).  Beyond Cycle 7, PK samples will be collected at pre-dose every two cycles up to cycle 12, and every 4 cycles thereafter. Additionally, PK samples 
will be collected at 28 days, 3 months, and 6 months after the end of MK-3475 treatment.  For patients in an expansion cohort, the same PK schedule will be followed for at 
least 10 patients in total from all expansion cohorts.  For other patients (all expansion cohorts), predose samples on Day 1 will be collected for Cycles 1, 3, 5 and 7.  Beyond 
Cycle 7, PK samples will be collected at pre-dose (Day 1), every 2 cycles up to Cycle 12, and every 4 cycles thereafter.  Timing of sampling may be modified based on 
emerging PK data.  For patients withdrawing from the study, a PK sample should be collected at the End of Treatment assessment.
24.
 
 
 
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25.
 
 
26. Banked Biospecimen (blood): A 4-mL blood biospecimen will be collected on Day 1 Cycle 1 (pre-dose) to be retained for potential pharmacogenomic/biomarker analyses 
related to drug response, unless prohibited by local regulations or ethics committee decision.
27. Blood for Pharmacogenomics (RNA): Blood samples will be collected during Cycle 1 Day 1 (pre-dose) and Cycle 2 Day 1 (pre-dose). 
28. Blood for T cell Receptor Quantitation: Blood sample taken pre-dose on Day 1 of Cycles 1 through 5, and at End of Treatment.
29. Blood for PF-05082566 Immunogenicity (ADA) Testing: Blood for PF-05082566 immunogenicity testing will be collected at pre-dose (Day 1), Cycles 1, 3, 5, 7, and 
subsequently pre-dose (Day 1) every 2 cycles up to Cycle 12, and every 4 cycles thereafter.  For patients discontinuing study drug treatment, immunogenicity samples should 
be collected at the End of Treatment assessment day.  If ADAs are detected, additional samples may be collected approximately every 3 months (coinciding with disease 
assessment visit) until ADA levels return to baseline.
30. Blood for MK-3475 Immunogenicity (ADA) Testing: Blood for MK-3475 immunogenicity testing will be collected at pre-dose in Cycles 1,3, 5, 7 and subsequently predose 
every 2 cycles up to Cycle 12 and every 4 cycles thereafter.  Additionally,  ADA samples will be collected at 28 days, and during Follow-Up (3 months and 6 months after the 
end of MK-3475 treatment).
31. End of Treatment: To be performed approximately 28 days after the last dose of study drug.  Obtain these assessments if not completed during the previous week on study 
(during the previous 6 weeks on study for tumor assessments).
32. Follow Up: Patients should be evaluated up to 90 days after last dose of study treatment.  Refer to the protocol for specific guidelines.  Patients continuing to experience 
toxicity following discontinuation of study 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.  PK and immunogenicity samples should be collected as described in the PK and Immunogenicity Assessment section 
in Schedule of Activities (Table 3).  Patients whose disease has not progressed at the end of treatment will enter into disease follow-up.  During this follow-up period, 
patients will have disease assessments performed every 12 weeks 7-days.  Once patients have exhibited disease progression or began a new anti-cancer therapy, or 6-month 
follow-up from the date of the first dose of the last enrolled patient, whichever occurs first, they will be withdrawn from the study.  See Section 4.3.1 Contraception for 
guidelines on contraception checks during this period. 
33. De novo tumor biopsy for biomarker assessment (Dose escalation): For patients in dose-escalation cohorts, unscheduled optional de novo tumor biopsies may be collected 
at the discretion of the investigator and sponsor to support the assessment of disease progression. 
34. De novo tumor biopsy for biomarker assessment (Expansion cohorts): Mandatory for patients in expansion cohorts only.  A de novo biopsy will be required at study entry 
followed by a second biopsy at the time of the Week 9 scans (after 3 cycles of treatment). 
35. Continued Treatment Beyond Cycle 8: This will be on a reduced visit schedule (Day 1 of each cycle), or as clinically indicated. 
36. Thyroid Function Tests: To be collected every 2 cycles for the first 8 cycles, and then every 4 cycles (Cycles 1, 3, 5, 7, 11, 15 etc.).
37. Hepatitis B and C Tests:  Conduct tests for hepatitis B surface antigen, core antibody, and anti-hepatitis C.  Other tests may be conducted per standard practice to confirm an 
active hepatitis infection.
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Table 4.
Required Laboratory Tests
SAFETY LABORATORY REQUIREMENTS 
Refer to the Schedule of Activities table for specific timepoints and instructions
Assessments
Hematology Panel:
Chemistry Panel:
Absolute Neutrophil Count
Sodium
Hemoglobin
Potassium
Total Calcium
Platelet Count
Creatinine
WBC with differential (5-part if available)
Albumin
Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST)
Glucose
Phosphorus
Magnesium
Total Bilirubin***
Blood urea nitrogen (BUN)
Alkaline phosphatase
Lactate dehydrogenase (LDH)
Immunoglobulin G
Total protein
Uric acid (or urate)
Coagulation Panel: international normalized ratio 
(INR) or prothrombin time (PT), Partial 
thromboplastin time (PTT)
Thyroid function assessments: T3, 
FT4 and TSH.  In the presence of clinical 
suspicion of hypopituitarism or 
hypoadrenalism, laboratory testing should 
include one or more of the following: 
ACTH, and cortisol levels before and 
30-60 minutes after corticotrophin 
stimulation.  
Urinalysis: measurement of pH, specific gravity, 
protein/albumin, glucose, blood/hemoglobin, 
ketones/acetone.  Urine dipstick for urine protein: if 
positive collect 24-hr and microscopic (Reflex 
Testing), Urine dipstick for urine blood: if positive 
collect a microscopic (Reflex Testing).
Pregnancy Test (serum or urine): Conducted for 
women of childbearing potential only.  
Hepatitis B and C tests: Conduct tests for 
hepatitis B surface antigen, core antibody, 
and anti-hepatitis C.  Other tests may be 
conducted per standard practice to confirm 
an active hepatitis infection.
*** For potential Hy’s Law cases, in addition to repeating AST and ALT, laboratory tests should 
include albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, gamma glutamyl 
transferase, prothrombin time (PT)/INR, alkaline phosphatase, and acetaminophen levels.


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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................28
LIST OF FIGURES .................................................................................................................28
APPENDICES .........................................................................................................................29
1. INTRODUCTION ...............................................................................................................30
1.1. Indication.................................................................................................................30
1.2. Background and Rationale ......................................................................................30
1.2.1. Scientific Rationale: 4-1BB Target Biology and Mechanism of 
Action...............................................................................................................30
1.2.2. Pre-clinical Development of PF-05082566 ................................................31
1.2.2.1. In Vitro PF-05082566 Data.......................................................31
1.2.3. In Vivo Data: Functional Activity of PF-05082566....................................32
1.2.3.1. Anti-tumor Activity of PF-05082566........................................33
1.2.4. Combination Studies...................................................................................33
1.2.5. Pre-Clinical Pharmacokinetics of PF-05082566 ........................................34
1.2.6. Pharmacokinetics 
 Relationship of 
PF-05082566....................................................................................................34
1.2.7. Preclinical Toxicology of PF-05082566.....................................................35
1.2.8. Clinical Safety of PF-05082566 .................................................................35
1.2.9. MK-3475.....................................................................................................36
1.2.9.1. Clinical Safety and Efficacy of MK-3475..................................38
1.2.9.2. MK-3475 Clinical Efficacy.......................................................38
1.3. Starting Dose Selection Strategy.............................................................................39
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................41
2.1. Objectives................................................................................................................41
2.2. Endpoints.................................................................................................................41
3. STUDY DESIGN.................................................................................................................42
3.1. Study Overview.......................................................................................................42
3.1.1. Starting Dose ..............................................................................................44
3.2. Criteria for Dose Escalation ....................................................................................44
3.3. DLT Definition........................................................................................................46
3.4. MTD Definition.......................................................................................................47
3.5. Dose Expansion Test Dose......................................................................................47
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3.6. Dose Expansion Phase ............................................................................................47
3.7. Recommended Phase 2 Dose ..................................................................................47
4. PATIENT SELECTION......................................................................................................47
4.1. Inclusion Criteria.....................................................................................................48
4.2. Exclusion Criteria....................................................................................................49
4.3. Life Style Guidelines...............................................................................................51
4.3.1. Contraception..............................................................................................51
4.4. Sponsor Qualified Medical Personnel.....................................................................52
5. STUDY TREATMENTS.....................................................................................................52
5.1. Allocation to Treatment ..........................................................................................52
5.2. Drug Supplies..........................................................................................................53
5.2.1. Dosage Form and Packaging ......................................................................53
5.2.1.1. PF-05082566.............................................................................53
5.2.1.2. MK-3475 ...................................................................................53
5.2.2. Preparation and Dispensing........................................................................53
5.3. Administration.........................................................................................................53
5.3.1. PF-05082566...............................................................................................54
5.3.2. MK-3475.....................................................................................................54
5.3.3. Treatment Duration.....................................................................................54
5.3.4. Treatment After Initial Evidence of Radiologic Disease Progression........55
5.3.5. Recommended Dose Modifications............................................................56
5.3.6. Dose Delays................................................................................................56
5.3.7. Dose Reductions .........................................................................................57
5.3.7.1. Study Drug Dose Modification Guidelines...............................57
5.3.7.2. Supportive Care Guidelines for Immune-Related Events 
of Clinical Interest (irECI) and Immune-Related Adverse 
Events (irAEs) ...................................................................................61
5.3.7.3. Supportive Care Guidelines for Pneumonitis............................62
5.3.7.4. Recommended Study Drug Dose Modification and 
Supportive Care Guidelines for Enterocolits.....................................62
5.4. Drug Storage ...........................................................................................................63
5.5. Drug Accountability................................................................................................64
5.6. Concomitant Treatments .........................................................................................64


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5.6.1. Prohibited Concomitant Medications .........................................................64
5.7. Rescue Medications and Supportive Care...............................................................65
5.7.1. Supportive Care Guidelines........................................................................65
5.7.2. Supportive Care Guidelines For Infusion Reactions to Either Study 
Drug .................................................................................................................66
5.8. Supportive Care.......................................................................................................68
5.8.1. Anti-inflammatory Therapy........................................................................68
5.8.2. Corticosteroids............................................................................................68
5.8.3. Concomitant Surgery..................................................................................68
5.8.4. Concomitant Radiotherapy.........................................................................68
6. STUDY PROCEDURES .....................................................................................................69
6.1. Screening.................................................................................................................69
6.2. Study Period ............................................................................................................69
6.3. Patient Withdrawal..................................................................................................70
7. ASSESSMENTS..................................................................................................................71
7.1. Safety Assessment...................................................................................................71
7.1.1. Pregnancy Testing ......................................................................................71
7.1.2. Adverse Events...........................................................................................71
7.1.2.1. MK-3475 Adverse Events of Special Interest...........................72
7.1.3. Laboratory Safety Assessment ...................................................................73
7.1.4. Vital Signs and Physical Examination........................................................73
7.1.5. ECG Assessments.......................................................................................73
7.2. Pharmacokinetics Assessments (Dose Escalation and Dose Expansion 
Cohorts).....................................................................................................................74
7.2.1. PF-05082566...............................................................................................74
7.2.2. MK-3475.....................................................................................................75
7.4. Banked Biospecimen (Blood) .................................................................................77
7.4.1. Markers of Drug Response.........................................................................77
7.4.2. Additional Research....................................................................................78
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7.5. Immunogenicity Assessments (ADA).....................................................................78
7.5.1. Immunogenicity to PF-05082566...............................................................78
7.5.2. Immunogenicity to MK-3475.....................................................................79
7.6. Tumor Biopsies for Mechanistic Exploratory Biomarkers .....................................79
7.8. Pharmacogenomic (RNA) Assessments..................................................................79
7.9. Tumor Response Assessments ................................................................................80
8. ADVERSE EVENT REPORTING......................................................................................81
8.1. Adverse Events........................................................................................................81
8.2. Reporting Period .....................................................................................................81
8.3. Definition of an Adverse Event...............................................................................82
8.4. Medication Errors....................................................................................................82
8.5. Abnormal Test Findings..........................................................................................83
8.6. Serious Adverse Events...........................................................................................84
8.6.1. Protocol-Specified Serious Adverse Events...............................................84
8.6.2. Potential Cases of Drug-Induced Liver Injury............................................84
8.7. Hospitalization ........................................................................................................86
8.8. Severity Assessment................................................................................................87
8.9. Causality Assessment..............................................................................................87
8.10. Exposure During Pregnancy..................................................................................88
8.11. Occupational Exposure .........................................................................................89
8.12. Withdrawal Due to Adverse Events (See also Section on Patient 
Withdrawal)...............................................................................................................89
8.13. Eliciting Adverse Event Information ....................................................................89
8.14. Reporting Requirements........................................................................................89
8.14.1. Serious Adverse Event Reporting Requirements .....................................89
8.14.2. Non-Serious Adverse Event Reporting Requirements .............................90
8.14.3. Sponsor Reporting Requirements to Regulatory Authorities ...................90
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................90
9.1. Analysis Sets ...........................................................................................................90
9.2. Statistical Methods for Dose Allocation: TITE-CRM ............................................91
9.3. Sample Size Determination.....................................................................................94
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9.4. Efficacy Analysis ....................................................................................................94
9.5. Analysis of Other Endpoints ...................................................................................94
9.5.1. Analysis of Pharmacokinetics.....................................................................94
9.5.1.1. Pharmacokinetics Analysis of PF-05082566 and 
MK-3475 ...........................................................................................94
9.5.1.2. Population Pharmacokinetic Analysis or PK
 Modeling .....95
9.5.1.3. Analysis of Immunogenicity Data.............................................95
9.5.1.4. Statistical Analysis of Biomarker Endpoints ............................95
9.6. Safety Analysis........................................................................................................96
9.6.1. Analysis of Primary Endpoint ....................................................................96
9.6.2. Analysis of Secondary Safety Endpoints....................................................96
9.6.2.1. Adverse Events..........................................................................96
9.6.2.2. Laboratory Test Abnormalities .................................................96
9.6.3. ECG ............................................................................................................97
9.7. Data Safety Monitoring Committee ........................................................................97
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................98
11. DATA HANDLING AND RECORD KEEPING .............................................................98
11.1. Case Report Forms/Electronic Data Record .........................................................98
11.2. Record Retention...................................................................................................99
12. ETHICS..............................................................................................................................99
12.1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ............99
12.2. Ethical Conduct of the Study ..............................................................................100
12.3. Patient Information and Consent.........................................................................100
12.4. Patient Recruitment.............................................................................................101
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP .........................................................................................................................101
13. DEFINITION OF END OF TRIAL.................................................................................101
13.1. End of Trial in a Member State...........................................................................101
13.2. End of Trial in all other Participating Countries.................................................101
14. SPONSOR DISCONTINUATION CRITERIA ..............................................................101
15. PUBLICATION OF STUDY RESULTS........................................................................102
15.1. Communication of Results by Pfizer ..................................................................102
15.2. Publications by Investigators ..............................................................................103
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16. REFERENCES ................................................................................................................104
LIST OF TABLES
Table 1.
Dose Escalation Cohorts.......................................................................................15
Table 2.
Schedule of Activities: (PF-05082566 Plus MK 3475: 21 Day Treatment 
Cycles) ..................................................................................................................16
Table 3.
Schedule of Activities: (PF-05082566 and MK 3475: Dose Escalation and 
Expansion): Pharmacokinetic, 
 and Pharmacogenomic 
Assessments..........................................................................................................18
Table 4.
Required Laboratory Tests ...................................................................................22
Table 5.
In Vitro Properties of PF 05082566......................................................................32
Table 6.
PF-05082566 Treatment Emergent, Treatment Related Adverse Events 
reported in at least 1 Patient (Study B1641001 Portion A) ..................................36
Table 7.
Available Dose Levels..........................................................................................58
Table 8.
Dose Modification Guidelines for Treatment Related Adverse Events ...............59
Table 9.
General Approach to Handling irAEs...................................................................61
Table 10.
Recommended Approach to Handling Pneumonitis.............................................62
Table 11.
MK-3475 Recommended Dose Modifications and Supportive Care 
Guidelines for Enterocolits...................................................................................63
Table 12.
Infusion Reaction Treatment Guidelines for Either Study Drug..........................67
Table 13.
Objective Response Status at each Evaluation...................................................111
Table 14.
Objective Response Status at each Evaluation for Patients with Non Target 
Disease Only.......................................................................................................112
LIST OF FIGURES
Figure 1.
Effect of PF-05082566 on the Growth of PC3 Prostate Carcinoma in a 
huPBL SCID Model .............................................................................................33
Figure 2.
Combinatorial Efficacy of Surrogate Anti-4-1BB combined with Surrogate 
Anti-PD-1 in a Colorectal Carcinoma Model.......................................................34
Figure 3.
Example Plot of Prior Dose Toxicity Curve.........................................................93
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APPENDICES
Appendix 1. Determination of Efficacy.................................................................................108
Appendix 2. Eastern Cooperative Oncology Group (ECOG) Performance Status ...............113
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1. INTRODUCTION
This is a Phase 1b study of PF-05082566, a novel fully humanized IgG2 monoclonal 
anti-body (mAb) agonist of 4-1BB (CD137, TNFRSF9), in combination with MK-3475, a 
PD-1 inhibitor mAb.  The study is designed to evaluate the safety, pharmacokinetics (PK) 
 of PF-05082566 administered intravenously in combination 
with MK-3475 to adults with advanced solid tumor malignancies.
1.1. Indication
Relapsed or refractory solid tumors. 
1.2. Background and Rationale
1.2.1. Scientific Rationale: 4-1BB Target Biology and Mechanism of Action
4-1BB (CD137, TNFRSF9), first identified as an inducible costimulatory receptor expressed 
on activated T cells, is a membrane spanning glycoprotein of the Tumor Necrosis Factor 
(TNF) receptor superfamily.  Current understanding of 4-1BB indicates that expression is 
generally activation dependent and encompasses a broad subset of immune cells including 
activated NK and natural killer T (NKT) cells; regulatory T cells; dendritic cells (DC) 
including follicular DC; stimulated mast cells, differentiating myeloid cells, monocytes, 
neutrophils, eosinophils (Wang et al. 2009),21 and activated B cells (Zhang et al. 2011).22  
4-1BB expression has also been demonstrated on tumor vasculature (Broll et al. 2001, 
Seaman et al. 2007)1,19 and atherosclerotic endothelium (Olofsson et al. 2008).16 The ligand 
that stimulates 4-1BB (4-1BBL) is expressed on activated antigen-presenting cells (APCs), 
myeloid progenitor cells and hematopoeitic stem cells. 
4-1BB is undetectable on the surface of  T cells but expression increases upon activation. 
Based on homology to other members of the TNFRSF, ligand binding is expected to induce 
receptor trimerization resulting in activation (Chan et al. 2007).2 Some members of the 
TNFRSF can cleave the extracellular domain from the cell surface and exist in a soluble 
form. Soluble 4-1BB and soluble 4-1BBL have been demonstrated in the serum of some 
patients with autoimmune diseases and cancers (Furtner et al. 2005; Hentschel et al. 2006; 
Michel et al. 1998).8,9,13
Upon 4-1BB activation, TRAF 1 and TRAF 2, pro-survival members of the TNFR-associated 
factor (TRAF) family are recruited to the 4-1BB cytoplasmic tail resulting in downstream 
activation of NFkB and the Mitogen Activated Protein (MAP) Kinase cascade including Erk, 
Jnk, and p38 MAP kinases.  NFkB activation leads to upregulation of Bfl-1 and Bcl-XL, 
pro-survival members of the Bcl-2 family.  The pro-apoptotic protein Bim is downregulated 
in a TRAF1 and Erk dependent manner (Sabbagh et al. 2008).18
Numerous studies of murine and human T cells indicate that 4-1BB promotes enhanced 
cellular proliferation, survival, and cytokine production (Croft 2009).4 Reports have shown 
that 4-1BB agonist mAbs increase costimulatory molecule expression and markedly enhance 
cytolytic T lymphocyte responses, resulting in anti-tumor efficacy in various models.  4-1BB
agonist mAbs have demonstrated efficacy in prophylactic and therapeutic settings and both 
monotherapy and combination therapy tumor models and have established durable anti-tumor 
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protective T cell memory responses (Lynch 2008).12 4-1BB agonists also inhibit 
autoimmune reactions in a variety of autoimmunity models (Vinay et al. 2006).20 This dual 
activity of 4-1BB offers the potential to provide anti-tumor activity while dampening 
autoimmune side effects that can be associated with immunotherapy approaches that break 
immune tolerance.
Interaction of 4-1BB on activated normal human B cells with its ligand at the time of B cell 
receptor engagement stimulates proliferation and enhances survival (Zhang et al. 2011).22  
The potential impact of 4-1BB engagement in B cell lymphoma has been investigated in two 
published studies.  Evaluation of several types of human primary non-Hodgkin’s lymphoma 
(NHL) samples indicated that 4-1BB was expressed predominantly on infiltrating T cells 
rather than the lymphoma cells (Houot et al. 2011).10 The addition of 4-1BB agonists to
in vitro cultures of B lymphoma cells with rituximab and NK cells resulted in increased 
lymphoma killing (Kohrt et al.2010).11
In addition, B cell immunophenotyping was performed in two experiments using 
PF-05082566 in cynomolgus monkeys with doses from 0.001-100 mg/kg; in these 
experiments peripheral blood B cell numbers were either unchanged or decreased.
1.2.2. Pre-clinical Development of PF-05082566
PF-05082566, an intravenous (IV) fully human IgG2 monoclonal antibody (mAb), binds to 
the extracellular domain of human 4-1BB with high affinity and specificity and is capable of 
4-1BB agonism.  Injection with PF-05082566 has been shown to correlate with tumor cell 
line growth inhibition in xenogenic tumor models as a single agent. In addition, 4-1BB
agonist mAbs demonstrate significant combinatorial efficacy with antibody-dependent 
cellular cytotoxicity (ADCC) antibodies in lymphoma models. Preclinical studies support 
the use of this 4-1BB agonist mAb as a promising candidate for treatment of cancer, alone or 
in combination with ADCC-inducing mAbs.
1.2.2.1. In Vitro PF-05082566 Data
PF-05082566 has shown immunomodulatory activity in various in vitro assays. In concert 
with a signal through the T-cell receptor, PF-05082566 has been shown to mediate ligation of 
4-1BB, which results in activation of NFkB culminating in T cell cytokine release and 
proliferation. The in vitro properties of PF-05082566 are summarized in Table 5.


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Table 5.
In Vitro Properties of PF 05082566
In vitro Assay
Activity (nM)
Affinity for 4-1BB
Biacore
     Affinity (KD)
     On rate (Ka)
     Off rate (Kd)
8.71.0
1.40.06 x106 M-1 s-1
0.0120.001s-1
Saturation Binding 
4-1BB ECD binding ELISA (EC50; n=3)
    Human
    Cyno
0.1240.041
0.1980.024
4-1BB expressing 300.19 cells (FACS EC50; n=2)
     Human
     Cyno
1.8
4.2
PHA stimulated primary cells
     Human PBMC (FACS EC50; n=12)
     Cyno PBMC (FACS EC50; n=7)
     Dog, rat, mouse (FACS; n=2)
48.924
14968
No binding up to 100 nM
Inhibition of ligand binding
Ligand competition ELISA (IC50; n=2)
0.2000.003
In vitro stimulation
4-1BB transfected cells (NF-kB luciferase reporter) (EC50)
     Human (n=3)
     Cyno (n=3)
0.150.04
0.40.039
Augmentation of primary human T cell activity
     CD3 induced IL-2 production (EC50{range max fold induction}; n=12)
22.67.63 {2-20}
Selectivity (FACS)
CD40, CD134
No binding up to 1000 nM
ECD = Extracellular Domain
ELISA = Enzyme Linked Immunosorbent Assay
FACS = Fluorescence Activated Cell Sorting
PHA = Phytohemagglutinin
PBMC = Peripheral Blood Mononuclear Cell
NF-kB = Nuclear Factor kappa B
IL-2 = Interleukin-2
1.2.3. In Vivo Data: Functional Activity of PF-05082566
In pre-clinical studies, PF-05082566 has exhibited the ability to increase lymphocyte 
proliferation. In small animal models developed to test the in vivo function of PF-05082566, 
PF-05082566 was able to enhance expansion of human leukocytes in a dose dependent 
manner as evidenced by an increase in the proportion of human CD45+ cells in the peripheral 
blood of engrafted mice.  Similarly, a dose dependent increase in the proportion of human 
leukocytes expressing the proliferation marker Ki-67 was noted. In addition, PF-05082566
treatment of cynomolgus monkeys in single or multiple dose studies increased proliferation 
among cytotoxic central memory T cells (CD8 TCM) in peripheral blood mononuclear cell 
(PBMC) samples. Taken together, these data demonstrate evidence of PF-05082566’s ability 
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1.2.3.1. Anti-tumor Activity of PF-05082566
Single agent PF-05082566 has demonstrated anti-tumor activity in pre-clinical studies. 
Tumor cell lines representing melanoma, colon, and prostate tumor types were tested in a
xenogenic tumor model. None of the tumor lines expressed 4-1BB; therefore, tumor cells 
were mixed with primary human peripheral blood mononuclear cells (PBMC) from a healthy 
volunteer donor prior to injection in all cases.  Once tumors were established, animals were 
treated with PF-05082566.  PF-05082566 was found to be efficacious against all 3 tumor 
types. An example growth curve demonstrating the response to a prostate carcinoma is 
shown in Figure 1.
Figure 1.
Effect of PF-05082566 on the Growth of PC3 Prostate Carcinoma in a 
huPBL SCID Model
PF-05082566 inhibits the growth of the PC3 prostate carcinoma in vivo Panel A: mean 
tumor volume at each time point measured.  Panel B: volume of each tumor on the final 
study day (Day 21).  The mean and standard error of the mean (SEM) are indicated by bars. 
*p<0.05, ** p<0.005. 
1.2.4. Combination Studies
As discussed in the Protocol Summary section, it is thought that tumor expression of
PD-L1 can limit the ability of cytotoxic T cells to directly kill the tumor cells.  Therefore, 
even if a 4-1BB agonist is used to stimulate cytotoxic T cells, capable of recognizing such 
tumors,  PD-L1 expressed on the tumor cells may down-modulate the activity of these 
stimulated T cells.  A 4-1BB agonist antibody resistant mouse MC38 colon cancer tumor 
model, that expresses PD-L1, was used to provide evidence for improved anti-tumor activity 
using the combination of a 4-1BB agonist antibody with PD-1 antagonist antibody compared 
with either single agent.  Figure 2 shows the results of this experiment in a mouse model, in 
which statistically significant anti-tumor activity versus the vehicle control is observed in the 
cohort of mice that received a combination of a PD-1 antagonist antibody with a 4-1BB 
agonist antibody but not with either antibody administered as a single agent. Consistent with 
the proposed mechanism for the combination, significant increases in CD8+ effector memory 
control
0.01mg/kg
0.1mg/kg
1mg/kg
0
200
400
600
800
1000
*
**
Tumor volume (mm3)
0
5
10
15
20
25
0
200
400
600
800
Vehicle control
PF-05082566 1.0 mg/kg
PF-05082566 0.1 mg/Kg
PF-05082566 0.01mg/kg
Day Post Implant
Tumor volume (mm3)
A
B


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cells and tumor responsive IFN-producing cells were found in the spleens of mice treated 
with the combination (data not shown).  In addition, preliminary toxicology data in mice 
suggest that the toxicity of an anti-4-1BB agonist is not increased by addition of an 
anti-PD-1 antagonist (data not shown).
Figure 2.
Combinatorial Efficacy of Surrogate Anti-4-1BB combined with Surrogate 
Anti-PD-1 in a Colorectal Carcinoma Model
Combination of a 4-1BB agonist antibody with a PD-1 antagonist antibody shows 
significant inhibition tumor growth in a colon carcinoma model.  C57BL6 mice were 
subcutaneously implanted with 1X106 MC38 murine colon carcinoma cells.  Tumor growth 
was monitored and animals randomized to four groups of 8 when the tumors reached an 
average size of 150 mm3 and intraperitoneal dosed with vehicle (phosphate-buffered saline; 
PBS), 1 mg/kg anti-mouse 41BB agonist (MAB9371), 10 mg/kg anti-mouse PD-1 antagonist 
(RMP1-14), or the simultaneous combination of the two once every 5 days for a total of two 
doses.  The study was terminated when tumor sizes of the controls reached 1000 mm3.  
Combination treatment of animals with 41BB agonist plus PD-1 antagonist resulted in 63.2% 
reduction in tumor growth when compared to vehicle controls (unpaired t test *p = 0.0125).  
Significant tumor growth inhibition by either agent dosed individually was not observed.
1.2.5. Pre-Clinical Pharmacokinetics of PF-05082566
Complete information for PF-05082566 pre-clinical PK studies may be found in Investigator 
Brochure (PF-05082566 IB).
1.2.6. Pharmacokinetics 
 Relationship of PF-05082566
PF-05082566 binds to recombinant human 4-1BB by Biacore analysis with an overall kinetic 
constant (KD) of 8.7 nM.  As noted above, PF-05082566, does not cross react with rodent 
4-1BB.  The pharmacokinetic
 (PK
) relationship of PF-05082566 and 
its PD response to anti 4-1BB and tumor growth index (TGI) in a subcutaneous 
transplantable CT-26 model was evaluated using a surrogate antibody, a rat anti-mouse 
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4-1BB antibody (MAB9371).  The surrogate antibody was administered as a single 
subcutaneous (SC) dose at 0.01, 0.1, 1 and 10 mg/kg to Balb/C mice 7 days after A20 murine 
lymphoma cells were implanted. The PK endpoints were represented by the serum 
concentration-time profile over 3 weeks post dose. 
 
