Conditions: Part 1 MELANOMA SCCHN OVCA SARCOMA OTHER SOLID TUMORS Part 1 and 2 NSCLC UROTHELIAL CARCINOMA
Keywords: efficacy safety pharmacokinetics pharmacodynamics open label dose response multiple ascending dose immunogenicity recommended phase 2 dose subcutaneous
Allocation: NON_RANDOMIZED | Intervention model: 
Enrollment: 147
Healthy volunteers: no

Brief summary:
Protocol B8011001 is a Phase 1, open-label, multi-center, multiple-dose, dose escalation and expansion, safety, pharmacokinetics (PK), and pharmacodynamics (PD) study of PF-06801591 in previously treated adult patients with locally advanced or metastatic melanoma, SCCHN, ovarian carcinoma, sarcoma, NSCLC, urothelial carcinoma or other solid tumors. This is a 2 Part study whereby the safety and tolerability of increasing dose levels of intravenous (IV) or subcutaneous (SC) PF-06801591 was assessed in Part 1. Part 2 expansion is designed to further evaluate the safety and efficacy of SC PF-06801591 in patients with NSCLC or urothelial carcinoma as well as confirm the recommended Phase 2 dose.

Detailed description:
Protocol B8011001 is a Phase 1, two part, open-label, multi center, multiple-dose, safety, efficacy, PK, and PD study of PF-06801591 administered intravenously (IV) or subcutaneous (SC) in previously treated adult patients with locally advanced or metastatic melanoma, squamous cell carcinoma head and neck (SCCHN), ovarian carcinoma, sarcoma, non-small cell lung carcinoma (NSCLC), urothelial carcinoma or other solid tumors.

The first part of the study, Part 1 dose escalation, was designed to assess the safety and tolerability of increasing dose levels of IV or SC administered PF-06801591 to establish the maximum tolerated dose (MTD) using a modified Toxicity Probability Interval (mTPI) design. Part 2 expansion is designed to further evaluate the safety and efficacy of 300 mg of PF-06801591 administered SC once every 4 weeks in patients with NSCLC or urothelial carcinoma as well as confirm the recommended Phase 2 dose (RP2D). Part 1 enrollment has completed, enrollment will only be allowed for Part 2.

Arms:
arm 1: 0.5 mg/kg IV every 21 days (Part 1) arm 2: 1.0 mg/kg IV every 21 days (Part 1) arm 3: 3.0 mg/kg IV every 21 days (Part 1) arm 4: 10 mg/kg IV every 21 days (Part 1) arm 5: 300 mg SC every 28 days (Part 1 and 2)

Interventions: intervention 1: PF-06801591 intervention 2: PF-06801591
Intervention descriptions: intervention 1: IV every 21 days (Part 1) intervention 2: 300 mg SC every 28 days (Part 1 and 2)

Protocol document:
Prot_000.pdf: 
PF-06801591
B8011001
Final Protocol Amendment 4, 07 August 2018
PFIZER CONFIDENTIAL
Page 1
A PHASE 1, OPEN-LABEL, DOSE ESCALATION AND EXPANSION STUDY OF 
PF-06801591 IN PATIENTS WITH LOCALLY ADVANCED OR METASTATIC 
MELANOMA, SQUAMOUS CELL HEAD AND NECK CANCER, OVARIAN 
CANCER, SARCOMA, NON-SMALL CELL LUNG CANCER, UROTHELIAL 
CARCINOMA OR OTHER SOLID TUMORS  
Compound:
PF-06801591
Compound Name:
Not applicable (N/A)
United States (US) Investigational New 
Drug (IND) Number:
European Clinical Trials Database 
(EudraCT) Number:
2016-003314-27
Protocol Number:
B8011001
Phase:
Phase 1
This document contains confidential information belonging to Pfizer.  Except as otherwise agreed to in writing, 
by accepting or reviewing this document, you agree to hold this information in confidence and not copy or 
disclose it to others (except where required by applicable law) or use it for unauthorized purposes.  In the event 
of any actual or suspected breach of this obligation, Pfizer must be promptly notified.
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Document History
Document
Version Date
Summary of Changes and Rationale
Original 
protocol
11 September 2015
N/A
Amendment 1
10 December 2015
Section 3.1.5 Modification of dose limiting 
toxicities by addition of the following criteria, as 
per a request of the FDA to define these toxicities: 
1.  Platelet transfusion requirement or a platelet 
count < 10,000/uL, 2.  Concurrent AST or ALT 
>3X ULN and total bilirubin >2X ULN (potential 
Hy’s law case).
Sections 4.1, 4.2 and 4.3: Update the period to 
require contraception require
that male patients who are able to father children 
and female patients of childbearing potential use 
two (2) effective methods of contraception 
throughout
the study and for at least 5 months following the 
last dose of PF-06801591, as per a request of the 
FDA based on compartmental modeling and 
allometric scaling of monkey PK data.
Schedule of Assessments: Added contraception 
check at days 63 and 120, to prolong monitoring of 
contraceptive use after last dose, during follow-up.
Section 8.1: Update as per a request of the FDA to 
include that adverse events the investigator deems 
immune-related and whether an 
immunosuppressive therapy (eg, corticosteroids, 
other immunosuppressant drugs) is indicated, will 
be recorded on the CRF.  For any adverse event, 
regardless of investigator determined causality, if 
the management requires administration of an 
immunosuppressive therapy, the use will be 
documented on a specific case report form that will 
record generic drug name, stop and start dates 
(duration), dose, units, route,  frequency of 
administration, and response to medication.


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Schedule of Assessments:
Due to alignment with laboratory analyses, 
changes were made to blood volumes for 
collection of whole blood biomarkers and receptor 
occupancy samples.  In addition, some editorial 
clarifications were made for the time collection of 
anti- PF-06801591 antibody measurement and 
PF-06801591 PK blood samples (ie, up to Cycle 
10), 
 was added 
 
 for the sake of clarification.
Schedule of Assessments: Update for serious 
adverse events (SAEs) to include that the active 
reporting period to Pfizer or its designated 
representative is through and including 
150 calendar days after the last administration of 
the investigational product or until administration 
of subsequent anti-cancer therapy whichever 
comes first, in order to align SAEs monitoring
with contraception use period.
Section 8.2: Update the reporting period for SAEs, 
ie, is through and including 150 days, after the last 
administration of the investigational product or 
until administration of subsequent anti-cancer 
therapy, whichever comes first, in order to align 
SAEs monitoring with contraception use period.  
Also, an update was made in this section to be 
consistent with the Schedule of Assessments, to 
mention that additional, immune-related AEs will 
be collected with a follow-up phone call at 63 and 
120 days after last dose administration date to 
collect post-treatment related AE information.
Amendment 2
21 July 2016
Updated TOC, lists of tables, figures, and 
appendices.  
Schedule of Activities split into 2 schedules: one 
for IV administration and one for subcutaneous 
administration of study treatment.
Schedule of Activities: Removal of Day 
63 (Post-treatment) and update of assessments on 
Day 28 and Day 90 (Post-treatment).  
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Schedule of Activities for SC Administration, 
added a “Day 21 of Cycle 1” column for clinical 
assessments: abbreviated physical examination, 
vital signs, hematology & chemistry laboratory 
panels, adverse events, and concomitant and 
non-drug supportive interventions.
Schedule of Activities, Vital Signs: added "X" to 
schedule for vital signs to be performed on Day 
3 of Cycle 1, which had been inadvertently 
omitted.
Schedules of Activities and Section 4.1. (Inclusion 
Criterion # 6) were updated to correct 
Appendix 6 to 7, to refer to the ECOG 
Performance Status.
Schedules of Activities: Subsequent Cycles 
updated to clarify that free T3 (triiodothyronine), 
and free T4 (thyroxine) testing are included in the 
Blood Chemistry panel, as per Table 4 in the 
Laboratory Safety Assessment Section (7.1.3).
Schedules of Activities: Footnote created to 
provide details on the blood collection for high 
sensitivity C-reactive protein.
Schedules of Activities: Footnote created to 
provide details on the blood collection for TBNK 
(Whole Blood).
 
 
Schedule of Activities IV and SC Administration 
footnotes: updated to indicate that standard of care 
radiographic assessments performed within 
28 days of C1D1 may not have to be repeated and 
used as the screening (baseline) tumor assessment.
Schedule of Activities for IV and SC 
Administration footnotes: Second scan changed 
from required to preferred.  Clarified “entire” 
study and defined end of entire study (2 years after 
LPFT). 
Schedules of Activities: updated to clarify which 
assessments must be performed on Day 8 and/or 
Day 15 after Cycle 2.
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Schedules of Activities, footnote ee: Added 
“entire” study and defined end of entire study 
(2 years after LPFT).  Wording on clinic visit 
during follow-up window can replace survival 
telephone call.
Schedule of Activities and Section 3.1. (Study 
Overview): Updated length of 
PF-06801591 treatment (up to 2 years).  Treatment 
until disease progression clarified as disease 
progression per irRECIST.
Schedule of Activities and Section 
3.1.5. (Dose-Limiting Toxicity Definition): 
Updates were made to include the SC cohort at a 
fixed dose of 300 mg administered over a cycle of 
28 days.
Schedule of Activities and Section 7.4. (Tumor 
Response Assessments): Extended tumor 
assessments beyond end of treatment if treatment 
did not end for disease progression, death, or 
consent withdrawal.
Pharmacokinetic and Pharmacodynamic Schedule 
of Activities: updated and split into 2 schedules: 
PF-06801591 IV and subcutaneous administration. 
PK & Pharmacodynamic Schedules of Activities: 
Clarifications were added to footnotes for the PK 
sampling on Day 1 of Cycle 1, and a new footnote 
was created to clarify the (±2) window on Day 8 of 
Cycle 2.
PK & Pharmacodynamic Schedules of Activities:
Clarified archival or fresh tumor biopsy required at 
Screening only in Part 2.
Section 1.2. (Background and Rationale): Updates 
were made as per recent publications.
Section 1.2.4. (SC Dose Rationale): New text was 
added to explain the rationale for the fixed dose of 
300 mg that is administered subcutaneously (SC) 
in the additional dose cohort.
Section 1.2.5. (Rationale for Pre-treatment and 
On-treatment Biopsies and Expansion of Various 
Dose Level Cohorts): Language was added to 
clarify the rule for the decision to dose escalate
(Part 1A) vs the MTD and RP2D determination.


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Section 1.2.5. (Rationale for Pretreatment and On 
treatment Biopsies and Expansion of Various Dose 
Level Cohorts): Wording on each dose level to 
enroll up to 15 patients.
Section 1.2.5. (Rationale for Pretreatment and On 
treatment Biopsies), and Section 3.1.1. (Study 
Overview Part 1): Part 1B to include 3 to 
5 minimum patients with available pre- and 
on-treatment biopsies.
Section 1.3. (Biomarker Rationale): Edits were 
made to clarify that potential effects of 
PF-06801591 on the PD-1 receptor and the 
PD-L1 ligand expression will not be assessed by 
flow cytometry.  PD-1 receptor cannot be 
adequately assessed by flow cytometry because 
PF-06801591 competes for binding with the flow 
cytometry antibody for PD-1.
Section 2.1.1. (Objectives for Part 1), & Section 
2.1.2. (Objectives for Part 2): Updates were made 
for the additional dose cohort with a SC 
administration.  
 
 
 
 
 
Section 3.1. (Study Overview): Added “or other 
solid tumors” to list of treated tumor types for the 
study in order to enable enrollment of other tumor 
types that have clinical evidence of response to 
anti PD-1 to PD-L1 agents at the discretion of the 
sponsor.
Section 3.1. (Study Overview): Text was edited to 
clarify that up to 15 patients, instead of 
approximately 8 to 15 patients will be enrolled per 
dose level (except for the 0.5 mg/kg dose level), in 
Part 1. In addition, a paragraph was added to 
explain the enrollment of the additional SC cohort 
at a fixed dose of 300 mg.  Text was deleted to 
remove the number of sites involved, allowing 
some flexibility.  
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Schedule of Activities for IV Administration, 
Section 3.1. (Study Overview), & Section 
5.4. (Administration): A window for the infusion 
time of PF-06801591 was added to have 
60 minutes ± 10 minutes.
Section 3.1.1. (Study Overview, Part 1): Text was 
added to introduce the SC dosing cohort.
Section 4.1. (Inclusion Criteria): Updated criterion 
#1a to allow for other tumor types with clinical 
evidence of response to anti PD-1 or PD-L1 agents 
to be considered at the discretion of the sponsor.  
Updated criterion #1 to remove an upper limit on 
prior lines of therapy.  
 
 
 
 
 
 Clarified in Part 1A or 2 that 
fresh biopsy can be used if archival biopsy is 
unavailable.  In Part 1B, archival sample 
encouraged, but waived if unavailable.
Section 4.2. Exclusion Criteria: Added wording on 
prior allogeneic bone marrow or hematopoietic 
stem cell transplant.
Section 5.4. (Administration) was divided into two 
(2) sections: 5.4.1. (IV Administration), and 
5.4.2. (SC Administration) to provide updated 
information on the SC administration for the 
additional cohort.  Study Treatment footnote in the 
Schedule of Activities was updated accordingly for 
the SC administration. 
Section 6.3. (Study Procedures/Follow-up Visit): 
Defined end of entire study as 2 years after last 
patient enrolled has been first treated and 
explained that clinic visit can replace telephone 
call for survival data
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Section 7.1.1. (Pregnancy Testing) & Section 
7.1.3. (Laboratory Safety Assessments, Table 4): 
FSH testing at Screening only was added to 
confirm the postmenopausal status for women who 
have not experienced their menses since at least 
12 months.  Confirmation of FSH level was 
already mentioned in inclusion criterion #15c, but 
it needed to be clarified in the above mentioned 
sections of the protocol.  Schedule of Activities 
was updated accordingly.
Section 7.1.6. (Local Site Injection Tolerability 
Assessment (SC Cohort Only): New text was 
added to include a site injection tolerability 
assessment for the additional SC dose level cohort.  
Footnote in the Schedule of Activities for 
subcutaneous drug administration was created 
accordingly to reflect this new procedure.
Section 7.5. (CA-125 Tumor Marker Assessment -
Ovarian Cancer Only): A new section was added 
to provide details on this test for ovarian cancer 
patients only.  Schedule of Activities footnote
created accordingly to reflect this new procedure.
Section 9.1.3. (Per-protocol Analysis Set): 
Clarified that SC patients with major deviations 
will not be evaluated for DLTs.
Section 9.3. (Sample Size Determination):
Updated wording on sample size and number of 
patients for Parts 1A and 1B.
References (Section 16): 
References added to Sec 1 Introduction: Tecentriq 
PI, web site links to other solid tumor types and 
mismatch repair. 
References by Rusin & DeVita were added for 
background on CA-125; References for Gillison 
and Ansell were added for updates on nivolumab.
Appendix 10. (SC Injection Site Location 
Diagram): A new appendix was added to the 
document to provide detailed instructions for the 
SC administration of PF-06801591. 


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Amendment 3
03 JUN 2017
Throughout document: removal of relapsed and 
refractory classic Hodgkin Lymphoma references 
in protocol title and protocol body.  Removal of 
lymphoma response criteria.  
Schedule of activities: added for Part 2, and 
administrative edits made for schedule of activities 
for Part 1, including addition of preexisting Day 8 
ECG, survival follow up visits, clarification of 
SAE collection up to 150 days after last treatment, 
and include information regarding collection tumor 
assessment information after end of treatment for 
patients who did not end treatment due to disease 
progression, death, or withdrawal of consent.
Section 1. Introduction: Addition of background 
information for urothelial carcinoma, and updated 
section with emerging data on pembrolizumab, 
nivolumab, atezolizumab, durvalumab, and 
avelumab in support of study rationale.
Section 1.9: Addition of clinical experience 
information for PF-06801591. Addition of risk 
benefit assessment.
Section 2. Objectives and Endpoints: Added 
objectives and endpoints specific for Part 2.
Section 3. Study design: administrative edits made 
to clarify design of study. Details of Part 2 
incorporated, including the enrollment of NSCLC 
patients in Arm 1, and Urothelial patients in Arm 
2. Included information on dose selected for Part 2 
expansion.
Section 4. patient selection: added specific 
inclusion/ exclusion criteria for Part 2.
Section 5.1.2. Allocation of treatment for dose 
expansion: Added interactive response technology 
(IRT) system for patient enrollment in Part 2.
Section 5.4.2. Dose Delays: Added dose delay 
information.
Section 6.3.2. Survival follow up: Added survival 
follow up section to align with information 
included in schedule of activities.
Section 7.1.3. Laboratory assessments:
Administrative edits made to align Table 4 with 
items included in schedule of activities.


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Section 7.3. Biomarker assessments: Clarified that 
archival sample for Part 2 must be taken within 
two year of start of study treatment.
Section 8.2. SAE reporting period: Clarified that 
death must be reported as an SAE if it occurs 
within 150 calendar days after last administration 
of the investigational product, irrespective of any 
intervening treatment.
Section 9.2. Statistical methods and properties:
Removed reference to optimal biological dose, and 
added statistical methods for Part 2.
Section 9.3. Sample size determination: Added 
information for Part 2.
Section 9.4. Efficacy information: Added 
information for Part 2.
Section 9.8 Data safety monitoring committee:
Added information on preliminary analysis for
safety and efficacy.
Section 13. Definition of end of trial: Clarified that 
end of trial will be 2 years after last patient first 
dose (LPFD), not last patient last visit (LPLV).
Appendix 8 Management of irAEs: Updated 
appendix with initial and follow-up irAE 
management information.
Amendment 4
07 August 2018
Study overview and section 9.3: The number of 
enrolled subjects has been changed throughout the 
part 2 of protocol from approximately 60 NSCLC 
and 40 urothelial cancer patients to approximately 
70 and 30, respectively, to more accurately reflect 
projected enrollment. Statistical justification for 
patient sample size in section 9.3 has also been 
adjusted accordingly.
Schedule of Activities, Part 2 and Section 7.1.1, 
Pregnancy testing: Per Poland competent authority 
request, added the following paragraph for 
pregnancy tests in Poland: In Poland, pregnancy 
tests should be performed after end of treatment on 
days 28, 60, 90, 120, and 150. Pregnancy tests on 
days 60, 90, 120, and 150 may be collected at 
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Schedule of Activities, Footnote O: Removed 
language: “No need to repeat on C1D1 if baseline 
assessment performed within 72 hours prior to that 
date.” Screening UA is not required within 72 
hours of C1D1.
Schedule of Activities For Part 1 Subcutaneous 
Administration of PF-06801591 – Changed Cycle 
1 Day 22 to Cycle 1 Day 21 to accommodate 
calendar scheduling for this visit.  
Section 1.2. Background and Rationale: updates 
from recent clinical trials provided in NSCLC and 
urothelial cancer sections.
Section 4.1.2. Part 2 Inclusion Criterion 5 for 
urothelial cancer patients, sub-bullet point e: 
Added the following sentence: If patients are
treatment naïve and eligible for platinum-
containing systemic therapy but are refusing 
platinum chemotherapy, they must also be 
documented to have previous PD-L1 high status.
Rationale: Two ongoing clinical studies 
(KEYNOTE-361 and IMVIGOR-130) evaluating
either single agent pembrolizumab or atezolizumab 
versus platinum chemotherapy in previously 
untreated metastatic urothelial carcinoma eligible 
for platinum-based chemotherapy treatment found 
that patients with PD-L1 low tumors in the 
monotherapy pembrolizumab or atezolizumab
arms had decreased survival compared to patients 
who received cisplatin- or carboplatin-based 
chemotherapy.
Section 4.2.2. Part 2 Exclusion Criterion 3: Added 
the following clarification: For example, patients
with HBV surface antigen positive or HCV RNA 
positive will be excluded.
Rationale: This provides examples of what 
constitutes “active” HBV or HCV infections.
Section 4.2.1. Part1 Exclusion Criterion 12 and 
Section 4.2.2. Part2 Exclusion Criterion 12: 
Corrected definition of bifascicular block.


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Section 4.2.2. Exclusion Criterion 17 added per 
South Korea competent authority request: For 
South Korea, vaccination except inactivated 
vaccine within 4 weeks prior to the enrolment of 
the study or during the study. 
Section 4.2.2. Exclusion Criterion 18 added per 
South Korea competent authority request: For 
South Korea, patients with active infection 
requiring systemic therapy will be excluded.
Section 7.1.1. Pregnancy testing or 
postmenopausal status: Removed requirements to 
collect pregnany test within 5 days of menses and 
added “If a urine test cannot be confirmed as 
negative (eg, an ambiguous result), a serum 
pregnancy test is required. In such cases, the
participant must be excluded if the serum 
pregnancy is positive.” to ensure consistency with 
newer Pfizer pregnancy testing language.
Section 7.4. Tumor response assessments: The 
phrase “and bone scans” has been removed and the 
phrase “Bone scans should be performed at 
baseline and on-study for patients with known or 
suspected bone metastases not well-visualized on 
other imaging or if disease is suspected or has been 
previously documented as appropriate to follow 
disease.“ has been added for clarification.
Section 7.7.1. Markers of drug response: Third 
paragraph has been modified to clarify collection 
of blood for DNA analysis will be collected at the 
screening and Cycle 2 Day 8 visits (Part 1 only) 
and Cycle 1 Day 1 visits (Part 2 only).
Rationale: To differentiate collections in part 1 vs. 
part 2.
Minor editorial changes throughout the protocol 
and schedule of changes.
This amendment incorporates all revisions to date, including amendments made at the 
request of the FDA. 


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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................18
LIST OF FIGURES .................................................................................................................19
APPENDICES .........................................................................................................................19
PROTOCOL SUMMARY.......................................................................................................20
SCHEDULE OF ACTIVITIES FOR PART 1 INTRAVENOUS ADMINISTRATION .......26
PHARMACOKINETIC AND PHARMACODYNAMIC SCHEDULE OF 
ACTIVITIES: PART 1 INTRAVENOUS ADMINISTRATION OF PF-06801591 .........32
SCHEDULE OF ACTIVITIES FOR PART 1 SUBCUTANEOUS 
ADMINISTRATION OF PF-06801591.............................................................................34
PHARMACOKINETIC AND PHARMACODYNAMIC SCHEDULE OF 
ACTIVITIES: PART 1 SUBCUTANEOUS ADMINISTRATION OF PF-06801591......40
SCHEDULE OF ACTIVITIES FOR PART 2: SUBCUTANEOUS 
ADMINISTRATION OF PF-06801591.............................................................................43
PHARMACOKINETIC AND PHARMACODYNAMIC SCHEDULE OF 
ACTIVITIES: PART 2 SUBCUTANEOUS ADMINISTRATION OF PF-06801591......49
1. INTRODUCTION ...............................................................................................................51
1.1. Mechanism of Action/Indication.............................................................................54
1.2. Background and Rationale ......................................................................................55
1.2.1. Melanoma ...................................................................................................55
1.2.2. Head and Neck Cancer ...............................................................................55
1.2.3. Ovarian Cancer ...........................................................................................56
1.2.4. Sarcomas.....................................................................................................56
1.2.5. Non-Small Cell Lung Cancer (NSCLC).....................................................56
1.2.6. Urothelial Carcinoma..................................................................................59
1.2.7. Background Summary ................................................................................62
1.3. Nonclinical Efficacy................................................................................................63
1.4. Nonclinical Safety...................................................................................................65
1.5. Starting Dose Rationale...........................................................................................67
1.6. Subcutaneous (SC) Dose Rationale.........................................................................67
1.7. Rationale for Pre-treatment and On-treatment Biopsies and Expansion of 
Various Dose Level Cohorts .....................................................................................68
1.8. Biomarker Rationale ...............................................................................................69
1.9. Clinical Experience .................................................................................................70


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1.9.1. Clinical Experience in Study B8011001.....................................................70
1.9.2. Clinical Experience in Study B7791001.....................................................71
1.9.3. Risk Benefit Assessment ............................................................................72
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................72
2.1. Part 1 Dose Escalation.............................................................................................72
2.2. Part 2 Dose Expansion ............................................................................................74
3. STUDY DESIGN.................................................................................................................75
3.1. Study Overview.......................................................................................................75
3.1.1. Part 1 Dose Escalation................................................................................77
3.1.2. Part 2 Dose Expansion................................................................................78
3.1.3. Starting Dose ..............................................................................................78
3.1.4. Criteria for Dose Finding............................................................................79
3.1.5. Dose-limiting Toxicity Definition..............................................................80
3.1.5.1. Late Immune-Related Dose-Limiting Toxicities ......................81
3.1.6. Maximum Tolerated Dose Definition.........................................................82
3.1.7. Optimal Biological Dose Definition...........................................................82
3.1.8. Recommended Phase 2 Dose (RP2D) Definition.......................................82
4. PATIENT SELECTION......................................................................................................82
4.1. Inclusion Criteria.....................................................................................................83
4.1.1. Part 1 Dose Escalation................................................................................83
4.1.2. Part 2 Dose Expansion................................................................................85
4.2. Exclusion Criteria....................................................................................................88
4.2.1. Part 1 Dose Escalation................................................................................88
4.2.2. Part 2 Dose Expansion................................................................................90
4.3. Lifestyle Guidelines ................................................................................................92
4.4. Sponsor’s Qualified Medical Personnel..................................................................93
5. STUDY TREATMENTS.....................................................................................................94
5.1. Allocation to Treatment ..........................................................................................94
5.1.1. Part 1 Dose Escalation................................................................................94
5.1.2. Part 2 Dose Expansion................................................................................95
5.2. Patient Compliance .................................................................................................95
5.3. Investigational Product Supplies.............................................................................95


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5.3.1. Dosage Form(s) and Packaging..................................................................95
5.3.2. Preparation and Dispensing........................................................................96
5.4. Administration.........................................................................................................96
5.4.1. IV Administration (Part 1 Only).................................................................96
5.4.2. SC Administration (Parts 1 and 2)..............................................................97
5.4.3. Recommended Dose Modifications............................................................97
5.4.3.1. Rules For Dose Delay/Interruption/Discontinuation.................98
5.4.3.2. Infusion Reactions.....................................................................99
5.4.3.3. Hypersensitivity Types 1 and 3.................................................99
5.4.3.4. Extravasation.............................................................................99
5.4.3.5. Immune-Related Adverse Events..............................................99
5.4.5. Dose Delays..............................................................................................100
5.4.6. Dose Reductions.......................................................................................100
5.5. Investigational Product Storage ............................................................................100
5.6. Investigational Product Accountability.................................................................101
5.6.1. Destruction of Investigational Product Supplies ......................................101
5.7. Concomitant Treatment(s).....................................................................................102
5.7.1. Other Anti-tumor/Anti-cancer or Experimental Drugs.............................102
5.7.2. Supportive Care ........................................................................................102
5.7.3. Hematopoietic Growth Factors.................................................................102
5.7.4. Anti-Diarrhea, Anti Emetic Therapy........................................................102
5.7.5. Anti-inflammatory and Narcotic Therapy ................................................103
5.7.6. Corticosteroids..........................................................................................103
5.7.7. Surgery......................................................................................................103
5.7.8. Radiation Therapy ....................................................................................103
6. STUDY PROCEDURES ...................................................................................................103
6.1. Screening...............................................................................................................103
6.2. Study Period ..........................................................................................................104
6.3. One Month Follow-up Visit ..................................................................................104
6.4. Follow-up for Late Immune-related Adverse Events............................................104
6.5. Survival Follow-up................................................................................................104
6.6. Patient Withdrawal................................................................................................105


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7. ASSESSMENTS................................................................................................................106
7.1. Safety Assessment.................................................................................................106
7.1.1. Pregnancy Testing or Postmenopausal Status ..........................................107
7.1.2. Adverse Events.........................................................................................107
7.1.3. Laboratory Safety Assessment .................................................................107
7.1.4. Vital Signs and Physical Examination......................................................110
7.1.5. (12-Lead) Electrocardiogram....................................................................110
7.1.6. Local Site Injection Tolerability Assessment (SC Only) .........................111
7.2. Pharmacokinetic Assessments...............................................................................112
7.2.1. Blood for PK analysis of PF-06801591....................................................112
7.3. Biomarker and Pharmacodynamic Assessments...................................................112
7.4. Tumor Response Assessments ..............................................................................114
7.5. CA-125 Tumor Marker Assessment (Ovarian Cancer Only)................................115
7.6. Immunogenicity Evaluations.................................................................................116
8. ADVERSE EVENT REPORTING....................................................................................118
8.1. Adverse Events......................................................................................................118
8.2. Reporting Period ...................................................................................................118
8.3. Definition of an Adverse Event.............................................................................119
8.4. Medication Errors..................................................................................................120
8.5. Abnormal Test Findings........................................................................................120
8.6. Serious Adverse Events.........................................................................................121
8.6.1. Protocol-Specified Serious Adverse Events.............................................121
8.6.2. Potential Cases of Drug-Induced Liver Injury..........................................121
8.7. Hospitalization ......................................................................................................123
8.8. Severity Assessment..............................................................................................124
8.9. Causality Assessment............................................................................................124
8.10. Exposure During Pregnancy................................................................................125
8.11. Occupational Exposure .......................................................................................126
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8.12. Withdrawal Due to Adverse Events (See Also the Section 6.6 Patient 
Withdrawal).............................................................................................................126
8.13. Eliciting Adverse Event Information ..................................................................126
8.14. Reporting Requirements......................................................................................126
8.14.1. Serious Adverse Event Reporting Requirements ...................................127
8.14.2. Non-Serious Adverse Event Reporting Requirements ...........................127
8.14.3. Medical Device Complaint Reporting Requirements.............................127
8.14.4. Sponsor’s Reporting Requirements to Regulatory Authorities ..............127
9. DATA ANALYSIS/STATISTICAL METHODS.............................................................127
9.1. Analysis Sets .........................................................................................................128
9.1.1. Safety Analysis Set...................................................................................128
9.1.2. Full Analysis Set.......................................................................................128
9.1.3. Per-protocol Analysis Set (evaluable for MTD).......................................128
9.1.4. PK Analysis Sets.......................................................................................128
9.1.5. Biomarker Analysis Set............................................................................128
9.1.6. Immunogenicity analysis set.....................................................................128
9.2. Statistical Methods and Properties ........................................................................129
9.2.1. Dose Escalation/De-Escalation and MTD Estimation (Part 1).................129
9.2.2. Dose Expansion (Part 2: 300 mg of SC PF-06801591)............................130
9.3. Sample Size Determination...................................................................................130
9.4. Efficacy Analysis ..................................................................................................131
9.5. Analysis of Pharmacokinetics and Pharmacodynamics ........................................132
9.5.1. PF-06801591 Pharmacokinetic Analysis..................................................132
9.5.3. Population Pharmacokinetic Analysis or Pharmacokinetic (PK)/ 
Pharmacodynamic Modeling .........................................................................133
9.6. Safety Analysis......................................................................................................133
9.6.1. Analysis of the Primary Endpoint in Part 1..............................................133
9.6.2. Analysis of Secondary Safety Endpoints..................................................134
9.6.3. Electrocardiogram.....................................................................................134
9.7. Analysis of Other Endpoints .................................................................................136
9.7.1. Analysis of Anti-Drug Antibody for PF-06801591..................................136
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9.8. Data Safety Monitoring Committee ......................................................................136
10. QUALITY CONTROL AND QUALITY ASSURANCE...............................................137
11. DATA HANDLING AND RECORD KEEPING ...........................................................137
11.1. Case Report Forms/Electronic Data Record .......................................................137
11.2. Record Retention.................................................................................................138
12. ETHICS............................................................................................................................138
12.1. Institutional Review Board/Ethics Committee....................................................138
12.2. Ethical Conduct of the Study ..............................................................................138
12.3. Patient Information and Consent.........................................................................139
12.4. Patient Recruitment.............................................................................................139
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP .........................................................................................................................139
13. DEFINITION OF END OF TRIAL.................................................................................140
13.1. End of Trial in a Member State...........................................................................140
13.2. End of Trial in All Other Participating Countries...............................................140
14. SPONSOR DISCONTINUATION CRITERIA ..............................................................140
15. PUBLICATION OF STUDY RESULTS........................................................................140
15.1. Communication of Results by Pfizer ..................................................................140
15.2. Publications by Investigators ..............................................................................141
16. REFERENCES ................................................................................................................143
LIST OF TABLES
Table 1.
Anti PD 1 Antibodies............................................................................................54
Table 2.
Table of Pre-Specified PF-06801591 IV Dose Levels .........................................79
Table 3.
Decision Rules for IV Administration..................................................................80
Table 4.
Laboratory Tests .................................................................................................109
Table 5.
Sampling and Assays for Biomarkers.................................................................114
Table 6.
CTCAE Criteria for Adverse Events ..................................................................124
Table 7.
Objective Response Status at each Evaluation...................................................158
Table 8.
Objective Response Status at each Evaluation for Patients with Non-Target 
Disease Only.......................................................................................................159
Table 9.
Overall Response Derived from Changes in Index, Non-index, and New 
Lesions................................................................................................................162


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LIST OF FIGURES
Figure 1: Basis for Immune Therapy.......................................................................................51
Figure 2.
PD-1 and PD-L1 in Soft Tissue Sarcomas ...........................................................53
Figure 3
PF-06801591 enhanced primary human T cell proliferation and cytokine 
secretion following 5-day stimulation with PD-L1 positive dendritic cells 
in a mixed lymphocyte reaction (MLR) assay......................................................64
Figure 4.
B8011001 Study Schematic..................................................................................75
APPENDICES
Appendix 1. Abbreviations....................................................................................................148
Appendix 2. Detailed Dose Escalation/De-Escalation Scheme for mTPI design..................153
Appendix 3. RECIST (Response Evaluation Criteria In Solid Tumors) version 
1.1 Guidelines.....................................................................................................155
Appendix 4. Immune-related RECIST (irRECIST)...............................................................160
Appendix 5. Overall Response Derived from Changes in Index, Non-index, and New 
Lesions................................................................................................................162
Appendix 6. ECOG Performance Status................................................................................163
Appendix 7. Recommendations for Management of Infusion Related Reactions 
Including Allergic/Hypersensitivity Reactions, Cytokine Release 
Syndrome or Anaphylaxis ..................................................................................164
Appendix 8. Management of Immune-related Adverse Events (irAEs)................................167
Appendix 9. Subcutaneous Injection Site Location Diagram................................................176


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PROTOCOL SUMMARY
Background
Binding of the programmed cell death protein-1 ligands, PD-L1 and PD-L2, to the 
programmed cell death protein-1 (PD-1) receptor found on T cells inhibits T-cell 
proliferation, cytokine production, and its cytotoxic functions. Upregulation of PD-1 ligands 
occurs in certain tumor types, and signaling through this pathway can contribute to the 
inhibition of active T-cell immune surveillance of tumors.1  In syngeneic mouse tumor 
models, blocking PD-1 activity resulted in decreased tumor growth. Approval of 
nivolumab/Opdivo(a fully human immunoglobulin G4 [IgG4] anti-PD-1 antibody [Ab]),
pembrolizumab/Keytruda(a humanized IgG4 anti-PD-1 Ab), atezolizumab/Tecentriq(a 
humanized IgG1 anti-PD-L1 Ab), durvalumab/Imfizi® (a humanize IgG1 anti-PD-1 
antibody), and avelumab/Bavencio(a fully human IgG1 anti-PDL-1 Ab) for the treatment of 
multiple tumor indications provide compelling evidence that blockage of the PD-1 pathway 
is a validated immunotherapeutic approach.2,3,4,5,6  
PF-06801591 is a humanized,  immunoglobulin G4 (IgG4) monoclonal antibody (mAb) that 
binds to the PD-1 receptor.  By blocking its interaction with PD-L1 and PD-L2, 
PD-1 pathway-mediated inhibition of the immune response is released, leading to an
anti-tumor immune response. In this clinical study, intravenous (IV) and subcutaneous (SC) 
administration of PF-06801591 will be evaluated for the treatment of adult patients with 
locally advanced or metastatic solid tumor types with clinical evidence of response to anti-
PD-1 or PD-L1 agents.
Study Overview
This is a Phase 1, open-label, multi-center, multiple-dose, dose escalation and expansion, 
safety, pharmacokinetics (PK), and pharmacodynamic study of PF-06801591. The primary 
purpose of this study is to evaluate safety and early signs of efficacy of PF-06801591. This 
clinical study will be divided into a dose escalation (Part 1) phase, and a dose expansion 
(Part 2) phase. Approximately 140 patients are expected to be enrolled into the study.  
Part 1 Dose Escalation
Part 1 dose escalation will evaluate 4 pre-specified IV dose levels (0.5, 1, 3, and 10 mg/kg), 
and 1 SC dose level (300 mg) in adult patients with locally advanced or metastatic 
melanoma, squamous cell cancer of head and neck (SCCHN), ovarian cancer, sarcoma, non-
small cell lung cancer (NSCLC), urothelial carcinoma, or other solid tumor types with 
clinical evidence of response to anti PD-1 or PD-L1 agents, who are unresponsive to 
currently available therapies or for whom no standard therapy is available. Approximately 
40 patients will be enrolled into Part 1. The actual number of patients enrolled in Part 1 will 
depend on the observed safety and tolerability profile of PF-06801591, and the number of 
dose levels required to identify the maximum tolerated dose (MTD).