 
The sCD137 increased in a dose- and time-dependent manner following 
MAB9371 administration in mouse.  Using the indirect-response model, the EC50 was 
estimated to be 11 nM (1650 ng/mL) and the derived EC10 was 4.2 nM (630 ng/mL).  
Administration of MAB9371 also resulted in a dose-dependent inhibition of tumor growth in 
the transplantable mouse lymphoma model.  Based on the simulation from the PK
 model 
of tumor growth inhibition, a 0.2 mg/kg dose corresponded to complete response of tumor 
inhibition during the study period.  The estimated average serum concentration (Cave) of 
MAB9371 at 0.2 mg/kg was 12 nM (1800 ng/mL), which was consistent with the EC50 of 
11 nM estimated from the sCD137 data. The 0.02 mg/kg dose corresponded to 10% 
response in tumor growth inhibition (TGI).  A mean drug serum concentration of 11.5 nM 
(1730 ng/mL) from the biomarker and TGI studies was used for human efficacious dose 
projection.  The average circulating sCD137 of 5.25 ng/mL was correlated with complete 
TGI, and was assumed to be the desired drug-induced biomarker level for efficacy.
1.2.7. Preclinical Toxicology of PF-05082566
The nonclinical safety summaries for PF-05082566 and MK-3475 can be found in their 
respective investigators procures (IBs).  No nonclinical toxicology studies have been 
conducted with the combination of PF-05082566 and MK-3475.  However, in order to study 
the toxicology of the combination of an agonist anti-4-1BB with an antagonist anti-PD-1, a 
2-week exploratory toxicology study was conducting in mice using subcutaneous injection of 
the surrogate anti-mouse 4-1BB (MAB9371) and the surrogate anti-mouse PD-1 (RMP-14).  
Male C57/Bl/6 mice were dosed once with vehicle, MAB9371, RMP 1-14, or a combination 
of RMP and MAB9371.  Administration of MAB9371 at 0.1 mg/kg or RMP 1-14 at 
20 mg/kg alone resulted in effects in white blood cell lineages.  Platelet effects occurred at 
1 mg/kg of MAB9371.  Administration of MAB9371 at 1 or 5 mg/kg, or the combination of 
RMP 1-14/MAB9371 at 20/0.1, 20/1 or 20/5 mg/kg resulted in mild hepatic and/or splenic 
histologic changes.  MAB9371 appeared to be the main contributor to the hepatic and splenic 
effects, as the effects were not significantly increased by the addition of RMP 1-14.  
Therefore, it did not appear that the anti-PD-1 mAb contributed significant additive toxicity 
when co-administered with the anti-4-1BB mAb.
1.2.8. Clinical Safety of PF-05082566
The safety of PF-05082566 is being assessed in an ongoing Phase 1, open-label, 
dose-escalation study (B1641001) aimed to evaluate the safety, pharmacokinetics 
 
 and Maximum Tolerated Dose (MTD) Recommended Phase 2 Dose 
(RP2D) of PF-05082566 given as a single agent in patients with solid tumors or relapsed or 
refractory B-cell lymphoma (Portion A), and given in combination with rituximab in patients 
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with relapsed or refractory CD20 positive non-Hodgkins Lymphoma (NHL) (Portion B).  As 
of the data cut-off date (16 July 2013) safety data were recorded in the study database for 
23 patients treated with PF-0502566 in 6 sequential dose levels between 0.006 and 
0.24 mg/kg in Portion A and for 13 patients treated in Portion B with PF-05082566 between 
0.03 and 0.3 mg/kg in combination with rituximab.  As with any ongoing study, the available 
data are preliminary in nature and are subject to change.
Adverse events (AEs) in Study B1641001 were assessed according to the National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events version 4.03 (CTCAE v 
4.03).  As of the data cutoff date, AEs possibly related to single agent PF-05082566 were all 
Grade 1 (see Table 6).
Table 6.
PF-05082566 Treatment Emergent, Treatment Related Adverse Events 
reported in at least 1 Patient (Study B1641001 Portion A)
NO.
(%)
EVALUABLE 
23
WITH ADVERSE EVENTS 
5
(21.7)
GASTROINTESTINAL DISORDERS 
4
(17.4)
Abdominal Pain
1
(4.3)
Diarrhoea 
1
(4.3)
Dyspepsia
1
(4.3)
Vomiting 
1
(4.3)
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
1
(4.3)
Pain
1
(4.3)
INVESTIGATIONS
1
(4.3)
Weight decreased
1
(4.3)
PSYCHIATRIC DISORDERS 
1
(4.3)
Insomnia
1
(4.3)
SKIN AND SUBCUTANEOUS TISSUE DISORDERS
1
(4.3)
Rash
1
(4.3)
Treatment-related adverse events are categorized by system organ class.  MedDRA (v16.0) coding dictionary 
applied.
Currently, the dose escalation is at the 2.4 mg/kg level, with no DLTs observed to date, either 
for PF-05082566 as a single agent or in combination with rituximab.
The preliminary PK results from the ongoing Phase 1 study suggest that exposure of 
PF-05082566 increases dose proportionally with a terminal half-life of approximately 
10 days. 
Complete pre-clinical and clinical information for PF-05082566, including PK data in 
patients, may be found in the single reference safety document (SRSD), which for this study 
is the PF-05082566 IB.
1.2.9. MK-3475
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades.23 Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies.24-28 In particular, the presence of CD8+ T-cells and the ratio of CD8+ 


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effector T-cells/FoxP3+ regulatory T-cells seems to correlate with improved prognosis and 
long-term survival in many solid tumors. 
The Programmed Death -1 (PD-1) receptor-ligand interaction is a major pathway hijacked by 
tumors to suppress immune control.  The normal function of PD-1, expressed on the cell 
surface of activated T-cells under healthy conditions, is to down-modulate unwanted or 
excessive immune responses, including autoimmune reactions.  PD-1 (encoded by the gene 
Pdcd1) is an Ig superfamily member related to CD28 and CTLA-4 which has been shown to 
negatively regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or 
PD-L2).29,30  The structure of murine PD-1 has been resolved.31  PD-1 and family members 
are type I transmembrane glycoproteins containing an Ig Variable-type (V-type) domain 
responsible for ligand binding and a cytoplasmic tail which is responsible for the binding of 
signaling molecules.  The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling 
motifs, an immunoreceptor tyrosine-based inhibition motif (ITIM) and an immunoreceptor 
tyrosine-based switch motif (ITSM).  Following T-cell stimulation, PD-1 recruits the tyrosine 
phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70 which are 
involved in the CD3 T-cell signaling cascade.32-35  The mechanism by which PD-1 down 
modulates T-cell responses is similar to, but distinct from that of CTLA-4 as both molecules 
regulate an overlapping set of signaling proteins.36,37 PD-1 was shown to be expressed on 
activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T regs and 
Natural Killer cells [38; 39].  Expression has also been shown during thymic development on 
CD4-CD8- (double negative) T-cells as well as subsets of macrophages and dendritic cells.40
The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in a 
variety of cell types, including non-hematopoietic tissues as well as in various 
tumors.36,41,42,43 Both ligands are type I transmembrane receptors containing both IgV- and 
IgC-like domains in the extracellular region and contain short cytoplasmic regions with no 
known signaling motifs.  Binding of either PD-1 ligand to PD-1 inhibits T-cell activation 
triggered through the T-cell receptor.  PD-L1 is expressed at low levels on various 
non-hematopoietic tissues, most notably on vascular endothelium, whereas PD-L2 protein is 
only detectably expressed on antigen-presenting cells found in lymphoid tissue or chronic 
inflammatory environments.  PD-L2 is thought to control immune T-cell activation in 
lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell function in peripheral 
tissues.36 Although healthy organs express little (if any) PD-L1, a variety of cancers were 
demonstrated to express abundant levels of this T-cell inhibitor.  PD-1 has been suggested to 
regulate tumor-specific T-cell expansion in patients with melanoma.44  This suggests that the 
PD-1/PD-L1 pathway plays a critical role in tumor immune evasion and should be 
considered as an attractive target for therapeutic intervention. 
MK-3475 is a potent and highly selective humanized monoclonal antibody (mAb) of the 
IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, 
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1.2.9.1. Clinical Safety and Efficacy of MK-3475
1.2.9.1.1. MK-3475 Safety Data
The safety of MK-3475 is being assessed in six ongoing clinical trials, PN001, PN002, 
PN006, PN010, PN011 and PN012.  Safety data of single-agent MK-3475 are only available 
from Study PN001 at this time.  Protocol 001 (PN001) is an open-label Phase I study, which 
includes a dose-escalation component in patients with solid tumors (Part A) and with 
subsequent expansion cohorts in patients with melanoma (Parts B and D) and NSCLC 
(Parts C and F).  PN001 Part A evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, 
administered Q2W.  All three dose levels were well tolerated and no dose-limiting toxicities 
were observed.  Based on PK data showing a half-life of 21 days, the protocol was amended 
to include a dosing frequency of Q3W in the expansion cohorts (Parts B through F).
Preliminary data (as of 26 July 2013) are available from 479 patients enrolled in PN001: 
Part A (n=30) 1 mg/kg, 3 mg/kg, and 10 mg/kg MK-3475 dosed q2wks to q3wks, Part B 
(n=308) 2 mg/kg or 10 mg/kg MK-3475 dosed q2wks to q3wks, Part C (n=38) 10 mg/kg 
MK-3475 dosed q3wks, and Part D (n=103) 2 or 10 mg/kg MK-3475 dosed q3wks.  Of the 
479 patients who have received MK-3475 in Protocol 001, 466 (97.3%) experienced 
treatment emergent AEs of which 368 (76.8%) were considered drug-related. Significant 
adverse events (SAEs) were reported in 30.1% of patients, but SAEs that were attributed as 
potentially (possibly, probably, or definitely) drug-related by Investigators were reported in 
6.7% of patients overall.  Potentially immune-related AEs have been observed, including 
pneumonitis (Grade 1-2) in both melanoma and NSCLC cohorts.  The most commonly 
reported treatment emergent AEs experienced are fatigue, nausea, cough, pruritus, diarrhea 
and rash.  Most patients continued treatment in spite of adverse events, and only 4.2% of 
patients discontinued study treatment due to an AE that was considered related to study 
treatment by Investigators.
Of the 162 patients who received 2 mg/kg MK-3475 dosed q3wks (Parts B1, B2 and D) in 
PN001, 160 (98.8%) experienced treatment emergent AEs of which 128 (79.0%) were 
considered to be drug-related.  SAEs were reported in 27.2% of patients, but SAEs that were 
attributed as potentially (possibly, probably, or definitely) drug-related by Investigators were 
reported in 9.3% of this subset of patients.  The most commonly reported treatment emergent 
AEs experienced in this subset of patients are fatigue, nausea, cough, pruritus, rash and 
diarrhea.
Thus, the overall AE summary suggests that MK-3475 is generally tolerable and AEs are 
generally manageable in patients.  Refer to the MK-3475 IB for specific details.
1.2.9.2. MK-3475 Clinical Efficacy
Study PN001 included a total of 135 patients with advanced melanoma who had initiated 
treatment by 06 September 2012.45 Efficacy data that were available as of 01 February
2013 were included in the analyses of efficacy.  The overall response rate (ORR) across all 
dose cohorts, evaluated by central radiologic review according to the RECIST v1.1, was 38% 
(95% CI, 25 to 44), with the highest confirmed response rate observed in the cohort that 
received 10 mg/kg q2wks (52%; 95% CI, 38 to 66).  The response rate did not differ 


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significantly between patients who had received prior ipilimumab treatment and those who 
had not (confirmed response rate, 38% [95% CI, 23 to 55] and 37% [95% CI, 26 to 49], 
respectively).  Responses were durable in the majority of patients (median follow-up, 
11 months among patients who had a response); 81% of the patients who had a response 
(42 of 52) were still receiving treatment at the time of analysis in March 2013.  The overall 
median progression-free survival (PFS) among the 135 patients was longer than 7 months.
Study PN001 Part C enrolled 38 patients with NSCLC who experienced progression of 
cancer after initiation of their second line of systemic therapy to receive monotherapy 
MK-3475. The preliminary ORR was 24% by investigator assessment. Clinical responses 
have been observed in patients with adenocarcinoma, squamous cell carcinoma, and large
cell carcinoma. The median duration of treatment amongst responders is a minimum of
34 weeks.
Complete information for MK-3475 may be found in the Single Reference Safety Document 
(SRSD), which for this study is the Investigator Brochure (MK-3475 IB).
1.3. Starting Dose Selection Strategy
In the ongoing first in human Phase 1 Study B1641001, PF-05082566 has been well tolerated 
up to the current dose of 2.4 mg/kg, with no dose-limiting toxicities, and dose escalation 
continues. However, in order to minimize the theoretical risk of synergistic toxicity due to 
the combination, the PF-05082566 starting dose for this study will be set to 0.45 mg/kg. 
The starting MK-3475 dose of 2 mg/kg (dosed q3wk) was well tolerated based on published 
single agent safety and tolerability data from the Phase 1 first-in-human study (PN001).  In 
this study, MK-3475 showed evidence of target engagement and objective evidence of tumor 
size reduction at all dose levels (1 mg/kg, 3 mg/kg and 10 mg/kg q2wks).  PK data analysis 
of MK-3475 administered q2wks and q3wks showed slow systemic clearance, limited 
volume of distribution, and a long half-life of about 3 weeks (21 days), typical for therapeutic 
antibodies (refer to IB).  
 
  This early PK 
 
data provides scientific rationale for testing q2wks or q3wks dosing schedules.
An interim analysis from the on-going MK-3475 protocol PN001 reported data from 
expansion cohorts with advanced melanoma that are naïve to or previously treated with 
ipilimumab who were treated on three different dosing regimens of MK-3475: 2 mg/kg every 
3 weeks, 10 mg/kg every 3 weeks, and 10 mg/kg every 2 weeks.  One of the key clinical 
findings from this analysis suggests that there are not major differences in the AE profile or 
overall objective response rate (ORR) of MK-3475 when given on an every 3 week schedule 
at doses of 2 mg/kg or 10 mg/kg.
In the ongoing first-in-human Phase 1 Study B1641001, PF-05082566 is administered on a 
q4wk schedule. However, since in the present study MK-3475 will be administered on a 
q3wk dosing schedule, PF-05082566 will also be administered on a q3wk schedule.
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Study Rationale
PF-05082566 is a fully humanized IgG2 mAb and promising new molecular entity that binds 
to human 4-1BB with high affinity and specificity.  MK-3475 is a potent and highly selective 
humanized mAb of the IgG4/kappa isotype designed to directly block the interaction between 
PD-1 (programmed death-1) and its ligands, PD-L1 and PD-L2.  In vitro and in vivo data 
demonstrated immunomodulatory activity and anti-tumor activity of PF-05082566 when 
dosed as a single agent, in combination with ADCC inducing antibodies, and significantly 
enhanced anti-tumor activity in combination with anti-PD1 antibodies.  The safety and 
tolerability of PF-05082566 is currently being evaluated in a Phase 1 study as a single agent 
and in combination with Rituximab (Study B1641001).  PF-05082566 has been well 
tolerated (thus far up to 1.2 mg/kg, q4wk) with no adverse events above Grade 1 attributed to 
PF-05082566.  The preliminary PK results from the ongoing first-in-human Phase 1 study 
suggest that exposure of PF-05082566 increases dose proportionally with a terminal half-life 
of approximately 10 days. 
While preclinical data demonstrated significant immunomodulatory activity and anti-tumor 
activity of PF-05082566 when dosed as a single agent, it is hypothesized that in some tumors 
upregulation of programmed death-1 (PD-1) in tumor-infiltrating lymphocytes, and its ligand 
PD-L1 on tumor cells, may down-modulate the activity of anti-tumor lymphocytes stimulated 
by an agonist anti-4-1BB antibody.  In multiple tumor models, an agonist anti-4-1BB 
antibody in combination with an anti-PD-1 antagonist antibody showed significantly 
improved anti-tumor activity compared with either single agent.  In addition, safety data in 
mice indicated that the addition of an anti-PD-1 antibody did not add to the toxicity of an 
anti-4-1BB agonist antibody.  Based upon the above considerations, this Phase 1b study will 
assess the safety and tolerability, establish the maximum tolerated dose (MTD) and the 
Recommended Phase 2 Dose (RP2D) of PF-05082566 in combination with MK-3475 in 
patients with advanced solid tumors. 
The Sponsor considers that the safety data in the ongoing Phase 1 first-in-human study 
B1641001 and the published safety data for MK-3475 support the development of the 
combination of PF-05082566 with MK-3475 for the treatment of advanced cancers and 
support the initiation of this Phase 1b clinical study B1641003.  The available data support 
the benefit-risk for the conduct of the trial, and the study includes monitoring and measures 
that potentially mitigate risks to the patients enrolled.
The name, title, address and telephone number(s) of the sponsor's medical expert for the trial 
is located in the coordinator’s manual.


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2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Objectives
Primary Objective

To estimate the Maximum Tolerated Dose (MTD) and select the Recommended 
Phase 2 Dose (RP2D) for the combination of PF-05082566 with MK-3475 in patients 
with advanced solid cancer.
Secondary Objectives

To evaluate the overall safety profile; 

To characterize the single dose and multiple dose pharmacokinetics of PF-05082566
and MK-3475 given in combination following IV administration;

To evaluate the immunogenicity of PF-05082566 and MK-3475 when given in 
combination;

To assess the anti-tumor effect of PF-05082466 in combination with MK-3475 (by 
RECIST criteria);

Expansion Cohorts Only: To characterize the mechanism of sensitivity and/or 
resistance to PF-05082566 in combination with MK-3475 in tumor tissue.

 

 
 
2.2. Endpoints
Primary Endpoint 

First 2 cycles Dose-Limiting Toxicity (DLT) of PF-05082566 in combination with 
MK-3475.
Secondary Endpoints

Adverse events as characterized by type, frequency, severity (as graded by NCI 
CTCAE v.4.03), timing, seriousness and relationship to study therapy PF-05082566
in combination with MK-3475;
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
Laboratory abnormalities as characterized by type, frequency, severity (as graded by 
NCI CTCAE v.4.03); 

Vital signs, weight, ECOG Performance Status;

PK parameters of PF-05082566 and MK-3475, including but not limited to Cmax, 
Ctrough, Tmax, AUC0-last,, AUC0-∞, CL and Vd (as data permits);

Anti-Drug Antibody levels for PF-05082566 and MK-3475;

Objective tumor response by Response Evaluation Criteria in Solid Tumors 
(RECIST) v1.1;

Time-to-response (expansion cohorts only);

Duration of response (expansion cohorts only);  

Progression–free survival (expansion cohorts only);

Expansion Cohorts Only: Paired de novo tumor biopsy collection at sequential time 
points for analysis of exploratory mechanistic biomarkers such as IHC assessment of 
tumor-infiltrating lymphocytes, quantitation of T cell receptor sequences, and gene 
expression.


 
.
3. STUDY DESIGN
3.1. Study Overview
This is a Phase 1b, open-label, multi-center, multiple-dose, safety, pharmacokinetic 
 
 study designed to estimate the maximum tolerated dose (MTD), and 
determine the Recommended Phase 2 Dose (RP2D) of PF-05082566 in combination with 
MK-3475 in patients with advanced solid tumors. 
PF-05082566 will be administered as a 1-hour intravenous infusion q3wks.  On Day 1 of 
each dosing cycle, in which the drugs are co-administered, the MK-3475 infusion will start 
30 minutes after completion of PF-05082566 infusion and after the post- PF-05082566 and 
pre-MK-3475 PK blood samples are drawn. 
A maximum of 45 patients will be treated during the dose escalation phase of this study.
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Treatment with study drugs will continue until completion of 32 cycles (approximately 
24 months) of treatment, confirmed objective disease progression, patient refusal, patient lost 
to follow up, unacceptable toxicity occurs, or the study is terminated by the Sponsor, 
whichever occurs first. 
Safety will be monitored at regular intervals throughout the study by means of laboratory 
tests and clinical visits. 
Antitumor activity will be assessed by radiological tumor assessments conducted at baseline, 
at 9 weeks, and every 6 weeks thereafter, whenever disease progression is suspected 
(eg, symptomatic deterioration), at the time of End of Treatment (if not done in the previous 
6 weeks), and during follow-up visits, using RECIST version 1.1. 
Discontinuation from treatment may be considered at the investigator’s discretion for patients 
who have attained a confirmed complete response (CR), that have been treated for at least 
24 weeks on study, and have at least two treatments with MK-3475 and PF-05082566 
beyond the date the initial CR was declared.  Patients who then experience radiologic disease 
progression will be eligible for treatment with both study drugs at the discretion of the 
investigator and by the approval of the Sponsor, if no cancer treatment was administered 
since the last dose of study drugs, the patient meets the safety parameters listed in the 
Inclusion/Exclusion criteria, and the trial is open.  Patients will resume therapy at the same 
dose and schedule at the time of initial discontinuation.  Patients who complete a maximum 
number of 32 cycles (approximately 24 months) on study treatment and demonstrate clinical 
benefit with manageable toxicity and are willing to continue receiving the study treatment 
will be given the opportunity to continue treatment upon agreement between investigator and 
sponsor.
 
 
 
 
 
 
 
 
 
  In addition, patients with RECIST defined disease progression who are 
continuing to derive clinical benefit from the study treatment will be eligible to continue 
treatment with PF-05082566 plus MK-3475 provided that the treating physician has 
determined that the benefit/risk for doing so is favorable.  (Refer to Section 5.3.4 and 
Section 7.4.1 for details).  Also in this case, the maximum period on-treatment will be 
32 cycles (approximately 24 months).
After estimation of the MTD for the combination on the q3wk schedule, PF-05082566 may 
be co-administered along with MK-3475 to study safety and tolerability on an alternative 
dosing schedule for both drugs.  Other study drug doses may also be tested based on 
emerging safety and tolerability data.  The initiation of additional patient cohorts to explore 
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additional dosing schedules or study drug doses will be done at the discretion of the Sponsor, 
and can occur in parallel with enrollment of patients in expansion cohorts on the q3wk 
dosing schedule.
In addition, once the MTD of PF-05082566 administered in combination with MK-3475 has 
been estimated with confidence, one or more expansion cohorts of patients with selected 
advanced solid tumors will be enrolled to further study the safety, tolerability, PK
 and 
preliminary anti-tumor activity for PF-05082566 in combination with MK-3475 to support 
RP2D selection, as well as to study tumor-associated biomarkers.  The tumor types for 
further study could include NSCLC and potentially other tumor types based on emerging 
data from the dose escalation phase of this study.
PK/Anti-Drug Antibody (ADA) sampling will be required for all patients (See Table 3 and 
Section 7.2 for details).  No drug interaction is anticipated between PF-05082566 and MK-
3475. Since PF-05082566 and MK-3475 are eliminated via a non-specific catabolic 
degradation process, it is unlikely that concomitant medication can alter its clearance even if 
target expression is affected. To assess any potential interactions, steady state 
pharmacokinetics and the formation of anti-drug antibodies will be monitored for both the
agents and compared with historical data.
For all patients in dose-expansion cohorts, a de-novo biopsy will be required at study entry 
followed by a second biopsy at the time of first follow up scans at 9 weeks (after 3 cycles of 
treatment).  Optional de novo biopsies may be collected for patients in dose-escalation 
cohorts to support the assessment of disease progression.  
 
 
3.1.1. Starting Dose
The PF-05082566 starting dose is 0.45 mg/kg (see Section 1.3).  The starting dose of 
MK-3475 will be 2 mg/kg (see Section 1.3).  Both study drugs will be administered on a 
q3wk schedule. See Section 1.3 for more details.
3.2. Criteria for Dose Escalation
No dose escalation of MK-3475 is foreseen for the estimation of the combination MTD.  
Dose escalation and de-escalation of PF-05082566 will follow the Time-to-Event Continual 
Reassessment Method (TITE-CRM) (Cheung and Chappell, 2000)3 up to 5.0 mg/kg.  The 
first three patients (first cohort) will be treated at the starting dose.  For each subsequent 
patient, the probability of DLT is estimated for each level based on all the collected data 
from all treated patients up to that time and the prior expectations of toxicity, and the patient 
is assigned to the currently estimated target level (with escalation restrictions as indicated 
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below), defined as the dose having an estimated probability of DLT closest to but not greater 
than the target rate (25%).  The probabilities of toxicity are estimated based on a Bayesian 
statistical model 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 
enrolled patient is treated.
The MTD is defined as the highest combination dose with a DLT rate <25% from the model 
estimate (explained in Section 9.2).
Dose escalation stops if: 

Maximum sample size (n=45, see Section 9.3) is reached; or 

9 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. 
In the TITE-CRM paradigm, patients who have enrolled in the trial, but have not experienced 
DLT, will be included in the probability calculation with an initial weight equal to the 
proportion of the 6-week (2 cycles of PF-05082566 and MK-3475) DLT observation period 
that the patients have completed (however, the weight function may be modified if 
accumulating safety data in suggest a different pattern).  Patients who experience DLT or 
complete the observation period without DLT will be assigned full weight (=1).  Details on 
the TITE-CRM method are provided in Section 9.2 and the Statistical Analysis Plan.
To avoid overly rapid escalation and to retain the efficiency of dose administration when 
enrollment is fast, the following restrictions and practical considerations will be followed.

Dose skipping in escalation to untested doses is not allowed (k −> k+1).  In particular, 
at least three patients should have been treated at dose level k before escalation to 
dose level k+1;

At least three patients should have been on treatment (for a minimum of 3 weeks or 
1 cycle) and observed DLT rate <33% at dose level k before a patient is assigned to 
dose level k+1 (Note that the waiting window depends on our knowledge in the 
time-to-event pattern of toxicity and accumulating safety data, and thereby the 
confidence in the associated weights.  However, intentional delay in enrollment in the 
absence of DLT or serious AEs should be minimized and discouraged);

Dose escalation recommendation by the TITE-CRM algorithm may be overruled by 
the sponsor if the nature of the existing data causes safety concern.
Dose escalation and de-escalation will be carried out according to Table 1.  Intra-patient dose 
escalation will not be permitted.


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Cumulative safety data will continue to be evaluated at the estimated MTD using the 
Bayesian statistical model.  Should emerging data in the expansion cohort indicate the 
selected dose is more toxic than previously estimated (>25%), or in the case of an exposure 
plateau or biomarker saturation (eg, sCD137) the next lower dose or an intermediate dose 
level will be explored, and may be declared as the RP2D. 
For the first cohort there will be a minimum 7-day window between the first dose of a patient 
and the first dose of the next patient.  For the first 3 patients enrolled in additional dose 
escalation cohorts, a minimum 24-hour time window will apply between their first doses.  
There will be no required time window between first doses for patients enrolled in dose 
cohorts with at least 3 previously treated patients.
3.3. DLT Definition
Severity of AEs will be graded according to CTCAE v 4.03. For the purpose of dose 
escalation, any of the following adverse events occurring during the DLT observation period 
(first 2 Cycles, ie, 6 weeks) that are attributable to one or both study drugs will be classified 
as DLTs:

Hematologic:

Grade 4 neutropenia;

Febrile neutropenia, defined as absolute neutrophil count (ANC) <1000/mm3 with a 
single temperature of >38.3 degrees C (101 degrees F) or a sustained temperature of 
38 degrees C (100.4 degrees F) for more than one hour; 

Grade 3 neutropenic infection;

Grade 3 thrombocytopenia with bleeding;

Grade 4 thrombocytopenia.

Non-hematologic:

Grade 3 toxicities (non-laboratory);  

Grade 3 nausea, vomiting or diarrhea despite maximal medical therapy;

Grade 4 aspartate aminotransferase (AST) and alanine aminotransferase (ALT).

Other (non AST/ALT) non-hematologic Grade 3 laboratory value if:

Medical intervention is required to treat the patient, or

The abnormality leads to hospitalization. 


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
Inability to complete two infusions of MK-3475 and PF-05082566 during the DLT 
observation period.
3.4. MTD Definition
The MTD is defined as the highest combination dose with a DLT rate <25% from the 
TITE-CRM model estimate (explained in Section 9.2).
3.5. Dose Expansion Test Dose
The Expansion Test Dose will be either the estimated MTD or a lower dose if emerging data 
suggest the estimated MTD is more toxic than originally believed.
3.6. Dose Expansion Phase
The Dose Expansion Phase will test PF-05082566 in combination with MK-3475 in patients 
with selected advanced solid tumor type to be determined based on emerging safety and 
clinical activity data from this study.
All patients in the Dose Expansion Phase may be enrolled simultaneously.  The total number 
of patients enrolled into one or more Dose Expansion Phase cohorts will be determined based 
on the tumor type, and patient population emerging data from this study.  PK samples will be 
collected from all evaluable patients in the Dose Expansion Phase Cohort.
Further experience in the Dose Expansion Phase Cohort may result in the need to explore a 
lower Expansion Test Dose.  Only doses declared safe in the Dose Escalation Phase will be 
considered.
3.7. Recommended Phase 2 Dose
The RP2D is the dose of PF-05082566 and MK-3475 in combination chosen for further study 
based on Phase 1 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.  
Once the MTD is estimated, additional patients may be enrolled at this dosing level.  In the 
expansion cohort, patients’ DLT data will be entered into the Bayesian statistical model of 
the TITE-CRM procedure.  If the posterior distribution of the model incorporating the 
additional data from the expansion cohort suggests the estimated MTD is associated with a 
higher than expected DLT rate the next lower dose or an intermediate dose level will be 
expanded, and may be declared as the RP2D.
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.
Patient eligibility should be reviewed and documented by an appropriately qualified member 
of the investigator’s study team before patients are included in the study.