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For the IV administration portion, a cycle is definied as 1 dose of PF-06801591 administered 
every 3 weeks (q3w). The IV dose-limiting toxicity (DLT) observation period is defined as 
starting on Day 1 of study drug administration through Day 21 of the treatment cycle. For 
the SC administration portion, a cycle is defined as 1 dose of PF-06801591 administered
every 4 weeks (q4w).  The SC administration DLT observation period is defined as starting 
on Day 1 of study drug administration through Day 28 of the treatment cycle. A staggered 
start will be employed for both IV and SC administration portions: a single patient will be 
dosed and observed for 48 hours.  If no safety concerns arise during this 48-hour period, 
additional patients may be enrolled into the same dose level. 
The 300 mg SC administration cohort will enroll patients concurrently with the IV 
administration portion, following evaluation of the 3 mg/kg IV administration dose level.  If 
the 300 mg dose administered by SC is deemed intolerable, a lower dose level of 150 mg 
maybe evaluated. 
Part 1 will be further divided into Part 1A (safety cohort) and Part 1B (pharmacodynamic 
cohort). For both IV and SC administration portions, each safety cohort will enroll 
2-4 patients per dose level. A modified toxicity probability interval (mTPI)
method,7 targeting a DLT rate of 27.5% will be utilized for dose escalation. In the IV 
administration portion, if based on Part 1A information the dose level is deemed safe and 
well- tolerated, an additional 2 to 5 patients will enroll into the same dose level in Part 1B.
In the SC administration portion, if based on Part 1A information the 300 mg dose level is
deemed safe and well- tolerated, an additional 11 (approximate) patients will be enrolled into 
Part 1B. Up to approximately 9 patients may be enrolled into each dose level in the IV 
administration portion, and up to approximately 15 patients may be enrolled into the 300 mg 
SC administration portion (Part 1A and Part 1B combined). The mTPI approach would be 
applied across Parts 1A and 1B to ensure that the administered doses do not surpass the 
toxicity boundaries. Safety data from all patients in Parts 1A (safety cohort) and available 
data at cutoff from Parts 1B (pharmacodynamic cohort) will be used to determine the MTD.
Tumor biopsies collected at pre and post treatment time points (screening and Cycle 2 
Day 8 [C2D8]) are mandatory for all Part 1B patients.
Part 2 Dose Expansion
Part 2 will enroll approximately 70 patients with anti-PD-1 or anti-PD-L1 treatment naïve 
NSCLC and approximately 30 patients with anti-PD-1 or anti-PD-L1 treatment naïve 
urothelial carcinoma who progressed on, or were intolerant to systemic therapy or for whom 
systemic therapy was refused or unavailable.  All patients will receive 300 mg of
PF-06801591 SC q4w. When the first tumor assessment has been completed for the first 
30 NSCLC patients, an interim analysis may be performed to evaluate safety and efficacy.  


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In this study, all patients in Part 1 and Part 2 will:
1. Undergo up to 4 weeks of screening prior to study entry.
2. Receive treatment with investigational product for up to 2 years, or until one of the 
following:
a.
Disease progression by immune-related Response Evaluation Criteria in Solid 
Tumors (irRECIST, confirmed progressive disease [PD] or initial PD followed by 
rapid clinical deterioration); or
b. Unacceptable toxicity occurs; or
c.
Withdrawal of consent; or
d. Patient no longer willing to participate in trial; or
e.
Study termination. 
Any additional treatment beyond 2 years shall be discussed and approved by the sponsor.
Patients will be allowed to stay on treatment in the case of initial radiological disease 
progression, if the investigator feels that it is in the patient’s best interest. For example, if 
a patient does not have rapid clinical deterioration, after initial assessment demonstrating 
unconfirmed PD. If a patient has a confirmed CR (ie, 2 consecutive CR assessments at 
least 4 weeks apart) by irRECIST, patient may also discontinue treatment at the 
discretion of the investigator and continue follow-up assessments.
3. Will complete a 1 month follow-up visit after the last dose for adverse event (AE)
collection and serious adverse event (SAE) follow-up if necessary.
4. Will undergo assessment for late immune related AEs (irAEs) up to 120 days after 
completion of PF-06801591 administration(see Section 3.1.5.1 Late Immune-Related 
Dose-Limiting Toxicities). Subsequent anti-cancer therapy will also be recorded during 
these follow up visits.
5. Will be contacted by telephone every 8 weeks for survival data collection after the 
120-day follow-up visit, until the end of the trial (defined as 2 years after last patient first 
dose [LPFD], see Section 13.2). Subsequent anti-cancer therapy will also be documented 
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Study Objectives and Endpoints
Part 1 Dose Escalation
Primary Objective(s): 
Primary Endpoint(s): 
•
To assess safety and tolerability of increasing dose 
levels of PF-06801591 administered IV in patients 
with locally advanced or metastatic melanoma, 
SCCHN, ovarian cancer, sarcoma, NSCLC, urothelial 
carcinoma or other solid tumor types with clinical 
evidence of response to anti PD-1 or PD-L1 agents to 
establish the MTD.
•
To assess safety and tolerability of PF-06801591 
administered SC in patients with locally advanced or 
metastatic melanoma, SCCHN, ovarian cancer, 
sarcoma, NSCLC, urothelial carcinoma or other solid 
tumor types with clinical evidence of response to anti 
PD-1 or PD-L1 agents.
•
Dose Limiting Toxicities (DLTs) at escalated doses of 
PF-06801591.
•
AEs as characterized by type, frequency, severity (as 
graded by National Cancer Institute Common 
Terminology Criteria for Adverse Events [NCI CTCAE] 
version 4.03), timing, seriousness, and relationship to 
study therapy PF-06801591.
•
Laboratory abnormalities as characterized by type, 
frequency, severity (as graded by NCI CTCAE version 
4.03), and timing.
Secondary Objective(s): 
Secondary Endpoint(s): 
•
To characterize the single dose and multiple dose PK 
of PF-06801591 following IV or SC administration.
•
PK parameters of PF-06801591: Cycle 1 and Cycle 4 
maximum drug concentration (Cmax), area under the 
concentration versus time curve (AUC) from time zero 
to the last quantifiable time point prior to the next dose 
(AUClast), and if data permit, clearance (CL), volume of 
distribution (Vd)/ volume of distribution at steady state 
(Vss), accumulation ratio (Rac) when feasible, and 
terminal elimination half-life (t1/2). 
•
To evaluate the immunogenicity of PF-06801591 
following repeated administration.
•
Incidence of anti-drug antibody (ADA) and neutralizing 
antibodies (NAb) against PF-06801591.
•
To characterize PD-1 Receptor Occupancy (RO) in 
peripheral blood T cells following IV or SC 
PF-06801591 administration at each dose level.
•
PD-1 RO by PF-06801591, as assessed by measuring the 
levels of unbound (free) cell surface PD-1 on circulating 
T cells over time following PF-06801591 administration.
•
To evaluate preliminary anti-tumor activity of 
PF-06801591.
•
Objective tumor response, as assessed using the 
Response Evaluation Criteria in Solid Tumor (RECIST) 
version 1.1 and immune related RECIST (irRECIST) 
and proportion of patients with partial response (PR) and 
immune related partial response (irPR), as appropriate 
>80%.
•
Time to event endpoints based on RECIST and 
irRECIST, and progression free survival (PFS), duration 
of stable disease (DOSD), and DOR (duration of 
response).
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Part 2 Dose Expansion
Primary Objective(s): 
Primary Endpoint(s): 
•
To further characterize the safety and tolerability of  
PF-06801591 following SC administration in NSCLC 
and urothelial carcinoma.
•
AEs as characterized by type, frequency, severity (as 
graded by NCI CTCAE version 4.03), timing, 
seriousness, and relationship to study therapy 
PF-06801591 administered by SC administration.
•
Laboratory abnormalities as characterized by type, 
frequency, severity (as graded by NCI CTCAE version 
4.03), and timing.
•
To estimate clinical efficacy by overall response rate
(ORR) of PF-06801591 following SC administration
in NSCLC and urothelial carcinoma.
•
Overall response rate (ORR) as assessed using RECIST 
version 1.1 and irRECIST.
Secondary Objective(s): 
Secondary Endpoint(s): 
•
To further evaluate preliminary anti-tumor activity of 
PF-06801591 following SC administration.
•
Time to event endpoints by PF-06801591 administered 
by SC based on RECIST and irRECIST, including time 
to response (TTR) and time to progression (TTP) as well 
as PFS (and irPFS as appropriate), DOSD (and irDOSD 
as appropriate), and DOR (and irDOR as appropriate).
•
To evaluate overall survival (OS).
•
Median time to death, proportion of patients alive at 
6 months, 1 year, and 2 years.
•
To collect PF-06801591 drug concentration data in 
patients following SC administration for evaluation of 
population PK.
•
Trough PF-06801591 concentrations for selected cycles.
•
To evaluate the immunogenicity of PF-06801591 
following repeated SC administration.
•
Incidence of ADA and NAb against PF-06801591
administered by SC.
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SCHEDULE OF ACTIVITIES FOR PART 1 INTRAVENOUS ADMINISTRATION
The Schedule of Activities tables provide an overview of the protocol visits and procedures.  Refer to the Assessments Section 7 of the 
protocol for detailed information on each assessment required for compliance with the protocol.
The investigator may schedule visits (unplanned visits) in addition to those listed on the schedule of activities, in order to conduct 
evaluations or assessments required to protect the well-being of the patient.
Schedule of Activities for Part 1 
Intravenous Administration of 
PF-06801591
Treatment Period
Post-Treatment
Cycle 1 Only
(Days 1 to 21)
Cycle 2
(Days 1 to 21)
Subsequent 
Cycles 
(Days 1 to 
21)cc
EOTdd
1 Month and Late 
irAE Follow upee
Survival 
Follow 
upff
Screeninga
(28 days 
prior to 
study entry)
Day 
1
Day 
2
Day 
3
Day 
8 
Day 
15 
Day 
1 
Day 
8 
Day 
15
Day 
1 
Day 
8
(C3 
Only)
Days after last dose
Every 2 
months 
after 120 
day 
follow up 
visit
28 
days 
90 
days
120 
days 
Visit Window (days)
1
2
2
2
2
2
2
+7
7
7
±7
Informed Consentb
X
Tumor Historyc
X
Medical Historyd
X
Complete Physical 
Examination
X
X
X
X
Abbreviated Physical 
Examinatione
X
X
X
X
X
X
X
X
Baseline Signs and 
Symptomsf
X
Height
X
Weightg
X
X
X
X
X
Vital Signs (BP/Pulse 
Rate/PO/Temp)h
X
X
X
X
X
X
X
X
X
X
X
X
ECOG Performance 
Statusi
X
X
X
X
X
X
Triplicate 12-Lead 
ECGj
X (single 
ECG only)
X
X
X
X
X
X
X


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Schedule of Activities for Part 1 
Intravenous Administration of 
PF-06801591
Treatment Period
Post-Treatment
Cycle 1 Only
(Days 1 to 21)
Cycle 2
(Days 1 to 21)
Subsequent 
Cycles 
(Days 1 to 
21)cc
EOTdd
1 Month and Late 
irAE Follow upee
Survival 
Follow 
upff
Screeninga
(≤28 days 
prior to 
study entry)
Day 
1
Day 
2
Day 
3
Day 
8 
Day 
15 
Day 
1 
Day 
8 
Day 
15
Day 
1 
Day 
8
(C3 
Only)
Days after last dose
Every 2 
months 
after 120 
day 
follow up 
visit
28 
days 
90 
days
120 
days 
Visit Window (days)
±1
±2
±2
±2
±2
±2
±2
+7
±7
±7
±7
Laboratory
Hematologyk
X
X
X
X
X
X
X
X
X
Blood
Chemistryl
X
X
X
X
X
X
X
X
X
Coagulationm
X
X
X
X
X
X
X
X
X
CA-125 (Ovarian 
Cancer Only)n
X
X
X
X
X
X
Urinalysiso
X
X
X
X
X
X
Pregnancy Test 
or FSH Levelp
X
X
X
X
X
X
C-Reactive Protein 
(CRP or hsCRP)q
X
X
X
X
X
TBNK (whole 
blood)r
X
X
X
X
X
Hepatitis B, C, and 
HIV testst
X
Registration and 
Treatment
Registrationu
X
Study
Treatmentv
X
X
X
Tumor Assessments
CT or MRI Scanw
X
Every 6 weeks (±5 days) up to 24 wks, and every 6 or 12 weeks (±5 days) 
thereafter according to calendar, regardless of treatment delays
X
X (Every 12 weeks as necessary)
Other Clinical 
Assessments
Adverse Eventsx
X
X
X
X
X
X
X
X
X
X
X
X
X
X
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Schedule of Activities for Part 1 
Intravenous Administration of 
PF-06801591
Treatment Period
Post-Treatment
Cycle 1 Only
(Days 1 to 21)
Cycle 2
(Days 1 to 21)
Subsequent 
Cycles 
(Days 1 to 
21)cc
EOTdd
1 Month and Late 
irAE Follow upee
Survival 
Follow 
upff
Screeninga
(28 days 
prior to 
study entry)
Day 
1
Day 
2
Day 
3
Day 
8 
Day 
15 
Day 
1 
Day 
8 
Day 
15
Day 
1 
Day 
8
(C3 
Only)
Days after last dose
Every 2 
months 
after 120 
day 
follow up 
visit
28 
days 
90 
days
120 
days 
Visit Window (days)
1
2
2
2
2
2
2
+7
7
7
±7
Serious Adverse 
Eventsy
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X 
Up to 150 
days after 
last 
treatment
Concomitant 
Medication and 
non-drug supportive 
interventionsz
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Subsequent anti-
cancer therapyaa
X
X
X
X
Survival follow-upff
X
Contraception 
checkbb
X
X
X
X
X
X
X
X
BP = blood pressure; C3 = cycle 3; CRP = C-reactive protein; CT = computed tomography; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology 
Group; EOT = end of treatment; FSH = follicle stimulating hormone; HIV = human immunodeficiency virus; Hs CRP = high sensitivity C-reactive protein;
IV = intravenous; MRI = magnetic resonance imaging; NAb = neutralizing antibodies; PO = pulse oximetry; TBNK = T cell/B cell/natural killer cell;
wks = weeks.
Footnotes for Schedule of Activities for Part 1 Intravenous Administration
a.
Screening: To be performed within 28 days prior to study entry.
b.
Informed Consent: Must be obtained prior to undergoing any study specific procedures.
c.
Tumor History: Will be collected within 28 days during screening prior to study entry.  Includes history of disease under study including details of primary diagnosis and 
treatment history.  Record tumor human papilloma virus (HPV) status for those patients with squamous cell cancer of head and neck (SCCHN) whenever available.
d.
Medical History: Includes history of disease process (eg, staging) other than the cancer under study (active or resolved) and concurrent illness.  Includes prior treatments and 
any current medical treatments for any condition.
e.
Abbreviated Physical Examination (PE): Abbreviated PEs should be performed as appropriate at each visit where complete PEs are not required. 
f.
Baseline Signs & Symptoms: On Day 1 prior to the start of study treatment, patients will be asked about any signs and symptoms experienced within the past 14 days prior 
to study entry.  Baseline signs and symptoms will be recorded on the Medical History CRF page.  During the study, any new or worsening conditions since baseline will be 
recorded on the Adverse Events (AE) CRF page.


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g.
Weight: Patient’s body weight will be measured at Day 1 of each treatment cycle or within 72 hours before dosing to check for weight gain/loss >10% from the prior weight 
used for PF-06801591 IV dose calculations.  The decision to recalculate PF-06801591 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 of >10% compared to the weight used to calculate the most recent dose, the amount of 
PF-06801591 required for study drug preparation and administration for the current cycle must be recalculated using this most recent weight.
h.
Vital Signs: includes temperature, sitting blood pressure (BP), pulse rate (to be recorded in the sitting position after 5 minutes of rest), and pulse oximetry (PO, at rest and 
after exertion).  On Day 1 of each cycle, vital signs should be measured prior to infusion start (pre-dose), BP, and pulse rate will be repeated 1 hour (±10 minutes) after the 
start of the infusion.
i.
Performance Status: Per Eastern Cooperative Oncology Group (ECOG) performance scale in Appendix 6.
j.
Triplicate 12-Lead Electrocardiogram (ECG): See Assessment Section 7.1.5.  ECGs will be collected at times specified in the Schedule Of Activities. The Screening ECG 
will be a single 12-lead ECG.  At all other times, at each time point, 3 consecutive 12-lead ECGs (triplicate) will be performed approximately 2 minutes apart to determine 
mean QTcF interval.  All 12-lead ECGs should be confirmed by a qualified person at the institution and will be reviewed by a central laboratory.  ECGs on Day 1 of each 
cycle will be collected both prior to dosing and at the end of infusion (approximately 1 hour) following administration of each dose of PF-06801591.  When coinciding with 
blood sample draws for pharmacokinetics (PK), ECG assessment should preferably be performed prior to blood sample collection, such that the blood sample is collected at 
the nominal time.  If the mean QTcF is prolonged (≥45 msec from the pre-dose baseline, or >500 msec), the ECGs should be re-evaluated by a qualified person at the 
institution for confirmation.  Additional triplicate ECGs may be performed as clinically indicated.  
k.
Hematology: See Assessments Section 7.1.3 for Laboratory Tests list. Assessments and physician’s evaluation must be performed prior to dosing.  No need to repeat on 
Cycle 1 Day 1 (C1D1) if baseline assessment performed within 72 hours prior to that date.  Assessments performed on Cycle 2 Day 1 (C2D1) and each subsequent cycle 
should be performed within 48 hours prior to dosing.  
l.
Blood Chemistry: See Assessments Section 7.1.3 for Laboratory Tests list. No need to repeat on C1D1 if screening assessment performed within 72 hours prior to that date.  
Assessments and physician’s evaluation should be performed prior to dosing.  Assessments performed on C2D1 and Day 1 of each subsequent cycle must be performed 
within 48 hours prior to dosing.  
m.
Coagulation assays: See Assessments Section 7.1.3 for Laboratory Tests list.  No need to repeat on C1D1 if baseline assessment performed within 72 hours prior to that date.  
Assessments performed on C2D1 and Day 1 of each subsequent cycle should be performed within 48 hours prior to dosing.
n.
CA-125 (Ovarian Cancer Only): The first measurement for CA-125 must be collected within 2 weeks before treatment is started, during the screening period.  Subsequent 
CA-125 levels will be measured on Day 1 of each cycle before treatment, at End of Treatment, and at Follow-up visit 28 days after last dose administration.  There is no need 
to repeat on C1D1, if the baseline (screening) assessment was performed within 72 hours prior to that day. 
o.
Urinalysis: Dipstick is acceptable.  Microscopic analyses if clinically indicated (eg, only after the second positive dipstick result for heme).  If ≥2+ protein on urine dipstick, 
then collect spot urine sample to calculate urine protein to creatinine ratio (UPCR) or collect 24hr urine.  See Section 7.1.3 for Laboratory Tests list.
p.
Pregnancy Test (Serum/Urine) or FSH Level (Serum): For female patients of childbearing potential, a serum or urine pregnancy test, with sensitivity of at least 
25 mIU/mL and assayed in a certified laboratory, will be performed on 2 occasions prior to starting study therapy, once at the start of screening and once at the baseline visit 
immediately before investigational product administration.  Pregnancy tests will also be routinely repeated at Day 1 of every treatment cycle during the active treatment 
period, at the End of Treatment visit, at the 28-day Follow-Up Visit, and additionally whenever one menstrual cycle is missed or when potential pregnancy is otherwise 
suspected.  Additional pregnancy tests may also be undertaken if requested by institutional review board/ethics committee (IRB/ECs) or if required by local regulations.  
Patients with confrmed positive pregnanct test(s) should not be dosed.  For female patients who achieved postmenopausal status and have not experienced their menses for at 
least 12 consecutive months, a serum FSH test must be conducted at screening only to confirm a FSH level within the laboratory’s reference ranges. 
q.
High Sensitivity C-Reactive Protein (hsCRP) or C-Reactve Protein (CRP): One 5 mL blood sample will be collected per schedule of activities to measure hsCRP or CRP.
r.
TBNK (Whole Blood): Whole blood absolute immune cell counts (T-cell/B-cell/Natural Killer cells [TBNK]) will be measured by collecting a 5 mL blood sample per 
schedule of activities. Sample collected on C1D1 should be completed pre-dose.
 
 
t.
Hepatitis B, C and HIV Tests: Conduct tests for hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), hepatitis C antibody (HCV Ab), and human 
immunodeficiency virus (HIV) serology.  In the case of apparent ongoing HBV or HCV infection, reflex serum viral load testing will be performed.
u.
Registration: Patient number and dose level allocation operated by Pfizer Inc.  Treatment should begin no longer than 3 days from registration.
C
C


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PFIZER CONFIDENTIAL
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v.
Study Treatment: PF-06801591 will be administered once every 21 days as an intravenous (IV) infusion over 60 minutes ±10 minutes.  Day 1 safety laboratory test results 
need to be reviewed by the investigator prior to dosing at the beginning of each cycle for dosing confirmation and administration rate.  Since processing of samples at the 
central laboratory has to be completed within 24 hours of collection, please try to accommodate the administration of study treatment on either: A Monday to Wednesday 
schedule for samples collected on Day 1 of Cycle 1; or, a Monday to Friday schedule for all subsequent new cycles of treatment (ie, Day 1 of Cycle 2 +).
w.
Tumor Assessments: See Section 7.4 Tumor Response Assessments. CT or MRI scans to be done every 6 weeks (5 days) from the start of study entry until disease 
progression by immune-related RECIST (irRECIST), death, withdraw consent, or subsequent administration of an anti-chemotherapy agent.  Tumor assessments should be 
fixed according to the calendar, regardless of treatment delays.  Radiographic assessments obtained per the patient’s standard of care prior to enrollment into the study do not 
need to be repeated and are acceptable to be used as baseline evaluation, if, (1) obtained within 28 days before C1D1, (2) performed using the method requirements (ie, 
RECIST v. 1.1 ), (3) the same technique/modality can be used to follow identified lesions throughout the trial for a given patient, and (4) appropriate documentation indicating 
that these radiographic tumor assessments were performed as standard of care is available in the patient’s source notes. CT or MRI scans may be assessed every 12 weeks (±5 
days) for patients who 1) have remained on treatment for ≥24 weeks, and 2) have no confirmed progression by irRECIST within the last 6 months, and 3) have demonstrated 
stability of disease. Confirmation of response (complete response [CR]/partial response [PR]) with a second consecutive scan at least 4 weeks later is preferred.  Tumor 
assessments should be repeated at the End of Treatment visit if more than 6 weeks have passed since the last evaluation.  CT or MRI scans should be completed before tumor 
biopsy samples are collected.  If a patient is classified as having progressive disease (PD) during an on treatment tumor assessment, then confirmation of PD by a second 
consecutive scan at least 4 weeks later in the absence of rapid clinical deterioration is required.  After End of Treatment for patients who did not end treatment due to disease 
progression, death, or withdrawal of consent, a tumor assessment will be performed every 12 weeks (1 week), until disease progression by irRECIST, or initiation of a new 
anti-cancer treatment, or end of the trial (2 years after last patient first dose [LPFD], see Section 13.2 End of Trial in All Other Participating Countries), whichever is first.
x.
Adverse Event (AE) Assessments: Adverse events should be documented and recorded at each visit using National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE) version 4.03.  AEs (serious and non-serious) should be recorded on the CRF from the time the patient has taken at least 1 dose of 
investigational product. 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.  Additional, immune related AEs (irAEs) will be collected with a 
follow up phone call at 90 and 120 days after last dose administration date to collect post treatment related AE information.
y.
Serious Adverse Event (SAE) Assessments: 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 150 calendar days after the last administration of the investigational product or until administration of subsequent 
anti-cancer therapy whichever comes first.  SAEs occurring to a patient after the active reporting period has ended should be reported to the sponsor if the investigator 
becomes aware of them; at a minimum, all SAEs that the investigator believes have at least a reasonable possibility of being related to investigational product are to be 
reported to the sponsor.  
z.
Concomitant Medications and Non Drug Supportive Interventions: all concomitant medications should be recorded in the CRF including supportive care drugs (eg, 
Anti-emetic treatment and prophylaxis), drugs used to treat adverse events or chronic diseases, and non-drug supportive interventions (eg, transfusions).
aa.
Subsequent anticancer therapy: After the completion of the EOT visit subsequent anti-cancer therapy will be documented and recorded for patients who discontinue 
investigational products and continue in 120 day safety follow-up, and  subsequently during survival follow-up.
bb. Contraceptive Check (frequency to match that of pregnancy tests): Male patients who are able to father children and female patients who are of childbearing potential 
will need to affirm that they meet the criteria for correct use of 2 of the selected methods of contraception.  The investigator or his or her designee will discuss with the patient 
the need to use 2 highly effective contraception methods consistently and correctly and document such conversation in the patient’s chart.  In addition, the investigator or his 
or her designee will instruct the patient to call immediately if one or both selected contraception methods are discontinued, or if pregnancy is known or suspected in the 
patient or the patient’s partner.
cc.
Subsequent Cycles: Day 8 and 15 visits are not required after Cycle 2.  Note: For ECG, refer to footnote “j” that mentions an assessment scheduled on Day 8 of Cycle 3.  For 
Blood PK samples for PF-06801591, refer to the separate PK & Pharmacodynamic Schedule of Activities that mentions blood collection scheduled on both Day 8 and Day 
15 of Cycle 4.  For PD-1 Receptor Occupancy samples (whole blood), refer to the separate PK & Pharmacodynamic Schedule of Activities and footnote “c” that mention 
blood collection scheduled on Day 15 of Cycle 4.
dd. End-of-treatment Visit: conducted at the visit that the patient is discontinued from the trial and no longer than 1 week after the patient has been discontinued.  Complete 
tumor assessments if not completed in the last 6 weeks.


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ee.
1-Month and Late irAE Follow-up: At least 28 days and no more than 35 days after discontinuation of treatment or last dose of study drug whichever is later, patients will 
return to undergo review of concomitant medications, vital signs, and assessment for resolution of any treatment-related toxicity.  Patients continuing to experience toxicity at 
this point following discontinuation of treatment will continue to be followed at least every 4 weeks until resolution or determination, in the clinical judgment of the 
Investigator, that no further improvement is expected. To collect additional late irAE information, all patients will have a follow- up phone call 90 and 120 days (7 days) 
after last dose administration date to collect post-treatment related AE information.  Subsequent anti-cancer therapies information will also be collected during these follow up 
visits. If any concern arises, the patient will be called in for an inpatient follow-up visit within 5 calendar days of the initial phone call (assessments will be the same as the 
assessments performed at the 1-month follow up visit completed after end of treatment [EOT]).  
ff.
Survival Follow-up: Subsequent to the 120-day follow-up period, overall survival (OS) follow-up will be conducted by telephone every 8 weeks (7 days) until end of the 
entire trial (2 years after LPFD, see Section 13.2 End of Trial in All Other Participating Countries).  If the patient is seen in the clinic during the window of time that a 
scheduled telephone call is to be made to collect survival data, then the clinic visit may replace the survival telephone call. Subsequent anti-cancer therapies information will 
also be collected.


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Final Protocol Amendment 4, 07 August 2018
PFIZER CONFIDENTIAL
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PHARMACOKINETIC AND PHARMACODYNAMIC SCHEDULE OF ACTIVITIES: PART 1 INTRAVENOUS 
ADMINISTRATION OF PF-06801591
Pharmacokinetic and Pharmacodynamic Schedule of Activities for Part 1 Intravenous Administration of PF-06801591
Screen
Cycle 1
(Days 1 to 21)
Cycle 2
Days 1 to 21)
Cycle 3
(Days 1 to
21)
Cycle 4
(Days 1 to 21)
Cycle 5
(Days 1
to 21)
Further 
Cycles
End 
of 
Treat-
ment
Visit Identifier
Day 
1
Day 3
(±8  hrs)
Day 8
(±1)
Day 15
(±2)
Day 
1
 
Day 
1
Day 
1
Day 
8
(±1)
Day 
15
(±2)
Day 
1
Day 
1
Pre-
dose* 1 hr* 24 hr**
Pre-
dose*1 hr*
Pre- dose*Pre- dose* 1 hr*
Pre-
dose*
Pre-dose*
Blood PK Sample for 
PF-06801591a
X
X
X
X
X
X
X
X
X
X
X
X
X
X
(Cycles 
6,8,10)
X
Blood Sample for 
Anti-PF-06801591-antibodyb
X
X
X
X 
(Cycles 
6,8,10)
X
Target engagement (TE) 
biomarkers
PD-1 Receptor Occupancy 
(whole blood)c
X
X
X
X
X
X
X
X
X
X
Pharmacodynamic and 
immune monitoring 
biomarkers
 
 
 
 
 
PK = pharmacokinetics; ADA = anti-drug antibody; SOA = Schedule of Activities; 
; NAb = neutralizing antibody.
* The 1-hr samples should be collected within 1 hr after the end of infusion and pre-dose samples should be collected within 6 hrs before the start of infusion.  Note: No day window is 
allowed for PK/Pharmacodynamic sampling on Day 1 of Cycle 1 and subsequent cycles as applicable.
**The 24-hr samples should be collected ±2 hours based on the 24-hr period after the end of the infusion. 
 
C
CI
CCI
CCI
CCI


PF-06801591
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Final Protocol Amendment 4, 07 August 2018
PFIZER CONFIDENTIAL
Page 33
Footnotes for Pharmacokinetics and Pharmacodynamic Schedule of Activities for Part 1 Intravenous Administration of PF-06801591
a.
Blood samples for determination of PF-06801591 concentration: Blood samples will be collected at each time point for PK analysis of PF-06801591. After cycle 4, pre-
dose PK samples will be collected only on every 2nd cycle (cycles 6, 8, and 10, etc.). An additional PK sample should also be taken at the end of treatment.
b.
Blood sample for Anti-PF-06801591 Antibody Measurement: Blood samples (approx. 10 mL each) will be collected at each time point for anti drug antibody (ADA)/
neutralizing antibodies (Nab) assessment. After cycle 4, pre-dose ADA/NAb will be collected only on every 2nd cycle (cycles 6, 8, and 10, etc.). An additional ADA/NAb 
sample should also be taken at the end of treatment.  
c.
Receptor Occupancy: A 4 mL whole blood sample will be collected at the time points indicated in the PK/Pharmacodynamic SOA. PD-1 occupancy by PF-06801591 on 
T cells will be measured using flow cytometry.
CCI


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Final Protocol Amendment 4, 07 August 2018
PFIZER CONFIDENTIAL
Page 34
SCHEDULE OF ACTIVITIES FOR PART 1 SUBCUTANEOUS ADMINISTRATION OF PF-06801591
The Schedule of Activities tables provide an overview of the protocol visits and procedures.  Refer to the Assessments Section 7 of the 
protocol for detailed information on each assessment required for compliance with the protocol.
The investigator may schedule visits (unplanned visits) in addition to those listed on the schedule of activities, in order to conduct 
evaluations or assessments required to protect the well-being of the patient.
Schedule of Activities for Part 1 
Subcutaneous Administration of 
PF-06801591
Treatment Period
EOTee
Post-Treatment
Cycle 1
(Days 1 to 28)
Cycle 2
(Days 1 to 28)
Sub-
sequent 
Cycles 
(Days 1 to 
28)dd
1 Month and Late 
irAE Follow upff
Survival 
Follow Upgg
Screening
(28 days 
prior to 
study 
entry)a
D1
D2
D3
D8
D15
D21
D1
D8
D15
D1
D8
C3 
only
Days after last dose
Every 2 months 
after 120 day 
follow up visit
28 
days 
90 
days 
120 
days 
Visit Window
1
2
2
2
±2
2
2
2
+7
±7
±7
±7
Informed Consent b
X
Tumor Historyc
X
Medical Historyd
X
Complete Physical 
Examination
X
X
X
X
Abbreviated Physical
Examinatione
X
X
X
X
X
X
X
X
X
Baseline Signs and 
Symptomsf
X
Height
X
Weightg
X
X
X
X
X
Vital Signs (BP/Pulse 
Rate/PO/Temp)h
X
X
X
X
X
X
X
X
X
X
X
X
X
ECOG Performance 
Statusi
X
X
X
X
X
X
Triplicate 12-Lead 
ECGj
X (single 
ECG only)
X
X
X
X
X
X
X


PF-06801591
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Final Protocol Amendment 4, 07 August 2018
PFIZER CONFIDENTIAL
Page 35
Schedule of Activities for Part 1 
Subcutaneous Administration of 
PF-06801591
Treatment Period
EOTee
Post-Treatment
Cycle 1
(Days 1 to 28)
Cycle 2
(Days 1 to 28)
Sub-
sequent 
Cycles 
(Days 1 to 
28)dd
1 Month and Late 
irAE Follow upff
Survival 
Follow Upgg
Screening
(≤28 days 
prior to 
study 
entry)a
D1
D2
D3
D8
D15
D21
D1
D8
D15
D1
D8
C3 
only
Days after last dose
Every 2 months 
after 120 day 
follow up visit
28 
days 
90 
days 
120 
days 
Visit Window
±1
±2
±2
±2
±2
±2
±2
±2
+7
±7
±7
±7
Laboratory
Hematologyk
X
X
X
X
X
X
X
X
X
X
Blood 
Chemistryl
X
X
X
X
X
X
X
X
X
X
Coagulation l
X
X
X
X
X
X
X
X
X
X
CA-125 (Ovarian 
Cancer Only)n
X
X
X
X
X
X
Urinalysiso
X
X
X
X
X
X
Pregnancy Test
or FSH Levelp
X
X
X
X
X
X
C-Reactive Protein 
(CRP or hsCRP)p
X
X
X
X
X
X
TBNK (whole 
blood)r
X
X
X
X
X
X
Hepatitis B, C, and 
HIV testst
X
Registration and 
Treatment
Registrationu
X
Study 
Treatmentv
X
X
X
Local Site Injection 
Tolerability 
Assessmentw
X
X
X
CCI


PF-06801591
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Final Protocol Amendment 4, 07 August 2018
PFIZER CONFIDENTIAL
Page 36
Schedule of Activities for Part 1 
Subcutaneous Administration of 
PF-06801591
Treatment Period
EOTee
Post-Treatment
Cycle 1
(Days 1 to 28)
Cycle 2
(Days 1 to 28)
Sub-
sequent 
Cycles 
(Days 1 to 
28)dd
1 Month and Late 
irAE Follow upff
Survival 
Follow Upgg
Screening
(28 days 
prior to 
study 
entry)a
D1
D2
D3
D8
D15
D21
D1
D8
D15
D1
D8
C3 
only
Days after last dose
Every 2 months 
after 120 day 
follow up visit
28 
days 
90 
days 
120 
days 
Visit Window
1
2
2
2
±2
2
2
2
+7
±7
±7
±7
Tumor Assessments
CT or MRI Scanw
X
Every 8 weeks (5 days) up to 24 wks, and every 8 or 12 weeks 
(5 days) thereafter according to calendar, regardless of treatment 
delays
X
X (Every 12 weeks)
Other Clinical 
Assessments
Adverse Eventsx
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serious Adverse 
Eventsz
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X 
Up to 150 days 
after last 
treatment
Concomitant 
Medication and 
non-drug supportive 
interventionsaa
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Subsequent anti-
cancer therapybb
X
X
X
X
Survival follow upgg
X
Contraception 
checkcc
X
X
X
X
X
X
X
X
BP = blood pressure; C = cycle; CRP = C-reactive protein CT = computed tomography; D = day; ECG = electrocardiogram; ECOG = Eastern Cooperative 
Oncology Group; EOT = end of treatment; FSH = follicle stimulating hormone; HIV = human immunodeficiency virus; Hs-CRP = high sensitivity C-reactive 
protein; MRI = magnetic resonance imaging; PK = pharmacokinetics; PO = pulse oximetry; SC = Subcutaneous; TBNK = T cell/B cell/natural killer cell; wks = 
weeks
Footnotes for Schedule of Activities for Part 1 Subcutaneous Administration
a.
Screening: To be performed within 28 days prior to study entry.
b.
Informed Consent: Must be obtained prior to undergoing any study-specific procedures.


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Page 37
c.
Tumor History: Will be collected within 28 days during screening prior to study entry.  Includes history of disease under study including details of primary diagnosis and 
treatment history.  Record tumor HPV status for those patients with SCCHN whenever available.
d.
Medical History: Includes history of disease process (eg, staging) other than the cancer under study (active or resolved) and concurrent illness.  Includes prior treatments and 
any current medical treatments for any condition.
e.
Abbreviated Physical Examination (PE): Abbreviated PEs should be performed as appropriate at each visit where complete PEs are not required.
f.
Baseline Signs & Symptoms: On Day 1 prior to the start of study treatment, patients will be asked about any signs and symptoms experienced within the past 14 days prior 
to study entry.  Baseline signs and symptoms will be recorded on the Medical History CRF page.  During the study, any new or worsening conditions since baseline will be 
recorded on the Adverse Events (AE) CRF page.
g.
Weight: Patient’s body weight will be measured at Day 1 of each treatment cycle.
h.
Vital Signs: includes temperature, sitting BP, pulse rate (to be recorded in the sitting position after 5 minutes of rest), and PO (at rest and after exertion).  On Day 1 of each 
cycle, vital signs should be measured prior to SC injection (pre-dose), BP, and pulse rate will be repeated 1 hour (±10 minutes) after the administration of the SC injection.
i.
Performance Status: Per ECOG performance scale in Appendix 6.
j.
Triplicate ECG: See Assessment Section 7.1.5. ECGs will be collected at times specified in the Schedule Of Activities.  The Screening ECG will be a single 12-lead ECG.  
At all other times, at each time point, 3 consecutive 12-lead ECGs (triplicate) will be performed approximately 2 minutes apart to determine mean QTcF interval.  All 12-lead 
ECGs should be confirmed by a qualified person at the institution and will be reviewed by a central laboratory.  ECGs on Day 1 of each cycle will be collected prior to dosing, 
and at the end of infusion (approximately 1 hour) following administration of each dose of PF-06801591.  When coinciding with blood sample draws for PK, ECG assessment 
should preferably be performed prior to blood sample collection, such that the blood sample is collected at the nominal time.  If the mean QTcF is prolonged (≥45 msec from 
the pre-dose baseline, or >500 msec), the ECGs should be re-evaluated by a qualified person at the institution for confirmation.  Additional triplicate ECGs may be performed 
as clinically indicated.  
k.
Hematology: See Assessments Section 7.1.3 for Laboratory Tests list. Assessments and physician’s evaluation must be performed prior to dosing.  No need to repeat on 
C1D1 if baseline assessment performed within 72 hours prior to that date.  Assessments performed on C2D1 and each subsequent cycle should be performed within 48 hours 
prior to dosing.  
l.
Blood Chemistry: See Assessments Section 7.1.3 for Laboratory Tests list. No need to repeat on C1D1 if screening assessment performed within 72 hours prior to that date.  
Assessments and physician’s evaluation should be performed prior to dosing.  Assessments performed on C2D1 and Day 1 of each subsequent cycle must be performed 
within 48 hours prior to dosing.  
m.
Coagulation assays: See Assessments Section 7.1.3 for Laboratory Tests list. No need to repeat on C1D1 if baseline assessment performed within 72 hours prior to that date.  
Assessments performed on C2D1 and Day 1 of each subsequent cycle should be performed within 48 hours prior to dosing.
n.
CA-125 (Ovarian Cancer Only): The first measurement for CA-125 must be collected within 2 weeks before treatment is started, during the screening period.  Subsequent 
CA-125 levels will be measured on Day 1 of each cycle before treatment, at End of Treatment, and at Follow-up visit 28 days after last dose administration.  There is no need 
to repeat on C1D1, if the baseline (screening) assessment was performed within 72 hours prior to that day.
o.
Urinalysis: Dipstick is acceptable.  Microscopic analyses if clinically indicated (eg, only after the second positive dipstick result for heme).  If ≥ 2+ protein on urine dipstick, 
then collect spot urine sample to calculate UPCR or collect 24hr urine.  
p.
Pregnancy Test (Serum/Urine) or FSH Level (Serum): For female patients of childbearing potential, a serum or urine pregnancy test, with sensitivity of at least 
25 mIU/mL and assayed in a certified laboratory, will be performed on 2 occasions prior to starting study therapy, once at the start of screening and once at the baseline visit 
immediately before investigational product administration.  Pregnancy tests will also be routinely repeated at Day 1 of every treatment cycle during the active treatment 
period, at the End of Treatment visit, at the 28-day Follow-Up Visit, 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/ECs or if required by local regulations.  Patients with confirmed positive pregnancy test(s) 
should not be dosed.  For female patients who achieved postmenopausal status and have not experienced their menses for at least 12 consecutive months, a serum FSH test 
must be conducted at screening only to confirm a FSH level within the laboratory’s reference ranges.
q.
CRP or hsCRP: One 5 mL blood sample will be collected per schedule of activities to measure C-reactive protein (CRP) or high sensitivity C-reactive protein (hsCRP) to 
monitor for potential immune activation or inflammation. Sample for C1D1 must be collected prior to dosing.
r.
TBNK (Whole Blood): Whole blood absolute immune cell counts (TBNK) will be measured by collecting a 5 mL blood sample per schedule of activities. Sample collected 
on C1D1 should be completed pre-dose.