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4.1. Inclusion Criteria
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. Histological or cytological diagnosis of advanced/metastatic solid tumor malignancy
which has progressed on standard therapy or for which no standard therapy is 
available.
2. Measurable disease per RECIST v1.1.
3. Expansion cohort patients must have tumor accessible for sequential biopsy (core 
needle biopsy or excision preferred).
4. Age 18 years or older.
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (see 
Appendix 2).
6. Adequate bone marrow function, defined as absolute neutrophil count (ANC) 
1.5 x 109/L (1,500/L), platelet count 100 x 109/L (100,000/L), and 
hemoglobin >9.0 g/dL (>5.6 mmol/L).  Patients must be transfusion independent
(ie, no blood product transfusions for a period of at least 14 days prior to study 
registration).
7. Adequate renal function, including serum creatinine 1.5 x upper limit of normal 
(ULN) or estimated creatinine clearance 60 mL/min as calculated using the method 
standard for the institution.
8. Adequate liver function, including: Total serum bilirubin 1.5 x ULN (unless the 
patient has documented Gilbert syndrome), Aspartate and Alanine Aminotransferase 
(AST and ALT) 2.0 x ULN, Alkaline phosphatase 2.5 x ULN; (5 x ULN in case 
of bone metastasis).
9. Resolved acute effects of any prior therapy to baseline severity or Grade 1 CTCAE
except for AEs not constituting a safety risk by investigator judgment.
10. Serum/urine pregnancy test (for females of childbearing potential) negative at 
screening and at the baseline visit (before the patient may receive the investigational 
product).
11. Male and female patients of childbearing potential must agree to use two (2) highly 
effective methods of contraception throughout the study and for 120 days after the 
last dose of assigned treatment. 
Female patients who are not of childbearing potential (ie, meet at least one of the 
following criteria):


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
Have undergone a documented hysterectomy and/or bilateral oophorectomy;

Have medically confirmed ovarian failure or; 

Achieved post-menopausal status, defined as follows: cessation of regular menses 
for at least 12 consecutive months with no alternative pathological or 
physiological cause; and have a serum follicle stimulating hormone (FSH) level 
within the laboratory’s reference range for postmenopausal women. 
12. Evidence of a personally signed and dated informed consent document indicating that 
the patient has been informed of all pertinent aspects of the study.
13. 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:
1. CNS primary malignancies, active seizure disorder or spinal cord compression, or 
carcinomatous meningitis. Patients with previously treated brain metastases may 
participate provided they are stable (without evidence of progression by imaging for 
at least four weeks prior to registration and any neurologic symptoms have returned 
to baseline), have no evidence of new or progressing brain metastases, have not used 
steroids for at least 14 days prior to study entry.  This exception does not include 
carcinomatous meningitis which is excluded regardless of clinical stability.
2. Chemotherapy, growth factors or investigational agents within 28 days before 
registration.
3. Systemic steroid therapy or any other form of immunosuppressive therapy within
14 days prior to registration. 
4. Radiation therapy within 14 days of study entry.  Therapeutic or experimental 
monoclonal antibodies in last 60 days prior to registration.
5. Therapeutic or experimental monoclonal antibodies in last 60 days prior to 
registration.
6. History of any of the following toxicities associated with a prior immunotherapy: 

Grade 3 immune-mediated adverse event that was considered related to previous 
immunotherapy and required immune suppressive therapy;

Grade 2 hepatic function-related adverse event that persisted more than 1 week, 
was considered related to immunotherapy, or required treatment discontinuation 
or immunosuppressive therapy (previous immunotherapies include any 
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ligand 1 (anti-PD-L1), anti-Programmed death ligand 2 (anti-PD-L2), or 
anti-Cytotoxic T lymphocyte-associated antigen 4 (anti-CTLA-4) antibody, or any 
other antibody or drug specifically targeting T-cell costimulation or checkpoint 
pathways). 
7. Major surgery within 28 days of registration.
8. History of active ethanol abuse, hepatitis (eg, alcohol or non-alcohol steatohepatitis 
[NASH], drug related, auto-immune, virally related), or liver lesions greater than 
4 cm on the longest axis.
9. Has received a live vaccine within 30 days prior to registration.
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 (HIV testing is not 
required), including patients who have an active infection requiring systemic therapy.
11. Any of the following within the 12 months prior to registration: myocardial 
infarction, uncontrolled angina, coronary/peripheral artery bypass graft, symptomatic 
congestive heart failure, cerebrovascular accident or transient ischemic attack and 
6 months for deep vein thrombosis or pulmonary embolism.
12. Diagnosis of any other malignancy within 2 years prior to registration, except for 
adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the 
breast or of the cervix.
13. Pregnant females; breastfeeding females; male patients with partners currently 
pregnant; male and female patients of childbearing potential who are unwilling or 
unable to use two (2) highly effective methods of contraception as outlined in this 
protocol for the duration of the study and for 120 days after last dose of 
investigational product.
14. Known prior or suspected hypersensitivity to study drugs or any component in their 
formulations.
15. Patients who previously had a severe hypersensitivity reaction to treatment with 
another monoclonal antibody or who are known to be positive for anti-drug
antibodies (ADA) to MK-3475 or PF-05082566.
16. 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
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17. History of or known presence of extensive, disseminated/bilateral or Grade 3 or 4
interstitial fibrosis or interstitial lung disease, including a history of pneumonitis, 
hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease, 
obliterative bronchiolitis, or pulmonary fibrosis, but not including a history of prior 
radiation pneumonitis.  Patients with clinically significant lung disease requiring 
oxygen therapy (eg, COPD).
18. Active autoimmune disease or a documented history of autoimmune disease or 
syndrome that requires systemic steroids or immunosuppressive agents.  Patients with 
vitiligo or resolved childhood asthma/atopy would be an exception.  Patients that 
require intermittent use of bronchodilators, inhaled steroids, or local steroid injections 
and patients with hypothyroidism stable on hormone replacement will not be 
excluded from the study.
19. Participation in other studies within 4 weeks before the current study begins and/or 
during study participation.
20. 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.
4.3. Life Style Guidelines
4.3.1. Contraception
In this study, patients of childbearing potential will receive PF-05082566 and MK-3475, 
agents for which the teratogenic risk is currently unknown.  Two (2) methods of highly 
effective contraception must be used throughout the study and continued for at least 120 days
after the last dose.  The investigator or his/her designee, in consultation with the patient, will 
select the most appropriate methods of contraception for the individual patient from the 
permitted list of contraception methods (see below), and instruct the patient 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 Table 2
Schedule of Activities (SOA) and document such conversation in the patient chart.  In 
addition, the investigator will instruct the patient to call immediately if the selected birth 
control 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:
1. Established use of oral, inserted, injected or implanted hormonal methods of 
contraception is allowed provided the patient remains on the same treatment 
throughout the entire study and has been using that hormonal contraceptive for an 
adequate period of time to ensure effectiveness.


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2. Correctly placed copper containing intrauterine device (IUD).
3. Male condom or female condom used WITH a spermicide (ie, foam, gel, film, cream, 
suppository).
4. Male sterilization with absence of sperm in the post-vasectomy ejaculate.
5. Bilateral tubal ligation or bilateral salpingectomy or bilateral tubal occlusive 
procedure (provided that occlusion has been confirmed in accordance with the 
device’s label).
4.4. Sponsor Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
trial is documented in the study contact list located in the study manual (coordinator’s 
manual).
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 number, 
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 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. Allocation to Treatment
Dose level allocation will be performed by the Sponsor after patients have given their written 
informed consent and have completed the necessary baseline assessments.  The site staff will 
fax or email a complete Registration Form to the designated Sponsor study team member.  
The Sponsor will assign a patient identification number, which will be used on all Case 
Report Form (CRF) pages and other trial-related documentation or correspondence 
referencing that patient and (email) to the site.
For the purposes of this protocol, study drug refers to both PF-05082566 and MK-3475.  No 
patient shall receive study drug until the Investigator or designee has received the following 
information in writing from the Sponsor:

Confirmation of the patient’s enrollment;


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
Specification of the dose level for that patient; 

Permission to proceed with dosing the patient. 
The Sponsor or designee will notify the other sites of the inclusion of a new patient, and will 
inform study sites about the next possible enrollment date.
5.2. Drug Supplies
PF-05082566 and MK-3475 will be supplied for the study by Pfizer Global Clinical Supply, 
Worldwide Research and Development.  Drug supplies will be shipped to the study sites with 
a Drug Shipment & Proof of Receipt form.  This form should be completed, filed, and the 
shipment confirmed as directed on the bottom of the Drug Shipment & Proof of Receipt 
form.
5.2.1. Dosage Form and Packaging
5.2.1.1. PF-05082566
PF-0508256 drug product will be supplied in glass vials at a 10 mg/mL concentration and 
labeled as open supplies.  Each vial is packed in an individual carton. 
5.2.1.2. MK-3475
MK-3475 will be supplied in single-use vials containing 100 mg/4mL sterile solution for 
intravenous administration.  Each vial is sealed with a coated stopper and oversealed and 
labeled according to local regulatory requirements. 
5.2.2. Preparation and Dispensing
The site will complete required dosage Preparation Record located in the study manual.  The 
use of the Preparation Record is preferred but it does not preclude the use of an existing 
appropriate clinical site documentation system.  The existing clinical site's documentation 
system should capture all pertinent/required information on the preparation and 
administration of the dose.  This may be used in place of the Preparation Record after 
approval from the Pfizer monitor. 
See the Dosage and Administration Instructions (DAI) form for instructions on how to 
prepare the investigational product for administration.  Investigational product should be 
prepared and dispensed by an appropriately qualified and experienced member of the study 
staff (eg, physician, nurse, physician’s assistant, practitioner, pharmacist, or medical 
assistant) as allowed by local, state, and institutional guidance.
5.3. Administration
A cycle is defined as the time from Day 1 dose to the next Day 1 dose of PF-05082566.  If 
there are no treatment delays, a cycle will be 3 weeks in duration. 
All trial treatments will be administered on an outpatient basis.  After Cycle 1, study drugs 
may be administered up to 2 days before or after the scheduled treatment day of each cycle 


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for administrative reasons. Patients will be observed in the clinic for at least 2 hours after 
each infusion of study drug.
All patients should be weighed within 72 hours prior to dosing for every cycle to ensure they 
did not experience either a weight loss or gain >10% from the prior weight used to calculate 
the amount of study drug required for dose preparation.  Decision to recalculate the study 
drug dose based on the weight obtained at each cycle can be in accordance with institutional 
practice, however if the patient experienced either a weight loss or gain >10% compared to 
the weight used to calculate the initial dose, the amount of study drug required for 
preparation and administration for the current cycle must be recalculated using this most 
recent weight obtained.
The study drug dose escalation levels are shown in Table 1.  In addition, doses of 
PF-05082566 and MK-3475 available for dose modification according to guidelines in 
Section 5.3.7, are shown below in Table 7.
5.3.1. PF-05082566
PF-05082566 will be administered intravenously (IV), q3wks on Day 1 of each cycle.
PF-0508256 will be administered as a 1 hour infusion. The infusion rate should be reduced 
or interrupted in the case of symptoms of infusion reaction, and symptomatic treatment 
administered. The infusion may be continued at one-half the previous rate upon 
improvement of symptoms. If symptoms persist or worsen, the infusion should be 
discontinued. 
5.3.2. MK-3475
MK-3475 will be administered IV, q3wks on Day 1 of each cycle, 30 minutes after 
completion of the PF-05082566 infusion and after the post-PF-05082566 and/or
pre-MK-3475 pharmacokinetic blood samples are drawn. 
MK-3475 will be administered as a 30 minute IV infusion.  Sites should make every effort to 
target infusion timing to be as close to 30 minutes as possible.  The exact duration of infusion 
should be recorded in both sources document and CRFs.  The infusion rate should be reduced 
or interrupted in the case of symptoms of infusion reaction, and symptomatic treatment 
administered.  The infusion may be continued at one-half the previous rate upon 
improvement of symptoms. If symptoms persist or worsen, the infusion should be 
discontinued. 
5.3.3. Treatment Duration
The study begins when the first patient signs the informed consent. 
The treatment duration with both study drugs is 32 cycles (approximately 24 months)
calculated from the date of the first combined doses of PF-05082566 and MK-3475.  Patients
may continue on treatment with both agents until disease progression (RECIST v. 1.1), 


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patient refusal, unacceptable toxicity occurs, or the study is prematurely terminated by the 
Sponsor; whichever comes first (see Section 6.3 for Patient Withdrawal).
Discontinuation from treatment may be considered at the investigator’s discretion for patients 
who have attained a confirmed CR, that have been treated for at least 24 weeks on study, and 
have at least two treatments with MK-3475 and PF-05082566 beyond the date the initial CR 
was declared. Patients who then experience radiologic disease progression will be eligible 
for re-treatment with both study drugs at the discretion of the investigator and by the 
approval of the Sponsor, if no cancer treatment was administered since the last dose of study 
drugs, the patient meets the safety parameters listed in the Inclusion/Exclusion criteria, and 
the trial is still open.  Patients will resume therapy at the same dose and schedule at the time 
of initial discontinuation. 
Patients who complete a maximum number of 32 cycles (approximately 24 months) on study 
treatment and demonstrate clinical benefit with manageable toxicity and are willing to 
continue receiving the study treatment will be given the opportunity to continue treatment 
upon agreement between investigator and sponsor.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
.
CCI
CCI


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
 
 
 
 
 
 
 
 
 
5.3.5. Recommended Dose Modifications
Every effort should be made to administer PF-05082566 and MK-3475 at the planned dose 
and on schedule.
In the event of significant toxicity dosing may be delayed and/or reduced as described below.  
In the event of multiple toxicities, dose modification should be based on the worst toxicity 
observed.  Patients are to be instructed to notify Investigators at the first occurrence of any 
adverse symptom.
Patients who experience an AE meeting the definition of a DLT may be removed from 
treatment, based on the dose modification guidelines listed in Section 5.3.7.1 and in 
consultation with the Sponsor.
Dose modifications may occur in two ways:

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.
Investigators are encouraged to employ best supportive care according to local institutional 
clinical practices and according to the guidance for selected adverse events provided below.
Dose modifications will be reported in the CRF.
5.3.6. Dose Delays
Re-treatment following treatment interruption for treatment related toxicity or at the start of 
any new cycle may not occur until all of the following parameters have been met:

ANC 1,000/L;

Platelet count 75,000/L;
CCI


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
Non-hematologic toxicities have returned to baseline or Grade 1 severity (or, at the 
investigator discretion, Grade 2 if not considered a safety risk for the patient).
If a treatment delay results from worsening of hematologic or biochemical parameters, the 
frequency of relevant blood tests should be increased as clinically indicated.
Withhold scheduled dose for liver function test (LFT) related AEs (including asymptomatic) 
Grade 3 until return to baseline or Grade 1 severity.  In cases of potential liver injury, see 
Section 8.6.2.  In such cases, consultation with a hepatologist should be considered in the 
decision to initiate treatment with anti-inflammatory medications.
After all toxicities have recovered within the limits described above, treatment with 
PF-05082566 and MK-3475 can be resumed. Both study drugs should be delayed 
simultaneously.  If non-hematogic toxicity does not resolve to Grade 1 (or Grade 2 if not 
considered a safety risk for the patient) within 9 weeks of last infusion, consider permanent 
discontinuation after consultation with the Sponsor.  With investigator and Sponsor 
agreement, patients with a laboratory adverse event still at Grade 2 after 9 weeks may 
continue treatment in the trial only if asymptomatic and controlled.  In addition, consider 
discontinuation for any severe or life-threatening event. 
5.3.7. Dose Reductions
After the first two cycles (the DLT evaluation period), dose reductions in 
PF-05082566 and/or MK-3475 may be required based on the worst toxicity experienced in 
the previous cycle (see Table 8).
No specific dose adjustments are recommended for Grade 1/2 treatment-related toxicity.  
However, investigators should always manage their patients according to their medical 
judgment based on the particular clinical circumstances.
Patients experiencing recurrent and intolerable Grade 2 non-hematologic toxicity may 
resume dosing, with specific dose modifications detailed in Section 5.3.7.1, once recovery to 
Grade 1 or baseline is achieved.  For guidance on dosing following immune related 
toxicities, see Section 5.3.7.2.
Patients requiring dose reductions in PF-05082566 may be decreased one dose level (see 
Table 7).  Patients treated at 2 mg/kg MK-3475 may be dose reduced to 1mg/kg due to AEs 
possibly attributed to MK-3475 alone.  Once a patient has a dose reduction in PF-05082566
or MK-3475 for a drug-related toxicity, the dose will not be re-escalated.  Patients requiring 
more than one dose reduction will be withdrawn from treatment unless otherwise agreed 
between the investigator and the Sponsor. 
5.3.7.1. Study Drug Dose Modification Guidelines
Table 7 below shows the PF-05082566 and MK-3475 doses available for this study.  
Suggested dose modification guidelines are presented in Table 8 below.  Both study drugs 
should be held for the listed toxicities with dose modifications as suggested. For information 


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on the management of immune-related adverse events (see Section 5.3.7.2 below).  Patients 
requiring dose reductions in PF-05082566 due to dose-limiting toxicities may have study 
drug doses decreased one dose level (see Table 7).  MK-3475 may be dose-reduced to 
1 mg/kg due to AEs which may be recurrent or intolerable (beyond the DLT evaluation 
period) and possibly related to MK-3475, rather than PF-05082566, based on emerging 
safety and tolerability data.
Table 7.
Available Dose Levels
PF-05082566*
MK-3475
5 0. mg/kg 
2 mg/kg 
3.6 mg/kg  
1 mg/kg 
1.8 mg/kg  
0.9 mg/kg  
0.45 mg/kg  
0.20 mg/kg


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Table 8.
Dose Modification Guidelines for Treatment Related Adverse Events
Toxicity
Grade
Hold 
Treatment
(Both Drugs)
Criteria for Treatment 
Restart
(Both Drugs)
Dose Modification
(Both Drugs*)
Discontinue Patient (after 
consultation with Sponsor)
(Both Drugs)
Hematologic Toxicity 
meeting any of the DLT 
criteria in Section 3.3
3 
Yes
Resolved to Grade 1 or better Decrease dose by one 
dose level (based on 
Table 1).
If toxicity does not resolve within 
9 weeks of last infusion, consider 
permanent discontinuation after 
consultation with the sponsor.  
4 
Yes
Resolved to Grade 1 or better Decrease dose by one
dose level (based on 
Table 1). 
If toxicity does not resolve within 
9 weeks of last infusion, consider 
permanent discontinuation after 
consultation with the sponsor. 
Non-Hematologic toxicity 
(other than immune-related 
toxicities described in 
Section 5.3.7.2, 5.3.7.3, 
5.3.7.4)
1 and 2 
(if not recurrent/
intolerable)
No
N/A
Continue at same dose 
level.
N/A
2 
(recurrent/
intolerable)
Consider 
withholding 
Resolved to Grade 1 or better Continue at same dose 
level.
(reference Section 5.3.7.3
for recommendations 
regarding pneumonitis 
and Section 5.3.7.1 for 
guidance on reduction of 
the MK-3475 dose. 
If toxicity does not resolve to Grade 
1 or better within 9 weeks of last 
infusion, consider permanent 
discontinuation after consultation 
with the sponsor.  


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Toxicity
Grade
Hold 
Treatment
(Both Drugs)
Criteria for Treatment 
Restart
(Both Drugs)
Dose Modification
(Both Drugs*)
Discontinue Patient (after 
consultation with Sponsor)
(Both Drugs)
3 (only of 
maximally 
treated)
Yes
Resolved to Grade 1 or 
baseline or, at the investigator 
discretion, to Grade 2 if not 
considered a safety risk for the 
patient.
For laboratory AEs only: 
resolved to Grade 2 and 
asymptomatic.
For LFTs: resolved to Grade 1 
or baseline.
Decrease dose by one 
dose level (based on 
Table 1).
If toxicity does not resolve to Grade 
1 or baseline (or, at the investigator 
discretion, to Grade 2 if not 
considered a safety risk for the 
patient) within 9 weeks of last 
infusion, consider permanent 
discontinuation after consultation 
with the sponsor (except as noted in 
Section 5.3.7.1 for laboratory AEs). 
Permanent discontinuation 
should be considered for any severe 
or life-threatening event.
4
Yes
Hold treatment until 
toxicity resolves to Grade 1 
or baseline.
For laboratory AEs only: 
resolved to Grade 2 and 
asymptomatic.
For LFTs: resolved to Grade 1 
or baseline.
Decrease dose by one 
dose level (based on 
Table 1).
If toxicity does not resolve within 9
weeks of last infusion, consider 
permanent discontinuation after 
consultation with the sponsor. 
Permanent discontinuation 
should be considered for any severe 
or life-threatening event.
*PF-05082566 dose will be modified based on dose levels listed in Table 1.  For AEs which are possibly related only to MK-3475, the dose may be reduced as 
described in Section 5.3.7.1.
See Table 9 for dose modification guidelines and suggested supportive care for immune-related Adverse Events (irAEs)
See Table 10 for dose modification guidelines and suggested supportive care in patients experiencing pneumonitis
See Table 11 for dose modification guidelines and suggested supportive care in patients enterocolitis.
See Table 12 for dose modification guidelines and suggested supportive care in patients experiencing infusion reactions.
N/A: not applicable.


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5.3.7.2. Supportive Care Guidelines for Immune-Related Events of Clinical Interest 
(irECI) and Immune-Related Adverse Events (irAEs)
Events of clinical interest of a potential immunologic etiology (irECIs) may be defined as an 
adverse event of unknown etiology, associated with drug exposure and is consistent with an 
immune phenomenon.  irAEs may be predicted based on the nature of the MK-3475 and/or 
PF-05082566 mAb, their mechanism of action, and reported experience with 
immunotherapies that have similar mechanisms of action.  Specific irAEs for MK-3475 and 
associated AE reporting requirements are listed in Section 7.1.2.1.  No irAEs have been 
observed with PF-05082566 to date.  However, it is suggested that special attention should be 
paid to AEs that may be suggestive of potential irAEs related to both study drugs.  An irAE 
can occur shortly after the first dose of either study drug or several months after the last dose 
of treatment. 
If an irAE is suspected, efforts should be made to rule out neoplastic, infectious, metabolic, 
toxin or other etiologic causes prior to labeling an adverse event as an irAE.  Information on 
how to identify and evaluate irAEs has been developed and is included in the Event of 
Clinical Interest and Immune-Related Adverse Event Guidance Document located in the 
Administrative Binder.  Patients who develop a Grade 2 or higher irAE should be discussed 
immediately with the Sponsor. 
Recommendations to managing irAEs not detailed elsewhere in the protocol are detailed in
Table 9. If a decision is made to re-start treatment following irAEs, the PF-05082566 dose 
may be decreased one dose level (see Table 7).  Patients treated at 2 mg/kg MK-3475 may be 
dose reduced to 1 mg/kg MK-3475 due to irAEs possibly attributed to MK-3475 alone.  Once 
a patient has a dose reduction in PF-05082566 or MK-3475 for a drug-related toxicity, the 
dose will not be re-escalated.  Patients requiring more than one dose reduction will be 
withdrawn from treatment unless otherwise agreed between the Investigator and the Sponsor. 
Table 9.
General Approach to Handling irAEs
irAE 
Management of Both Study 
Drugs
Supportive Care 
Grade 1
No action 
Provide symptomatic treatment 
Grade 2
May withhold 
Consider systemic corticosteroids in addition to 
appropriate symptomatic treatment 
Grade 3
Withhold 
Discontinue if unable to reduce 
corticosteroid dose to <10 mg per 
day prednisone equivalent within 
9 weeks of toxicity 
Systemic corticosteroids are indicated in addition to 
appropriate symptomatic treatment.  May utilize 1 to 
2 mg/kg prednisone or equivalent per day. 
Steroid taper should be considered once symptoms 
improve to Grade 1 or less and tapered over at least 
4 weeks. 
Grade 4
Discontinue 


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5.3.7.3. Supportive Care Guidelines for Pneumonitis
Patients with symptomatic pneumonitis should immediately stop receiving MK-3475 and 
PF-05082566 and have a clinical evaluation.  The evaluation may include bronchoscopy and 
pulmonary function tests to rule out other causes such as infection.  If the patient is 
diagnosed with study drug-associated pneumonitis, the suggested treatment plan is described 
in Table 10.
Table 10.
Recommended Approach to Handling Pneumonitis
Study Drug Associated 
Pneumonitis
Management of Both Study 
Drugs
Supportive Care
Grade 1 (asymptomatic) 
No action 
Intervention not indicated 
Grade 2
Withhold both study drugs.
May return to treatment if 
improves to Grade 1 or resolves 
within 9 weeks 
Systemic corticosteroids are 
indicated.  Taper if necessary. 
Grade 3 and Grade 4
Discontinue study drugs
Systemic corticosteroids are 
indicated. 
The use of infliximab may be 
indicated as appropriate.  Refer 
to Section 5.3.7.3 for additional 
recommendations.
For Grade 2 pneumonitis that improves to Grade 1 within 9 weeks, the following rules 
should apply: 

First episode of pneumonitis - follow above recommended approach to handling 
pneumonitis.

Second episode of pneumonitis – permanently discontinue MK-3475 and 
PF-05082566 if upon rechallenge patient develops pneumonitis Grade 2. 
5.3.7.4. Recommended Study Drug Dose Modification and Supportive Care Guidelines 
for Enterocolits 
Patients should be carefully monitored for signs and symptoms of enterocolitis (such as 
diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus).  In symptomatic patients, infectious 
etiologies should be ruled out, and if symptoms are persistent and/or severe, endoscopic 
evaluation should be considered. 


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Table 11.
MK-3475 Recommended Dose Modifications and Supportive Care 
Guidelines for Enterocolits
Study Drug Associated 
Enterocolits
Management of Both Study 
Drugs
Supportive Care
Grade 1 
No action 
Provide symptomatic treatment 
Grade 2 
Both study drugs should be 
withheld
Anti-diarrheal treatment should 
be started. 
If symptoms are persistent for 
more than one week, systemic 
corticosteroids should be 
initiated (eg, 0.5 mg/kg/day of 
prednisone or equivalent).  
When symptoms improve to 
Grade 1, corticosteroid taper 
should be started and continued 
over at least 1 month.  
Grade 3 and 4
Both study drugs should be 
withheld
Treatment with systemic 
corticosteroids should be 
initiated at a dose of 1 to 
2 mg/kg/day of prednisone or 
equivalent.  When symptoms 
improve to Grade 1, 
corticosteroid taper should be 
started and continued over at 
least 1 month
5.4. Drug Storage 
PF-05082566 and MK-3475 will be shipped and stored at a temperature between 2C and 
8C. 
The storage conditions stated in the investigator brochures of both study drugs will be 
superseded by the label storage statement. The storage conditions and stability of the 
reconstituted product are detailed in the Dosing Administration Instructions. If a deviation to 
the storage condition occurs, contact Pfizer via the study team. 
The Investigator or an approved representative (eg, pharmacist) will ensure that all 
investigational product is stored in a strictly controlled, secure area, at appropriate 
temperatures and in accordance with applicable regulatory requirements.
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, should be regularly inspected to 
ensure it is maintained in working order. 
Any excursions from the product label storage conditions should be reported upon discovery.  
The site should actively pursue options for returning the product to labeled storage 


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conditions, as soon as possible.  Deviations from the storage requirements, including any 
actions taken, must be documented and reported to the sponsor. 
The investigational product(s) must be stored as indicated.  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.
5.5. Drug Accountability 
The Investigator or designated personnel must maintain adequate records documenting the 
receipt, use, loss or other disposition of the investigational product(s).  Pfizer may supply 
drug accountability forms that must be used or may approve use of standard institution 
forms.  In either case, the forms must identify the investigational product, including batch or 
code numbers, and account for its disposition on a patient by patient basis, including specific 
dates and quantities.  The forms must be signed by the individual who dispensed the drug and 
copies must be provided to Pfizer when directed.
At the end of the trial, Pfizer will provide instructions as to disposition of any unused 
investigational product.  If Pfizer authorizes destruction at the trial site, the Investigator must 
ensure that the materials are destroyed in compliance with applicable environmental 
regulations, institutional policy and any special instructions provided by Pfizer.  Destruction 
must be adequately documented.
5.6. Concomitant Treatments
Concomitant treatment considered necessary for the patient’s well being may be given at 
discretion of the treating physician.  Medications intended solely for supportive care 
(ie, antiemetics, analgesics, megestrol acetate for anorexia) are allowed.
Concomitant medications and treatments, including prescription, over-the-counter (OTC), 
herbal supplements, IV medications and fluids, antiemetic treatment and prophylaxis, and 
transfusions will be recorded in the CRF from 28 days prior to the start of study treatment 
and up to 28 days post the last dose of study treatment.  Concomitant medications 
administered after 28 days after the last dose of trial treatment should be recorded for SAEs 
and ECIs as defined in Section 8.14.1. 
5.6.1. Prohibited Concomitant Medications 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial, except in the case of hematopoietic growth factors and the use of 
steroids for symptomatic treatment.  If there is a clinical indication for one of these or other 
medications or vaccinations specifically prohibited during the trial, discontinuation from trial 
therapy or vaccination may be required.  The investigator should discuss any questions 
regarding this with the Sponsor Clinical Director and/or Medical Monitor.  The final decision 
on any supportive therapy or vaccination rests with the investigator and/or the patient
patient's primary physician.  However, the decision to continue the patient on trial therapy or 


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vaccination schedule requires the mutual agreement of the Investigator, the Sponsor, and the 
patient. 
Patients are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial: 

Anti-cancer systemic chemotherapy or biological therapy. 

Immunotherapy not specified in this protocol. 

Chemotherapy. 

Investigational agents other than MK-3475 or PF-05082566. 

Radiation therapy. 
Note: Radiation therapy to a symptomatic solitary lesion or to the brain may be 
allowed after consultation with Sponsor. 

Live vaccines.

Glucocorticoids for any purpose other than to modulate symptoms from an event of 
clinical interest of suspected immunologic etiology, except as agreed upon by the 
Sponsor. 
Consider withholding or discontinuing concomitant therapy with monoclonal antibodies of 
the same subclass as the study drugs (ie, IgG2 and IgG4), in patients where anti-drug 
antibodies are detected while on-study.
The concurrent use of vitamins or herbal supplements should be considered with caution. 
5.7. Rescue Medications and Supportive Care 
5.7.1. Supportive Care Guidelines 
Patients should receive appropriate supportive care measures as deemed necessary by the 
treating investigator including but not limited to the items outlined below: 

Diarrhea: All patients who experience diarrhea should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion.  Patients may receive prophylaxis 
of treatment-induced diarrhea.  Symptomatic care such as loperamide (Imodium) is 
recommended.

Nausea/Vomiting: Nausea and vomiting should be treated aggressively, and 
consideration should be given in subsequent cycles to the administration of 
prophylactic antiemetic therapy according to standard institutional practice.  Patients
should be strongly encouraged to maintain liberal oral fluid intake. 


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
Anti-infectives: Patients with a documented infectious complication should receive 
oral or IV antibiotics or other anti-infective agents as considered appropriate by the 
treating investigator for a given infectious condition, according to standard 
institutional practice.]

Anti-inflammatory or narcotic analgesics may be offered as needed.  Acetaminophen/ 
paracetamol to a MAXIMUM total daily dose of 2 g is permitted.  Daily intake over 
2 g is prohibited.
5.7.2. Supportive Care Guidelines For Infusion Reactions to Either Study Drug
Acute infusion reactions (which can include cytokine release syndrome, angioedema, or 
anaphylaxis) are different from allergic/hypersensitive reactions, although some of the 
manifestations are common to both AEs.  Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hours of completion of 
infusion.  Signs/symptoms may include: Allergic reaction/hypersensitivity (including drug 
fever); Arthralgia (joint pain); Bronchospasm; Cough; Dizziness; Dyspnea (shortness of 
breath); Fatigue (asthenia, lethargy, malaise); Headache; Hypertension; Hypotension; 
Myalgia (muscle pain); Nausea; Pruritis/itching; Rash/desquamation; Rigors/chills; Sweating 
(diaphoresis); Tachycardia; Tumor pain (onset or exacerbation of tumor pain due to 
treatment); Urticaria (hives, welts, wheals); and Vomiting. 
Table 12 below shows treatment guidelines for patients who experience an infusion reaction 
associated with administration of either study drug.
In the event that a site does not have established procedures for the treatment of study drug 
associated infusion reactions, the following guidelines are provided in Table 12.