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Page 38
 
t.
Hepatitis B, C and HIV Tests: See Assessments Section 7.1.3 for Laboratory Tests list. In the case of apparent ongoing HBV or HCV infection, reflex serum viral load 
testing will be performed.
u.
Registration: Patient number and dose level allocation operated by Pfizer Inc.  Treatment should begin no longer than 3 days from registration.
v.
Study Treatment: PF-06801591 will be administered 300 mg once every 28 days as a subcutaneous (SC) injection.  Day 1 safety laboratory test results need to be reviewed 
by the investigator prior to dosing at the beginning of each cycle for dosing confirmation and administration rate.  Since processing of samples at the central laboratory has to 
be completed within 24 hours of collection, please try to accommodate the administration of study treatment on either: A Monday to Wednesday schedule for samples 
collected on C1D1; or, a Monday to Friday schedule for all subsequent new cycles of treatment (ie, C2D1 +).
w.
Local Site Injection Tolerability Assessment (SC Administration Cohort Only): Assessment of each injection should be conducted for at least 1 hour following treatment 
administration on Day 1 of each cycle.  Site tolerability assessments should continue after each dosing visit, only if injection site pain or injection site reaction (ISR) 
characteristics continue to persist.  The assessments should continue at regularly scheduled visits until the symptoms resolve.
x.
Tumor Assessments: See Section 7.4 Tumor Response Assessments. CT or MRI scans to be done every 8 weeks (±5 days), from the start of study entry until disease 
progression by irRECIST, death, withdrawal of consent, or subsequent administration of an anti-chemotherapy agent. Bone scans should be performed at baseline and on-
study for patients with known or suspected bone metastases not well-visualized on other imaging or if disease is suspected or has been previously documented as appropriate 
to follow disease.  Tumor assessments should be fixed according to the calendar, regardless of treatment delays.  Radiographic assessments obtained per the patient’s standard 
of care prior to enrollment into the study do not need to be repeated and are acceptable to be used as baseline evaluation, if, (1) obtained within 28 days before C1D1, (2) 
performed using the method requirements (ie, RECIST v. 1.1), (3) the same technique/modality can be used to follow identified lesions throughout the trial for a given patient, 
and (4) appropriate documentation indicating that these radiographic tumor assessments were performed as standard of care is available in the patient’s source notes. CT or 
MRI scans may be assessed every 12 weeks (±5 days) for patients who 1) have remained on treatment for ≥24 weeks, and 2) have no confirmed progression by irRECIST 
within the last 6 months, and 3) have demonstrated stability of disease. Confirmation of response (CRPR) with a second consecutive scan at least 4 weeks later is preferred.  
Tumor assessments should be repeated at the End of Treatment visit if more than 8 weeks have passed since the last evaluation.  CT or MRI scans should be completed before 
tumor biopsy samples are collected.  If a patient is classified as having PD during an on-treatment tumor assessment, then confirmation of PD by a second consecutive scan at 
least 4 weeks later in the absence of rapid clinical deterioration is required. After End of Treatment for patients who did not end treatment due to disease progression, death, 
or withdrawal of consent, a tumor assessment will be performed every 12 weeks (±1 week), until disease progression by irRECIST, or initiation of a new anti-cancer 
treatment, or end of trial (2 years after last patient first dose, see Section 13.2 End of Trial in All Other Participating Countries), whichever is first.
y.
AE Assessments: Adverse events should be documented and recorded at each visit using NCI CTCAE version 4.03.  AEs (serious and non-serious) should be recorded on the 
CRF from the time the patient has taken at least 1 dose of investigational product.  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.  Additional, 
immune related AEs (irAEs) will be collected with a follow up phone call at 90 and 120 days after last dose administration date to collect post treatment related AE 
information. 
z.
SAE Assessments: 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 
150 calendar days after the last administration of the investigational product or until administration of subsequent anti-cancer therapy whichever comes first. SAEs occurring 
to a patient after the active reporting period has ended should be reported to the sponsor if the investigator becomes aware of them; at a minimum, all SAEs that the 
investigator believes have at least a reasonable possibility of being related to investigational product are to be reported to the sponsor.  
aa.
Concomitant Medications and Non Drug Supportive Interventions: all concomitant medications should be recorded in the CRF including supportive care drugs (eg, 
Anti-emetic treatment and prophylaxis), drugs used to treat adverse events or chronic diseases, and non-drug supportive interventions (eg, transfusions).
bb. Subsequent anticancer therapy: After the completion of the EOT visit subsequent anti-cancer therapy will be documented and recorded for patients who discontinue 
investigational products and continue in 120 day safety follow-up, and  subsequently during survival follow-up.
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cc.
Contraceptive Check (frequency to match that of pregnancy tests): Male patients who are able to father children and female patients who are of childbearing potential 
will need to affirm that they meet the criteria for correct use of 2 of the selected methods of contraception throughout the study and continue for at least 5 months after the last 
dose.  The investigator or his or her designee will discuss with the patient the need to use 2 highly effective contraception methods consistently and correctly and document 
such conversation in the patient’s chart.  In addition, the investigator or his or her designee will instruct the patient to call immediately if one or both selected contraception 
methods are discontinued, or if pregnancy is known or suspected in the patient or the patient’s partner.
dd. Subsequent Cycles: Day 8 (except C3D8) and Day 15 visits are not required after Cycle 2.  Note: For ECG, refer to footnote “j” that mentions an assessment scheduled on 
Day 8 of Cycle 3.  For Blood PK samples for PF-06801591 and for PD-1 Receptor Occupancy samples (whole blood), refer to the separate PK & Pharmacodynamic Schedule 
of Activities.
ee.
End-of-treatment Visit: conducted at the visit that the patient is discontinued from the trial and no longer than 1 week after the patient has been discontinued.  Complete 
tumor assessments if not completed in the last 8 weeks.
ff.
1-Month and Late irAE Follow-up: At least 28 days and no more than 35 days after discontinuation of treatment or last dose of study drug whichever is later, patients will 
return to undergo review of concomitant medications, vital signs, and assessment for resolution of any treatment-related toxicity.  Patients continuing to experience toxicity at 
this point following discontinuation of treatment will continue to be followed at least every 4 weeks until resolution or determination, in the clinical judgment of the 
Investigator, that no further improvement is expected. To collect additional late immune-related AE information, all patients will have a follow- up phone call 90 and 
120 days (7 days) after last dose administration date to collect post-treatment related AE information. If any concern arises, the patient will be called in for an inpatient 
follow-up visit within 5 calendar days of the initial phone call (assessments will be the same as the assessments performed 28 days (range 28-35 days) after EOT follow-up 
visit).
gg. Survival Follow-up: Subsequent to the 120-day follow-up period, overall survival (OS) follow-up will be conducted by telephone every 8 weeks (7 days) until end of the 
entire trial (2 years after last patient first dose, see Section 13.2 End of Trial in All Other Participating Countries).  If the patient is seen in the clinic during the window of time 
that a scheduled telephone call is to be made to collect survival data, then the clinic visit may replace the survival telephone call.  After the completion of the EOT visit 
subsequent anti-cancer therapy will be documented and recorded for patients who discontinue investigational products and continue in 120 day safety follow-up, and  
subsequently during survival follow-up.


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PHARMACOKINETIC AND PHARMACODYNAMIC SCHEDULE OF ACTIVITIES: PART 1 SUBCUTANEOUS 
ADMINISTRATION OF PF-06801591
Pharmacokinetic and Pharmacodynamic Schedule of Activities for Part 1 Subcutaneous Administration of PF-06801591
Screen
Cycle 1
(Days 1 to 28)
Cycle 2
(Days 1 to 28)
Cycle 
3
(Days 
1 to 
28)
Cycle 4
(Days 1 to 28)
Cycle 5
(Days 1 to 
28)
Further 
Cycles
End 
of 
Treat-
ment
Visit Identifier
Day 
1
Day 
3
(±8 
hrs)
Day 
8
(±1)
Day 
15
(±2)
Day 
21
(±2)
Day 
1
 
 
 
 
Day 
1
Day 
1
Day 
8
(±1)
Day 
15
(±2)
Day 
21
(±2)
Day 
1
Day 
1
Pre-
dose*
1
hr*
24
hr**
Pre-
dose* 1 hr*
Pre-
dose*
Pre-
dose*
1
hr*
Pre-dose* Pre-dose*
Blood PK Sample for 
PF-06801591a
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
(Cycles 
6,8, 10)
X
Blood Sample for 
Anti-PF-06801591-anti
bodyb
X
X
X
X
(Cycles 
6,8, 10)
X
Target engagement 
(TE) biomarkers
PD-1 Receptor 
Occupancy (whole 
blood)a
X
X
X
X
X
X
X
X
X
X
X
X
Pharmacodynamic 
and immune 
monitoring 
biomarkers
 
 
 
CC
I
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Pharmacokinetic and Pharmacodynamic Schedule of Activities for Part 1 Subcutaneous Administration of PF-06801591
Screen
Cycle 1
(Days 1 to 28)
Cycle 2
(Days 1 to 28)
Cycle 
3
(Days 
1 to 
28)
Cycle 4
(Days 1 to 28)
Cycle 5
(Days 1 to 
28)
Further 
Cycles
End 
of 
Treat-
ment
Visit Identifier
Day 
1
Day 
3
(±8 
hrs)
Day 
8
(±1)
Day 
15
(±2)
Day 
21
(±2)
Day 
1
Day 
8
(±2)*** or (±5 
for fresh 
tumor biopsy 
only)e
Day 
1
Day 
1
Day 
8
(±1)
Day 
15
(±2)
Day 
21
(±2)
Day 
1
Day 
1
Pre-
dose*
1
hr*
24
hr**
Pre-
dose* 1 hr*
Pre-
dose*
Pre-
dose*
1
hr*
Pre-dose* Pre-dose*
 
 
 
PK = pharmacokinetics; ADA = anti-drug antibody; SOA = Schedule of Activities; 
; NAb = neutralizing antibody; SC = Subcutaneous.
* The 1-hr samples should be collected within 1 hr after the end of SC injection and pre-dose samples should be collected within 6 hrs before the administration of the SC 
injection. Note: No day window is allowed for PK/Pharmacodynamic sampling on Day 1 of Cycle 1 and subsequent cycles as applicable.
**The 24-hr samples should be collected ±2 hours based on the 24-hr period after the end of the SC injection. 
Footnotes for Pharmacokinetics and Pharmacodynamic Schedule of Activities for Part 1 Subcutaneous Administration of PF-06801591
a.
Blood samples for determination of PF-06801591 concentration: Blood samples will be collected at each time point for PK analysis of PF-06801591. After cycle 4, pre-
dose PK samples will be collected only on every 2nd cycle (cycles 6, 8, and 10, etc.). An additional PK sample should also be taken at the end of treatment.  
b.
Blood sample for Anti-PF-06801591 Antibody Measurement: Blood samples (approx. 10 mL each) will be collected at each time point for ADA/NAb assessment. After 
cycle 4, pre-dose ADA/NAb will be collected only on every 2nd cycle (cycles 6, 8, and 10, etc.). An additional ADA/NAb sample should also be taken at the end of 
treatment.  
c.
Receptor Occupancy: A 4 mL whole blood sample will be collected at the time points indicated in the PK/Pharmacodynamic SOA. PD-1 occupancy by PF-06801591 on 
T cells will be measured using flow cytometry.
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SCHEDULE OF ACTIVITIES FOR PART 2: SUBCUTANEOUS ADMINISTRATION OF PF-06801591 
The Schedule of Activities tables provide an overview of the protocol visits and procedures.  Refer to the Assessments Section 7 of the 
protocol for detailed information on each assessment required for compliance with the protocol.
The investigator may schedule visits (unplanned visits) in addition to those listed on the schedule of activities, in order to conduct 
evaluations or assessments required to protect the well-being of the patient.
Schedule of Activities for Part 2 SC 
Administration of PF-06801591
Treatment Period
EOTbb
Post-Treatment
Cycle 1 Only
(Days 1 to 28)
Cycle 2
(Days 1 to 28) 
Subsequent 
Cycles
(Days 1 to 28)aa
1-Month and Late irAE 
Follow upcc
Survival 
Follow 
Updd
Protocol Activity
Screeninga
(28 days 
prior to 
study entry)
Day 
1
Day 
8
Day 
15
Day
22
Day 
1
Day 
1
28 
days
90 
days
120 
days
Every 2 
months 
after 120 
day follow 
up visit
Visit Window
1
2
2
2
2
7
7
7
7
Informed Consentb
X
Tumor Historyc
X
Medical Historyd
X
Complete Physical 
Examination
X
X
X
X
Abbreviated Physical
Examinatione
X
X
X
X
X
Baseline Signs and 
Symptomsf
X
Height
X
Weightg
X
X
X
X
X
Vital Signs (BP/pulse 
rate/PO/Temp)h
X
X
X
X
X
X
X
X
X
ECOG Performance 
Statusi
X
X
X
X
X
X
Triplicate 12-Lead 
ECGj
X (single 
ECG only)
X
X
X
X
X


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Schedule of Activities for Part 2 SC 
Administration of PF-06801591
Treatment Period
EOTbb
Post-Treatment
Cycle 1 Only
(Days 1 to 28)
Cycle 2
(Days 1 to 28) 
Subsequent 
Cycles
(Days 1 to 28)aa
1-Month and Late irAE 
Follow upcc
Survival 
Follow 
Updd
Protocol Activity
Screeninga
(≤28 days 
prior to 
study entry)
Day 
1
Day 
8
Day 
15
Day
22
Day 
1
Day 
1
28 
days
90 
days
120 
days
Every 2 
months 
after 120 
day follow 
up visit
Laboratory
Hematologyk
X
X
X
X
X
X
X
X
X
Blood 
Chemistryl
X
X
X
X
X
X
X
X
X
Coagulationm
X
X
X
X
X
X
X
X
X
Urinalysisn
X
X
X
X
X
X
Pregnancy Test
or FSH Levelo
X
X
X
X
X
X
Pregnancy Test or 
FSH Level in Post-
Treatment Follow-up 
(Specific for Poland 
only)o
(Days)
28
60
90
120
150
X
X
X
X
X
Hepatitis B, C, and 
HIV testsq
X
Registration and 
Treatment
Registrationr
X
Study 
Treatments
X
X
X
Local Site Injection 
Tolerability 
Assessmentt
X
X
X
Tumor Assessments
CT or MRI Scanu
X
Every 8 weeks (±5 days) up to 24 wks, and every 8 or 12 weeks (±5 days) 
thereafter according to calendar, regardless of treatment delays
X
X (Every 12 weeks)
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Schedule of Activities for Part 2 SC 
Administration of PF-06801591
Treatment Period
EOTbb
Post-Treatment
Cycle 1 Only
(Days 1 to 28)
Cycle 2
(Days 1 to 28) 
Subsequent 
Cycles
(Days 1 to 28)aa
1-Month and Late irAE 
Follow upcc
Survival 
Follow 
Updd
Protocol Activity
Screeninga
(28 days 
prior to 
study entry)
Day 
1
Day 
8
Day 
15
Day
22
Day 
1
Day 
1
28 
days
90 
days
120 
days
Every 2 
months 
after 120 
day follow 
up visit
Other Clinical 
Assessments
Adverse Eventsv
X
X
X
X
X
X
X
X
X
X
Serious Adverse 
Eventsw
X
X
X
X
X
X
X
X
X
X
X
X 
Up to 150 
days after 
last 
treatment
Concomitant 
Medication and 
non-drug supportive 
interventionsx
X
X
X
X
X
X
X
X
X
X
X
Subsequent anti-cancer 
therapyy
X
X
X
X
Survival follow updd
X
Contraception checkz
X
X
X
X
X
X
X
X
BP = blood pressure; CT = computed tomography; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = end of treatment; FSH = follicle stimulating 
hormone; HIV = human immunodeficiency virus; MRI = magnetic resonance imaging; PK = pharmacokinetics; PO = pulse oximetry; TBNK = T cell/B cell/natural killer cell; wks 
= weeks.
Footnotes for Schedule of Activities for Part 2 Subcutaneous Administration
a.
Screening: To be performed within 28 days prior to study entry.
b.
Informed Consent: Must be obtained prior to undergoing any study-specific procedures.
c.
Tumor History: Will be collected within 28 days during screening prior to study entry.  Includes history of disease under study including details of primary diagnosis, 
treatment history and history of tumor diagnostics.  
d.
Medical History: Includes history of disease process (eg, staging) other than the cancer under study (active or resolved) and concurrent illness.  Includes prior treatments and 
any current medical treatments for any condition.
e.
Abbreviated Physical Examination (PE): Abbreviated PEs should be performed as appropriate at each visit where complete PEs are not required.
f.
Baseline Signs & Symptoms: On Day 1 prior to the start of study treatment, patients will be asked about any signs and symptoms experienced within the past 14 days prior 
to study entry.  Baseline signs and symptoms will be recorded on the Medical History CRF page. During the study, any new or worsening conditions since baseline will be 
recorded on the Adverse Events (AE) CRF page. 
g.
Weight: Patient’s body weight will be measured at Day 1 of each treatment cycle.


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h.
Vital Signs: includes temperature, sitting BP, pulse rate (to be recorded in the sitting position after 5 minutes of rest), and pulse oximetry (PO, at rest and after exertion).  On 
Day 1 of each cycle, vital signs should be measured prior to infusion start (pre-dose), BP, and pulse rate will be repeated 1 hour (±10 minutes) after the start of the infusion.
i.
Performance Status: Per ECOG performance scale in Appendix 6.
j.
Triplicate 12-Lead Electrocardiogram (ECG): See Assessment Section 7.1.5. ECGs will be collected at times specified in the Schedule Of Activities.  The Screening ECG 
will be a single 12-lead ECG.  At all other times, at each time point, 3 consecutive 12-lead ECGs (triplicate) will be performed approximately 2 minutes apart to determine 
mean QTcF interval.  All 12-lead ECGs should be confirmed by a qualified person at the institution and will be reviewed by a central laboratory.  ECGs on Day 1 of each 
cycle will be collected prior to dosing, and at the end of infusion (approximately 1 hour) following administration of each dose of PF-06801591. When coinciding with blood 
sample draws for PK, ECG assessment should preferably be performed prior to blood sample collection, such that the blood sample is collected at the nominal time.  If the 
mean QTcF is prolonged (≥45 msec from the pre-dose baseline, or >500 msec), the ECGs should be re-evaluated by a qualified person at the institution for confirmation.  
Additional triplicate ECGs may be performed as clinically indicated.  
k.
Hematology: See Assessments Section 7.1.3 for Laboratory Tests list. Assessments and physician’s evaluation must be performed prior to dosing.  No need to repeat on 
C1D1 if baseline assessment performed within 72 hours prior to that date.  Assessments performed on C2D1 and each subsequent cycle should be performed within 48 hours 
prior to dosing.  
l.
Blood Chemistry: See Assessments Section 7.1.3 for Laboratory Tests list. No need to repeat on C1D1 if screening assessment performed within 72 hours prior to that date.  
Assessments and physician’s evaluation should be performed prior to dosing.  Assessments performed on C2D1 and Day 1 of each subsequent cycle must be performed
within 48 hours prior to dosing.  
m.
Coagulation assays: See Assessments Section 7.1.3 for Laboratory Tests list. No need to repeat on C1D1 if baseline assessment performed within 72 hours prior to that date.  
Assessments performed on C2D1 and Day 1 of each subsequent cycle should be performed within 48 hours prior to dosing.
n.
Urinalysis: Dipstick is acceptable.  Microscopic analyses if clinically indicated (eg, only after the second positive dipstick result for heme).  If ≥2+ protein on urine dipstick, 
then collect spot urine sample to calculate UPCR or collect 24hr urine.
o.
Pregnancy Test (Serum/Urine) or FSH Level (Serum): For female patients of childbearing potential, a serum or urine pregnancy test, with sensitivity of at least 
25 mIU/mL and assayed in a certified laboratory, will be performed on 2 occasions prior to starting study therapy, once at the start of screening and once at the baseline visit 
immediately before investigational product administration.  Pregnancy tests will also be routinely repeated at Day 1 of every treatment cycle during the active treatment 
period, at the End of Treatment visit, at the 28-day Follow-Up Visit, 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/ECs or if required by local regulations.  In Poland, pregnancy tests have to be performed 
after end of treatment on Days 28, 60, 90, 120 and 150. Pregnancy tests on Days 60, 90, 120 and 150 may be collected at home by the patient.  Patients with confirmed
positive pregnancy test(s) should not be dosed.  For female patients who achieved postmenopausal status and have not experienced their menses for at least 12 consecutive 
months, a serum FSH test must be conducted at screening only to confirm a FSH level within the laboratory’s reference ranges.
 
 
q.
Hepatitis B, C and HIV Tests: See Assessments Section 7.1.3 for Laboratory Tests list. In the case of apparent ongoing HBV or HCV infection, reflex serum viral load 
testing will be performed.
r.
Registration: the patient enrollment number will be assigned through the use of an interactive response technology (IRT) system. 
s.
Study Treatment: PF-06801591 will be administered once every 28 days as either a flat dose SC injection of  300 mg.  Day 1 safety laboratory test results need to be 
reviewed by the investigator prior to dosing at the beginning of each cycle for dosing confirmation and administration rate.  
t.
Local Site Injection Tolerability Assessment: Assessment of each injection should be conducted for at least 1 hour following treatment administration on Day 1 of each 
cycle.  Site tolerability assessments should continue after each dosing visit, only if injection site pain or ISR characteristics continue to persist.  The assessments should 
continue at regularly scheduled visits until the symptoms resolve. 
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u.
Tumor Assessments: See Section 7.4 Tumor Response Assessments. CT or MRI scans to be done every 8 weeks (±5 days), from the start of study entry until disease 
progression by irRECIST, death, withdrawal of consent, or subsequent administration of an anti-chemotherapy agent. Bone scans should be performed at baseline and on-
study for patients with known or suspected bone metastases not well-visualized on other imaging or if disease is suspected or has been previously documented as appropriate 
to follow disease.  Tumor assessments should be fixed according to the calendar, regardless of treatment delays.  Radiographic assessments obtained per the patient’s 
standard of care prior to enrollment into the study do not need to be repeated and are acceptable to be used as baseline evaluation, if, (1) obtained within 28 days before C1D1, 
(2) performed using the method requirements (ie, RECIST v. 1.1 ), (3) the same technique/modality can be used to follow identified lesions throughout the trial for a given 
patient, and (4) appropriate documentation indicating that these radiographic tumor assessments were performed as standard of care is available in the patient’s source notes. 
CT or MRI scans may be assessed every 12 weeks (±5 days) for patients who 1) have remained on treatment for ≥24 weeks, and 2) have no confirmed progression by 
irRECIST within the last 6 months, and 3) have demonstrated stability of disease. Confirmation of response (complete response [CR]/partial response [PR]) with a second 
consecutive scan at least 4 weeks later is preferred.  Tumor assessments should be repeated at the End of Treatment visit if more than 8 weeks have passed since the last 
evaluation.  CT or MRI scans should be completed before tumor biopsy samples are collected.  If a patient is classified as having progressive disease (PD) during an on-
treatment tumor assessment, then confirmation of PD by a second consecutive scan at least 4 weeks later in the absence of rapid clinical deterioration is required. After End 
of Treatment for patients who did not end treatment due to disease progression, death, or withdrawal of consent, a tumor assessment will be performed every 12 weeks 
(1 week), until disease progression by irRECIST, or initiation of a new anti-cancer treatment, or end of trial (2 years after last patient first dose, see Section 13.2 End of Trial 
in All Other Participating Countries), whichever is first.
v.
AE Assessments: Adverse events should be documented and recorded at each visit using NCI CTCAE version 4.03.  AEs (serious and non-serious) should be recorded on the 
CRF from the time the patient has taken at least 1 dose of investigational product.  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.  Additional, 
irAEs will be collected with a follow up phone call at 90 and 120 days after last dose administration date to collect post treatment related AE information. 
w.
SAE Assessments: 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 
150 calendar days after the last administration of the investigational product or until administration of subsequent anti-cancer therapy whichever comes first.  SAEs occurring 
to a patient after the active reporting period has ended should be reported to the sponsor if the investigator becomes aware of them; at a minimum, all SAEs that the 
investigator believes have at least a reasonable possibility of being related to investigational product are to be reported to the sponsor.  
x.
Concomitant Medications and Non Drug Supportive Interventions: all concomitant medications should be recorded in the CRF including supportive care drugs (eg, 
Anti-emetic treatment and prophylaxis), drugs used to treat adverse events or chronic diseases, and non-drug supportive interventions (eg, transfusions).
y.
Subsequent anticancer therapy: After the completion of the EOT visit subsequent anti-cancer therapy will be documented and recorded for patients who discontinue 
investigational products and continue in 120 day safety follow-up, and  subsequently during survival follow-up.
z.
Contraceptive Check (frequency to match that of pregnancy tests): Male patients who are able to father children and female patients who are of childbearing potential 
will need to affirm that they meet the criteria for correct use of 2 of the selected methods of contraception throughout the study and continue for at least 5 months after the last 
dose. The investigator or his or her designee will discuss with the patient the need to use 2 highly effective contraception methods consistently and correctly and document 
such conversation in the patient’s chart.  In addition, the investigator or his or her designee will instruct the patient to call immediately if one or both selected contraception 
methods are discontinued, or if pregnancy is known or suspected in the patient or the patient’s partner.
aa.
Subsequent Cycles: For Blood PK samples for PF-06801591 and for PD-1 Receptor Occupancy samples (whole blood) refer to the separate PK & Pharmacodynamic 
Schedule of Activities.
bb. End-of-Treatment Visit: conducted at the visit that the patient is discontinued from the trial and no longer than 1 week after the patient has been discontinued.  Complete 
tumor assessments if not completed in the last 8 weeks.
cc.
1-Month and Late irAE Follow-up: At least 28 days and no more than 35 days after discontinuation of treatment or last dose of study drug whichever is later, patients will 
return to undergo review of concomitant medications, vital signs, and assessment for resolution of any treatment-related toxicity.  Patients continuing to experience toxicity at 
this point following discontinuation of treatment will continue to be followed at least every 4 weeks until resolution or determination, in the clinical judgment of the 
Investigator, that no further improvement is expected. To collect additional late immune-related AE information, all patients will have a follow- up phone call 90 and 
120 days (7 days) after last dose administration date to collect post-treatment related AE information. If any concern arises, the patient will be called in for an inpatient 


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follow-up visit within 5 calendar days of the initial phone call (assessments will be the same as the assessments performed 28 days (range 28-35 days) after EOT follow-up 
visit).
dd. Survival Follow-up: Subsequent to the 120-day follow-up period, overall survival (OS) follow-up will be conducted by telephone every 8 weeks (7 days) until end of the 
trial (2 years after last patient first dose, see Section 13.2 End of Trial in All Other Participating Countries).  If the patient is seen in the clinic during the window of time that a 
scheduled telephone call is to be made to collect survival data, then the clinic visit may replace the survival telephone call.  After the completion of the EOT visit subsequent 
anti-cancer therapy will be documented and recorded for patients who discontinue investigational products and continue in 120 day safety follow-up, and subsequently during 
survival follow-up.


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PHARMACOKINETIC AND PHARMACODYNAMIC SCHEDULE OF ACTIVITIES: PART 2 SUBCUTANEOUS 
ADMINISTRATION OF PF-06801591
Pharmacokinetic and Pharmacodynamic Schedule of Activities for Subcutaneous Administration of PF-06801591
Screen
Cycle 1
(Days 1 to 28)
Cycle 2
(Days 1 to 
28)
Cycle 3
(Days 1 to 
28)
Cycle 4
(Days 1 to 
28)
Cycle 5
(Days 1 to 
28)
Subsequent 
Cycles
End of 
Treatment
Post-
Treatment
Visit Identifier
Day 1 Day 8
(±1)
Day 
15
(±2)
Day 
22
(±2)
Day 
1
Day 
1
Day 
1
Day 
1
Day 
1
28 day follow-
up (±7)
Pre-
dose*
Pre-dose*
Pre-dose*
Pre-dose*
Pre-dose*
Pre-dose*
Blood PK Sample for 
PF-06801591a
X
X
X
X
X
X
X
(Every 3 
Cycles eg, 6, 9, 
12, etc.)
X
Blood Sample for 
Anti-PF-06801591-
Antibodyb
X
X
X
X
(Every 3 
Cycles eg, 6, 9, 
12, etc.)
X
Pharmacodynamic and 
immune monitoring 
biomarkers
 
 
 
 
PK = pharmacokinetics; ADA = anti-drug antibody; SOA = Schedule of Activities; 
; NAb = neutralizing antibody.
* The pre-dose samples should be collected within 6 hrs before the administration of SC injection. Note: No day window is allowed for PK/Pharmacodynamic sampling on 
Day 1 of Cycle 1 and subsequent cycles as applicable.
Footnotes for Pharmacokinetics and Pharmacodynamic Schedule of Activities for Part 2 Subcutaneous Administration of PF-06801591
a.
Blood samples for determination of PF-06801591 concentration: Blood samples will be collected at each time point for PK analysis of PF-06801591. After cycle 6, pre-
dose PK samples will be collected only on every 3rd cycle (cycles 9, 12, etc.). An additional PK sample should also be taken at the 28-day follow up visit post-treatment.  
CCI
CCI


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b.
Blood sample for Anti-PF-06801591 Antibody Measurement: Blood samples (approx. 10 mL each) will be collected at each time point for ADA/NAb assessment. After 
Cycle 5, blood samples for ADA/NAb assessment should be collected pre-dose on Day 1 every 3 cycles (eg, Cycles 6, 9, 12, etc.) and at the 28-day follow up visit post-
treatment. A companion blood sample for the determination of PF-06801591 concentration will be collected in conjunction with the ADA sample collection to facilitate 
immunogenicity assessment.
CCI


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1. INTRODUCTION
Cancerous cells often evade detection by the immune system which normally attacks and 
kills abnormal cells.8 The ability to escape immune recognition is a hallmark of cancer 
progression.  While T cells specific to tumor antigens (Ags) can be readily isolated from 
patients, it is clear that T cell activation is not mediated by Ag stimulation alone.9 Even in 
the presence of tumor Ags, T cells may exhibit exhaustion, rendering them unable to 
proliferate and hypo responsive to further Ag encounter.  The T-cell response is regulated by 
immune checkpoints that include both co-stimulatory and co-inhibitory molecules.  The 
positive signal delivered by co-stimulatory molecules is essential for an effective immune 
response, while the negative signal delivered by co-inhibitory molecules is essential for the 
prevention of autoimmunity and mediation of T-cell tolerance.10
Immune checkpoint inhibitors represent a novel class of antitumor agents which have 
demonstrated activity in certain types of cancers (eg, metastatic melanoma, non-small-cell 
lung cancer [NSCLC], squamous cell cancer of head and neck [SCCHN], renal cell 
carcinoma [RCC] and classical Hodgkin lymphoma [cHL]); these agents continue to be 
explored in broad set of malignancies, including ovarian cancers.  One of the most studied 
checkpoints in the immune system is the human programmed cell death protein-1 (PD-1), a 
member of the cluster of differentiation (CD) 28 family of T-cell regulators that is highly 
expressed on activated effector tumor-infiltrating lymphocytes (TILs) and which interacts 
with 2 known ligands: programmed death ligand 1 (PD-L1) and programmed death ligand 
2 (PD-L2).1 While PD-L2 is expressed primarily on macrophages and dendritic cells, 
PD-L1 is expressed on tumor cells, as well as diverse immune cells.11 Upon interaction with 
either of its two ligands, PD-1 negatively regulates antigen receptor signaling, resulting in 
immune tolerance.  Blocking PD-1 promotes therapeutic anti-tumor response in diverse 
preclinical tumor models (Figure 1).
Figure 1: Basis for Immune Therapy
PD-1 = programmed cell death protein-1; PD-L1 = programmed death ligand-1.
Deactivated T cell: When PD-1 on the T cell binds to PD-L1 on the tumor cell, the T cell becomes deactivated, 
allowing the cancer cell to evade immune attack.  Activated T cell:  Inhibitors of PD-1 and PD-L1 can prevent 
the tumor cell from binding to PD-1, enabling the T cell to remain active and co-ordinate an attack.12
PD-L1 inhibitor


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Receptors for PD-1 are expressed on several immune cells, in particular on cytotoxic T cells, 
and PD-1 expression has been found to be elevated in TILs isolated from patients with 
metastatic melanoma and SCCHN.13,14,15 Although in resting immune cells PD-1 is 
minimally expressed, broad expression of this receptor is evident following immune 
activation.16 Since PD-L1 is expressed on a wide variety of solid tumors including 
melanoma, SCCHN, NSCLC, ovarian, bladder, and renal cell carcinomas, it is hypothesized 
that high PD-L1 expression is the major mechanism of T-cell exhaustion in diverse 
malignancies.17-19 Indeed, for some tumor types including RCC, ovarian, and urothelial 
cancers, high PD-1/PD-L1 expression is associated with poor prognosis and overall survival
(OS).18,20 These observations have led to development of potent inhibitors of the 
PD-1 pathway and form the basis for an immunotherapeutic approach to cancer.10,21
Sarcomas comprise a group of connective tissue neoplasms that are broadly classified as 
originating from soft tissues or bones.  A recent sarcoma publication of tumor specimens 
from 105 cases showed that PD-1 positive lymphocytes and PD-L1 expression in tumor 
tissue were seen in 65% and 58%, respectively, of 105 soft tissue sarcomas. The degree of 
PD-1 positivity in TILs and PD-L1 overexpression in tumor specimens correlated with a 
poorer prognosis and more aggressive disease.22 In a study of 38 human osteosarcoma 
samples, PD-L1 messenger ribonucleic acid (mRNA) gene expression ranged over 4 log 
(>5,000-fold difference). When absolute expression was normalized to that of housekeeping 
gene -actin and categorized by log-transcript detection (low = 1 log; intermediate = 2 log; 
and high = 3 and 4 log), 9/38 samples (24%) showed high-level expression. A further
19 samples (50.0%) showed intermediate expression, 4 (10.5%) showed low-level 
expression, and 6 (15.8%) were negative.23 Therefore, although anti-PD-1 therapy has not 
been widely tested in sarcoma patients, there is ample rationale for using anti-PD-1 treatment 
alone and possibly in combination with other checkpoint inhibitors in patients with advanced 
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Figure 2.
PD-1 and PD-L1 in Soft Tissue Sarcomas
Programmed death ligand (PDL)-1 and PDL-2 molecules are expressed on the surface of sarcoma cells.  
Interaction between sarcoma associated PDL-1/2 and T cell PD-1 on the CD8 T cells leads to inactivation of 
tumor-directed CD8 T-cells, allowing the sarcoma to evade CD8 T-cell mediated killing. Use of 
anti-PD-1 antibodies blocks this T cell inactivation and allows the tumor-directed CD8 T-cells to remain active 
in destroying the sarcoma cells.24
The United States (US) Food and Drug Administration (FDA) has approved a number of 
anti-PD-1 and anti-PD-L1 molecules including:
1. Nivolumab/Opdivo(a fully human immunoglobulin G4 [IgG4] anti-PD-1 Ab) for 
unresectable or metastatic melanoma, metastatic NSCLC, advanced renal cell 
carcinoma (RCC), classical Hodgkin lymphoma (cHL), locally advanced or 
metastatic urothelial carcinoma, and recurrent or metastatic squamous cell carcinoma 
of the head and neck (SCCHN).
2. Pembrolizumab/Keytruda(a humanized IgG4 anti-PD-1 antibody) for unresectable 
or metastatic melanoma, metastatic NSCLC, cHL, and recurrent or metastatic
SCCHN; approval of atezolizumab/Tecentriq(a humanized 
IgG1 anti-PD-L1 antibody) for locally advanced or metastatic urothelial carcinoma,
and metastatic NSCLC.
3. Durvalumab/Imfizi® (a humanize IgG1 anti-PD-1 antibody) for locally advanced or 
metastatic urothelial carcinoma.