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Table 12.
Infusion Reaction Treatment Guidelines for Either Study Drug
NCI CTCAE Grade
Treatment
Premedication at 
subsequent dosing
Grade 1
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated
Increase monitoring of vital signs as 
medically indicated until the patient is 
deemed medically stable in the opinion of 
the investigator.
None
Grade 2
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (eg, antihistamines, 
NSAID, narcotics, IV fluids); 
prophylactic medications indicated 
for < = 24 hours
Stop Infusion and monitor symptoms.
Additional appropriate medical therapy may 
include but is not limited to:
IV fluid
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Increase monitoring of vital signs as 
medically indicated until the patient is 
deemed medically stable in the opinion of 
the investigator.
If symptoms resolve within one hour of 
stopping drug infusion, the infusion may be 
restarted at 50% of the infusion rate 
(eg, from 100 mL/hr to 50 mL/hr).  
Otherwise dosing will be held until 
symptoms resolve and the patient should be 
premedicated for the next scheduled dose. 
Patients who develop Grade 2 toxicity 
despite adequate premedication should 
be permanently discontinued from 
further trial treatment administration.
Patients may be 
premedicated 1.5 h 
(30 minutes) prior to 
infusion of PF-05082566 
and MK-3475) with:
Diphenhydramine 50 mg PO 
(or equivalent dose of 
antihistamine).
Acetaminophen 
500-1000 mg po (or 
equivalent dose of 
antipyretic).
Grades 3 or 4
Grade 3;
Prolonged (ie, not rapidly 
responsive to symptomatic 
medication and/or brief interruption 
of infusion); recurrence of 
symptoms following initial 
improvement; hospitalization 
indicated for other clinical sequelae 
(eg, renal impairment, pulmonary 
infiltrates)
Grade 4:
Life-threatening; pressor of 
ventilatory support indicated
Stop infusion.
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Epinephrine
Increase monitoring of vital signs as 
medically indicated until the patient is 
deemed medically stable in the opinion of 
the investigator.
Hospitalization may be indicated.
Patient is permanently discontinued from 
further trial treatment administration.
No subsequent dosing
Appropriate resuscitation equipment should be available in the room and a physician readily available during the 
period of drug administration
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.03 (CTCAE) at 
http://ctep.cancer.gov


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5.8. 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. 
Primary prophylactic use of granulocyte-colony stimulating factors is not permitted during 
the first two cycles of treatment but they may be used to treat treatment emergent neutropenia 
as indicated by the current American Society of Clinical Oncology (ASCO) guidelines. 
(J Clin Oncol, 2006. 24(19): p. 3187-3205).
Erythropoietin may be used at the investigator’s discretion for the supportive treatment of 
anemia. 
5.8.1. Anti-inflammatory Therapy
Anti-inflammatory or narcotic analgesic may be offered as needed assuming there is no 
known or expected drug-drug interaction and assuming the drug is not included in the 
Concomitant Treatments section.  Systemic anti-inflammatory therapies may be used to treat 
SAEs potentially related to the study drugs (see Section 5.3.7). 
5.8.2. Corticosteroids
Chronic, systemic corticosteroid use for palliative or supportive purpose is not permitted. 
Use of corticosteroids as symptomatic treatment may be allowed on individual basis and 
upon discussion with the Sponsor. Acute emergency administration, topical applications, 
inhaled sprays, eye drops or local injections of corticosteroids are allowed and guidelines are 
provided in Section 5.3.7.
5.8.3. Concomitant Surgery
No formal studies have been conducted to determine whether there is a risk to perform 
concomitant surgery in patients under treatment with either PF-05082566 or MK-3475.  As 
safety risks in this setting are unknown it is suggested that the study drugs be withheld for 
21 days before performing major surgery.  This will provide a margin of safety of one drug 
half-life (for MK-3475, which has the longer half-life of the two study drugs) before 
resuming therapy with the combination.
5.8.4. Concomitant Radiotherapy
Palliative radiotherapy to specific sites of disease is permitted if considered medically 
necessary by the treating physician.  All attempts should be made to rule out disease 
progression in the event of increased localized pain.  It is suggested that the smallest 
radiation doses and smallest fields possible be used for palliation to minimize the 
inflammatory effects of radiotherapy.  It is suggested that PF-05082566 and
MK-3475 treatment be interrupted during palliative radiotherapy, in consultation with the 
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6. STUDY PROCEDURES
For screening, treatment period and follow-up procedures, see Schedule Of Activities.

Informed Consent must be obtained prior to undergoing any study specific procedure 
and may occur prior to the 28-day screening period.
For the treatment period discussed below, where multiple procedures are scheduled at the 
same nominal time point(s) relative to dosing, the following prioritization of events should be 
adhered to, where possible:

Pharmacokinetic blood specimens- obtain at the scheduled time.

Electrocardiograms (ECGs) – obtain as close as possible to the scheduled time, but 
prior to blood specimen collection and within 30 minutes of the nominal time.

Blood pressure/pulse rate – may be obtained prior to or after ECG collection but must 
be obtained prior to blood specimen collection and within 60 minutes of the nominal 
time.

Clinical safety laboratory tests – obtain as close as possible to the scheduled time.

Other procedures – All other procedures should be obtained as close as possible to the 
scheduled time, but may be obtained before or after blood specimen collection, unless 
sampling is determined by the study personnel to potentially impact the results.
6.1. Screening
For screening procedures see the Schedule Of Activities and ASSESSMENTS sections.
Screening is to be performed within 28 days of registration.  For medical history, include
history of other diseases (active or resolved) and concomitant illnesses.
6.2. Study Period
For treatment period procedures, see the Schedule Of Activities and ASSESSMENTS
sections.  The End of Treatment assessments are to be performed approximately 28 days after 
the last dose of study drug.  Obtain these assessments if not completed during the previous 
week on study (during the previous 6 weeks on study for tumor assessments).
Patients whose disease has not progressed at the end of treatment will enter into disease 
follow-up. During this follow-up period, patients will have disease assessments performed 
every 12 weeks 7-days. Once patients have exhibited disease progression or began a new 
anti-cancer therapy (not including radiotherapy to a non-target tumor), whichever occurs 
first, the date of progression will be recorded on the appropriate CRF page and they will be 
withdrawn from the study.  No further data will be collected from these patients.  Patients 
continuing to experience treatment-related toxicity following discontinuation of study
treatment will continue to be followed at least every 4 weeks until resolution or 
determination, in the clinical judgment of the Investigator, that no further improvement is 
expected.


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For follow-up procedures see Schedule Of Activities.
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. 
Reasons for discontinuation of study treatment may include:

Confirmed objective disease progression according to RECIST version 1.1 (see the
Study Design Section 3 for details and exceptions);

Global deterioration of health status requiring discontinuation;

Unacceptable toxicity (possibly associated with both study drugs);

Pregnancy;

Significant protocol violation;

Lost to follow-up;

Patient refused 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;

Death.
If a patient does not return for a scheduled visit, every effort should be made to contact the 
patient.  All attempts to contact the patient and information received during contact attempts 
must be documented in the patient’s medical record.  In any circumstance, every effort 
should be made to document patient outcome, if possible.  The investigator should inquire 
about the reason for withdrawal, request the patient to return for a final visit, if applicable, 
and follow-up with the patient regarding any unresolved AEs.


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If the patient refuses further visits, no further study specific evaluations should be performed, 
and no additional data should be collected.  The sponsor may retain and continue to use any 
data collected before such withdrawal of consent.
7. ASSESSMENTS
Every effort should be made to ensure that the protocol required tests and procedures are 
completed as described. However it is anticipated that from time to time there may be 
circumstances, outside of the control of the investigator, that may make it unfeasible to 
perform the test. In these cases the investigator will take all steps necessary to ensure the 
safety and well-being of the patient. When a protocol required test cannot be performed the 
investigator will document the reason for this and any corrective and preventive actions 
which he/she has taken to ensure that normal processes are adhered to as soon as possible. 
The study team will be informed of these incidents in a timely fashion.
7.1. Safety Assessment
Safety assessments will include collection of AEs, SAEs, vital signs and physical 
examination, ECG (12-lead), laboratory assessments, including pregnancy tests and 
verification of concurrent medications.
7.1.1. Pregnancy Testing
MK-3475 may have adverse effects on a fetus in utero.  Furthermore, it is not known if 
MK-3475 has transient adverse effects on the composition of sperm.  See Section 8.10 for 
exposure during pregnancy.  The current MK-3475 IB contains a full description of 
non-clinical reproductive toxicology.  In the case of PF-05082566, reproductive toxicology 
has not been characterized.
For female patients of childbearing potential, a serum or urine pregnancy test, with 
sensitivity of at least 25 mIU/mL, 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, and at the End of Treatment visit .  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 before the patient 
may receive the investigational product.  Pregnancy tests will also be routinely repeated at 
every cycle during the active treatment period, at the end of study therapy and additionally 
whenever one menstrual cycle is missed or when potential pregnancy is otherwise suspected.  
In the case of a positive hCG test, the patient will be withdrawn from study medication but 
may remain in the study. 
Additional pregnancy tests may also be undertaken if requested by IRB/Ethics Committee 
(EC) or if required by local regulations.
7.1.2. Adverse Events
Assessment of AEs will include the type, incidence, severity (graded by the National Cancer 
Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] version 4.03) 
timing, seriousness, and relatedness.


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AEs that occur during the study, including baseline signs and symptoms, will be recorded on 
the AEs CRF page.
7.1.2.1. MK-3475 Adverse Events of Special Interest
Selected non-serious and serious AEs are also known as Events of Clinical Interest (ECI) and 
must be recorded as such on the Adverse Event case report forms and reported within 
24 hours to the Sponsor either by electronic media or paper.
ECIs for this trial include:
1. An overdose of Sponsor's product, as defined in Section 8.4 - Medication Errors, that 
is not associated with clinical symptoms or abnormal laboratory results.
2. An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit 
of normal and an elevated total bilirubin lab value that is greater than or equal to 
2X the upper limit of normal and, at the same time, an alkaline phosphatase lab value 
that is less than 2X the upper limit of normal, as determined by way of 
protocol-specified laboratory testing or unscheduled laboratory testing.
Note: These criteria are based upon available regulatory guidance documents.  The
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may 
require an additional evaluation for an underlying etiology.  The trial site guidance for
assessment and follow up of these criteria can be found in the Investigator Trial File
Binder (or equivalent).
3. In the event a patient develops any of the following AEs, a detailed narrative of the 
event should be reported as an ECI to the Sponsor within 24 hours of the event:
a.
Grade 3 diarrhea;
b. Grade 2 colitis;
c.
Grade 2 pneumonitis;
d. Grade 3 hypo- or hyperthyroidism.
A separate guidance document has been provided entitled “Event of Clinical Interest and
Immune-Related Adverse Event Guidance Document.” This document can be found in the
administrative binder and provides guidance regarding identification, evaluation and 
management of ECIs and irAEs.  Additional ECIs are identified in this guidance document
and also need to be reported to the SPONSOR within 24 hours of the event.
Patients should be assessed for possible ECIs prior to each dose.  Laboratory results should 
be evaluated and patients should be asked for signs and symptoms suggestive of an immune 
related event.  Patients who develop an ECI thought to be immune-related should have 
additional testing to rule out other etiologic causes.  If laboratory results or symptoms 


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indicate a possible immune-related ECI, then additional testing should be performed to rule 
out other etiologic causes.  If no other cause is found, then it is assumed to be 
immune-related.
ECIs that occur to any patient from the date of first dose through 90 days following cessation
of treatment, or the initiation of a new anticancer therapy, whichever is earlier, whether or
not related to the Sponsor's product, must be reported within 24 hours to the Sponsor either
by electronic media or paper.  Sponsor Contact information can be found in the
administrative binder.
7.1.3. Laboratory Safety Assessment
Hematology, blood chemistry, coagulation and urinalysis will be carried out at the time 
points described in the Schedule of activities (see the Schedule Of Activities and Table 4)
and analyzed at local laboratories.  Thyroid function assessments will include T3, FT4, and 
thyroid stimulating hormone (TSH).  In the presence of clinical suspicion of hypopituitarism 
or hypoadrenalism, laboratory testing should include one or both of the following: 
adrenocorticotropic hormone (ACTH) and cortisol levels before and 30-60 minutes after 
corticotrophin stimulation.  Urinalysis will include measurement of pH, specific gravity, 
protein/albumin, glucose, blood/hemoglobin, ketones/acetone.  Urine dipstick for urine 
protein: if positive collect 24-hr and microscopic (Reflex Testing).  Urine dipstick for urine 
blood: if positive collect a microscopic (Reflex Testing).
7.1.4. Vital Signs and Physical Examination
Patients will have a physical exam that will include major body systems, weight, blood 
pressure, heart rate, assessment of ECOG status and height; height will be measured at 
baseline only. Physical exams will be performed at the time points described in the Schedule 
Of Activities.
7.1.5. ECG Assessments
Electrocardiogram (ECG): Triplicate 12-lead (with a 10-second rhythm strip) tracing in the 
supine or semi-recumbent position will be used for all ECGs.  It is preferable that the 
machine used has a capacity to calculate the standard intervals automatically.  At each time 
point, three consecutive 12 lead ECGs will be performed approximately 2 minutes apart to 
determine mean QTc.  When coinciding with blood sample draws for PK, ECG assessment 
should be performed prior to blood sample collection, such that the blood sample is collected 
at the nominal time.  If the mean QTc interval is prolonged (>500 msec), then the ECGs 
should be re-evaluated by a qualified person at the center for confirmation.  Clinically 
significant abnormal findings in baseline ECGs will be recorded as medical history.  
Clinically significant findings seen on the follow-up ECGs should be recorded as adverse 
events.  ECG assessments beyond Screening will not be required for patients in dose 
expansion cohorts (see the Schedule Of Activities).  Additional ECGs may be performed as 
clinically indicated.  While pre-dose ECG assessments will be required for all patients, 
post-dose ECG assessments will be required only for patients in dose escalation cohorts.


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Prior to concluding that an episode of prolongation of the QTcF interval is due to study drug, 
thorough consideration should be given to potential precipitating factors (eg, change in 
patient clinical condition, effect of concurrent medication, electrolyte disturbance) and 
possible evaluation by specialist.
If patient experiences a cardiac or neurologic AE (specifically syncope, dizziness, seizures, 
or stroke), an ECG (triplicate) should be obtained at the time of the event. 
When matched with PK sampling, the ECG must be carried out before each PK sample 
drawing such that the PK sample is collected at the nominal time (ie, the timing of the PK 
collections over rides the timing of the ECG collections). 
7.2. Pharmacokinetics Assessments (Dose Escalation and Dose Expansion Cohorts)
PK samples will be assayed for PF-05082566, and MK-3475 using a validated analytical 
method in compliance with Pfizer (PF-05082566) or Merck (MK-3475) standard operating 
procedures.  Details regarding the collection, processing, storage and shipping of the blood 
samples will be provided in the study manual.
 
 
All efforts will be made to obtain the pharmacokinetic samples at the scheduled nominal time 
relative to dosing.  However, samples obtained within 10% of the nominal time (eg, within 
6 minutes of a 60 minute sample) will be considered protocol compliant, and the exact time 
of the sample collection noted on the CRF.  If a scheduled blood sample collection cannot be 
completed for any reason, the missed sample time may be re-scheduled with agreement of 
clinical investigators, patient and Sponsor.
In addition to samples collected at the scheduled times, an additional blood sample should be 
collected from patients experiencing unexpected and/or serious AE’s and the date and time 
documented in the CRF.
As part of understanding the pharmacokinetics of the study drug, samples may be used for 
evaluation of the bioanalytical method.  This additional characterization will be used for 
internal exploratory purposes and will not be included in the clinical report.  Samples 
collected for this purpose will be retained in accordance to local regulations and if not used 
within this timeframe, will be destroyed.
7.2.1. PF-05082566
Blood samples will be collected for PK of PF-05082566 at the following time points:

During Cycle 1-4 on (a) Day 1 at pre-dose and end of infusion;

During Cycle 5 on (b) Day 1 at pre-dose, end of infusion, and at 2, 6 and 24 hr post 
start of infusion; (c) on Days 8 (192 hours) and 15 (360 hours) after start of infusion 
(See Section 7.2 above for guidelines on timing of blood draws);
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
During Cycle 6 on (d) Day 1 at pre-dose only;

During Cycle 7 on (e) Day 1 at pre-dose, end of infusion, 24 hrs post start of infusion 
and on Day 8. 
Beyond Cycle 7, PK samples will be collected at pre-dose, every two cycles up Cycle 12,
every 4 cycles thereafter, and at the End of Treatment visit. 
For patients in expansion cohorts: The same PK schedule will be followed for at least
10 patients in total from all expansion cohorts.  For other patients (in all expansion cohorts), 
predose samples on Day 1 will be collected for Cycles 1, 3, 5, 6 and 7.  Beyond Cycle 7, PK 
samples will be collected at pre dose (Day 1), for every 2 cycles up to Cycle 12, and every 
4 cycles thereafter.  Timing of sampling may be modified based on emerging PK data.  For 
patients discontinuing from the study, a PK sample should be collected at the End of 
Treatment assessment day.
7.2.2. MK-3475
Blood samples will be collected for PK of MK-3475 at the following time points:

During Cycle 1- 4 on (a) Day 1 at pre-dose and end of infusion;

During Cycle 5 on (b) Day 1 at pre-dose and end of infusion;

During Cycle 7 on (c) Day 1 at pre-dose, end of infusion, 24 hrs, and on Day 8
(192 hours) post start of infusion (See Section 7.2 for guidelines on timing of blood 
draws). 
Beyond Cycle 7, PK samples will be collected at pre-dose, every two cycles up to Cycle 12,
and every 4 cycles thereafter.  Additionally, PK samples will be collected at 28 days after end 
of MK-3475 treatment (during the End of Treatment visit) and during follow-up at 3 months 
and 6 months after the end of MK-3475 treatment. 
For patients in expansion cohorts: The same PK schedule will be followed for at least 
10 patients in total from all expansion cohorts.  For other patients (in all expansion cohorts), 
predose samples on Day 1 will be collected for Cycles 1, 3, 5 and 7.  Beyond Cycle 7, PK 
samples will be collected at pre dose (Day 1), for every 2 cycles up to Cycle 12, and every 
4 cycles thereafter.  Additionally, PK samples will be collected at 28 days after end of 
MK-3475 treatment (during the End of Treatment visit) and during follow-up at 3 months 
and 6 months after the end of MK-3475 treatment.
For patients ending from the study, PK samples should be collected at the End of Treatment 
assessment day.  PK sampling schedule may be modified based on emerging PK data.


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7.4. Banked Biospecimen (Blood)
7.4.1. Markers of Drug Response
Studying the variation in genetic markers and other biomarkers may help to explain some of 
the variability in response seen with some drugs among different individuals.  This is referred 
to as pharmacogenomic/biomarker research.  Comparing the deoxyribonucleic acid (DNA), 
ribonucleic (RNA), protein, and metabolite variation patterns of patients who respond well 
and those who respond poorly to treatment may help to better define the most appropriate 
group of patients in which to target a given treatment.  Collecting biospecimens for 
exploratory pharmacogenomic/biomarker analyses and retaining them in the Pfizer BioBank 
makes it possible to better understand the drug’s mechanism of action and to seek 
explanations for differences in, for example, exposure, efficacy, tolerability, or safety not 
anticipated prior to the beginning of the study.  Providing these biospecimens is a required 
study activity for study sites and patients, unless prohibited as such by local regulations or 
ethics committee decision. 
To protect patients’ confidentiality, the banked biospecimens and data generated from them 
will be coded with the patient’s study identification (ID) number.  Samples will be kept in a 
facility accessible only by badge-swipe.  Data will be stored on password-protected computer 
systems. The key between the code and the patient’s personal identifiers will be held at the 
study site; the researchers using the biospecimens and data generated from them will not 
have access to the key nor any personally identifying information.  Biospecimens will only 
be used for the purposes described here and in the informed consent document/patient 
information sheet; any other uses require additional ethical approval.  Unless a time 
limitation is required by local regulations or ethical requirements, biospecimens will be 
stored indefinitely to allow for future research on the topics described here, including 
research conducted during the lengthy drug development process and also postmarketing 
research.  Patients can withdraw their consent for the use of their biospecimens at any time 
by making a request to the investigator, in which case any remaining biospecimen will be 
destroyed; data already generated from the biospecimens will continue to be stored to protect 
the integrity of existing analyses.  It is very unlikely that results generated from the 
biospecimens will have any clinical, diagnostic, or therapeutic implications for the individual 
study participants.  Patients are notified in the informed consent document/patient 
information sheet that their results will not be given to them, unless required by local laws or 
regulations, in which case results will be returned via the investigator.  Results will not be 
provided to family members or other physicians, nor will they be recorded in the patient’s 
medical record.  There is no intention to contact patients after completion of the clinical 
study.
A 4-mL blood biospecimen, Prep D1 (K2 edetic acid (ethylenediaminetetraacetic 
acid)(EDTA)) whole blood collection optimized for DNA analysis), will be collected on Day 
1 of Cycle 1 (pre-dose) to be retained for potential pharmacogenomic/biomarker analyses 
related to drug response, unless prohibited by local regulations or ethics committee decision.  
For example, putative safety biomarkers, drug-metabolizing enzyme genes, drug-transport 
protein genes, or genes thought to be related to the mechanism of drug action may be 
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Detailed collection, processing, storage, and shipment instructions are provided in the central 
laboratory manual.
It is possible that the use of these biospecimens may result in commercially viable products.  
Patients will be advised in the informed consent document/patient information sheet that they 
will not be compensated in this event.
7.4.2. 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;

Biospecimens may be used as controls.  This includes use in case-control studies of 
diseases for which Pfizer is researching drug therapies; use in characterizing the 
natural variation amongst people in genes, RNA, proteins, and metabolites; and use in 
developing new technologies related to pharmacogenomics/biomarkers.
Patients need not provide additional biospecimens for the uses described in this section; the 
biospecimens specified in 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.
7.5. Immunogenicity Assessments (ADA)
ADA (anti-drug antibodies) blood samples will be assayed for anti-PF-05082566, and 
anti-MK-3475 antibodies using a validated analytical method in compliance with Pfizer 
(anti-PF-05082566) or Merck (anti-MK-3475) standard operating procedures.  All the 
samples that are positive for ADA may also undergo characterization for neutralizing
antibodies.
As part of understanding the pharmacokinetics of the study drug, samples may be used for 
evaluation of the bioanalytical method.  This additional characterization will be used for 
internal exploratory purposes and will not be included in the clinical report.  Samples 
collected for this purpose will be retained in accordance to local regulations and if not used 
within this timeframe, will be destroyed.
Blood samples (2 mL for PF-0508 2566 and 6 ml for MK-3475) for evaluation of 
immunogenicity of PF-05082566/MK-3475 will be collected at the following time points:
7.5.1. Immunogenicity to PF-05082566

In Cycle 1, 3,5, 7 Day 1 at pre-dose;

Cycles >7, Day 1 at predose for every two cycles up to Cycle 12, and every 4 cycles 
thereafter.


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For patients discontinuing study drug treatment, immunogenicity samples should be collected 
at the End of Treatment assessment day.  If ADAs are detected, additional samples may be 
collected approximately every 3 months (coinciding with disease assessment visits) until 
ADA levels return to baseline.  Samples will be analyzed by a laboratory to be identified by 
Pfizer.  See the Laboratory Manual for additional details. 
7.5.2. Immunogenicity to MK-3475

Cycle 1, 3, 5, and 7 Day 1 at pre-dose; 

Cycles >7, Day 1 at predose for every two cycles up to Cycle 12, and every 4 cycles 
thereafter;

Additionally, ADA samples will be collected at 28 days, and during Follow-up 
(3 months and 6 months after end of MK-3475 treatment).
For patients ending from the study, immunogenicity samples should be collected at the End 
of Treatment assessment.  MK-375 samples will be analyzed by a laboratory to be identified 
by Merck.  See the Laboratory Manual for additional details. 
7.6. Tumor Biopsies for Mechanistic Exploratory Biomarkers
Tumor growth inhibition following treatment with 4-1BB agonist monoclonal antibodies or 
with PD-1 antagonist monoclonal antibodies has been associated with increases in 
tumor-infiltrating lymphocytes.  Paired de novo tumor biopsies are mandatory for the 
patients enrolled in the expansion cohorts in order to determine whether the combination of 
PF-05082566 and MK-3475 has this effect.  A de novo biopsy will be required at study entry 
followed by a second biopsy at the time of the Cycle 3 tumor assessment.  For patients in 
dose escalation cohorts, unscheduled optional de novo tumor biopsies may be collected at the 
discretion of the Sponsor and Investigator to support the assessment of disease progression.  
Biomarkers that will be assayed may include but will not be limited to IHC assessment of 
tumor-infiltrating lymphocytes, PD-L1 IHC, quantitation of T cell receptor sequences, and 
gene expression.
Please refer to the Study Manual for details pertaining to specific days of sample collection, 
and sample preparation and shipping
 
 
7.8. Pharmacogenomic (RNA) Assessments
Blood samples for pharmacogenomic analysis will be required and will be collected on Day 1 
of Cycles 1 and 2 (pre-dose).  Samples will be used to explore gene expression signatures in 
PBMCs that would be predictive for or characteristic of responses to treatment.  Candidate 
genes that might influence patient response, may include but will not be limited to CXCR3, 
IFNG, EOMES, CD28, ICOS, CD40LG, IL2RA, CD80, CCL5, FOXP3, CDC25A, GZMA, 
IL23A, SOCS1, IL10; PD-1, PD-L1.
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7.9. 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; 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.
Antitumor activity will be assessed through radiological tumor assessments conducted at 
baseline, at Week 9, and every 6 weeks thereafter.  Timing should follow calendar days and 
should not be adjusted for treatment delays.  Follow up bone scans is required every 
16 weeks only if bone metastases are present at baseline.  Otherwise bone imaging is 
required only if new bone metastasis are suspected and at the time of confirmation of 
response for patients who have bone metastases.  In addition, radiological tumor assessments 
will also be conducted whenever disease progression is suspected (eg, symptomatic 
deterioration), and at the time of End of Treatment (if not done in the previous 6 weeks).  
Note that a post-treatment biopsied lesion or a lesion that is radiated during the study should 
no longer count as a target lesion.
Assessment of response will be made using RECIST version 1.1 (Appendix 1).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
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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 a SAE
requiring immediate notification to Pfizer or its designated representative.  For all AEs, 
sufficient information should be obtained by the investigator to determine the causality of the 
AE.  The investigator is required to assess causality.  Follow-up by the investigator may be 
required until the event or its sequelae resolve or stabilize at a level acceptable to the 
investigator, and Pfizer concurs with that assessment.
As part of ongoing safety reviews conducted by the Sponsor, any non-serious AE that is 
determined by the Sponsor to be serious will be reported by the Sponsor as an SAE. To 
assist in the determination of case seriousness further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study.
8.2. Reporting Period
For SAEs, the active reporting period to Pfizer or its designated representative begins from 
the time that the patient provides informed consent, which is obtained prior to the patient’s 
participation in the study, ie, prior to undergoing any study-related procedure and/or 
receiving investigational product, through and including 90 calendar days after the last 
administration of study drug.  SAEs occurring to a patient after the active reporting period
has ended should be reported to the Sponsor if the investigator becomes aware of them; at a 
minimum, all SAEs that the investigator believes have at least a reasonable possibility of 
being related to study drug are to be reported to the Sponsor.
AEs (serious and nonserious) should be recorded on the Case Report Form (CRF)from the 
time the subject has taken at least 1 dose of study treatment through the last subject visit.  
If a patient begins a new anticancer therapy, the AE reporting period for non-serious AEs
ends at the time the new treatment is started.  Death must be reported if it occurs during the 
SAE reporting period after the last dose of investigational product, irrespective of any 
intervening treatment.
Pregnancy or breast feeding that occur during the trial, within 120 days of discontinuing
treatment with MK-3475, or within 28 days after the cessation of study treatment if the
patient begins a new anticancer therapy, whichever is earlier, should be reported as in 
Section 8.10 (Exposure During Pregnancy).


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8.3. Definition of an Adverse Event
An AE is any untoward medical occurrence in a clinical investigation patient administered a 
product or medical device; the event need not necessarily have a causal relationship with the 
treatment or usage.  Examples of AEs include but are not limited to: 

Abnormal test findings;

Clinically significant symptoms and signs;

Changes in physical examination findings;

Hypersensitivity;

Drug abuse;

Drug dependency.
Additionally, they may include the signs or symptoms resulting from:

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 drug, 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 


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case report form (CRF) which is a specific version of the adverse event (AE) page, and on 
the SAE form when appropriate.  In the event of medication dosing error, the sponsor should 
be notified immediately.
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:

Medication errors involving patient exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating patient.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error should be captured on the medication error version of the 
adverse event (AE) page and, if applicable, any associated adverse event(s) is captured on an 
adverse event (AE) CRF page. 
For purposes of this trial, an overdose will be defined as any dose exceeding the prescribed 
dose for MK-3475 or PF-05082566 by 20% over the prescribed dose for the dosing cohort 
under study.  No specific information is available on the treatment of overdose for either of 
the study drugs.  In the event of overdose, both study drugs should be discontinued and the 
patient should be observed closely for signs of toxicity.  Appropriate supportive treatment 
should be provided if clinically indicated. 
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 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 adverse event 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.


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8.6. Serious Adverse Events
A SAE is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect;

Progression of the malignancy under study (including signs and symptoms of 
progression) should not be reported as a 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 a 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 adverse event and as a SAE with Common Terminology 
Criteria (CTC) Grade 5 (see Section 8.8).
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.  In addition, an overdose of study 
medication should only be captured as an SAE when it meets one of the criteria listed above.
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 8.14.1 for SAE Reporting Requirements).
8.6.2. Potential Cases of Drug-Induced Liver Injury
Abnormal values in aspartate transaminase (AST) and/or alanine transaminase (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. 


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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 (X ULN) concurrent with a total bilirubin value 2 X ULN with no evidence 
of hemolysis and an alkaline phosphatase value 2 X ULN or not available.

For patients with preexisting ALT OR, AST OR total bilirubin values above the 
upper limit of normal, the following threshold values should be used in the definition 
mentioned above:

For patients with pre-existing AST or ALT baseline values above the normal 
range: AST or ALT values 2 times the baseline values and 3 X ULN, or 8 X 
ULN (whichever is smaller).

Concurrent with:

For patients with pre-existing values of total bilirubin above the normal range: 
Total bilirubin level increased from baseline by an amount of at least 1 X ULN or 
if the value reaches 3 X 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.


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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 to an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit should be assessed for medical 
importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same day surgeries (as outpatient/same day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
AE is not in itself a serious adverse event.  Examples include: 

Admission for treatment of a preexisting condition not associated with the 
development of a new adverse event or with a worsening of the preexisting condition 
(eg, for work-up 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;

Pre-planned 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.


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Diagnostic and therapeutic non-invasive 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 CTC 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 a SAE. For example headache may be severe (interferes significantly with the 
patient’s usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs listed above.
8.9. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious); the investigator must record the causal relationship in the CRF, as appropriate, 
and report such an assessment in accordance with the serious adverse 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.


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8.10. Exposure During Pregnancy
For investigational products and for marketed products, an exposure during pregnancy occurs 
if:
1. A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes, or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product;
An example of environmental exposure would be a case involving direct contact with 
a Pfizer product in a pregnant women (eg, a nurse reports that she is pregnant and has 
been exposed to chemotherapeutic products).
2. A male 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 a Serious Adverse Event (SAE) Report Form 
and Exposure During Pregnancy (EDP) supplemental form, regardless of whether an SAE 
has occurred.  In addition, the investigator must submit information regarding environmental 
exposure to a Pfizer product in a pregnant woman (eg, a patient reports that she is pregnant 
and has been exposed to a cytotoxic product by inhalation or spillage) using the EDP 
supplemental form.  This must be done irrespective of whether an AE has occurred and 
within 24 hours of awareness of the exposure.  The information submitted should include the 
anticipated date of delivery (see below for information related to termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion or until pregnancy termination and notify Pfizer of the outcome as a follow-up to 
the initial EDP supplemental form.  In the case of a live birth, the structural integrity of the 
neonate can be assessed at the time of birth.  In the event of a termination, the reason(s) for 
the termination should be specified and, if clinically possible, the structural integrity of the 
terminated fetus should be assessed by gross visual inspection (unless preprocedure test 
findings are conclusive for a congenital anomaly and the findings are reported). 
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live born, 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;


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
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 investigational product.
Additional information regarding the exposure during pregnancy 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 safety within 24 hours of 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 study 
master file.
8.12. Withdrawal Due to Adverse Events (See also Section on Patient Withdrawal)
Withdrawal due to AE should be distinguished from withdrawal due to other causes, 
according to the definition of adverse event noted earlier, and recorded on the appropriate 
adverse event CRF page.
When a patient withdraws because of an SAE, the SAE must be reported in accordance with 
the reporting requirements defined below.
8.13. Eliciting Adverse Event Information
The investigator is to report all directly observed AEs and all AEs spontaneously reported by 
the study patient.  In addition, each study patient will be questioned about AEs.
8.14. Reporting Requirements
Each AE is to be assessed to determine if it meets the criteria for SAEs.  If a SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate.
8.14.1. Serious Adverse Event Reporting Requirements
If a SAE occurs, Pfizer is to be notified within 24 hours of investigator awareness of the 
event.  In particular, if the serious adverse event is fatal or life-threatening, notification to 
Pfizer must be made immediately, irrespective of the extent of available adverse event 


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information.  This timeframe also applies to additional new information (follow-up) on 
previously forwarded SAE reports as well as to the initial and follow-up reporting of 
exposure during pregnancy, exposure via breastfeeding and occupational exposure cases.
In the rare event that the investigator does not become aware of the occurrence of a 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 timeframes 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 case report form.  In general, this will include a description of the AE in sufficient 
detail to allow for a complete medical assessment of the case and independent determination 
of possible causality.  Information on other possible causes of the event, such as concomitant 
medications, vaccines and/or illnesses must be provided.  In the case of a patient death, a 
summary of available autopsy findings must be submitted as soon as possible to Pfizer or its 
designated representative. 
8.14.2. Non-Serious Adverse Event Reporting Requirements
All AEs will be reported on the AE page(s) of the CRF.  It should be noted that the form for 
collection of SAE information is not the same as the AE CRF.  Where the same data are 
collected, the forms must be completed in a consistent manner.  For example, the same AE
term should be used on both forms.  AEs should be reported using concise medical 
terminology on the CRFs as well as on the form for collection of SAE information.
8.14.3. Sponsor 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 trial 
will be documented in a Statistical Analysis Plan (SAP), which will be maintained by Pfizer. 
This document may modify the plans outlined in the protocol; however, any major 
modifications of the primary endpoint and/or its analysis will also be reflected in a protocol 
amendment.
9.1. Analysis Sets
1. Safety analysis set.
The safety analysis set includes all enrolled patients who receive at least one dose of 
study medication.


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2. Full analysis set.
The full analysis set includes all enrolled patients.
3. DLT evaluable set.
All enrolled patients who are eligible, receive study treatment and who either 
experience a DLT during the first 2 cycles of PF-05082566, or complete the two 
cycles’ DLT observation period. Note that every patient will contribute to the 
determination of the MTD including patients who are lost to follow-up prior to 
completion of the two cycles’ DLT observation period.
4. Response analysis set.
All enrolled patients who are eligible, receive study treatment, have baseline tumor 
assessments and at least 1 on-study tumor assessment will be considered evaluable for 
response.  Patients who are treated and removed from study prior to on-study tumor 
assessment because of disease progression will be considered evaluable for efficacy 
and counted as failures.  Response analysis will be performed for both the safety 
analysis set and the response analysis set.
5. PK analysis sets.
The PK concentration population is defined as all enrolled patients treated who have 
at least one concentration of either PF-05082566 or MK-3475. 
The PK parameter analysis population is defined as all enrolled patients treated who 
have at least 1 of the PK parameters of interest. 
6. Biomarker Analysis set.
Treated patients who have baseline and at least 1 on study biomarker assessment will 
be considered evaluable. 
7. ECG/QTc Analysis set
8. Treated patients who have baseline and at least 1 on study ECG/QTc measurement 
will be considered evaluable.
9.2. Statistical Methods for Dose Allocation: TITE-CRM
A number of alternative designs have been proposed to the standard 3+3 design for Phase I 
dose escalation trials that improve its accuracy, efficiency and statistical validity, including 
the continual reassessment method (CRM),17 and its variants. 
Delayed-onset toxicities are a particular challenge for phase I trials of combination 
therapies.14 Most of the available dose-escalation designs, including the 3+3 design, the 
up-and-down designs and the CRM design, require all patients to have completed a fixed 


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observation period for toxicity (eg, 1-2 cycles of the experiment regimen, or 6-8 weeks after 
start of treatment) before additional cohorts of patients can be enrolled. Thus, trial accrual is 
patient to opening and closing which may pose logistical risk on the success and completion 
of the study. In addition, patients who are either lost to follow-up or die of events unrelated 
to treatment are usually required to be replaced. Due to these reasons, the trial duration could 
be unacceptably long in case of prolonged observation window and unexpected high rate of 
patient drop-out.
The time-to-event continual reassessment method (TITE-CRM), a variant of the original 
CRM method, is open to accrual continually, and maintains other advantages of the CRM 
relative to the 3+3 design. Like CRM, TITE-CRM seeks to determine the target MTD dose, 
defined as the dose most closely identified with the target rate, which is the largest acceptable 
DLT rate determined by the investigators based on the relative costs and benefits of the 
treatment.
TITE-CRM is to be implemented as described by Cheung et al.3 and Normolle et al.15 for the 
dose-escalation of PF-05082566.  PF-05082566 may be administered intravenously at the 
following available dose levels of 0.20, 0.45, 0.9, 1.8, 3.6, and 5 mg/kg on an every 3 week 
schedule (q3wk).  PF-05082566 will be co-administered with MK-3475 on Day 1 of each 
treatment Cycle.  MK-3475 will be administered at 2 mg/kg, MK-3475 will be administered 
q3wk.  Higher dose levels may be available based on the emerging safety data from single 
agent PF-05082566 dosed at 5 mg/kg in the Phase 1 first-in-human study.  The MTD is 
defined as highest dose that is associated with a DLT rate 25%.  A power function modeling 
DLT rate at each dose di (i=1, …, 6) expressed as Pr (DLT | di) = Fi () will be used:
)
exp(
)
(


i
i
p
F

where pi is the prior estimate of DLT rate at dose level di, and p1p2…p6. These estimates 
will be projected based model sensitivity to DLTs, together with single agent safety data for 
both study drugs.  is an unknown single parameter modeling the dose-toxicity relationship, 
with prior distribution 
)
,0
(
2
0

N
, where 
0
is the standard deviation of the normal prior 
distribution with mean=0. At the beginning of the trial, the initial prior value of is set as 0, 
the prior mean, which gives a prior dose-toxicity model of 
i
i
p
F

)
(
based on the power 
function. 
In the Bayesian paradigm, the prior distribution 
)
,0
(
2
0

N
expresses the researchers’ belief in 
the quality of the initial estimates pi. The smaller the standard deviation
0
, the more 
confidence researchers have in the precision of pi. and vice versa. As the trial progresses, 
this prior distribution is combined mathematically with the observed data to yield the 
posterior distribution of the parameter (the posterior mean of will be calculated to model 
the dose-toxicity relationship). The prior distribution determines how responsive TITE-CRM 
is to the accumulated data. With a small
0
upfront, the posterior toxicity probability 
estimates remain close to the prior estimates unless significantly discrepant data otherwise 


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occur; with a large
0
, the model will tend to be more immediately responsive to data. In this 
trial,
0
=1, which provides a reasonably flat prior distribution of , with 90% Bayesian 
credible interval of 
)
exp(: [0.19, 5.21], sufficiently wide to cover a wide spectrum of 
dose-toxicity scenarios.  Figure 3 illustrates the dose-toxicity curve (blue curve) with 
90% upper and lower bounds (red curves) when the initial prior estimates
ip are (0.01, 0.04, 
0.08, 0.16, 0.25, 0.35).
Figure 3.
Example Plot of Prior Dose Toxicity Curve
Prior dose-toxicity curve with 90% confidence limits
Dose Level of PF-05082566 (mg/kg)
DLT Rate
0.2
0.45
0.9
1.8
3.6
5
0
0.1
0.2
0.25
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
target
In the TITE-CRM paradigm, patients who have enrolled in the trial but have not experienced 
a DLT will be included in the probability calculation with an initial weight equal to the 
proportion of the 6-week (2 cycles) DLT observation period the patients have completed.
However the weight function will be modified if safety data suggest different weight 
(toxicity) patterns in Cycle 1 and Cycle 2 of PF-05082566. An adaptive cyclical weight 
function as proposed by Huang et al. (2014) will be implemented.


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Patients who experience a DLT or complete the observation period without a DLT will be 
assigned full weight (=1).
Extensive simulation results comparing the TITE-CRM using the adaptive cyclical weight 
function with the 3+3 design and other weight functions can be found in Huang et al. 
(2014)47.
Section 3.2 describes the dose escalation/de-escalation criteria, stopping rules and some 
restrictions and practical considerations on dose escalation.
9.3. Sample Size Determination
Due to the dynamic nature of the Bayesian allocation procedure, the sample size of the 
TITE-CRM approach cannot be determined in advance. The maximum sample size is set 
as 45 for dose escalation cohorts in order to have a reliable and accurate estimate of the MTD 
based on simulation results. Based on probability theory, a sample size of 45 will ensure the 
estimates of any binary variable (eg, objective response rate) have a 95% confidence interval 
of width <0.30. A sample size of 45 also enables the detection of any unexpected toxicity 
that occurs at 5% rate (in a non-dose-dependent fashion) with a probability of 0.90, and that 
occurs at 10% rate with a probability of 0.99. 
A stopping rule (see Section 3.2) will also be implemented for possible early stopping if there 
is strong confidence in the estimated MTD.
Additional patients will be required for expansion cohorts.  The total number of patients in 
expansion cohorts will be determined based on emerging data from this study, cancer 
indication, and the patient population of interest. 
9.4. Efficacy Analysis
Assessment of anti-tumor activity is a secondary objective.  Only descriptive efficacy 
summaries will be performed for this part of the study.
Tumor response will be presented in the form of patient data listings that include, but are not 
limited to, tumor type, received (maximum) dose, overall tumor response at each visit, and 
best overall response. In addition, disease progression date, death date, date of first response,
and last tumor assessment date will be listed, together with Duration of Response, and PFS 
for the expansion cohort.  Kaplan-Meier plot will be created for TTR, DR and PFS in the 
expansion cohort.  A bar plot for TTR and DR will also be created for confirmed responders 
defined by RECIST 1.1. 
9.5. Analysis of Other Endpoints
9.5.1. Analysis of Pharmacokinetics
9.5.1.1. Pharmacokinetics Analysis of PF-05082566 and MK-3475
Standard plasma pharmacokinetic parameters including the maximum plasma concentration
(Cmax), time to maximum plasma concentration (Tmax), and area under the plasma
concentration versus time curve (AUC) for PF-05082566 will be estimated using 


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non-compartmental analysis, as data permits. If data permit or if considered appropriate, 
minimum plasma concentration (Cmin), average plasma concentration (Cave), area under the 
plasma concentration versus time curve to infinity (AUCinf), terminal elimination half-life 
(t1/2), total systemic clearance (CL), volume of distribution (Vd), accumulation ratio (Rac)
will be estimated. Descriptive statistics will be provided for these PK parameters in tabular 
form (n, mean, SD, CV, median, minimum, maximum, geometric mean and its associated 
CV) by dose, cycle and day.
Dose normalized AUCinf (AUCτ at steady state), AUClast, and Cmax for PF-05082566 may be 
plotted against dose (using a logarithmic scale).  These plots will include individual patient 
values and the geometric means for each dose.  These plots will be used to help understand 
the dose proportionality for PF-05082566.
For MK-3475, plasma pharmacokinetic parameters will be determined by Merck using a 
validated population pharmacokinetic model.
For PF-05082566 and MK-3475 concentrations, individual values and descriptive statistics 
(n, mean, SD, CV, median, minimum, maximum, geometric mean and its associated CV) will 
be presented by dose, cycle, day of assessment, and nominal time in tabular form.  Individual 
patient and median profiles of the concentration-time data will be plotted by dose, cycle and 
day using nominal times.  Median profiles will be presented on both linear-linear and 
log-linear scales.
No drug interaction is anticipated  between PF-05082566 and  MK-3475. Since 
PF-05082566 and MK-3475 are eliminated via a non-specific catabolic degradation process, 
it is unlikely that concomitant medication can alter their clearance even if target expression is 
affected. To assess any potential interactions, steady state pharmacokinetics and the 
formation of anti-drug antibodies will be monitored for both the agents and compared with 
historical data.
9.5.1.2. Population Pharmacokinetic Analysis or PK
 Modeling
Pharmacokinetic 
 data from this study may be analyzed using 
modeling approaches and may also be pooled with data from other studies to investigate any 
causal relationship between PF-05082566/ MK-3475 exposure and biomarkers or significant 
safety endpoints. The results of these analyses, if performed, may be reported separately.
9.5.1.3. Analysis of Immunogenicity Data
ADA data will be listed and summarized for each dosing interval for PF-05082566 and 
MK-3475.  The effect of ADA on PF-5082566 and MK-3475 concentration will be 
evaluated.
9.5.1.4. Statistical Analysis of Biomarker Endpoints
For tumor biopsy samples, the mean and standard deviation, median, and 
minimum/maximum levels of biomarker measures, including but not limited to percentage of 
CD3-positive T cells, will be determined at baseline and post-treatment.  For each pair of 
CCI
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specimens, the percent change from baseline of these same parameters will also be 
calculated.  The minimum percent change from baseline needed to declare proof of 
pharmacology will be based on assay precision and size of the expansion cohort.
 
  The statistical 
approach will examine correlations of biomarker results with pharmacokinetic parameters 
and measures of anti-tumor efficacy.
 
9.6. Safety Analysis
Summaries and analyses of the primary safety endpoint will be based on the per protocol 
analysis set. Summaries and analyses of all other safety parameters will include all patients 
in the Safety Analysis Set.
9.6.1. Analysis of Primary Endpoint
Dose-Limiting Toxicity (DLT) is the primary endpoint of the dose escalation component of 
the study. The occurrence of DLTs observed in the dose level cohorts is used to estimate the 
MTD as described in Study Design Section 3. AEs constituting DLTs will be listed by dose 
level.
9.6.2. Analysis of Secondary Safety Endpoints
9.6.2.1. 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, 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 >2). 
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, Cycle 2, 
and Cycles beyond 2). 
For laboratory tests without CTC grade definitions, results will be categorized as normal, 
abnormal or not done.
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9.6.3. ECG
The analysis of ECG results will be based on safety analysis set patients with baseline and 
on-treatment ECG data.  The most recent ECG collected prior to the first day of dosing will 
be considered the baseline ECG.  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 as individual values obtained at unscheduled time 
points.
QT intervals will be corrected for heart rate (QTc) using standard correction factors [ie, 
Fridericia’s (default correction), Bazett’s, and possibly a study specific factor, as 
appropriate].  Data will be summarized and listed for QT, HR, response rate (RR), PR, QRS, 
QTcF (and other correction factors, eg,  QTcB as appropriate) by dose.  Individual QT (all 
evaluated corrections) intervals will be listed by time and dose.  The most appropriate 
correction factor will be selected and used for the following analyses of central tendency and 
outliers and used for the study conclusions.  Descriptive statistics (n, mean, median, standard 
deviation, minimum, and maximum) will be used to summarize the absolute corrected QT 
value and changes from baseline in corrected QT after treatment, by dose and time point.  For 
each patient and by treatment, the maximum change from baseline will be calculated as well 
as the maximum post-baseline 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. 
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.
Shift tables will be provided for baseline vs. worst on study QTc (one or more correction 
method will be used) using Maximum CTCAE Grade.  As well as tables of ECG abnormality 
at baseline (yes, no, not done: (n, %)).  Patients experiencing clinically-relevant 
morphological ECG changes will be summarized (including frequency and percentage).
9.7. Data Safety Monitoring Committee
An external Data Safety Monitoring Committee will not be established for this study. For the 
purpose of this protocol, Pfizer procedures for periodic safety review will be applied by an 
internal safety review team consisting of physician, safety specialist, and statistician to 
review individual and summary data collected in the safety and clinical databases.
Procedures include:

Surveillance for SAEs according to regulatory guidelines;

Discussions between the Investigators and the Sponsor of AEs, laboratory test 
abnormalities, vital signs, and ECG findings observed at each dose level in an 
ongoing manner at regular teleconferences and/or meetings to determine the safety 


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profile and make a benefit/risk assessment and decide if further enrollment is 
appropriate;

Findings having immediate implication for the management of patients on study will 
be communicated to all Principal Investigators in the timeframe associated with 
unexpected and drug-related SAEs.
During the dose-escalation phase, a Dose-Escalation Steering Committee (DESC) will be 
established to perform periodic review of the accumulating safety data, specifically, the 
DLTs.  The guidance for dosing and enrollment decisions is based on the Bayesian statistical 
model of TITE-CRM.  Other considerations may include lower grade AEs, nature and timing 
of the AEs, existing PK/PD data that may cause safety concerns.  Following each review, the 
DESC will inform the study team and participating investigators on dosing and enrollment 
decisions.  A DESC Charter will be prepared and will be available before the first DESC 
meeting. 
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 is 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.
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term Case Report Form (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 


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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 is true. Any corrections to entries made in the CRFs, 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, telephone calls reports).  The records should be 
retained by the investigator according to ICH, local regulations, or as specified in the Clinical 
Study Agreement, whichever is longer.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer. 
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.  The 
investigator must obtain Pfizer's written permission before disposing of any records, even if 
retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC)
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/IEC.  All correspondence with the 
IRB/IEC should be retained in the Investigator File.  Copies of IRB/IEC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/IEC approval is 
where the change is necessary to eliminate apparent immediate hazards to the patients.  In 


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that event, the investigator must notify the IRB/IEC 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 Patients (Council for International Organizations of Medical 
Sciences 2002), Guidelines for Good Clinical Practice (International Conference on 
Harmonization 1996), and the Declaration of Helsinki (World Medical Association 1996 & 
2008). 
In addition, the study will be conducted in accordance with the protocol, the International 
Conference on Harmonisation guideline on Good Clinical Practice, 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 
on any sponsor forms, reports, publications, or in any other disclosures, except where 
required by laws. 
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 document must be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements including applicable privacy laws.
The informed consent document(s) used during the informed consent process must be 
reviewed by the sponsor, approved by the IRB/IEC before use, and available for inspection. 
The investigator must ensure that each study patient, or his or her legally acceptable 
representative, is fully informed about the nature and objectives of the study and possible 
risks associated with participation. 
Whenever consent is obtained from a patient’s legally acceptable representative, the patient’s 
assent (affirmative agreement) must subsequently be obtained when the patient has the 
capacity to provide assent, as determined by the IRB/EC.  If the investigator determines that 
a patient’s decisional capacity is so limited he/she cannot reasonably be consulted, as 
permitted by the IRB/EC and consistent with local regulatory and legal requirements, then 
the patient’s assent may be waived with source documentation of the reason assent was not 
obtained.  If the study patient does not provide his/her own consent, the source documents 
must record why the patient did not provide consent (eg, minor, decisionally impaired adult), 


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how the investigator determined that the person signing the consent was the patient’s legally 
acceptable representative, the consent signer’s relationship to the study patient (eg, parent, 
spouse) and that the patient’s assent was obtained, or waived.  If assent is obtained verbally it 
must be documented in the source documents.
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each subject before any study-specific activity is performed.  The investigator 
will retain the original of each subject'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 which 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 Study 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 Patient Last Visit. 
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/IEC, drug safety problems, or at the discretion of Pfizer.  In 
addition, Pfizer retains the right to discontinue development of PF-05082566 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 5 business days.  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), www.pfizer.com, and/or the 
European Clinical Trials Database (EudraCT), and other public registries in accordance with 
applicable local laws/regulations. 
www.clinicaltrials.gov
Pfizer posts clinical trial Basic Results on www.clinicaltrials.gov for all Pfizer-sponsored 
interventional studies that evaluate the safety and/or efficacy of a Pfizer product.
The timing of the posting depends on whether the Pfizer product is approved for marketing in 
any country at the time the study is completed:

For studies involving products applicable under the US Food and Drug 
Administration Amendments Act of 2007 (FDAAA), ie, Food and Drug 
Administration (FDA)-approved products, Pfizer posts results within 1 year of the 
primary completion date (PCD).  For studies involving products approved in any 
country, but not FDA approved, Pfizer posts results one year from last subject, last 
visit (LSLV); 

For studies involving products that are not yet approved in any country, Pfizer posts 
the results of already-completed studies within 30 days of US regulatory approval or 
1 year after the first ex-US regulatory approval of the product (if only submitted for 
approval ex-US);

For studies involving products whose drug development is discontinued before 
approval, Pfizer posts the results within 1 year of discontinuation of the program (if 
there are no plans for outlicensing, or within 2 years if outlicensing plans have not 
completed).
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.
www.pfizer.com
Pfizer posts clinical trial results on www.pfizer.com for all Pfizer-sponsored interventional 
studies in patients that assess the safety and/or efficacy of an FDA-approved Pfizer product 
with a LSLV on or after 27-Sep-2007 for which Basic Results were posted on 
www.clinicaltrials.gov.


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EudraCT
Pfizer posts clinical trial results on EudraCT in accordance with Commission Guideline 
2012/C 302/03 Guidance on posting and publication of result-related information on clinical 
trials in relation to the implementation of Article 57(2) of Regulation (EC) No 726/2004 and 
Article 41(2) of Regulation (EC) No 1901/2006 for studies with centers in the European 
Economic Area and with LSLV on or after 01-May-2004, regardless of the marketing status 
of the compound.
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.
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 multi-center 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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Tumori 2008; 94:426-30. 
37.
Hodi FS, Dranoff G. The biologic importance of tumor-infiltrating lymphocytes. J 
Cutan Pathol 2010; 37(Suppl 1):48-53. 
38.
Kloor M. Lymphocyte infiltration and prognosis in colorectal cancer. Lancet 2009;
10(840):841. 
39.
Hillen F, Baeten CIM, van de Winkel A, Creytens D, van der Schaft DWJ, 
Winnepenninckx V, et al. Leukocyte infiltration and tumor cell plasticity are parameters 
of aggressiveness in primary cutaneous melanoma. Cancer Immunol Immunother 2008;
57:97-106. 


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40.
Lee HE, Chae SW, Lee YJ, Kim MA, Lee HS, Lee BL, et al. Prognostic implications of 
type and density of tumour-infiltrating lymphocytes in gastric cancer. Br J Cancer 2008;
99(10):1704-11. 
41.
Leffers N, Gooden MJM, de Jong RA, Hoogeboom B-N, ten Hoor KA, Hollema H, et 
al. Prognostic significance of tumor-infiltrating T-lymphocytes in primary and 
metastatic lesions of advanced stage ovarian cancer. Cancer Immunol Immunother 
2009; 58:449-59. 
42.
Nishimura H, Honjo T, Minato N. Facilitation of β selection and modification of 
positive selection in the thymus of PD-1-deficient mice. J Exp Med 2000; 191(5):891-7. 
43.
Liotta F, Gacci M, Frosali F, Querci V, Vittori G, Lapini A, et al. Frequency of 
regulatory T cells in peripheral blood and in tumour-infiltrating lymphocytes correlates 
with poor prognosis in renal cell carcinoma. BJU Intern 2010; 107:1500-6. 
44.
Ropponen KM, Eskelinen MJ, Lipponen PK, Alhava E, Kosma V-M. Prognostic value 
of tumour-infiltrating lynmphocytes (TILs) in colorectal cancer. J Pathol 1997;
182:318-24. 
45.
Hamid O, Robert C, Daud AF, Hodi S, Hwu W-J, Kefford R, Wolchok JD, Hersey P, 
Joseph RW, Weber JS, et al. Safety and tumor responses with lambrolizumab (anti-PD-
1) in melanoma. N Engl J Med. 2013 369(2): 134–144.
46.
Wochok JD, Hoos A, O’Day S et al., Guidelines for the evaluation of immune therapy 
activity in solid tumors: Immune-related response criteria. Clin Cancer Res. 2009; 12: 
7412-7420.
47.
Huang B, Kuan P. Time-to-event continual reassessment method incorporating 
treatment cycle information with application to an oncology phase I trial. Biometrical 
Journal (in press).


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Appendix 1. Determination of Efficacy 
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. 


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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. 


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
PD: Unequivocal progression of pre-existing lesions. Generally the overall tumor 
burden must increase sufficiently to merit discontinuation of therapy.  In the presence
of SD or PR in target disease, progression due to unequivocal increase in non-target 
disease should be rare. 

Indeterminate: Progression has not been determined and one or more non-target sites 
were not assessed or assessment methods were inconsistent with those used at 
baseline.
New Lesions 
The appearance of any new unequivocal malignant lesion indicates PD.  If a new lesion is 
equivocal, for example due to its small size, continued assessment will clarify the etiology.  
If repeat assessments confirm the lesion, then progression should be recorded on the date of 
the initial assessment.  A lesion identified in an area not previously scanned will be 
considered a new lesion.
Supplemental Investigations

If CR determination depends on a residual lesion that decreased in size but did not 
disappear completely, it is recommended the residual lesion be investigated with 
biopsy or fine needle aspirate.  If no disease is identified, objective status is CR.

If progression determination depends on a lesion with an increase possibly due to 
necrosis, the lesion may be investigated with biopsy or fine needle aspirate to clarify 
status. 
Objective progression
Patients requiring discontinuation of treatment without objective evidence of disease 
progression should not be reported as PD on tumor assessment CRFs.  This should be 
indicated on the end of treatment CRF as off treatment due to Global Deterioration of Health 
Status.  Every effort should be made to document objective progression even after 
discontinuation of treatment. 
Table 13.
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 14.
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.


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Appendix 2. Eastern Cooperative Oncology Group (ECOG) Performance Status
ECOG 
Grade
Description
Karnofsky 
Score*
0
Fully active, able to carry on all predisease performance without 
restriction
100
1
Restricted in physically strenuous activity, but ambulatory and 
able to carry out work of a light or sedentary nature, ie, light 
house work, office work.
80 or 90
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
60 or 70
3
Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours.
40 or 50
4
Completely disabled.  Cannot carry on any self-care.  Totally 
confined to bed or chair.
20 or 30
* Karnofsky Performance Score is provided for reference.  Please record corresponding ECOG grade only.