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4. Avelumab/Bavencio(an anti-PD-L1 antibody), for the treatment of metastatic 
merkel cell carcinoma (MCC) and urothelial carcinoma.
These therapies have provided compelling evidence that blocking the PD-1 pathway is a 
viable immunotherapeutic approach for variety of tumor types.1-6  Recently PD-1 antibodies 
in development (Table 1) have shown promising results in clinical trials with durable 
anti-tumor responses (ie, tumor shrinkage, extending OS time) seen early and continuing 
after treatment discontinuation, in other multiple tumor types including ovarian cancer, 
certain sarcomas, triple negative breast cancer, hepatocellular carcinoma, mismatch repair 
deficient cancers, small cell lung cancer, and gastric cancer4-25  The PD-1/PD-L1 inhibitors 
also are less labor-intensive to administer than some other types of immunotherapies, and do 
not require personal preparation for each patient as do dendritic cell vaccines and chimeric 
antigen receptor (CAR) T-cell therapy.12
Table 1.
Anti PD 1 Antibodies
Agent
Target
Description
Binding 
Affinity (KD)
PF-06801591
PD-1
Humanized 
IgG4 anti-PD-1
23 pM
Nivolumab (Opdivo®)
(BMS-936558, ONO-4538, 
MDX-1106)
PD-1
Fully human IgG4
3 nM
Pembrolizumab (Keytruda®)
(MK-3475, pembrolizumab)
PD-1
Humanized 
IgG4 kappa
28 pM
Ig = immunoglobulin; L1 = ligand; NA = not available; PD-1 = programmed cell death protein-1; PD-L1 = 
programmed death ligand 1.
Source: Kim JW, Eder JP: Prospects for Targeting PD-1 and PD-L1 in Various Tumor Types.  Oncology 
Cancer Network 2014.13
1.1. Mechanism of Action/Indication
PF-06801591 is a humanized, hinge region-stabilized IgG4 monoclonal antibody (mAb) 
specific for human PD-1 that can selectively binds to human PD-1 and block the interaction 
between PD-1 and PD-L1/PD-L2.  PF-06801591 has been shown to induce T cell 
proliferation and interferon gamma (IFN-) and other proinflammatory cytokines secretion in 
human activated CD8+ T cells [Figure 3].
PF-06801591 showed similar binding affinity to human PD-1 compared to pembrolizumab
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The projected half-life (t½) of approximately 3 weeks for PF-06801591 is similar to that of 
nivolumab and pembrolizumab.2,4
In this study, PF-06801591 will be used to assess safety and tolerability of increasing dose 
levels in patients with locally advanced or metastatic melanoma, SCCHN, ovarian cancer, 
sarcoma, NSCLC, or other solid tumor types with clinical evidence of response to anti 
PD-1 or PD-L1 agents. 
1.2. Background and Rationale
1.2.1. Melanoma
Melanoma is the most serious form of skin cancer and strikes adults of all ages. The 5-year 
prevalence of melanoma in the European Union (EU) is approximately 159,000 patients with 
an incidence of approximately 41,000 per year and approximately 11,000 deaths annually, as 
described in the World Health Organization (WHO) Europe region.23 Melanoma accounts 
for approximately 5% of all new cases of cancer in the US. The incidence of melanoma 
continues to rise by almost 3% per year in the US. This translates to 76,000 new cases a year 
with 9,000 associated deaths. The male: female incidence ratio of melanoma is 1.4:1.27 The 
5-year survival rate is 15% for late-stage disease.28 The activity of anti-PD-1 antibodies in 
melanoma is well-established, and anti-PD-1 antibodies are a standard of care in advanced 
melanoma.2,4
1.2.2. Head and Neck Cancer
Approximately 650,000 new cases of head and neck cancer are diagnosed globally each year 
with the most common form being SCCHN.29, 30, 31 The SCCHN form represents an 
aggressive tumor type with a 10.1 month OS rate for patients with recurrent and/or metastatic 
disease.32 In addition, SCCHN is considered to be an immunosuppressive tumor:33 the 
circulating and tumor-infiltrating T cells of patients with SCCHN have signaling 
defects,34 and immune effector cell anergy has been well described.  Taken together with the 
ability of TILs to act against SCCHN tumor Ags, SCCHN tumors are suitable targets for 
immunotherapy.  To date, the only FDA-approved immunotherapeutic agent for SCCHN is 
cetuximab; an anti-epidermal growth factor receptor (EGFR) Ab.  EGFR antibody (Ab) is a 
tumor Ag expressed on >90% of all SCCHN tumors.  In Phase 3 studies, recurrent and 
metastatic SCCHN patients treated with cetuximab plus concomitant chemotherapy had an 
increased OS rate of 7.4 months, compared to 10.1 months in SCCHN patients treated with 
chemotherapy alone.30 Pembrolizumab has received accelerated approval from the FDA for 
recurrent or metastatic SCCHN with disease progression on or after platinum-containing 
chemotherapy based on the results of KEYNOTE-012, with an overall response rate (ORR)
of 16% and complete response (CR) rate of 5%.4  Nivolumab received FDA approval in the 
same setting based on the results of CheckMate 141 with ORR of 13.3% and CR rate of 2.5% 
and meaningful improvement in OS (hazard ratio [HR] 0.7, 95% confidence interval [CI]
0.52-0.92).2


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1.2.3. Ovarian Cancer
In 2014 it was estimated that ovarian cancer resulted in the deaths of >14,000 women, more 
deaths than any other gynecologic cancers, making it the fifth leading cause of cancer-related 
death among women.35 The incidence of ovarian cancer increases with age and is most 
prevalent during the eighth decade of life.  In 2011, it was estimated that approximately 
188,867 women living in the US had ovarian cancer. In a Phase II study with nivolumab in 
ovarian cancer, an ORR of 15% (3 of 20 patients) was seen with 1 partial response (PR) at 
1 mg/kg and 2 CR at 3 mg/kg, and disease control rate (DCR) was 45%.2,36  Median OS was 
20 months, and  median progression free survival (PFS) was 3.5 months. A study with 
pembrolizumab in PD-L1 positive ≥1% of tumor cells (51% of ovarian cancer patients) also 
had an ORR of 11.5% (3 of 26 patients) with 1 CR and DCR of 34.6%.4  
1.2.4. Sarcomas
Sarcomas comprise a group of about 70 rare connective tissue neoplasms of mesenchymal 
origin that are broadly classified as originating from soft tissues or bones.37 In 2014, an
estimated 12,000 cases of soft tissue sarcoma and 3,000 cases of bone sarcomas were 
diagnosed in the US; approximately 4,700 and 1,500 people were expected to die from soft 
tissue and bone sarcomas, respectively.38 Standard management is usually determined by 
multidisciplinary teams at sarcoma referral centers and from European Society for Medical 
Oncology (ESMO) and National Comprehensive Cancer Network (NCCN) guidelines. For 
metastatic disease and locally advanced tumors for which local control is not an option, 
chemotherapy and targeted agents are used.39 Although multimodality treatments have 
improved outcomes for pediatric sarcomas, there is no treatment for metastatic refractory 
disease, and median OS for most metastatic adult sarcomas is only one year.40 SARC028, a 
Phase II study of pembrolizumab in 86 patients with various sarcomas, demonstrated ORR of 
0% (0 of 10) in leiomyosarcoma, 44% (4 of 9) in pleomorphic sarcoma, 22% (2 of 9) in 
liposarcoma, 11% (1 of 9) in synovial sarcoma, 17% (1 of 6) in chondrosarcoma, 0% (0 of 
13) in Ewing’s sarcoma, and 5% (1 of 19) in osteosarcoma. Median PFS was 18 weeks.4, 11.
1.2.5. Non-Small Cell Lung Cancer (NSCLC)
There are extensive clinical data leading to the approval of nivolumab and pembrolizumab 
for the treatment of advanced or metastatic NSCLC.
Nivolumab
In the Phase 1 study, a maximum tolerated dose for nivolumab was not identified, and the 
safety profile was similar across tumor types and dose levels (0.1–10 mg/kg).2 ORRs were 
similar across doses in melanoma and renal cell carcinoma (RCC), while higher ORRs were 
observed in NSCLC at 3 mg/kg and 10 mg/kg versus 1 mg/kg. Peripheral receptor 
occupancy was saturated at doses ≥0.3 mg/kg. In dose-response/exposure-response analyses, 
a positive dose-dependent objective response trend was observed for each tumor type, but 
appeared to plateau at nivolumab doses of ≥1 mg/kg for melanoma and RCC, and at 
≥3 mg/kg for NSCLC. Although there was no apparent relationship between tumor 
shrinkage rate and exposure, tumor progression rate diminished with increasing exposure up 
to a dose of 3 mg/kg (every 2 weeks) in NSCLC.


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A clinical research trial enrolled 582 patients, randomized (1:1), to receive nivolumab 
3 mg/kg every 2 weeks (n=292) or docetaxel 75 mg/m2 q3w (n=290) until disease 
progression or unacceptable toxicity, excluding patients with autoimmune disease, medical 
conditions requiring systemic immunosuppression, symptomatic interstitial lung disease, or 
untreated brain metastasis.  The trial demonstrated OS improvement with a hazard ratio of 
0.73 (95% CI: 0.60, 0.89); p <0.002, and a median OS of 12.2 months in patients on 
nivolumab and 9.4 months in patients on docetaxel.  The trial also demonstrated significant 
improvement in ORR (19% vs 12%), with median response duration of 17 months for 
nivolumab and 6 months for the docetaxel, and no significant difference in progression-free 
survival (PFS).
The most common (≥20%) Grade 1-4 adverse reactions in the nivolumab arm included 
fatigue, musculoskeletal pain, cough, decreased appetite, and constipation.  The most 
common (≥2%) Grade 3-4 adverse reactions were dyspnea, fatigue, pneumonia, pulmonary 
embolism, pleural effusion, hyperglycemia, respiratory failure, and pain.  The most common 
(≥2%) Grade 3-4 laboratory abnormalities included lymphopenia, hyponatremia, anemia, 
increased aspartate aminotransferase (AST), and increased alanine aminotransferase
(ALT). Serious adverse events (SAEs) were reported in 47 of patients receiving nivolumab.  
The most common SAEs were pneumonia, pulmonary embolism, dyspnea, and pleural 
effusion.  Immune-mediated AEs that occurred in patients treated with nivolumab included 
hypothyroidism/thyroiditis, rash, pneumonitis, diarrhea/colitis, hyperthyroidism, hepatitis, 
nephritis, limbic encephalitis, and polymyalgia rheumatica.2
On October 9, 2015, the U. S. Food and Drug Administration (FDA) approved nivolumab at 
an intravenous dose of 3 mg/kg every 2 weeks, for the treatment of patients with metastatic 
NSCLC, including non-squamous histologies, with progression on or after treatment with 
platinum-based chemotherapy.  Patients with EGFR or ALK genomic tumor aberrations 
should have confirmed disease progression on FDA-approved therapy for these aberrations 
prior to receiving nivolumab.
A phase 3 trial CheckMate-227 randomized 1739 NSCLC patients 1:1:1 to nivolumab 
combined with ipilimumab, nivolumab alone, or systemic chemotherapy as first line 
treatment. In all patients, the one year and median PFS was 30.9% and 4.9 months in 
patients treated with combination of nivolumab and ipilimumab vs 17.0% and 5.5 months in 
patients treated with chemotherapy alone (HR 0.83, 95% CI, 0.72 to 0.96). For patients 
whose tumor mutational burden was at least 10 mutations per megabase (n = 444), the one 
year and median PFS in patients who received combination therapy of nivolumab and 
ipilimumab was 42.6% and 7.2 months versus 13.2% and 5.5 months for patients who 
received chemotherapy (HR 0.58, 97.5% CI, 0.41 to 0.81 P‹0.001). PFS benefit in the high 
tumor mutation burden population was seen in patients with tumor PD-L1 expression <1% 
and ≥1% as well as non-squamous and squamous histologies. In patients with less than 
10 mutations per megabase, the median PFS was 3.2 months in the nivolumab with 
ipilimumab arm and 5.5 months in the chemotherapy arm with HR 1.07(95% CI, 0.84 to 
1.35). The rate of grade 3 and higher adverse events in nivolumab and ipilimumab was 
similar to that of the chemotherapy group.41


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Pembrolizumab
In a three-arm trial of 1033 patients who were previously treated for metastatic NSCLC with 
PD-L1 expression on greater than or equal to 1% of tumor cells, those randomized to 
pembrolizumab (2 mg/kg q3w) (HR 0.71 (95% CI: 0.58, 0.88]; p<0.001) or pembrolizumab 
(10 mg/kg q3w) (HR 0.61 [95% CI: 0.49, 0.75]; p<0.001) had an improved OS compared 
with patients receiving docetaxel.4 Median survival was 10.4 months in the pembrolizumab 
2 mg/kg arm, 12.7 months in the pembrolizumab 10 mg/kg arm, and 8.5 months in the 
docetaxel arm. ORR was also significantly improved at 29-30% for pembrolizumab vs 8% 
for docetaxel.
The most common side effects of treatment with pembrolizumab included decreased appetite, 
fatigue, nausea, dyspnea, cough, and constipation. Rare but serious adverse events included 
immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis.
On October 2, 2015, the U.S. FDA approved pembrolizumab for the treatment of metastatic 
NSCLC with expression of PD-L1 on ≥1% of tumor cells with disease progression on or 
after platinum-based chemotherapy. Disease with ALK or EGFR mutations should have 
progressed on FDA-approved targeted therapy for these mutations prior to receiving 
pembrolizumab.
In a clinical research trial of 305 patients with no prior treatment for metastatic NSCLC with 
PD-L1 expression on greater than or equal to 50% of tumor cells, those who received 
pembrolizumab (200 mg q3w) had a significant improvement in PFS 
(HR 0.50 [95% CI: 0.37, 0.68]; p<0.001) with a median PFS of 10.3 months versus 
6.0 months for those receiving platinum-based chemotherapy. A pre-specified interim 
analysis demonstrated a statistically significant improvement in OS for patients randomized 
to pembrolizumab as compared with chemotherapy (HR 0.60 [95% CI: 0.41, 0.89]; p<0.005). 
ORR was also significantly improved at 45% to 28%.
On October 24, 2016, the U.S. FDA approved pembrolizumab at a dose of 200 mg 
administered intravenously q3w for the treatment of patients with metastatic NSCLC whose 
tumors express PD-L1 on ≥50% of tumor cells as determined by an FDA-approved test.
In KEYNOTE-042, pembrolizumab was compared with platinum-containing chemotherapy 
(carboplatin + paclitaxel or carboplatin + pemetrexed) in 1274 first line metastatic NSCLC 
patients, randomized 1:1 and analyzed in 3 different subgroups with 1-19%, ≥20% and 
≥50% PD-L1 tumor proportion score (TPS). In the pembrolizumab arm subgroups, median 
survival in months were 16.7 (HR 0.81, 95% CI, 13.9 to 19.7), 17.7 (HR 0.77, 95% CI, 
15.3 to 22.1) and 20.0 (HR 0.69, 95% CI, 15.4 to 24.9), respectively, whereas in the 
chemotherapy arm subgroups they were 12.1 (95% CI, 11.3 to 13.3), 13.0 (95% CI, 11.6 to 
15.3) and 12.2 (95% CI, 10.4 to 14.2), respectively. Further exploratory analysis of this data 
revealed that dividing the patients in two groups with ≥1-49% TPS revealed median OS of 
13.4 months vs 12.1 months with HR of 0.92 (95% CI, 0.77 to 1.11) suggesting that  survival 
benefit may be largely driven by the ≥50% TPS group. As expected, pembrolizumab had 
better safety profile than chemotherapy except for immune-mediated adverse events 
experienced.42


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Recently, in May 2017, FDA also granted approval of pembrolizumab in combination with 
pemetrexed and carboplatin as first line treatment for metastatic non-squamous NSCLC
following results from the KEYNOTE-021 study.  In this study, 123 locally advanced or 
metastatic non-squamous NSCLC patients with no prior systemic treatment for metastatic 
disease, regardless of PD-L1 expression, were randomized to the pembrolizumab arm 
(60 patients) or to the chemotherapy only arm (63 patients). In this study, a statistically 
significant improvement in ORR was observed; an ORR of 55% was reported in patients 
treated with pembrolizumab plus pemetrexed and carboplatin, whereas an ORR of 29% was 
reported in patients treated with pemetrexed and carboplatin only. Greater than 93% of 
patient treated with pembrolizumab experienced response duration of ≥6 months.
KEYNOTE-189 subsequently compared use of pembrolizumab or placebo in combination 
with pemetrexed and a platinum-based systemic chemotherapy in 616 metastatic non-
squamous NSCLC patients randomized (2:1) in the first line setting. At the time of the 
published analysis, the median OS was not reached in the pembrolizumab combination arm 
and was 11.3 months for the placebo combination arm. The 12-month OS rate was 73.0% in 
pembrolizumab arm and 48.1% in the placebo arm. The median PFS was 8.8 months 
(95% CI, 7.6 to 9.2) in the pembrolizumab arm and 4.9 months (95% CI, 4.7 to 5.5) in the 
placebo arm. Grade 3 or higher adverse events occurred in 67.2% of patients in the 
pembrolizumab arm and 65% in the placebo arm. Improvement in OS was seen across all 
levels of tumor PD-L1 expression. Discontinuation of treatment due to all drugs occurred in 
13.8% of the patients treated with the combination arm and 7.9% in patients in the placebo 
arm.43
In KEYNOTE407, 559 patients with metastatic squamous NSCLC were randomized (1:1) to 
receive either chemotherapy (carboplatin + paclitaxel or nab-paclitaxel) combined with 
pembrolizumab or chemotherapy with placebo drug in the first line setting. In the 
pembrolizumab combination arm, median OS was 15.9 months (HR 0.64, 95% CI, 13.2 to 
not evaluable) whereas in the chemotherapy arm median OS was 11.3 months (95% CI, 9.5 
to 14.8). PFS was 6.4 months (HR 0.56, 95% CI, 6.2 to 8.3) in the pembrolizumab 
combination arm and 4.8 months (95% CI, 4.3 to 5.7) in chemotherapy arm. As expected 
safety profiles were consistent with chemotherapy and pembrolizumab with no additional 
safety signals identified.44
1.2.6. Urothelial Carcinoma
For urothelial carcinoma, tumor infiltration of CD3+ and CD8+ T cells has been associated 
with better overall survival.45,46 Urothelial cancer was the first indication with an FDA 
approved immunotherapy, and vaccination using weakened, live bacterium bacillus calmette-
guérin (BCG) first took place in the 1970s.45 Worldwide, it is estimated that 386,000 new 
cases of bladder cancer will occur each year, with approximately 105,000 deaths.29  
Approximately 75% of cases of bladder cancer are non- muscle invasive bladder cancer 
(NMIBC).  Whilst treatment with BCG has been shown to reduce the risk of tumor 
recurrence,47 approximately 40% of patient with NMIBC will fail BCG therapy.48  Thus, 
other immunotherapeutic approaches for urothelial cancer were evaluated, and studies with 
pembrolizumab, nivolumab, atezolizumab, durvalumab and alemtuzumab are summarized 
below.  