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SAP_001.pdf: 
PF-05082566
B1641003 Statistical Analysis Plan
Page 1
B1641003
A PHASE 1 STUDY OF THE 4-1BB AGONIST PF-05082566 IN COMBINATION 
WITH THE PD-1 INHIBITOR MK-3475 IN PATIENTS WITH ADVANCED SOLID 
TUMORS
STATISTICAL ANALYSIS PLAN
Compounds:
PF-05082566
Compound Name:
NA
Version:
Amendment 2
Date:
20-Mar-2017


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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................5
LIST OF FIGURES ...................................................................................................................5
1. VERSION HISTORY............................................................................................................6
2. INTRODUCTION .................................................................................................................8
2.1. Study Objectives .......................................................................................................8
2.2. Study Design .............................................................................................................9
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ................................................................................................................10
3.1. Primary Endpoints...................................................................................................10
3.2. Secondary Endpoints...............................................................................................11
3.2.1. Safety Endpoints.........................................................................................11
3.2.2. Efficacy Endpoints......................................................................................11
3.2.3. Pharmacokinetic Endpoints ........................................................................11
3.2.4. Immunogenicity Endpoints.........................................................................12
3.2.5. Biomarker Endpoints..................................................................................12
3.4. Baseline Variables...................................................................................................13
3.4.1. Study Drug, Study Treatment and Baseline Definitions ............................13
3.4.2. Baseline Characteristics..............................................................................14
3.5. Safety Endpoints .....................................................................................................14
3.5.1. Adverse Events...........................................................................................14
4. ANALYSIS SETS ...............................................................................................................14
4.1. Full Analysis Set .....................................................................................................15
4.2. Safety Analysis Set..................................................................................................15
4.3. Other Analysis Set...................................................................................................15
4.3.1. DLT-evaluable Set......................................................................................15
4.3.2. PK Analysis Set ..........................................................................................15
4.3.3. Biomarker Analysis Set..............................................................................15
4.3.4. Immunogenicity Analysis Set.....................................................................15
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................16
5.1. Hypotheses and Decision Rules ..............................................................................16
5.1.1. Hypotheses and Sample Size Determination..............................................16
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5.1.2. Decision Rules Using the TITE-CRM Method ..........................................16
5.2. General Methods .....................................................................................................19
5.2.1. Data Handling After the Cut-off Date ........................................................20
5.2.2. Pooling of Centers ......................................................................................20
5.2.3. Presentation of Continuous and Qualitative Variables...............................20
5.2.4. Definition of Study Day..............................................................................20
5.2.5. Definition of Start of New Anti-cancer Drug Therapy...............................20
5.2.6. Definition of Start of New Anti-cancer Therapy........................................21
5.2.7. Definition of On-treatment Period..............................................................21
5.2.8. Standard Derivations and Reporting Conventions .....................................21
5.2.9. Unscheduled Visits.....................................................................................22
5.2.10. Adequate Baseline Tumor Assessment ....................................................22
5.2.11. Adequate Post-baseline Tumor Assessment.............................................22
5.3. Methods to Manage Missing Data ..........................................................................22
5.3.1. Missing Data...............................................................................................22
5.3.1.1. Pharmacokinetic Concentrations...............................................23
5.3.1.2. Pharmacokinetic Parameters .....................................................23
5.3.2. Handling of Incomplete Dates....................................................................24
5.3.2.1. Disease History .........................................................................24
5.3.2.2. Adverse Events..........................................................................24
5.3.2.3. Prior and Concomitant Medications..........................................25
5.3.2.4. Exposure....................................................................................26
5.3.3. Imputation Rules for Date of Last Contact and Efficacy Assessments......26
5.3.3.1. Date of Last Contact..................................................................26
5.3.3.2. Death Date.................................................................................26
5.3.3.3. Tumor Assessments...................................................................27
5.3.3.4. Date of Start of New Anti-cancer Therapy ...............................27
6. ANALYSES AND SUMMARIES ......................................................................................28
6.1. Primary Endpoints...................................................................................................28
6.1.1. DLT.............................................................................................................28
6.1.1.1. Primary Analysis.......................................................................28
6.2. Secondary Endpoint(s) ............................................................................................28
6.2.1. Safety Endpoints.........................................................................................28


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6.2.2. Efficacy Endpoints......................................................................................28
6.2.2.1. Objective Response as Assessed by the Investigator per 
RECIST v1.1 .....................................................................................28
6.2.2.2. Tumor Shrinkage.......................................................................30
6.2.2.3. Duration of Response (Expansion Cohort Only) ......................30
6.2.2.4. Time to Response (Expansion Cohort Only) ............................31
6.2.2.5. Progression-Free Survival (Expansion Cohort Only) ...............31
6.2.3. Pharmacokinetic Endpoints ........................................................................33
6.2.4. Population Pharmacokinetic Endpoints......................................................34
6.2.5. Biomarker Endpoints..................................................................................34
6.2.6. Endpoints for Immunogenicity Data of PF-05082566 and MK-3475........34
6.3. Other Endpoints.......................................................................................................35
6.4. Subset Analyses.......................................................................................................35
6.5. Baseline and Other Summaries and Analyses.........................................................35
6.5.1. Baseline summaries ....................................................................................35
6.5.1.1. Demographic characteristics .....................................................35
6.5.1.2. Medical History.........................................................................36
6.5.1.3. Disease Characteristics..............................................................36
6.5.1.4. Prior Anti-Cancer Therapies .....................................................36
6.5.2. Study Conduct and Patient Disposition......................................................38
6.5.2.1. Patient Disposition ....................................................................38
6.5.2.2. Protocol Deviations...................................................................38
6.5.3. Study Treatment Compliance and Exposure ..............................................39
6.5.3.1. Exposure to PF-05082566.........................................................40
6.5.3.2. Exposure to MK-3475...............................................................41
6.5.3.3. Dose Reductions........................................................................42
6.5.3.4. Dose Delays...............................................................................42
6.5.3.5. Infusion Rate Reductions ..........................................................42
6.5.3.6. Infusion Interruptions................................................................42
6.5.4. Concomitant Medications and Non-Drug Treatments................................42
6.5.5. Subsequent Anti-cancer Therapies .............................................................43
6.6. Safety Summaries and Analyses .............................................................................43
6.6.1. Adverse Events...........................................................................................44


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6.6.1.1. All Adverse Events....................................................................44
6.6.1.2. Adverse Events Leading to Treatment Discontinuation............46
6.6.2. Deaths .........................................................................................................46
6.6.3. Serious Adverse Events ..............................................................................47
6.6.4. Other Significant Adverse Events ..............................................................47
6.6.5. Laboratory Data..........................................................................................48
6.6.5.1. Hematology and Chemistry Parameters....................................48
6.6.5.2. Other Laboratory Parameters ....................................................51
6.6.6. Vital Signs ..................................................................................................52
6.6.7. Electrocardiogram.......................................................................................52
6.6.8. Physical Examination .................................................................................54
6.6.9. ECOG Performance Status .........................................................................54
7. INTERIM ANALYSES.......................................................................................................54
7.1. Introduction .............................................................................................................54
7.2. Interim Analyses and Summaries............................................................................54
8. REFERENCES ....................................................................................................................55
LIST OF TABLES
Table 1.
Summary of Major Changes in SAP Amendments................................................6
Table 2.
PK Parameters to be Determined for PF-05082566 and MK-3475......................12
Table 3.
Outcome and Event Dates for PFS and DR Analyses ..........................................32
Table 4.
PFS Censoring Reasons and Hierarchy................................................................33
LIST OF FIGURES
Figure 1.
Example Plot of Prior Dose Toxicity Curve.........................................................18


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1. VERSION HISTORY
This Statistical Analysis Plan (SAP) for study B1641003 is based on the protocol amendment 
2 dated 8JUL2014. The SAP amendment reflects updates to the imputation algorithms for 
missing data as applicable to the data collected in this study. 
Table 1.
Summary of Major Changes in SAP Amendments
Version
Version Date
Summary of Changes
1.0
16-Jun-2014
Not applicable (original SAP)
Amendment 1
09-Mar-2016
Re-structured the content of the SAP for ease of 
review and to include additional details (new 
sections).
Aligned content with revisions from protocol 
amendments 1 and 2.

 
 
 
 
 
Removed the Response Evaluable set since 
efficacy analyses will be performed based on the 
Full Analysis Set.
Added more details on the analyses of secondary 
endpoints including safety, efficacy.
Added more details on the analyses of baseline 
and other summaries.
Refinements made in endpoint definition and 
description of analysis methods.
Amendment 2
20-Mar-2017
Section 3.5.1 and Section 6.6 referenced the 
pembrolizumab Even of Clinical Interest 
document to identify Adverse Events of Special 
Interest.
Added Section 5.2.5 “Definition of start of new 
anti-cancer drug therapy” and Section 5.2.6 
“Definition of start of new anti-cancer therapy” to 
provide specific details regarding these 
derivations.
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Version
Version Date
Summary of Changes
Added Section 5.2.10 “Adequate baseline tumor 
assessment” and 5.2.11 “Adequate post-baseline 
tumor assessment” to provide derivation details.
Section 5.3 “Methods to Manage Missing Data” 
and subsections - revised the imputation 
algorithms for missing data applicable to the data 
collected in the study.
Section 6.2.2 “Efficacy endpoints” – added 
definitions for BOR for patients without 
measurable disease at baseline and separated 
reasons for BOR of ‘no post-baseline assessment’ 
between death and other reasons; provided more 
details regarding censoring reasons for PFS to 
take into account the change in schedule of tumor 
assessments and provided further details for the 
derivation of censoring reasons.
Section 6.2.3 “Pharmacokinetic endpoints” –
updated definitions and descriptions for 
consistency.
Section 6.5.3 “Study treatment compliance and 
exposure” – added cycle definition and further 
details regarding derivations of DI and RDI; 
added derivations for infusion interruptions; 
changed the definition of infusion rate reductions 
to take into account the first infusion rate.
Section 6.6.2 “Deaths” – aligned the primary 
reason for death with the wording in the 
associated eCRF.
Section 6.6.5 “Laboratory data” and Section 6.6.7 
“Electrocardiogram” provided further details 
regarding denominators used in the analyses.
Section 6.6.7 “Electrocardiogram” – changed the 
study-specific correction from linear regression to 
log-linear regression.
Deleted Appendix 1 since details are provided in 
Section 6.5.3.


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Version
Version Date
Summary of Changes
Throughout all sections, corrected references to 
eCRF to use actual eCRF designation.
2. INTRODUCTION
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in study B1641003.  This document may modify the plans outlined in the protocol; 
however, any major modifications of the primary endpoint definition or its analysis will also 
be reflected in a protocol amendment.
Statistical analyses will be performed using cleaned eCRF data as well as non-CRF data (ie,
biomarker data, PK data). The primary analysis will include all data up to a clinical cut-off 
date corresponding to 24 months (104 weeks) after the last patient receive the first dose of 
the study drug.  The final analysis of the data will be performed after last patient last visit 
(LPLV). 
Additional analyses of the data may be performed for publication or regulatory reporting
purposes.
Throughout this document ‘start date’ refers to first dose of study treatment.
2.1. Study Objectives
Primary Objectives

To estimate the Maximum Tolerated Dose (MTD) and select the Recommended 
Phase 2 Dose (RP2D) for the combination of PF-05082566 with MK-3475 in patients 
with advanced solid cancer.
Secondary Objectives

To evaluate the overall safety profile; 

To characterize the single dose and multiple dose pharmacokinetics (PK) of 
PF-05082566 and MK-3475 given in combination following IV administration;

To evaluate the immunogenicity of PF-05082566 and MK-3475 when given in 
combination;

To assess the anti-tumor effect of PF-05082566 in combination with MK-3475 (by 
RECIST criteria);

Expansion Cohorts Only: To characterize the mechanism of sensitivity and/or 
resistance to PF-05082566 in combination with MK-3475 in tumor tissue.


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
 

 
 
2.2. Study Design
This is a Phase 1b, open-label, multi-center, multiple-dose, safety, pharmacokinetic 
 
 study designed to estimate the MTD, and determine the RP2D of 
PF-05082566 in combination with MK-3475 in patients with advanced solid tumors. 
PF-05082566 will be administered as a 1-hour intravenous infusion q3wks. On Day 1 of each 
dosing cycle, in which the drugs are co-administered, the MK-3475 infusion will start 30 
minutes after completion of PF-05082566 infusion and after the post- PF-05082566 and pre-
MK-3475 PK blood samples are drawn.
Treatment with study drugs will continue until completion of 32 cycles (approximately 
24 months) of treatment, confirmed objective disease progression, patient refusal, patient lost 
to follow up, unacceptable toxicity occurs, or the study is terminated by the Sponsor, 
whichever occurs first.
Once the MTD of PF-05082566 administered in combination with MK-3475 has been 
estimated with confidence, one or more expansion cohorts of patients with selected advanced 
solid tumors will be enrolled to further study the safety, tolerability, PK
and preliminary 
anti-tumor activity for PF-05082566 in combination with MK-3475 to support RP2D 
selection, as well as to study tumor-associated biomarkers.  The tumor types for further study 
could include NSCLC and potentially other tumor types based on emerging data from the 
dose escalation phase of this study.
Antitumor activity will be assessed by radiological tumor assessments conducted at baseline, 
at 9 weeks after the first dose of study drug, and every 6 weeks thereafter, whenever disease 
progression is suspected (eg, symptomatic deterioration), and at the time of End of 
Treatment/Withdrawal (if not done in the previous 6 weeks), using RECIST v1.1.  Safety 
will be monitored at regular intervals throughout the study by means of laboratory tests and 
clinical visits.  PK
blood endpoints will also be monitored in all patients. 
For all patients in dose-expansion cohorts, a de novo biopsy will be required at study entry 
followed by a second biopsy at the time of the week 9 scans (after 3 cycles of treatment).  
Optional de novo biopsies may be collected from patients in dose-escalation cohorts to 
support the assessment of disease progression.  
 
 
 
 
 
 
  
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3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoints

First 2 cycles Dose-Limiting Toxicity (DLT) of PF-05082566 in combination with 
MK-3475.
Severity of adverse events (AEs) will be graded according to CTCAE v 4.03. any of the 
following AEs occurring during the DLT observation period (first 2 Cycles, ie, 6 weeks) 
that are attributable to one or both study drugs will be classified as DLTs:

Hematologic:

Grade 4 neutropenia;

Febrile neutropenia, defined as absolute neutrophil count (ANC) <1000/mm3
with a single temperature of >38.3 degrees C (101 degrees F) or a sustained 
temperature of ≥38 degrees C (100.4 degrees F) for more than one hour;

Grade ≥3 neutropenic infection;

Grade ≥3 thrombocytopenia with bleeding;

Grade 4 thrombocytopenia.

Non-hematologic:

Grade ≥3 toxicities (non-laboratory);

Grade ≥3 nausea, vomiting or diarrhea despite maximal medical therapy;

Grade 4 aspartate aminotransferase (AST) and alanine aminotransferase 
(ALT).

Other (non AST/ALT) non-hematologic Grade ≥3 laboratory value if:

Medical intervention is required to treat the patient, or

The abnormality leads to hospitalization.

Inability to complete two infusions of MK-3475 and PF-05082566 during the DLT
observation period.


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3.2. Secondary Endpoints
3.2.1. Safety Endpoints

Adverse Events as characterized by type, severity (as graded by NCI CTCAE  v.4.03), 
timing, seriousness, and relationship to study therapy PF-05082566 in combination with 
MK-3475;
AEs will be graded by the investigator according to the CTCAE version 4.03 and coded 
using the Medical Dictionary for Regulatory Activities (MedDRA)

Laboratory abnormalities as characterized by type, severity (as graded by NCI CTCAE 
v.4.03);

Vital signs, weight, ECOG Performance Status.
3.2.2. Efficacy Endpoints

Objective tumor response by RECIST v1.1;
OR is defined as complete response (CR) or partial response (PR) according to RECIST 
v1.1 from ‘start date’ until documented disease progression. Both CR and PR must be 
confirmed by repeat assessments performed no less than 4 weeks after the criteria for 
response are first met.

Time-to-response (TTR, expansion cohorts only);
TTR is defined, for patients with an objective response, as the time from the ‘start date’
to the first documentation of objective response (CR or PR) which is subsequently 
confirmed. 

Duration of response (DR, expansion cohorts only);
DR is defined, for patients with an objective response, as the time from first 
documentation of objective response (CR or PR) to the date of first documentation of 
objective progression of disease (PD) or death due to any cause.  

Progression–free survival (PFS, expansion cohorts only);
PFS is defined as the time from ‘start date’ to the date of the first documentation of PD or 
death due to any cause, whichever occurs first.
3.2.3. Pharmacokinetic Endpoints

PK parameters of PF-05082566 and MK-3475, including but not limited to Cmax, Ctrough, 
Tmax, AUC0-last, CL and Vd (as data permits);


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Table 2.
PK Parameters to be Determined for PF-05082566 and MK-3475
Parameter
Definition
Method of Determination
AUClast
Area under the serum 
concentration-time profile from time 
zero to the time of the last quantifiable 
concentration (Clast)
Linear/Log trapezoidal method
AUC,
Area under the serum
concentration-time over dosing interval 

Linear/Log trapezoidal method
Cmax
Maximum observed serum
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.
Ctrough
Predose concentration during multiple 
dosing
Observed directly from data
CL
Clearance
Dose / AUCτ for steady state
Vd
a
volume of distribution
Dose / (AUCτ ·kel) for steady state
AUClast(dn)
Dose normalized AUClast
AUClast / Dose
AUC
Dose normalized AUC
AUC/Dose
Cmax(dn)
Dose normalized Cmax
Cmax / Dose
a If data permit
3.2.4. Immunogenicity Endpoints

Anti-Drug Antibody (ADA)/Neutralizing antibodies (Nab) titers for PF-05082566 and 
MK-3475.
3.2.5. Biomarker Endpoints

Expansion Cohorts Only: Paired de novo tumor biopsy collection at sequential time 
points for analysis of exploratory mechanistic biomarkers such as IHC assessment of 
tumor-infiltrating lymphocytes, quantitation of T cell receptor sequences, and gene 
expression.


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
 
 

 
3.4. Baseline Variables
3.4.1. Study Drug, Study Treatment and Baseline Definitions
In this study, ‘study drug’ refers to PF-05082566 or MK-3475 and ‘study treatment’ (or 
‘treatment group’) refers to one of the following:

Cohort -1: PF-05082566 0.2 mg/kg q3wks + MK-3475 2mg/kg q3wks;

Cohort 1: PF-05082566 0.45 mg/kg q3wks + MK-3475 2mg/kg q3wks;

Cohort 2: PF-05082566 0.9 mg/kg q3wks + MK-3475 2mg/kg q3wks;

Cohort 3: PF-05082566 1.8 mg/kg q3wks + MK-3475 2mg/kg q3wks;

Cohort 4: PF-05082566 3.6 mg/kg q3wks + MK-3475 2mg/kg q3wks;

Cohort 5: PF-05082566 5 mg/kg q3wks + MK-3475 2mg/kg q3wks.
Start of study treatment is the first dose of study drug administered.
Definition of baseline: 
The last available assessment prior to the start of study treatment is defined as ‘baseline’
value or ‘baseline’ assessment for safety and efficacy analyses.  If an assessment is planned 
to be performed prior to the first dose of study treatment in the protocol and the assessment is 
performed on the same day as the first dose of study treatment, it will be assumed that it was 
performed prior to study treatment administration, if assessment time point is not collected or 
is missing. If assessment time points are collected, the observed time point will be used to 
determine pre-dose on study day 1 for baseline calculation. Unscheduled assessments will be 
used in the determination of baseline. However, if time is missing, an unscheduled 
assessment on study day 1 will be considered to have been obtained after study treatment 
administration.
Patients who start treatment and discontinue from the study on the same day may have two 
different sets of data collected on study day 1 (one during study and one in the End of 
Treatment (EOT) visit. Data reported at the EOT visit are not eligible for baseline selection. 
CCI
CCI
CCI


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If a scheduled pre-dose measurement actually occurred post-dose, then the corresponding 
measurement will be treated and analyzed similar to an unscheduled post-dose measurement.
Baseline for heart rate (HR) and QT/QTc interval assessments will be derived from the visit 
where both HR and QT are not missing. Triplicate ECGs are collected in the study and the
baseline for each ECG measurement is the average of the pre-dose replicate measurements 
on the baseline day. Unscheduled assessments will not be included in the calculation of the 
average. QTcB and QTcF will be derived based on HR and QT.  The average of the replicate 
measurements will be determined after the derivation of the individual parameter at each 
time point.
3.4.2. Baseline Characteristics
Baseline characteristics (including demographics, physical measurements, disease history 
and prior anti-cancer therapies) are described in Section 6.5.1.  These baseline characteristics 
are not planned to be included as stratification variables or covariates in statistical models 
unless otherwise specified in Section 6.
3.5. Safety Endpoints
3.5.1. Adverse Events
Treatment-Emergent Adverse Events
Treatment-emergent adverse events (TEAEs) are those events with onset dates occurring 
during the on-treatment period for the first time, or if the worsening of an event is during the 
on-treatment period. 
On-treatment period is defined as the time from the first dose of study treatment through 
minimum (30 days + last dose of study treatment, start day of new anti-cancer drug therapy –
1 day).  The start day of new anti-cancer drug therapy after the first dose of study treatment is 
derived as outlined in Section 5.2.5.
Adverse Events of Special Interest (AESIs)
AESIs are immune-related adverse events (irAE) and infusion-related reactions (IRRs).  The 
criteria for classification of an AE as an irAE or IRR are documented separately in the 
pembrolizumab Event of Clinical Interest (ECI) document.
4. ANALYSIS SETS
Data for all patients will be assessed to determine if patients meet the criteria for inclusion in 
each analysis population prior to releasing the database and classifications will be 
documented per Pfizer’s standard operating procedures.
Only patients who signed informed consent will be included in the analysis sets below.


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4.1. Full Analysis Set
The FAS will include all patients who receive at least one dose of study drug.  Patients will 
be classified according to the study treatment actually received.  If a patient receives more 
than one treatment the patient will be classified according to the first treatment received.
4.2. Safety Analysis Set
The safety analysis set will include all patients who receive at least one dose of study drug.  
Patients will be classified according to the study treatment actually received.  If a patient 
receives more than one study treatment, the patient will be classified according to the first 
treatment received. In this non-randomized study, the FAS and the safety analysis set are 
identical.
4.3. Other Analysis Set
4.3.1. DLT-evaluable Set
The DLT evaluable set is a subset of the safety analysis set and will include all patients who 
are eligible, receive both study treatments and who either experience a DLT during the first 
2 cycles of PF-05082566 or complete the two cycles’ DLT observation period.  Note that 
every patient will contribute to the determination of the MTD including patients who are lost 
to follow-up prior to completion of the two cycles’ DLT observation period.
4.3.2. PK Analysis Set
The PK concentration analysis set is a subset of the safety analysis set and will include 
patients who have at least one post-dose concentration measurement above the lower limit of 
quantitation (LLQ) for PF-05082566 or MK-3475.
The PK parameter analysis set is a subset of the safety analysis set and will include patients 
who have at least one of the PK parameters of interest for PF-05082566 or MK-3475.
4.3.3. Biomarker Analysis Set 
The biomarker analysis set is a subset of the safety analysis set and will include all patients 
who receive at least one dose of study drug and have baseline and at least 1 on study 
biomarker assessment. 
4.3.4. Immunogenicity Analysis Set
The immunogenicity analysis set is a subset of the safety analysis set and will include 
patients who have at least one ADA/Nab sample collected for either PF-05082566 or 
MK-3475.


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5. GENERAL METHODOLOGY AND CONVENTIONS
5.1. Hypotheses and Decision Rules
5.1.1. Hypotheses and Sample Size Determination
No formal statistical hypothesis testing is planned.
Due to the dynamic nature of the Bayesian allocation procedure, the sample size of the 
Time-to-Event Continual Reassessment Method (TITE-CRM) cannot be determined in 
advance.  The maximum sample size is set as 45 for dose escalation cohorts in order to have 
a reliable and accurate estimate of the MTD based on simulation results.  Based on 
probability theory, a sample size of 45 will ensure the estimates of any binary variable (eg, 
objective response rate) have a 95% confidence interval of width <0.30.  A sample size of 
45 also enables the detection of any unexpected toxicity that occurs at 5% rate (in a 
non-dose-dependent fashion) with a probability of 0.90, and that occurs at 10% rate with a 
probability of 0.99. 
A stopping rule will also be implemented if:

Maximum sample size (n=45) is reached; or 

9 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. 
Additional patients will be required for expansion cohorts.  The total number of patients in 
expansion cohorts will be determined based on emerging data from this study, cancer 
indication, and the patient population of interest. 
5.1.2. Decision Rules Using the TITE-CRM Method
The doses of PF-05082566 will be assigned to each enrolled patient using a TITE-CRM 
method with an adaptive cyclical weight function (Huang and Kuan, 2014), a modified 
version of the original method proposed by Cheung and Chappell (2000).
Delayed-onset toxicities are a particular challenge for phase I trials of combination therapies.  
Most of the available dose-escalation designs, including the 3+3 design, the up-and-down 
designs and the CRM design, require all patients to have completed a fixed observation 
period for toxicity (eg, 1-2 cycles of the experiment regimen, or 6-8 weeks after start of 
treatment) before additional cohorts of patients can be enrolled.  Thus, trial accrual is patient 
to opening and closing which may pose logistical risk on the success and completion of the 
study.  In addition, patients who are either lost to follow-up or die of events unrelated to 
treatment are usually required to be replaced.  Due to these reasons, the trial duration could 
be unacceptably long in case of prolonged observation window and unexpected high rate of 
patient drop-out.


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The time-to-event continual reassessment method (TITE-CRM), a variant of the original 
CRM method, is open to accrual continually, and maintains other advantages of the CRM 
relative to the 3+3 design.  Like CRM, TITE-CRM seeks to determine the target MTD dose, 
defined as the dose most closely identified with the target rate, which is the largest acceptable 
DLT rate determined by the investigators based on the relative costs and benefits of the 
treatment.
TITE-CRM is to be implemented as described by Cheung et al. and Normolle et al. for the 
dose-escalation of PF-05082566.  PF-05082566 may be administered intravenously at the 
following available dose levels of 0.20, 0.45, 0.9, 1.8, 3.6, and 5 mg/kg on an every 3 week 
schedule (q3wk).  PF-05082566 will be co-administered with MK-3475 on Day 1 of each 
treatment Cycle.  MK-3475 will be administered at 2 mg/kg, MK-3475 will be administered 
q3wk.  Higher dose levels may be available based on the emerging safety data from single 
agent PF-05082566 dosed at 5 mg/kg in the Phase 1 first-in-human study.  The MTD is 
defined as highest dose that is associated with a DLT rate 25%.  A power function modeling 
DLT rate at each dose di (i=1, …, 6) expressed as Pr (DLT | di) = Fi () will be used:
)
exp(
)
(


i
i
p
F

where pi is the prior estimate of DLT rate at dose level di, and p1p2…p6.  These estimates 
will be projected based model sensitivity to DLTs, together with single agent safety data for 
both study drugs.  is an unknown single parameter modeling the dose-toxicity relationship, 
with prior distribution 
)
,0
(
2
0

N
, where 
0
is the standard deviation of the normal prior 
distribution with mean=0.  At the beginning of the trial, the initial prior value of is set as 0, 
the prior mean, which gives a prior dose-toxicity model of 
i
i
p
F

)
(
based on the power 
function. 
In the Bayesian paradigm, the prior distribution 
)
,0
(
2
0

N
expresses the researchers’ belief in 
the quality of the initial estimates pi.  The smaller the standard deviation
0
, the more 
confidence researchers have in the precision of pi. and vice versa.  As the trial progresses, 
this prior distribution is combined mathematically with the observed data to yield the 
posterior distribution of the parameter (the posterior mean of will be calculated to model 
the dose-toxicity relationship).  The prior distribution determines how responsive TITE-CRM 
is to the accumulated data.  With a small
0
upfront, the posterior toxicity probability 
estimates remain close to the prior estimates unless significantly discrepant data otherwise 
occur; with a large
0
, the model will tend to be more immediately responsive to data.  In this 
trial, 
0
=1, which provides a reasonably flat prior distribution of , with 90% Bayesian 
credible interval of 
)
exp(: [0.19, 5.21], sufficiently wide to cover a wide spectrum of 
dose-toxicity scenarios.  Figure 1 illustrates the dose-toxicity curve (blue curve) with 
90% upper and lower bounds (red curves) when the initial prior estimates
ip are (0.01, 0.04, 
0.08, 0.16, 0.25, 0.35).


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Figure 1.
Example Plot of Prior Dose Toxicity Curve
Prior dose-toxicity curve with 90% confidence limits
Dose Level of PF-05082566 (mg/kg)
DLT Rate
0.2
0.45
0.9
1.8
3.6
5
0
0.1
0.2
0.25
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
target
In the TITE-CRM paradigm, patients who have enrolled in the trial but have not experienced 
a DLT will be included in the probability calculation with an initial weight equal to the 
proportion of the 6-week (2 cycles) DLT observation period the patients have completed. 
However the weight function will be modified if safety data suggest different weight 
(toxicity) patterns in Cycle 1 and Cycle 2 of PF-05082566.  An adaptive cyclical weight 
function as proposed by Huang et al. (2014) will be implemented.
Patients who experience a DLT or complete the observation period without a DLT will be 
assigned full weight (=1).
Extensive simulation results comparing the TITE-CRM using the adaptive cyclical weight 
function with the 3+3 design and other weight functions can be found in Huang et al. (2014).


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To avoid overly rapid escalation and to retain the efficiency of dose administration when 
enrollment is fast, the following restrictions and practical considerations will be followed.

Dose skipping in escalation to untested doses is not allowed (k −> k+1).  In particular, 
at least three patients should have been treated at dose level k before escalation to 
dose level k+1;

At least three patients should have been on treatment (for a minimum of 3 weeks or 
1 cycle) and observed DLT rate <33% at dose level k before a patient is assigned to 
dose level k+1 (Note that the waiting window depends on our knowledge in the 
time-to-event pattern of toxicity and accumulating safety data, and thereby the 
confidence in the associated weights.  However, intentional delay in enrollment in the 
absence of DLT or serious AEs should be minimized and discouraged);

Dose escalation recommendation by the TITE-CRM algorithm may be overruled by 
the sponsor if the nature of the existing data causes safety concern.
5.2. General Methods
As described in Section 3.4, in this study ‘treatment group’ refers to one of the following:

Cohort -1: PF-05082566 0.2 mg/kg q3wks + MK-3475 2mg/kg q3wks;

Cohort 1: PF-05082566 0.45 mg/kg q3wks + MK-3475 2mg/kg q3wks;

Cohort 2: PF-05082566 0.9 mg/kg q3wks + MK-3475 2mg/kg q3wks;

Cohort 3: PF-05082566 1.8 mg/kg q3wks + MK-3475 2mg/kg q3wks;

Cohort 4: PF-05082566 3.6 mg/kg q3wks + MK-3475 2mg/kg q3wks;

Cohort 5: PF-05082566 5 mg/kg q3wks + MK-3475 2mg/kg q3wks.
Baseline characteristics, disposition and efficacy data will be summarized based on the FAS 
by treatment group.
DLTs will be summarized based on the DLT-evaluable set by treatment group.
Other safety data, exposure data, concomitant medications and non-drug treatments will be 
summarized based on the safety analysis set by treatment group. 
PK data will be summarized based on the PK analysis set by treatment group.
Biomarker data will be summarized based on the biomarker analysis set by treatment group.
Immunogenicity data will be summarized   based on the immunogenicity analysis set by 
treatment group.


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5.2.1. Data Handling After the Cut-off Date
Data after the cut-off date may not undergo the cleaning process and will not be displayed in 
any listings or used for summary statistics, statistical analyses or imputations.
5.2.2. Pooling of Centers
In order to provide overall estimates of treatment effects, data will be pooled across centers.  
The ‘center’ factor will not be considered in statistical models or for subgroup analyses due 
to the high number of participating centers in contrast to the anticipated small number of 
patients randomized/treated at each center.
5.2.3. Presentation of Continuous and Qualitative Variables
Continuous variables will be summarized using descriptive statistics ie, number of non-
missing values and number of missing values [ie, n (missing)], mean, median, standard 
deviation (SD), minimum, maximum and first and third quartile (Q1 and Q3). 
Qualitative variables will be summarized by frequency counts and percentages. Unless 
otherwise specified, the calculation of proportions will include the missing category. 
Therefore counts of missing observations will be included in the denominator and presented 
as a separate category.
In case the analysis refers only to certain visits, percentages will be based on the number of 
patients still present in the study at that visit, unless otherwise specified.
5.2.4. Definition of Study Day
Start day of study treatment is the day of the first dose of study treatment.
The study day for assessments occurring on or after the start of study treatment (eg, adverse 
event onset, tumor measurement) will be calculated as:
Study day = Date of the assessment/event - start of study treatment + 1. 
The study day for assessments occurring prior to the first dose of study treatment (eg,
baseline characteristics, medical history) will be negative and calculated as:
Study day = Date of the assessment/event - start of study treatment.
The study day will be displayed in all relevant data listings.
5.2.5. Definition of Start of New Anti-cancer Drug Therapy
Start date of new anti-cancer drug therapy is used to determine the end of the on-treatment 
period (see Section 5.2.7).
The start date of new anti-cancer drug therapy is the earliest start date of anti-cancer drug 
therapy recorded in the ‘Prior and Concomitant Drug Treatment’ eCRF page that is after the 
first dose of study treatment.  This date will be identified based on clinical review.


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5.2.6. Definition of Start of New Anti-cancer Therapy
Start date of new anti-cancer therapy (drug, radiation, surgery) is used for censoring in 
efficacy analyses (see Section 6.2.2).
The start date of new anti-cancer therapy is the earliest date after the ‘start date’ amongst the 
following:

Start date of anti-cancer drug therapy as identified in Section 5.2.5.

Start date of radiation therapy as identified by clinical review based on data recorded 
in the ‘Prior and Concomitant Non-drug Treatment’ eCRF page

Surgery date recorded in ‘Concomitant Surgery’ when “Surgery Outcome’ = 
‘Resected’ or ‘Partially Resected’.
When start date of anti-cancer therapy is missing or partially missing, the imputation rules 
described in Section 5.3.3.4 should be applied.
5.2.7. Definition of On-treatment Period
Safety endpoints will be summarized based on the on-treatment period unless otherwise 
specified.
On-treatment period is defined as the time from the first dose of study treatment through 
minimum (30 days + last dose of study treatment, start day of new anti-cancer drug therapy –
1 day).
Safety data collected outside the on-treatment period as described above will be listed and 
flagged in listings but not summarized.
5.2.8. Standard Derivations and Reporting Conventions
The following conversion factors will be used to convert days into weeks, months or years:   
1 week = 7 days, 1 month = 30.4375 days, 1 year = 365.25 days.
Demographics and physical measurements:

Age [years]: 

(date of given informed consent - date of birth + 1) / 365.25

In case of missing day, day only: Age [years]: (year/month of given informed consent 
– year/month of birth)

In case only year of birth is given: Age [years]: (year of given informed consent -
year of birth)


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The integer part of the calculated age will be used for reporting purposes. 

BMI (kg/m2) = weight (kg)/[height (m)]2

BSA (m²) = ([height (cm) × weight (kg)] / 3600)0.5
For reporting conventions, mean and median should generally be displayed one more 
decimal place than the raw data and standard deviation should be displayed to two more 
decimal places than the raw data. Percentages will be reported to one decimal place. The 
rounding will be performed to closest integer / first decimal using the common mid-point 
between the two consecutive values. E.g., 5.1 to 5.4 will be rounded to an integer of 5, and 
5.5 to 5.9 will be rounded to an integer of 6.
5.2.9. Unscheduled Visits
Generally, data collected at unscheduled visits will be included and analyzed for both safety 
and efficacy analyses in the same fashion as the data collected at scheduled visits except 
where otherwise noted in the sections that follow. Descriptive statistics (mean, SD, median, 
minimum, maximum, quartiles) by nominal visit or time point for safety endpoints such as 
laboratory measurements, ECGs and vital signs will include only data from scheduled visits.
5.2.10. Adequate Baseline Tumor Assessment
Adequate baseline is defined using the following criteria:

All baseline assessments must be within 28 days prior to and including ‘start date’.

All documented lesions must have non-missing assessments (ie, non-missing 
measurements for target lesions and non-missing lesions status at baseline for non-target 
lesions).

Computerized tomography (CT) or magnetic resonance imaging (MRI) is required at 
baseline and may include chest, abdomen and pelvis CT or MRI scans, brain CT or MRI 
scan, and bone scans. The CT scans should be performed with contrast agents unless 
contraindicated for medical reasons.  
5.2.11. Adequate Post-baseline Tumor Assessment
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 (see Section 6.2.2.1).  Time points where 
the response is NE or no assessment was performed will not be used for determining the 
censoring date.
5.3. Methods to Manage Missing Data
5.3.1. Missing Data
Unless otherwise specified, all data will be evaluated as observed, and no imputation method 
for missing values will be used.


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In all patient data listings imputed values will be presented.  In all listings imputed 
information will be flagged.
Missing statistics, eg, when they cannot be calculated, should be presented as ‘ND’ or ‘NA’.  
For example, if N=1, the measure of variability (SD) cannot be computed and should be 
presented as ‘ND’ or ‘NA’.
5.3.1.1. Pharmacokinetic Concentrations
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 will 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, concentrations will be set to missing if one 
of the following cases is true:
1. A concentration has been reported as ND (ie, not done) or NS (ie, no sample);
2. A deviation in sampling time is of sufficient concern or a concentration has been 
flagged as anomalous by the clinical pharmacologist.
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.
5.3.1.2. 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 patient’s concentration data, the parameter will be coded as NC (ie, 
not calculated).  NC values will not be generated beyond the day that a patient discontinues.
In summary tables, statistics will be calculated by setting NC values to missing. 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 patient has a known biased estimate of a PK parameter (due for example to a 
deviation from the assigned dose level), this will be footnoted in summary tables and will not 
be included in the calculation of summary statistics or statistical analyses.


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5.3.2. Handling of Incomplete Dates
5.3.2.1. Disease History
Incomplete dates for disease history (eg, initial diagnosis date, date of documented, locally 
advanced, inoperable or metastatic disease diagnosis, date of response or progression in prior 
treatment) will be imputed as follows:

If the day is missing, it will be imputed to the 1st day of the month. 

If both day and month are missing, the month and day will be imputed as January 1st.

If the date is completely missing, no imputation will be performed.
5.3.2.2. Adverse Events
Incomplete AE-related dates will be imputed as follows:

If only the day part of the AE onset date is missing, then the AE onset date will be 
replaced by 1st of the month. For example, if the AE onset date is --/JAN/2015, then the 
imputed AE onset date will be 01/JAN/2015.

If both the day and month of the AE onset date are missing, then the onset date will be 
replaced by January 1st of the year. For example, if AE onset date is --/---/2014, then the 
imputed AE onset date will be 01/JAN/2014.In all other cases the missing onset day or 
missing onset month will be replaced by 1.

If after above imputation, the imputed onset date with same month and year of the start of 
study treatment but less than the start of study treatment, and stop date is not less than the 
start of study treatment, then the imputed AE onset date will be re-assigned as the start of 
study treatment. 

If the AE onset date is missing completely, then the onset date will be imputed as 
following: If not missing the visit date and visit date is less than the start of study 
treatment and less than or equal to the stop date, then the visit date will be used to 
impute the onset date.

Else if previous visit date is greater than or equal to the start of study treatment 
and less than or equal to the stop date, then the previous visit date will be used to 
impute the onset date.

Else if previous visit date is less than the start of study treatment and the start of 
study treatment is less than or equal to stop date, then the start of study treatment 
will be used to impute the onset date.

Else Stop date will be used to impute the onset date.

Incomplete stop date will be replaced by the last day of the month (if day is missing 
only).


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
Incomplete stop date will be replaced by the last month of the year (if month is missing).

If the AE stop date is missing completely and still present, then the stop date will be 
imputed as following:

If not missing death date, then death date will be used to impute the stop date.

Else if not missing withdrawal date or Date Decision to Discontinue Treatment, 
the stop date will be imputed as the maximum of Withdrawal date, Date Decision 
to Discontinue Treatment, Onset date or AE visit date.

Else if missing withdrawal date and Date Decision to Discontinue Treatment, the 
stop date will be imputed as the maximum of subject summary visit date, Onset 
date or AE visit date.

Else the stop date will be imputed as the maximum of onset date or last dosing 
date.

If the AE stop date is missing completely and event resolved, then the stop date will be 
imputed as following:

If visit date is greater than onset date, then the visit date will be used to impute the 
stop date.

Else the onset date will be used to impute the stop date.

If after above imputation, the imputed stop date is less than the start of study treatment, 
then the imputed AE stop date will be re-assigned as the start of study treatment. 

In all other cases the incomplete stop date will not be imputed.  If stop date of AE is after 
date of cut-off outcome of AE is ongoing at cut-off. 
5.3.2.3. Prior and Concomitant Medications
Incomplete prior/concomitant medication dates will be imputed as follows:

If the medication date is missing completely, no imputation will be performed.

If the day of medication date is missing, then the medication date will be replaced by 1st
of the month. For example, if the medication start date is --/JAN/2015, then the imputed 
medication start date will be 01/JAN/2015. 

If both the day and month of medication start date are missing, then the medication date 
will be replaced by January 1st of the year. For example, if the medication start date is --
/---/2014, then the imputed medication start date will be 01/JAN/2014.

In all other cases the missing medication day or missing medication month will be 
replaced by 1.


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
Incomplete stop date will be replaced by the last day of the month (if day is missing). 

Incomplete stop date will be replaced by the last month of the year (if month is missing).

In all other cases the incomplete medication stop date will not be imputed. 
5.3.2.4. Exposure
No imputation will be done for first dose date or last dose date.  
5.3.3. Imputation Rules for Date of Last Contact and Efficacy Assessments
5.3.3.1. Date of Last Contact
The date of last contact will be derived for patients not known to have died at the analysis 
cut-off using the latest complete date among the following:

All patient assessment dates (blood draws (laboratory, PK), vital signs, performance 
status, ECG, tumor assessments).

Start and end dates of anti-cancer therapies administered after study treatment 
discontinuation.

AE start and end dates.

Last date of contact collected on the ‘Survival Follow-up’ eCRF (do not use date of 
survival follow-up assessment unless status is ‘alive’).

Study drug start and end dates.

Date of discontinuation on disposition eCRF pages (do not use if reason for 
discontinuation is lost to follow-up).
Only dates associated with actual examinations of the patient will be used in the derivation.  
Dates associated with a technical operation unrelated to patient status such as the date a 
blood sample was processed will not be used. Assessment dates after the cut-off date will 
not be applied to derive the last contact date.
5.3.3.2. Death Date
Partial death dates will be imputed based on the last contact date:

If the day or both the day and the month is missing, death will be imputed to the 
maximum of the full (non-imputed) day after the date of last contact and the following:

Missing day:
1st day of the month and year of death.

Missing day and month:
January 1st of the year of death.


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5.3.3.3. Tumor Assessments
All investigation dates (eg, X-ray, CT scan) must be completed with day, month and year.
If there are multiple scan dates associated with an evaluation, ie, radiological assessments 
occur over a series of days rather than the same day, the choice of date of assessment could 
impact the date of progression and/or date of response.  If there are multiple scan dates 
associated with an evaluation, the earliest of the scan dates associated with the evaluation 
will be used as the date of assessment.
If one or more investigation dates for an evaluation are incomplete but other investigation 
dates are available, the incomplete date(s) are not considered for calculation of the 
assessment date and assessment date is calculated as the earliest of all investigation dates 
(eg, X-ray, CT-scan).  
If all measurement dates for an evaluation have no day recorded, the 1st of the month is used. 
If the month is not completed, for any of the investigations for an evaluation, the respective 
assessment will be considered to be at the date which is exactly between the previous and the 
following assessment.  If both a previous and following assessments are not available, this 
assessment will not be used for any calculations.
5.3.3.4. Date of Start of New Anti-cancer Therapy
Incomplete dates for start date of new anti-cancer therapy (drug therapy, radiation, surgery) 
will be imputed as follows and will be used for determining censoring dates for efficacy 
analyses and in the derivation of the end of on-treatment period.  

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.

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:

completely missing then it will be ignored in the imputations below.

partially missing with only year (YYYY) available then the imputations below will 
consider 01JANYYYY as the start date of the new anti-cancer therapy.


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
partially missing with only month and year available then the imputations below will 
consider the first day of the month for MMMYYYY as the start date of the new anti-
cancer therapy.
6. ANALYSES AND SUMMARIES
Refer to Section 4 for definitions of analysis sets and Section 5.2 for general methodology.
6.1. Primary Endpoints
6.1.1. DLT 
6.1.1.1. Primary Analysis
The primary analyses will be based on the DLT-evaluable set.  DLTs will be listed and 
summarized by treatment group.
6.2. Secondary Endpoint(s)
6.2.1. Safety Endpoints
Refer to Section 6.6.
6.2.2. Efficacy Endpoints
The following analyses will be based on the FAS by treatment group.   Assessment of 
response will be made using RECIST v1.1.
6.2.2.1. Objective Response as Assessed by the Investigator per RECIST v1.1
The following analyses will be based on the FAS by treatment group.   Assessment of 
response will be made using RECIST v1.1.
Best Overall Response (BOR) will be assessed based on reported overall lesion responses at 
different evaluation time points from the ‘start date’ until documented disease progression, 
according to the following rules:

CR = at least two determinations of CR at least 4 weeks apart and before progression.

PR = at least two determinations of PR or better at least 4 weeks apart and before 
progression (and not qualifying for a CR).

SD (applicable only to patients with measurable disease at baseline) = at least one SD 
assessment (or better) ≥6 weeks after ‘start date’ and before progression (and not 
qualifying for CR or PR).

Non-CR/non-PD (applicable only to patients with non-measurable disease at baseline) = 
at least one non-CR/non-PD assessment (or better) ≥6 weeks after ‘start date’ and before 
progression (and not qualifying for CR or PR).


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
PD = progression ≤12 weeks after start date (and not qualifying for CR, PR SD, or non-
CR/non-PD).

Not Evaluable (NE):  all other cases.
Only tumor assessments performed before the start of any further anti-cancer therapies will 
be considered in the assessment of BOR.  Clinical deterioration will not be considered as 
documented disease progression.
Objective Response (OR) is defined as complete response (CR) or partial response (PR) 
according to RECIST v1.1 from start date until documented disease progression. Both CR 
and PR must be confirmed by repeat assessments performed no less than 4 weeks after the 
criteria for response are first met.
Patients who do not have an on-treatment radiographic tumor assessment (including due to 
early clinical progression), who receive anti-tumor treatments other than the study treatments 
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 OR. Each 
patient will have an objective response status (0: no OR; 1: OR).  OR rate (ORR) is the 
proportion of patients with OR in the analysis set.
ORR by treatment group will also be calculated along with the two-sided 95% CI using the 
Clopper-Pearson method (exact CI for a binomial proportion as computed by default by the 
FREQ procedure using the EXACT option).
In addition, the frequency (number and percentage) of patients with BOR of CR, PR, SD, 
PD, non-CR/non-PD (applicable only to patients with non-measurable disease at baseline), 
and NE (not-evaluable) will be tabulated. Patients with BOR of NE will be summarized by 
reason for having NE status. The following reasons will be used:

Inadequate baseline assessment (includes missing assessment or non-measurable disease 
at baseline).

No post-baseline assessment due to death.

No post-baseline assessments due to other reasons.

All post-baseline assessments have overall response NE.

New anticancer therapy started before first post-baseline assessment.

SD of insufficient duration  (<6 weeks after start date).

PD too late (>12 weeks 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’.


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6.2.2.2. Tumor Shrinkage
Tumor shrinkage will be summarized as the percent change from baseline in target lesions 
(sum of longest diameter for non-nodal lesion and short axis for nodal lesion) per time point. 
It will be derived as:

((Sum of target lesions at week XX – sum of target lesions at baseline)/sum of target 
lesions at baseline) x 100.
The maximum reduction in target lesions from baseline will be derived across all the post-
baseline assessments until documented disease progression, excluding assessments after start 
of subsequent anticancer therapy, as:

Minimum of ((sum of target lesions at week XX – sum of target lesions at baseline)/sum 
of target lesions at baseline) x 100.
A waterfall plot of maximum percent reduction in the sum of longest diameter for non-nodal 
lesions and short axis for nodal lesions from baseline will be created. This plot will display 
the best percentage change from baseline in the sum of the diameter of all target lesions for 
each patient with measurable disease at baseline and at least one adequate post-baseline 
assessment.
6.2.2.3. Duration of Response (Expansion Cohort Only)
Duration of Response (DR) is defined, for patients with OR, as the time from first 
documentation of objective response (CR or PR) to the date of first documentation of 
objective progression of disease (PD) or death due to any cause.  If a patient has not had an 
event (PD or death), DR is censored at the date of last adequate tumor assessment. The 
censoring rules for DR are as described below for PFS in Table 3.
DR (months) = [date of event or censoring– first date of OR +1]/30.4375
Kaplan-Meier estimates (product-limit estimates) will be presented by treatment group 
together with a summary of associated statistics including the median DR time with two-
sided 95% CIs.  In particular, the DR rate at 3, 6 and 12 months will be estimated with 
corresponding two-sided 95% CIs.  The CIs for the median will be calculated according to 
Brookmeyer and Crowley and the CIs for the survival function estimates at the time points 
defined above will be derived using the log-log transformation according to Kalbfleisch and 
Prentice (conftype=loglog default option in SAS Proc LIFETEST) with back transformation 
to a CI on the untransformed scale. The estimate of the standard error will be computed 
using Greenwood’s formula.
DR will be displayed graphically and analyzed using Kaplan-Meier methodology. If the 
number of patients with OR is small, the Kaplan-Meier method may not provide reliable 
estimates.  In this case, only descriptive statistics or listings will be provided.


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6.2.2.4. Time to Response (Expansion Cohort Only)
Time to response (TTR) is defined, for patients with OR, as the time from the ‘start date’ to 
the first documentation of objective response (CR or PR) which is subsequently confirmed. 
TTR (in months) = [first date of OR – ‘start date’ +1]/30.4375
TTR will be summarized using simple descriptive statistics (mean, SD, median, min, max. 
Q1, Q3).
6.2.2.5. Progression-Free Survival (Expansion Cohort Only)
Progression-Free Survival (PFS) is defined as the time from start date to the date of the first 
documentation of objective progression of disease (PD) or death due to any cause, whichever 
occurs first.  PFS data will be censored on the date of the last adequate tumor assessment for 
patients who do not have an event (PD or death), or for patients with an event after two or 
more missing tumor assessments. For patients who start a new anti-cancer therapy prior to 
an event, PFS data will be censored on the date of the last adequate tumor assessment prior to 
starting the new anti-cancer therapy. Patients who do not have an adequate baseline tumor 
assessment or who do not have an adequate post-baseline tumor assessment will be censored 
on the ‘start date’ unless death occurred on or before the time of the second planned tumor 
assessment in which case the death will be considered an event (Table 3). 
In this study antitumor activity will be assessed through radiological tumor assessments 
conducted at screening, at 9 weeks after the first dose of study drug, and every 6 weeks until 
disease progression, and at the time of End of Treatment/Withdrawal (if not done in the 
previous 6 weeks).  The allowable time window for disease assessments is ±7 days while on 
treatment and whenever disease progression is suspected (eg, symptomatic deterioration).  
The censoring and event date options to be considered for the PFS and DR analysis are 
presented in Table 3.  
PFS (months) = [date of event or censoring– start date +1]/30.4375


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Table 3.
Outcome and Event Dates for PFS and DR Analyses
Scenario
Date of event/censoring
Outcome
No adequate baseline assessment
‘Start date’ a
Censored a
PD or death 
-
After at most one missing or inadequate 
post-baseline tumor assessment, OR
-
≤ 15 weeks after ‘start date’
Date of PD or death
Event
PD or death after 2 or more missing or inadequate 
post-baseline tumor assessments
Date of last adequate tumor 
assessment b documenting no 
PD before new anti-cancer 
therapy is given or missed tumor 
assessments
Censored
No PD and no death
Date of last adequate tumor 
assessment b documenting no 
PD before new anti-cancer 
therapy is given or missed tumor 
assessments
Censored
Treatment discontinuation due to ‘Disease 
progression’ without documented progression
Not applicable
Information is ignored. Outcome 
is derived based on documented 
progression only.
New anti-cancer therapy given 
Date of last adequate tumor 
assessment b documenting no 
PD before new anti-cancer 
therapy is given or missed tumor 
assessments
Censored
a However if the patient dies ≤15 weeks after ‘start date’ the death is an event with date on death date.
b  If there are no adequate post-baseline assessments prior to the PD or death, then the time without adequate assessment 
should be measured from the ‘start date’; if the criteria were met the censoring will be on the ‘start date.’
Kaplan-Meier estimates (product-limit estimates) will be presented by treatment group 
together with a summary of associated statistics including the median PFS time with two-
sided 95% CIs.  In particular, the PFS rate at 3, 6, 9, 12 and 15 months will be estimated with 
corresponding two-sided 95% CIs.  The CIs for the median will be calculated according to 
Brookmeyer and Crowley and the CIs for the survival function estimates at the time points 
defined above will be derived using the log-log transformation according to Kalbfleisch and 
Prentice (conftype=loglog default option in SAS Proc LIFETEST) with back transformation 
to a CI on the untransformed scale. The estimate of the standard error will be computed 
using Greenwood’s formula.  
Frequency (number and percentage) of patients with each event type (PD or death) and 
censoring reasons will be presented by treatment group. Reasons for censoring will be 
summarized according to the categories in Table 4 following the hierarchy shown.


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Table 4.
PFS Censoring Reasons and Hierarchy
Hierarchy
Condition
Censoring Reason
1
No adequate baseline assessment
No adequate baseline assessment
2
Start of new anti-cancer therapy before event. 
Start of new anti-cancer therapy
3 
Event after 2 or more missing or inadequate post-baseline 
tumor assessments/’start date’
Event after missing assessments a
4
No event and End of study (EOS) = Subject refused further 
follow-up 
Withdrawal of consent
5
No event and lost to follow-up in any disposition page 
Lost to follow-up
6
No event and EOS present and no adequate post-baseline 
tumor assessment 
No adequate post-baseline tumor 
assessment
7 
No event and none of the conditions in the prior hierarchy 
are met 
Ongoing without an event
a 2 or more missing or inadequate post-baseline tumor assessments.   
The PFS time or censoring time and the reasons for censoring will also be presented in a 
patient listing.
Time of Follow-Up for PFS
A plot will be generated to compare planned and actual relative day of tumor assessments by 
treatment group. A Kaplan-Meier plot for PFS follow-up duration will also be generated to 
assess the follow-up time in the treatment groups reversing the PFS censoring and event 
indicators.
6.2.3. Pharmacokinetic Endpoints
The following pharmacokinetic analyses will be conducted by treatment group.  
Standard parameters including, but not limited to Cmax, Ctrough, Tmax, AUC, t1/2, CL, and Vss,
as data permit will be estimated using non-compartmental analysis.
Descriptive statistics (n, mean, SD, %CV, median, minimum, maximum, geometric mean, its 
associated 95% confidence interval and geometric %CV) of serum concentrations for 
PF-05082566 and MK-3475 will be presented in tabular form by study day, cycle, dose and 
nominal time.  Concentrations with zero values will be excluded from the calculation of 
geometric means, its associated 95% confidence interval and geometric %CV. Linear and 
semi-log plots of median serum concentrations vs nominal time will be prepared by study 
day, cycle and dose. Similar plots will be prepared for each individual patient’s serum 
concentrations.  


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Pharmacokinetic parameters will be listed and summarized by cycle and dose using 
descriptive statistics (n, mean, SD, %CV, median, minimum, maximum, and geometric 
mean, its associated 95% confidence interval and geometric %CV).  Dose-normalized 
parameters (eg, Ctrough, Cmax and AUC) will also be listed and summarized. Pharmacokinetic 
parameters with zero values will be excluded from the calculation of geometric means, its 
associated 95% confidence interval and geometric %CV. 
Cmax and Ctrough for PF-05082566 may be plotted against dose (using a logarithmic scale).  
These plots will include individual patient values and the geometric means for each dose.  
These plots will be used to help understand the dose proportionality for PF-05082566.
6.2.4. Population Pharmacokinetic Endpoints
Pharmacokinetic 
 data from this study may be analyzed using 
modeling approaches and may also be pooled with data from other studies to investigate any 
association between PF-05082566 and MK-3475 exposure and biomarkers or significant 
safety/efficacy endpoints. The results of these analyses, if performed, may be reported 
separately.
6.2.5. Biomarker Endpoints
For tumor biopsy samples, the mean and standard deviation, median, and 
minimum/maximum levels of biomarker measures, including but not limited to percentage of 
CD3-positive T cells, will be determined at baseline and post-treatment.  For each pair of 
specimens, the percent change from baseline of these same parameters will also be 
calculated.  The minimum percent change from baseline needed to declare proof of 
pharmacology will be based on assay precision and size of the expansion cohort.
 
  The statistical 
approach will examine correlations of biomarker results with pharmacokinetic parameters 
and measures of anti-tumor efficacy.
 
6.2.6. Endpoints for Immunogenicity Data of PF-05082566 and MK-3475
ADA/ Nab data will be listed and summarized for PF-05082566 and MK-3475 by dose and 
for the entire study population. The percentage of patients with positive ADA and Nab will 
be summarized by dose and overall study population (eg. at baseline, post-dose, treatment-
induced, treatment-boosted or anytime of the study). For patients with positive ADA, the 
magnitude (titer), time of onset, and duration of ADA response will also be described, if data 
permit. The impact of ADA/Nab on PK, safety/efficacy will also be assessed, if data permit.
CCI
CCI
CCI


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6.3. Other Endpoints
 
6.4. Subset Analyses
The number of patients expected in each treatment group is small and therefore no subset 
analyses are planned in this study.
6.5. Baseline and Other Summaries and Analyses
6.5.1. Baseline summaries
The following analyses will be based on the FAS overall and separately by treatment group.
6.5.1.1. Demographic characteristics
Demographic characteristics and physical measurements will be summarized by treatment 
group using the following information from the ‘Screening/Baseline Visit’ eCRF pages.

Demographic characteristics:

Gender: Male, Female.

Race: White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or other Pacific Islander, Other, Unknown.

Ethnic origin: Hispanic/Latino (Yes/No).

Age (years): summary statistics.

Age categories : 

< 65 years, ≥ 65 years.

< 65, 65-<75, 75-<85, ≥ 85 years.

Eastern Cooperative Oncology Group (ECOG) Performance Status: 0, 1, 2, 3, and 4.

Physical measurements:

Height (cm).

Weight (kg).

Body Mass Index (BMI) (kg/m2).

Body Surface Area (BSA) (m2).
CCI


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Site codes will be used for the determination of the patient’s geographic region.
The listing of demographics and baseline characteristics will include the following 
information: patient identifier, treatment group, age, sex, race, ethnicity, height (cm), weight 
(kg), BMI (kg/m2), BSA (m2) and ECOG performance status.
6.5.1.2. Medical History
Medical history will be coded using the most current available version of Medical Dictionary 
for Regulatory Activities (MedDRA) and will be summarized from the ‘Medical History’
eCRF page. Medical history will be summarized as the numbers and percentages of patients 
by MedDRA preferred term (PT) as event category and MedDRA primary system organ 
class (SOC) as summary category. Each patient will be counted only once within each PT or 
SOC.
Medical history will be displayed in terms of frequency tables: ordered by primary SOC and 
PT in alphabetical order.
6.5.1.3. Disease Characteristics
Information on disease characteristics collected on ‘Primary Diagnosis’ and RECIST eCRF 
pages will be summarized overall and by treatment group. Summary statistics will be 
presented for the following.
From the ‘Primary Diagnosis’ eCRF page:

Site of primary tumor.

Primary diagnosis (summarize all categories collected in the ‘Primary Diagnosis’ eCRF 
page).

Time since initial diagnosis to start date (months), defined as (start date – date of initial 
diagnosis)/30.4375.

Time since diagnosis of local/regional recurrence of disease (months), defined as (‘start 
date’ – date of diagnosis of local/regional recurrence of disease)/30.4375.
From the RECIST eCRF page:

Measurable disease (lesions) at baseline (Yes, No).

Involved tumor sites at baseline.
6.5.1.4. Prior Anti-Cancer Therapies
The prior anti-cancer therapies are collected under the ‘Previous systemic therapy’, ‘Prior 
Radiation Therapy’ and ‘Prior Surgery’ eCRF pages.


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The number and percentage of patients in each of the following anti-cancer therapy 
categories will be tabulated:

Patients with at least one type of prior anti-cancer treatment.

Patients with at least one prior anti-cancer drug therapy.

Patients with at least one prior anti-cancer radiotherapy.

Patients with at least one prior anti-cancer surgery.
Prior anti-cancer drug therapy will be summarized as follows based on the number and 
percentage of patients with the following:

At least one prior anti-cancer drug therapy.

Any prior anti-cancer therapy regimens: missing / 1 / 2 / 3 / ≥4.

Type of prior anti-cancer therapy.

Prior anti-cancer immune therapy (including PD-1, PD-L1, anti-CTLA4, others).

Intent of Therapy: Neo-Adjuvant / Adjuvant / Advanced – Metastatic.

Best response: Complete Response (CR) / Partial Response (PR) / Stable Disease (SD) / 
Progressive Disease (PD) / Unknown / Not applicable (Adjuvant only). Best response is 
derived from the last treatment regimen.
The prior anti-cancer drugs will also be summarized based on the number and percentage of 
patients by the drug class and preferred term. A patient will be counted only once within a 
given drug class and within a given drug name, even if he/she received the same medication 
at different times. The summary will be sorted on decreasing frequency of drug class and 
decreasing frequency of drug name in a given drug class. In case of equal frequency 
regarding drug class (respectively drug name), alphabetical order will be used.
The listings of prior anti-cancer treatments and procedures will also be provided as follows. 
These will include the patient identification number, and all the relevant collected data-fields 
on the corresponding eCRF pages.

Listing of prior anti-cancer drug therapies.

Listing of prior anti-cancer radiotherapy.

Listing of prior anti-cancer surgeries.


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6.5.2. Study Conduct and Patient Disposition
The following analyses will be performed based on the FAS overall and separately by
treatment group.
6.5.2.1. Patient Disposition
The percentages below will be calculated based on the number of patients in the FAS.

Total number of patients screened overall.

Number of patients who discontinued from the study prior to treatment with study drug
overall and by the main reason for discontinuation.

Number and percentage of treated patients in each of the analysis sets defined in
Section 4.

Number and percentage of patients with study drug ongoing (separately for each study 
drug when administered in combination).

Number and percentage of patients who discontinued study drug overall and by the main 
reason for discontinuation of study drug (separately for each study drug when 
administered in combination).

Number and percentage of patients who entered safety follow-up.

Number and percentage of patients who discontinued safety follow-up overall and by the 
main reason for discontinuation.
In addition the following will be summarized:

Number and percentage of treated patients by center.
6.5.2.2. Protocol Deviations
All protocol violations that impact the safety of the patients and/or the conduct of a study 
and/or its evaluation will be reported. These include:

Patients who are dosed on the study despite not satisfying the inclusion criteria.

Patients who develop withdrawal criteria whilst on the study but are not withdrawn.

Patients who receive the wrong treatment or an incorrect dose.

Patients who receive an excluded concomitant medication.

Deviations from GCP.
The identification of these and other CSR-reportable deviations will be based on the 
inclusion/exclusion criteria or other criteria presented in the protocol.


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6.5.3. Study Treatment Compliance and Exposure
The following analyses will be based on the safety analysis set by treatment group.
All dosing calculations and summaries will be based on ‘DOSE_PF-05082566’ and 
‘DOSE_MK-3475’ eCRFs pages. A listing of study drug administration will be created with 
the information collected on the ‘DOSE_PF-05082566’ and ‘DOSE_MK-3475’ eCRF pages.
Cycle definitions for study drugs that are administered in combination apply to all the study 
drugs in the combination.  Ie, cycle is patient-dependent, rather than study-drug-dependent 
when study drugs are administered in combination.  
For Cycle X, actual cycle start date for each patient is

the earliest start date of dosing in the Cycle X day 1 visit CRF exposure page, if the 
patient received study treatment on that visit (ie, any study drug with dose>0 at that visit).

the first day of assessments in the Cycle X day 1 visit, if the patient did not receive study 
treatment on that visit (ie, all study drugs had dose=0 at that visit).  Use start date in the 
exposure page if available; if start date is not available then use date of collection of vital 
signs on Cycle X day 1 visit.
Actual cycle end date for each patient is, 

for all cycles X except the last cycle, actual cycle end date =  actual cycle (X+1) start date 
– 1 day;

for the last cycle, actual cycle end date = actual cycle start date + 28 days – 1 day.
Cycle duration (weeks) = (actual cycle end date – actual cycle start date + 1)/7.
When summarizing exposure for each study drug, only cycles from first dose of study 
treatment until the last cycle with non-zero dose of at least one of the study drugs should be 
included.
Exposure will be summarized (overall) as dose received (cumulative dose, actual dose 
intensity) and as dose received relative to intended dose (relative dose intensity [RDI]).  
The formulae below should be applied to each study drug separately.
The derivations below are provided for the following:

PF-05082566 administered as a 1-hour IV infusion at a dose of 0.20 mg/kg, 0.45 mg/kg, 
0.9 mg/kg, 1.8 mg/kg, 3.6 mg/kg or 5 mg/kg once every 3 weeks in 3-week cycles.

MK-3475 will be administered as a 30-minute IV infusion at a dose of 2 mg/kg once 
every 3 weeks.


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Analysis of exposure will be based on the calculated actual dose levels:

PF-05082566 - total dose / weight.

MK-3475 - total dose / weight.
6.5.3.1. Exposure to PF-05082566
The dose level for PF-05082566 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.
Intended duration of treatment with PF-05082566 (weeks) =
(end date–date of first dose of PF-05082566 +1)/7,
where end date = start date of last cycle with non-zero dose of PF-05082566 + 21 – 1
Duration of exposure to PF-05082566 (weeks) = 
(last dose date of PF-05082566 – first dose date of PF-05082566 + 21)/7  
Cumulative dose overall is the sum of the actual doses of PF-05082566 received overall.  
Each cycle for PF-05082566 is defined by a 3-week period. The dose intensity (DI) and the 
relative dose intensity (RDI) will be calculated for each patient across all cycles. Actual 
Dose Intensity (DI)

Overall actual DI (mg/kg/3-week cycle) = [overall cumulative dose (mg/kg)] / [intended 
duration of treatment with PF-05082566 (weeks)/3].  
Relative Dose Intensity (RDI) 

Intended DI (mg/kg/3-week cycle) = [intended cumulative dose per cycle] / [intended 
number of 3-weeks in a cycle] = [d (mg/kg)] / [1 (3-week cycle)]  = d (mg/kg/3-week 
cycle).

Overall RDI (%) = 100 ×  [overall actual DI] / [intended DI]                                                                
= 100 ×  [overall actual DI] / [d (mg/kg/3-week cycle)].
where d is 0.20 mg/kg, 0.45 mg/kg, 0.9 mg/kg, 1.8 mg/kg, 3.6 mg/kg or 5 mg/kg.
The summary of treatment exposure and compliance for PF-05082566 will include the 
following information:

Treatment duration (weeks).

Total number of infusions received.

Cumulative dose (mg/kg).


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
Dose intensity (mg/kg/cycle).

Relative dose intensity (%).
6.5.3.2. Exposure to MK-3475
The dose level for MK-3475 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.
Intended duration of treatment with MK-3475 (weeks) =
(end date–date of first dose of MK-3475 +1)/7,
where end date = start date of last cycle with non-zero dose of MK-3475 + 21 – 1
Duration of exposure to MK-3475 (weeks) = 
(last dose date of MK-3475 – first dose date of MK-3475 + 21)/7  
Cumulative dose overall is the sum of the actual doses of MK-3475 received overall.  
Each cycle for MK-3475 is defined by a 3-week period. The dose intensity (DI) and 
the relative dose intensity (RDI) will be calculated for each patient across all cycles. 
Actual Dose Intensity (DI)

Overall actual DI (mg/kg/3-week cycle) = [overall cumulative dose (mg/kg)] / [intended 
duration of treatment with MK-3475 (weeks)/3].  
Relative Dose Intensity (RDI) 

Intended DI (mg/kg/3-week cycle) = [intended cumulative dose per cycle] / [intended 
number of 3-weeks in a cycle] = 2 (mg/kg/3-week cycle).

Overall RDI (%) = 100 ×  [overall actual DI] / [intended DI]                                                                
= 100 ×  [overall actual DI] / [2 (mg/kg/3-week cycle)].
The summary of treatment exposure and compliance for MK-3475 will include the following 
information:

Treatment duration (weeks).

Total number of infusions received.

Cumulative dose (mg/kg).

Dose intensity (mg/kg/cycle).

Relative dose intensity (%).


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6.5.3.3. Dose Reductions
Dose reduction is defined as actual non-zero dose < 90% of the planned dose. 
Number and percentage of patients with at least one dose reduction as well as a breakdown of 
dose reductions (1 / 2 / 3 / ≥4) will be summarized. 
6.5.3.4. Dose Delays
Delays will be derived based on study drug administration date and will be grouped into the 
following categories based on the deviation of the actual to the planned treatment 
administration day (relative to the previous treatment administration date): 

No delay (including 1-2 days delays).

3-6 days delay.

7 or more days delay.
For example, for PF-05082566, administered on a 3-week schedule, if one patient receives 
PF-05082566 on Day 1, then the next PF-05082566  administration date will be on Day 22; 
however, if the patient receives PF-05082566 at Day 23 or 24, this is considered as ‘no 
delay’. 
Number and percentage of patients with delayed study drug administration and maximum 
length of delay, ie, the worst case of delay if patients have multiple dose delays will be 
summarized. 
6.5.3.5. Infusion Rate Reductions
The number and percentage of patients with at least one infusion rate reduction of ≥50% 
compared to the first infusion rate reported in the CRF (first entry on the first dosing record 
page) as well as the frequency of patients with 1, 2, 3 or ≥4 infusion rate reductions of ≥50% 
will be summarized.
6.5.3.6. Infusion Interruptions
An infusion interruption is defined as an infusion that is stopped and re-started on the same 
day (ie, for a visit more than one infusion start time and infusion end time are recorded).
The number and percentage of patients with at least one infusion interruption as well as the 
frequency of patients with 1, 2, 3, or ≥4 infusion interruptions will be summarized.
6.5.4. Concomitant Medications and Non-Drug Treatments
The following analyses will be based on the safety analysis set by treatment group.
Concomitant medications are medications, other than study medications, which started 
prior to first dose date of study treatment and continued on on-treatment period as well as 
those started during the on-treatment period.  Prior medications are medications, other than 
study medications and pre-medications for study drug, which are started before the first dose 
of study treatment. 


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Prior and concomitant medications will be summarized from the ‘Prior and Concomitant 
Drug Treatment’ eCRF page. 
Summary of prior and concomitant medications will include the number and percentage of 
patients by Anatomical Therapeutic Chemical (ATC) Classification level 2 and preferred 
term. A patient will be counted only once within a given drug class and within a given drug 
name, even if he/she received the same medication at different times. If any prior or 
concomitant medication is classified into multiple ATC classes, the medication will be 
summarized separately under each of these ATC classes. The summary tables will be sorted 
on decreasing frequency of drug class and decreasing frequency of drug name in a given drug 
class. In case of equal frequency regarding drug class (respectively drug name), alphabetical 
order will be used. In case any specific medication does not have ATC classification level 2 
coded term, it will be summarized under ‘Unavailable ATC classification’ category. 
A listing of concomitant medications will be created with the relevant information collected 
on the ‘Prior and Concomitant Drug Treatment’ eCRF page.
All concurrent procedures, which were undertaken any time during the on-treatment period, 
will be summarized according to the eCRF page ‘Prior and Concomitant Non-drug 
Treatment’. 
Number and percentage of patients with concurrent procedures will be tabulated overall and 
by reason for procedure as collected in the eCRF page ‘Prior and Concomitant Non-drug 
Treatment’.
A listing of concurrent procedures will be created with the relevant information collected on 
the ‘Prior and Concomitant Non-drug Treatment’ eCRF page.
6.5.5. Subsequent Anti-cancer Therapies
Anti-cancer treatment will be provided in a data listing with data retrieved from 
‘Concomitant Drug Treatment’, ‘Prior and Concomitant Non-drug Treatment’ and 
‘Concomitant Surgery’ eCRF pages based on clinical review. 
The earliest date of start of new anti-cancer drug therapy after ‘start date’ will be used for the 
definition of the on-treatment period and the earliest date of start of new anti-cancer therapy
after ‘start date’ will be used for the censoring for efficacy analyses (see Section 5.2.5 and 
5.2.6). 
6.6. Safety Summaries and Analyses
The Safety Analysis Set will be the primary population for safety evaluations. Summaries of
AEs and other safety parameters will be based on the safety analysis set by treatment group.  
All summaries of related AEs (PF-05082566 plus MK-3475) will further be presented as 
PF-05082566-related, MK-3475 -related, or related to both study treatments.
All summaries described below by SOC and PT will further be presented by PT in decreasing 
frequency based on the frequencies observed in all treatment groups combined.


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6.6.1. Adverse Events
Treatment-emergent adverse events (TEAEs) are those events with onset dates occurring 
during the on-treatment period for the first time, or if the worsening of an event is during the 
on-treatment period as defined in Section 3.5.1.
All analyses described will be based on TEAEs (started during the on-treatment period) if not 
otherwise specified. The AE listings will include all AEs (whether treatment-emergent or 
not). AEs outside the on-treatment period will be flagged in the listings.

Related Adverse Events: adverse events with relationship to study treatment (as 
recorded on the AE eCRF page, Relationship with study treatment = Related) reported by 
the investigator and those of unknown relationship (ie, no answer to the question 
‘Relationship with study treatment’).

Serious Adverse Events (SAE): serious adverse events (as recorded on the AE eCRF 
page, Serious Adverse Event = Yes).

Adverse Events Leading to Permanent Treatment Discontinuation: adverse events 
leading to permanent discontinuation of study treatment (as recorded on the AE eCRF 
page, Action taken with study treatment = Drug withdrawn).

Adverse Events Leading to Death: adverse event leading to death (as recorded on the 
AE eCRF page, Outcome = Fatal, as well as AEs of Grade 5).

Immune-related Adverse Events (irAE): irAEs (as identified according to a pre-
specified search list of MedDRA PTs, documented in the Merck ECI document and 
finalized for analysis of the current studies data prior to DB lock).

Infusion-related Reactions (IRR): IRRs (as identified according to a pre-specified 
search list of MedDRA PTs, documented in the Merck ECI document and finalized for 
analysis of the current studies data prior to DB lock) with onset on study drug dosing date 
(not prior to infusion of study drug) or the day following study drug infusion.
Unless otherwise specified, AEs will be summarized by number and percentage of patients 
with the AE in the category of interest as described above, by treatment group, primary SOC 
and PT in decreasing frequency observed in all treatment groups combined. 
Each patient will be counted only once within each SOC or PT. If a patient experiences more 
than one AE within a SOC or PT for the same summary period, only the AE with the 
strongest relationship or the worst severity, as appropriate, will be included in the summaries 
of relationship and severity.
6.6.1.1. All Adverse Events
Adverse events will be summarized by worst severity (according to NCI-CTCAE version 
4.03) per patient, using the  latest version of MedDRA preferred term (PT) as event category 
and MedDRA primary system organ class (SOC) body term as Body System category. 


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In case a patient has events with missing and non-missing grades, the maximum of the non-
missing grades will be displayed. No imputation of missing grades will be performed. 
The following tables will be created: 

The overall summary of AEs table will include the frequency (number and percentage) of 
patients with each of the following by treatment group:

TEAEs;

TEAEs, Grade ≥3;

Related TEAEs;

Related TEAEs, Grade ≥3;

TEAEs leading to permanent treatment discontinuation;

Related TEAEs leading to permanent treatment discontinuation;

Serious TEAEs;

Related Serious TEAEs;

TEAEs leading to death;

Related TEAEs leading to death;

TEAEs of irAEs;

Related TEAEs of irAEs;

Treatment-emergent IRRs;

Related treatment-emergent IRRs.

TEAEs by SOC and PT and worst grade.

Related TEAEs by SOC and PT and worst grade.

TEAEs leading to death by SOC and PT.

Related TEAEs leading to death by SOC and PT.

TEAEs by SOC and PT: displaying in separate columns the All TEAEs / Related TEAEs 
/ Grade ≥3 TEAEs / Related Grade ≥3 TEAEs.

TEAEs Excluding SAEs, with frequency ≥5% in any treatment group by SOC and PT.


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6.6.1.2. Adverse Events Leading to Treatment Discontinuation
The frequency (number and percentage) of patients with each of the following will be 
presented for TEAEs leading to permanent discontinuation of each study drug and study 
treatment, by treatment group:

TEAEs leading to discontinuation of PF-05082566 by SOC and PT.

Related TEAEs leading to discontinuation of PF-05082566 by SOC and PT.

TEAEs leading to discontinuation of MK-3475 by SOC and PT.

Related TEAEs leading to discontinuation of MK-3475 by SOC and PT.

TEAEs leading to permanent discontinuation of study treatment. 

Related TEAEs leading to permanent discontinuation of study treatment. 
The listing of all AEs leading to treatment discontinuation will also be provided with the 
relevant information. 
6.6.2. Deaths
The frequency (number and percentage) of patients in the safety analysis set who died and 
who died within 30 days after last dose of study treatment as well as the primary reason for 
death, will be tabulated based on information from the ‘Notice of Death’ and ‘Survival 
Follow-Up’ eCRFs, by treatment group. 

All deaths.

Deaths within 30 days after last dose of study treatment.

Primary Reason for Death:

Disease under study.

Study treatment toxicity.

Unknown.

Other.
In addition, date and cause of death will be provided in individual patient data listing together 
with selected dosing information (study treatment received, date of first / last administration, 
dose) and will include the following information:

AEs with fatal outcome (list preferred terms of AEs with outcome=Fatal, as well as AEs 
of Grade 5), 


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
Flag for death within 30 days of last dose of study treatment.
6.6.3. Serious Adverse Events
The frequency (number and percentage) of patients with each of the following will be 
presented for treatment-emergent SAEs by treatment group:

SAEs by SOC and PT;

Related SAEs by SOC and PT.
The listings of all SAEs will also be provided with the relevant information with a flag for 
SAEs with onset outside of the on-treatment period.
6.6.4. Other Significant Adverse Events
The frequency (number and percentage) of patients with each of the following will be 
presented for treatment-emergent irAEs, by treatment group:

irAEs leading to death, by SOC and PT;

Related irAEs leading to death, by SOC and PT;

irAEs, by SOC and PT;

irAEs, Grade ≥ 3, by SOC and PT;

Related irAEs, by SOC and PT;

Related irAEs, Grade ≥ 3, by SOC and PT;

irAEs leading to permanent treatment discontinuation, by SOC and PT;

Related irAEs leading to permanent treatment discontinuation, by SOC and PT;

Serious irAEs, by SOC and PT;

Related serious irAEs, by SOC and PT.
The listing of all irAEs will also be provided with the relevant information with a flag for 
irAEs with onset outside of the on-treatment period. 
The frequency (number and percentage) of patients with each of the following will be 
presented for treatment-emergent IRRs, by treatment group:

IRRs leading to death, by PT;

Related IRRs leading to death, by PT;


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
IRRs, by PT;

IRRs, Grade ≥ 3, by PT;

Related IRRs, by PT;

Related IRRs, Grade ≥ 3, by PT;

IRRs leading to permanent treatment discontinuation, by PT;

Related IRRs leading to permanent treatment discontinuation, by PT;

Serious IRRs, by PT;

Related serious IRRs, by PT;

Time related to first onset of an IRR (infusion 1, infusion 2, infusion 3, infusion 4 or 
later).
The listing of all IRRs will also be provided with the relevant information with a flag for 
IRRs with onset outside of the on-treatment period.
6.6.5. Laboratory Data
6.6.5.1. Hematology and Chemistry Parameters
Laboratory results will be classified according to the NCI-CTCAE criteria version 4.03. 
Non-numerical qualifiers (with the exception of fasting flags) will not be taken into 
consideration in the derivation of CTCAE criteria (eg, hypokalemia Grade 1 and Grade 2 are 
only distinguished by a non-numerical qualifier and therefore Grade 2 will not be derived).
Additional laboratory results that are not part of NCI-CTCAE will be presented according to 
the categories: below normal limit, within normal limits and above normal limit (according to 
the laboratory normal ranges). 
Quantitative data will be summarized using simple descriptive statistics (mean, SD, median, 
Q1, Q3, minimum, and maximum) of actual values and changes from baseline for each 
nominal visit over time (unscheduled measurements would therefore not be included in these 
summaries as described in Section 5.2.9). End of Treatment visit laboratory results will be 
summarized separately. The changes computed will be the differences from baseline. 
Qualitative data based on reference ranges will be described according to the categories (ie,
Low, Normal, High). 
Abnormalities classified according to NCI-CTCAE toxicity grading version 4.03 will be 
described using the worst grade. For those parameters which are graded with two toxicities 
such as potassium (hypokalemia/hyperkalemia), the toxicities will be summarized separately. 
Low direction toxicity (eg, hypokalemia) grades at baseline and post baseline will be set to 
0 when the variables are derived for summarizing high direction toxicity (eg, hyperkalemia), 
and vice versa.  


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For WBC differential counts (total neutrophil [including bands], lymphocyte, monocyte, 
eosinophil, and basophil counts), the absolute value will be used when reported.  When only 
percentages are available (this is mainly important for neutrophils and lymphocytes, because 
the CTCAE grading is based on the absolute counts), the absolute value is derived as follows: 
Derived differential absolute count = (WBC count) * (Differential %value / 100)
If the range for the differential absolute count is not available (only range for value in % is 
available) then Grade 1 will be attributed to as follows: 

Lymphocyte count decreased:  

derived absolute count does not meet Grade 2-4 criteria, and

% value < % LLN value, and

derived absolute count  ≥800/mm3

Neutrophil count decreased 

derived absolute count does not meet Grade 2-4 criteria, and

% value < % LLN value, and

derived absolute count ≥1500/mm3
For calcium, CTCAE grading is based on Corrected Calcium and Ionized Calcium 
(CALCIO). Corrected Calcium is calculated from Albumin and Calcium as follows:
Corrected calcium (mmol/L) = measured total Calcium (mmol/L) + 0.02 (40 - serum 
albumin [g/L])
Liver function tests: Alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
and total bilirubin (TBILI) are used to assess possible drug induced liver toxicity. The ratios 
of test result over upper limit of normal (ULN) will be calculated and classified for these 
three parameters during the on-treatment period.   
Summary of liver function tests will include the following categories.  The number and 
percentage of patients with each of the following during the on-treatment period will be 
summarized by treatment group:

ALT ≥ 3×ULN, ALT ≥ 5xULN, ALT ≥ 10×ULN, ALT ≥ 20×ULN.

AST ≥ 3×ULN, AST ≥ 5xULN, AST ≥ 10×ULN, AST ≥ 20×ULN.

(ALT or AST) ≥ 3×ULN, (ALT or AST) ≥ 5×ULN, (ALT or AST) ≥ 10×ULN, (ALT or 
AST) ≥ 20×ULN.


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
TBILI ≥ 2×ULN.

Concurrent ALT ≥ 3×ULN and TBILI ≥ 2×ULN.

Concurrent AST ≥ 3×ULN and TBILI ≥ 2×ULN.

Concurrent (ALT or AST) ≥ 3×ULN and TBILI ≥ 2×ULN.

Concurrent (ALT or AST) ≥ 3×ULN and TBILI ≥ 2×ULN and ALP > 2×ULN.

Concurrent (ALT or AST) ≥ 3×ULN and TBILI ≥ 2×ULN and (ALP ≤ 2×ULN or 
missing).
Concurrent measurements are those occurring on the same date.
Categories will be cumulative, ie, a patient with an elevation of AST ≥10×ULN will also 
appear in the categories ≥5×ULN and ≥3×ULN. Liver function elevation and possible Hy’s 
Law cases will be summarized using frequency counts and percentages. 
An evaluation of Drug-Induced Serious Hepatotoxicity (eDISH) plot will also be created, 
with different symbols for different treatment groups, by graphically displaying

peak serum ALT(/ULN) vs peak total bilirubin (/ULN) including reference lines at
ALT=3×ULN and total bilirubin =2×ULN. 

peak serum AST(/ULN) vs peak total bilirubin (/ULN) including reference lines at
AST=3×ULN and total bilirubin =2×ULN. 
In addition, a listing of all TBILI, ALT, AST and ALP values for patients with a post-
baseline TBILI ≥2×ULN, ALT≥3×ULN or AST ≥3×ULN will be provided.
Parameters with NCI-CTC grades available: 
The laboratory toxicities will be tabulated using descriptive statistics (number of patients and 
percentages) during the on-treatment period. The denominator to calculate percentages for 
each laboratory parameter is the number of patients evaluable for CTCAE grading (ie, those 
patients for whom a Grade 0, 1, 2, 3 or 4 can be derived).

The summary of laboratory parameters by CTCAE grade table will include number and 
percentage of patients with Grade 1, 2, 3, 4, Grade 3/4 and any grade (Grades 1-4), 
laboratory abnormalities during the on-treatment period.

The shift table will summarize baseline CTCAE grade versus the worst on-treatment 
CTCAE grade. The highest CTCAE grade during the on-treatment period is considered 
as the worst grade for the summary. 


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The above analyses apply to hematology and chemistry evaluations which can be graded per 
CTCAE, ie:

Hematology: 
Hemoglobin (HB), Leukocytes (white blood cell decreased), Lymphocytes (lymphocyte 
count increased/decreased), Neutrophils / Absolute Neutrophils Count (ANC) 
(neutrophil count decreased), Platelet Count (PLT) (platelet count decreased), 
Coagulation (activated partial thromboplastin time (aPTT) and prothrombin time (INR)).

Serum Chemistry:
Albumin (hypoalbuminemia), Alkaline Phosphatase (alkaline phosphatase increased), 
Alanine Aminotransferase (ALT) (ALT increased), Amylase (serum amylase increased), 
Aspartate Aminotransferase (AST) (AST increased), Total Bilirubin (blood bilirubin
increased, Cholesterol (cholesterol high), Creatinine (creatinine increased), Creatine 
Kinase (CPK increased), Potassium (hypokalemia/ hyperkalemia), Sodium 
(hyponatremia/ hypernatremia), Magnesium (hypomagnesemia/hypermagnesemia), 
Calcium (hypocalcemia/ hypercalcemia), Glucose (hypoglycemia/hyperglycemia), 
Gamma Glutamyl Transferase (GGT) (GGT increased), Lipase (lipase increased), 
Phosphates (hypophosphatemia), Triglycerides (hypertriglyceridemia).
Parameters with NCI-CTC grades not available:
Hematology and chemistry evaluations which cannot be graded per CTCAE criteria will be 
summarized as frequency (number and percentage) of patients with: 

shifts from baseline normal to at least one result above normal during on-treatment 
period.

shifts from baseline normal to at least one result below normal during on-treatment 
period.
In this study, these apply to the following parameters: 

Hematology: Absolute Monocytes, Absolute Eosinophils, Absolute Basophils.

Serum Chemistry: Chloride, Total Urea, Uric Acid, Total Protein, C-Reactive Protein, 
Lactate Dehydrogenase (LDH).
6.6.5.2. Other Laboratory Parameters
All other parameters collected on the eCRF will be listed in dedicated listings presenting all 
corresponding collected information on the eCRF. 

Urinalysis: all urinalysis parameters (except for Proteinuria, which will be 
summarized with CTCAE grades).


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
Other parameters: hormone, and immunology parameters.

Pregnancy test.
The listings of laboratory results will be provided for all laboratory parameters. The listings 
will be sorted by parameters and assessment dates or visits for each patient. Laboratory 
values that are outside the normal range will also be flagged in the data listings, along with 
corresponding normal ranges.  A listing of CTCAE grading will also be generated for those 
laboratory tests. 
In addition, listings of abnormal values will be provided for hematology, chemistry, 
urinalysis, coagulation parameters. If there is at least one abnormal assessment for any 
parameter, all the data for that laboratory parameter will be included into the listing. 
For all tests not mentioned above but present in the clinical data, a listing of patients with at 
least one result for the relevant test will be provided.
6.6.6. Vital Signs
Weight for the purposes of dose calculation will be recorded at screening and within 3 days 
pre-dose Day 1 of each cycle. Weight will not be collected at End of Treatment. Height will 
be measured at screening only.
Vital sign summaries will include all vital sign assessments from the on-treatment period.  
All vital sign assessments will be listed, and those collected outside the on-treatment period 
will be flagged in the listing. 
All vital sign parameters will be summarized using descriptive statistics (mean, SD, median, 
Q1, Q3, minimum, and maximum) of actual values and changes from baseline for each visit 
over time. End of Treatment visit will be summarized separately. The changes computed 
will be the differences from baseline. 
6.6.7. Electrocardiogram
ECG summaries will include all ECG assessments from screening and the on-treatment 
period.  All ECG assessments will be listed, and those collected outside the on-treatment 
period will be flagged in the listing. QTcB and QTcF will be derived based on HR and QT 
(see below). The average of the replicate measurements should be determined after the 
derivation of the individual parameter at each time point.
Selecting Primary QT Correction for Heart Rate
The analysis of QT data is complicated by the fact that the QT interval is highly correlated 
with heart rate.  Because of this correlation, formulas are routinely used to obtain a corrected 
value, denoted QTc, which is independent of heart rate. This QTc interval is intended to 
represent the QT interval at a standardized heart rate. Several correction formulas have been 
proposed in the literature. For this analysis we will use some of those methods of correction, 
as described below. The QT interval corrected for heart rate by the Bazett’s formula, QTcB, 
is defined as:


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RR
QT
QTcB 
,
the QT interval corrected for heart rate by the Fridericia’s formula, QTcF, is defined as 
3 RR
QT
QTcF 
,
where RR represents the RR interval of the ECG, in seconds, and can be estimated as 
60/Heart Rate.  
Both formula produce similar results when the range of heart rates is not extreme. If QTcB 
and QTcF methods do not adequately correct QT for heart rate, an empirical correction 
specific to the study population can be derived.
These corrections were obtained by starting with the simple power model:
QT = a × RRb                                 (1)
and then used the natural log transformation to derive the equation:
ln(QT) = ln(a) + b ln(RR)              (2) 
The power model can be used to derive an empirical correction based on the reference group 
by fitting a linear mixed-effects regression model to the ln(QT) and ln(RR) data, estimating 
the slope b from Equation 2, and then applying that as a power in QTcP(msec) = 
QT(msec)/RR(sec)b to correct all the singlet data (on-drug as well as off-drug.)
Data will be summarized using QTcF and QTcB. However, if these are not appropriate 
correction method for the data set, the results will also be summarized using QTcP.  
ECG Summaries
The following analyses will be performed for each applicable ECG parameters (RR, PR, 
QRS, QT, ventricular rate -denoted as HR in what follows-, and QTc) by treatment group, 
during the on-treatment period. The denominator to calculate percentages for each category 
is the number of patients evaluable for the category.

Pearson correlation between QT and RR, QTc (QTcB, QTcF and, if applicable, QTcP) 
and HR using individual (non-averaged) baseline assessments.

For each of the ECG parameters (HR, and QT, QTc, QRS, PR intervals), descriptive 
statistics at baseline, at each post-baseline time point and changes from baseline at each 
post-baseline time point.

Frequency (number and percentage) of patients with notable ECG values according to the 
following categories:           

QT/QTc increase from baseline >30 ms,  >60 ms.


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
QT/QTc > 450 ms, > 480 ms, >500 ms.

HR ≤ 50 bpm and decrease from baseline ≥20 bpm.

HR ≥ 120 bpm and increase from baseline ≥20 bpm.

PR ≥ 220 ms and increase from baseline ≥20 ms.

QRS ≥120 ms.
Frequency (number and percentage) of patients with post-baseline qualitative ECG 
abnormalities (morphology) will be summarized.
Patients with notable ECG interval values and qualitative ECG abnormalities will be listed 
for each patient and time point and the corresponding notable values and abnormality 
findings will be included in the listings.
Unscheduled ECG measurements will not be used in computing the descriptive statistics for 
change from baseline at each post-baseline time point. However, they will be used in the 
analysis of notable ECG changes and the shift table analysis of notable QT parameters.
6.6.8. Physical Examination
Number and percentage of patients with abnormal findings in physical examination will be 
summarized by body system.
6.6.9. ECOG Performance Status
The ECOG shift from baseline to highest score during the on-treatment period will be 
summarized by treatment group. ECOG performance status with shift from ECOG=0 or 1 to 
ECOG 2 or higher will also be presented in a data listing.
7. INTERIM ANALYSES
There is no formal interim analysis planned for this study. A Dose Escalation Steering 
Committee (DESC) was established to review safety data. Periodical DESC meetings will be 
scheduled to make decisions on escalation and de-escalation following the TITE-CRM 
design. 
7.1. Introduction
Not Applicable.
7.2. Interim Analyses and Summaries
Not Applicable.


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