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Pembrolizumab
Pembrolizumab received approval from the FDA in May 2017 for the treatment of locally 
advanced or metastatic urothelial carcinoma not eligible for cisplatin containing 
chemotherapy or with disease progression following platinum-containing chemotherapy or 
within 1 year of neo-adjuvant or adjuvant therapy with platinum-containing chemotherapy.
In a Phase 3 study of 543 urothelial cancer patients who have progressed on platinum-based 
chemotherapy, treatment with pembrolizumab prolonged overall survival of patients to 
8 months, as compared to 5.2 months in the chemotherapy group.4, 49 As of data cutoff date, 
median duration of response in the pembrolizumab group was not reached, but approximately 
68% of patients had duration of response (DOR) of at least 12 months. This is in comparison 
to DOR for chemotherapy, which was 4.3 months. The ORR also increased significantly in 
patients treated with pembrolizumab, with 21.1% versus 11.4% in the chemotherapy group.
Grade 3 or greater adverse events was also significantly reduced, with 15% observed in the 
pembrolizumab group versus 49.4% observed in the chemotherapy group.
In patients who were treated with pembrolizumab, 0.4% experienced sepsis that led to death, 
and 0.8% of patients experienced pneumonia that led to death. The most common serious 
adverse reactions experienced by ≥2% of patients were urinary tract infection, hematuria, 
acute kidney injury, pneumonia and urosepsis.4
In May 2018, FDA issued a general public alert that in KEYNOTE-361 evaluating either 
single agent pembrolizumab versus platinum chemotherapy in previously untreated 
metastatic urothelial carcinoma eligible for platinum-based chemotherapy treatment, an 
interim analysis found that patients with PD-L1 low status had worse survival with 
pembrolizumab versus platinum-based chemotherapy. The pembrolizumab label in 
urothelial carcinoma has subsequently been updated to limit treatment in patients not 
previously treated with platinum containing therapy to those with PD-L1 combined positive 
score ≥10 who are not eligible for cisplatin-containing chemotherapy, or patients who are not 
eligible for any platinum-containing chemotherapy regardless of PD-L1 status.4
Nivolumab
In February 2017, nivolumab was granted accelerated approval for patients with locally 
advanced or metastatic urothelial carcinoma with disease progression following platinum-
containing chemotherapy or within 1 year of neo-adjuvant or adjuvant therapy with platinum-
containing chemotherapy. In a Phase 2 study Checkmate 275 of nivolumab in 270 patients 
with locally advanced urothelial carcinoma in patients who progressed following treatment 
with at least one line of platinum-based chemotherapy, 19.6% of patients achieved a 
sustained and confirmed clinical response.2, 50 Of these, 2% had a CR, and 19% had a PR. 
Confirmed objective response was highest in the patients who had ≥5% PD-L1 expression, 
with 28.4% achieving objective response. This is compared to only 16.1% of patients with 
≤1% PD-L1 expression who achieved objective response. Overall survival for patients with 
≥1% PD-L1 expression was 11.3 months, compared to 5.95 months for patients with ≤1% 
PD-L1 expression.


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In this study, 1.5% of patients died from treatment related pneumonitis or cardiovascular 
failure. Serious adverse reactions occurred in 54% of patients, and the most common serious 
adverse reactions experienced by ≥2% of patients were urinary tract infection, sepsis, 
diarrhea, small intestine obstruction, and general physical health deterioration.4
Atezolizumab
In the IMvigor 210 Phase 2 clinical trial of 310 patient study of atezolizumab in locally
advanced or metastatic urothelial carcinoma whose disease had progressed after previous 
platinum-based chemotherapy, confirmed ORR by independent review was 14.8% and 
patients with ≥5% PD-L1 expression had an ORR of 27%.3, 51 This is compared to historical 
control of 10%. Median DOR was not reached and response duration ranged from 2.1+ to 
13.8+ months. Of the 46 responders, 37 patients had an ongoing response for greater than or 
equal to 6 months and 6 for greater than or equal to 12 months.  Atezolizumab was well 
tolerated, with Grade 3–4 immune-mediated adverse events observed in 5% of patients. The 
IMvigor 210 Phase 2 clinical trial also included a cohort of 123 cisplatin-ineligible patients. 
In this cohort, Balar et al52 reported median overall survival of 15.9 months, ORR of 23% 
and CR rate of 9% in patients treated with atezolizumab, regardless of PD-L1 status. When 
the results were further evaluated based on PD-L1 expression, 28% ORR was observed in 
patients with ≥5% PD-L1 expression, whilst 10% ORR was observed for patients with ≥1% 
but <5% PD-L1 expression. Atezolizumab subsequently received accelerated approval for 
second-line treatment of urothelial carcinoma in May 2016, and first-line treatment for 
platinum-ineligible urothelial carcinoma in April 2017. However, the confirmatory Phase 3
IMvigor211 trial comparing atezolizumab versus chemotherapy in a second-line or greater 
setting for urothelial carcinoma failed to meet a primary endpoint of overall survival 
improvement in May 2017.
It has been reported that 0.9% of patients who received atezolumab experienced sepsis, 
pneumonitis or intestinal obstruction that led to death.  Serious adverse reactions occurred in 
45% of patients.  The most frequent (>2%) serious adverse reactions were urinary tract 
infection, hematuria, acute kidney injury, intestinal obstruction, pyrexia, venous 
thromboembolism, urinary obstruction, pneumonia, dyspnea, abdominal pain, sepsis and 
confusional state.3
In May 2018, the FDA issued a general public alert that in an ongoing clinical study 
IMVIGOR-130 evaluating either single agent atezolizumab versus platinum chemotherapy in 
previously untreated metastatic urothelial carcinoma eligible for platinum-based 
chemotherapy treatment, an interim analysis found that patients with PD-L1 low status had 
worse survival with atezolizumab compared to patients who received platinum-based 
chemotherapy. The atezolizumab label in urothelial carcinoma has subsequently been 
updated to limit treatment in patients not previously treated with platinum containing therapy 
to those with PD-L1 tumor-infiltrating immune cells covering ≥5% of the tumor area who are 
not eligible for cisplatin-containing chemotherapy, or patients who are not eligible for any 
platinum-containing chemotherapy regardless of PD-L1 status.3


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Durvalumab
Durvalumab received accelerated approval from the FDA in May 2017 based on the results 
reported in Study 1108, a Phase 1/2 trial in 182 patients with locally-advanced or metastatic 
urothelial carcinoma of the bladder.5 Though PD-L1 status was evaluated using the 
VENTANA PD-L1 (SP263) assay, patients were enrolled into the study regardless of their 
PD-L1 status. An ORR of 17.0% was achieved in all evaluable patients. The ORR was 
highest (26.3%) in patients with ≥25% PD-L1 expression. In patients who had PD-L1 low or 
negative expression, ORR decreased to 4.1%. Overall, 14.3% of all evaluable patients 
achieved PR and 2.7% achieved CR. Amongst the 31 patients who responded, 45% had 
ongoing responses of 6 months or longer, and 16% had ongoing responses of 12 months or 
longer. 
In patients who were treated with durvalumab, 4.4% experienced cardiorespiratory arrest, 
general physical health deterioration, sepsis, ileus, pneumonitis, or immune-mediated 
hepatitis that led to death. The most frequent serious adverse reactions include acute kidney 
injury (4.9%), urinary tract infection (4.4%), musculoskeletal pain (4.4%), liver injury 
(3.3%), general physical health deterioration (3.3%), sepsis, abdominal pain, and 
pyrexia/tumor associated fever (2.7% each).5
Avelumab
In May 2017, FDA also granted accelerated for avelumab for the treatment of patients with 
locally advanced or metastatic urothelial carcinoma who have disease progression during or 
following platinum-containing chemotherapy, or who have disease progression within 
12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. 
The FDA approval was granted following a review of data from the JAVELIN Bladder 
100 study.6  JAVELIN Bladder 100 is a single-arm, multi-center clinical study of 
242 urothelial carcinoma patients. Patients were included regardless of their PD-L1 status.
An ORR of 13.3% was observed.  Amongst the patients that did respond, 73% had an 
ongoing response of 6 months or longer, and 13% had ongoing response of 12 months or 
longer.
In the JAVELIN study, 6% of patients treated with avelumab experienced either 
pneumonitis, respiratory failure, sepsis/ urosepsis, cerebrovascular accident, or 
gastrointestinal adverse events that led to death. The most common serious adverse reactions 
reported in ≥2% of patients were urinary tract infection/ urosepsis, abdominal pain, 
musculoskeletal pain, creatinine increased/ renal failure, dehydration, hematuria/ urinary tract 
hemorrhage, intestinal obstruction/ small intestine obstruction, and pyrexia.6
1.2.7. Background Summary
This protocol is the first clinical study of PF-06801591 in patients with locally advanced or 
metastatic melanoma, SCCHN, ovarian cancer, sarcoma, NSCLC, urothelial carcinoma, or 
other solid tumors with clinical evidence of response to anti PD-1 or PD-L1 agents, who are 
unresponsive to existing therapies, or for whom standard treatment is not available. After 
preliminary determination of safe and effective exposure levels of PF-06801591 in Part 1 in 


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multiple solid tumor types, Part 2 will enroll two cohorts of NSCLC and urothelial carcinoma 
patients in order to evaluate whether the safety and efficacy of 300 mg SC PF-06801591 will 
be comparable to what has been seen with other approved anti-PD-1 agents intravenously in 
NSCLC and urothelial carcinoma.
Additional information for this compound may be found in the single reference safety 
document (SRSD), which for this study is the investigator’s brochure.  
1.3. Nonclinical Efficacy
PF-06801591, a humanized hinge region stabilized PD-1 specific mAb, binds to PD-1 with 
high affinity and specificity and efficiently inhibits the interaction between PD-1 and its 
ligands (PD-L1 and PD-L2).  The functional activity of PF-06801591 was confirmed in vitro,
in a mixed lymphocyte reaction.  Using naïve allogeneic T cells cultured with the PD-L1+
primary dendritic cells, PF-06801591 exhibited a dose-dependent increase in T cell 
proliferation as well as IFN-and tumor necrosis factor (TNF) secretion (Figure 3) at 
concentrations of 0.0001 to 10 g/mL.  An increase in T cell proliferation, measured by 
tritiated thymidine incorporation, was approximately 50% higher when cells were treated 
with PF-06801591 compared to the negative control Ab at concentrations of 0.0001 to 
10 g/mL of PF-06801591(Figure 3).  These data concur with data from other 
PD-1 antagonists used as positive control 1 and 2 in Figure 3.  Positive control 1 and 2 are 
anti-human PD-1 Abs that were generated from sequences published in previous patents, in 
IgG4-kappa hinge stabilized framework.  All control Abs were generated at Rinat/Pfizer.  
Production of IFN-and TNF was increased in the PF-06801591-treated group when 
compared to the negative control Ab group; IFN-and TNF increase after 
PF-06801591 treatment was elevated up to 8- and 4-fold, respectively. The magnitude of this 
increase was comparable with that observed with positive controls 1 and 2 (Figure 3).  In 
addition to IFN-and TNF secretion, PF-06801591 elevated IL-2 secretion in a similar 
experimental setting when dendritic cells were replaced with tumor cell lines expressing high 
PD-L1 (Rinat internal data), consistent with the antagonism of PD-1.


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Figure 3
PF-06801591 enhanced primary human T cell proliferation and cytokine
secretion following 5-day stimulation with PD-L1 positive dendritic cells in a 
mixed lymphocyte reaction (MLR) assay
PD-L1+ immature dendritic cells (DCs) were differentiated from CD14+ monocytes isolated 
from healthy donor peripheral blood mononuclear cells (PBMCs) that were cultured for 
7 days.  Naïve T cells were isolated from PBMCs of allogeneic healthy donors.  A mixed 
lymphocyte reaction (MLR) was performed using naïve allogeneic T cells cultured with 
irradiated PD-L1+ DCs at a ratio of 10:1 (T cells: DCs).  PF-06801591 IgG4 hinge stabilized 
(HS), positive control 1, positive control 2, or negative control antibodies were added to 
these cultures at the range of 0.001-10 g/mL.  Cultures were incubated in triplicates using 
X-vivo 15 media and incubated at 37C with 5% CO2 for 5 days.  On Day 5 culture 
supernatants were collected and cytokine concentrations were measured using cytometric 
bead array (CBA).  On Day 5, 1 Ci/well of tritiated thymidine was added to each culture 
well and further incubated for 16-18 hours before being harvested.  Thymidine incorporation, 
which correlates with cell proliferation, was measured as counts per minutes (CPM).  Data 
are presented as mean ± standard error of mean (SEM) of triplicates.
Specificity of PF-06801591 to human PD-1 has been confirmed in cell binding and biosensor 
experiments. The binding affinities of PF-06801591 in solution towards human PD-1 and 
cynomolgus monkey PD-1 were shown to be very similar by the kinetic exclusion assay 
(KinExA) with KD = 23 and 28 pM for human and cynomolgus PD-1, respectively.  In cell 
binding experiments using primary activated human T cells or transfected cell lines with 
human PD-1, the half maximal effective concentration (EC50) observed for PF-06801591 was 
approximately 50 to 100 pM.  The EC50 on transfected cells lines with cyno-PD-1 was 
around 200 pM.  The half maximal inhibitory concentration (IC50) of PD-L1 binding to 


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PD-1 on primary activated human T cells was approximately 800 to 1000 pM for 
PF-06801591.
1.4. Nonclinical Safety
The nonclinical safety profile of PF-06801591 has been well characterized in nonclinical 
toxicology studies.  Because PF-06801591 does not cross react with mouse or rat PD-1, but 
cross reacts with cynomolgus monkey PD-1 with similar affinity as human PD-1, monkeys 
are considered the most relevant toxicology species to assess human risk.  In addition to in 
vivo monkey studies, in vitro tissue cross reactivity using monkey and human tissues and in 
vitro cytokine release assays using human whole blood or peripheral blood mononuclear cells 
(PBMC) were performed.
In the pivotal, Good Laboratory Practice (GLP) repeat-dose study, cynomolgus monkeys 
were treated once weekly for 1 month (5 times in total) at the dose levels of 0 (control), 
20, 60, and 200 mg/kg PF-06801591 with a 2-month recovery period (control and 200 mg/kg 
groups only).  Clinical and anatomic pathology were assessed at the end of the dosing and 
recovery phases.  In order to assess the level of pharmacological inhibition of PD-1, an 
ex vivo Staphylococcal enterotoxin B (SEB) stimulation assay was performed on blood 
collected at various time points.  In addition, immunophenotyping was performed to 
determine any effects on specific lymphocyte populations.
Repeated administration of PF-06801591 was well tolerated in cynomolgus monkeys when 
administered IV once weekly for 1 month (5 times in total) at doses up to 200 mg/kg. There 
were no test article-related abnormalities in food consumption, body weight change, 
electrocardiogram (ECG), blood pressure (BP), ophthalmology, urinalysis, hematology, gross 
pathology, or organ weights.  Clinical pathology findings were limited to increases in 
globulin and total serum protein at the end of the dosing phase which reversed during the 
recovery phase.  Anatomical pathology findings consisted of increased incidence and/or 
severity of mononuclear infiltration.  At the end of the recovery phase, the infiltration in the 
brain was either similar to or slightly more severe compared with the dosing phase; 
additionally, there was also test article-related increased incidence and/or severity of 
mononuclear infiltrates in the spinal cord, peripheral nerve, pituitary, kidney and thyroid.  
None of the findings were considered severely toxic.  The findings are consistent with the 
expected pharmacology of PD-1 blockade, and are similar to findings described for the 
marketed PD-1 antagonist drugs nivolumab and pembrolizumab; their presence at the end of 
recovery is consistent with exposure and target inhibition throughout the recovery period.
Results from the SEB assay demonstrate saturation of PD-1 in the peripheral blood of 
monkeys in all dose groups (≥20 mg/kg) during the dosing phase and in the 200 mg/kg group 
at the twenty-fourth day of the recovery phase (the last day evaluated).  Immunophenotyping 
analysis demonstrated test article-related increases only on Day 15 for activated 
(CD8+HLA-DR+), and proliferating (CD4+Ki-67+, and CD8+Ki-67+) T cell 
sub-populations.  These increases were not dose-related, suggesting maximal 
pharmacological effects at all dose levels.  PF-06801591 serum levels at the end of the 
recovery phase were similar to serum levels in the 20 mg/kg group during the dosing phase, 
indicating saturation of PD-1 throughout the recovery phase.


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In summary, weekly intravenous (IV) administration of PF-06801591 for 1 month was well 
tolerated up to 200 mg/kg without display of severe toxicity. Therefore, 200 mg/kg was 
considered the highest non-severely toxic dose (HNSTD) with associated area under the 
curve (AUC)0-168 and maximum drug concentration (Cmax) on Day 22 of 1,060,000 µg•h/mL 
and 10,500 µg/mL, respectively.  Furthermore, the exposures and SEB assay results during 
the dosing and recovery phases indicate saturation of PD-1 throughout the entire 3 months of 
the study (dosing and recovery phases combined), and therefore recovery from test 
article-induced effects was not assessed.
In a separate GLP study on Days 1 and 29, male cynomolgus monkeys (4/sex/group) were 
administered either vehicle by IV and SC injection or PF-06801591 by SC injection at dose 
of 20 mg/kg.  The terminal necropsy was on Day 43.  PF-06801591 was well-tolerated up to 
the highest dose tested (20 mg/kg/month).  There was no PF-06801591-related mortality, or 
changes in hematology, coagulation, clinical chemistry, urinalysis, body weight, body 
temperature, food consumption, local irritation, clinical observations, or macroscopic and 
microscopic findings.  The no-observed-adverse-effect-level (NOAEL) was considered to be 
the highest dose tested, 20 mg/kg/month and was associated with a mean AUC670 on 
Day 29 of 166,000 g•h/mL.  Because PF-06801591 was well-tolerated and there were no 
signs of local irritation, as assessed by clinical signs and microscopic observations, this study 
supports clinical dosing via the SC route of administration.
In the tissue cross-reactivity study, PF-06801591 stained the cytoplasm and plasma 
membrane of mononuclear leucocytes primarily located within lymphoid tissues in both the 
human and cynomolgus monkey tissues, and staining was similar between the two species.  
No unexpected tissue cross-reactivity was observed in the human or cynomolgus monkey 
tissue panels.
To evaluate the potential for acute cytokine release syndrome, PF-06801591 was tested in 
two different in vitro cytokine release assays: a soluble phase assay with test articles added to 
human whole blood, and a solid-phase assay with human peripheral blood mononuclear cells 
(PBMCs) cultured with plate-bound test article.  PF-06801591 did not elicit release of 
cytokines (TNF-, IL-6, and IFN-) in the soluble phase assay.  In the solid phase assay, 
there was substantial cytokine release above negative controls in a sample from 1 out of 
10 donors.  The cytokine release from this sample was not likely related to intended 
pharmacology and may have been an anomaly because two other samples from this donor 
were retested in two independent cultures and did not show significant cytokine release 
above the isotype control upon retest.  Overall, the risk for acute cytokine toxicity with 
PF-06801591 in humans is considered low for several reasons, including: 1) the variability of 
in vitro findings (which do not provide strong evidence for consistent cytokine response), 
2) the lack of clinical signs of cytokine toxicity in the GLP cynomolgus monkey study, and 
3) the lack of clinical evidence for cytokine storm reactions with the marketed 
PD-1 antagonist drugs nivolumab and pembrolizumab.2,4


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1.5. Starting Dose Rationale
The process for selecting the starting dose for this FIP study began with International 
Conference on Harmonization (ICH) Guidance S9.  Specifically, it involved the calculation 
of 1/6 of the HNSTD, which yields a starting dose of 33 mg/kg or lower using a no observed 
adverse effect level of 200 mg/kg from a GLP 1-month toxicity study in non-human primates 
(NHP).  However, it is expected based on in vitro data from functional assays and predictions 
of human PK derived from NHP data that PF-06801591 PK and pharmacodynamic results, as 
well as safety and tolerability information at lower doses, can be informative.  Therefore, a 
pharmacology-based approach was applied for dose selection consideration.  As a result, in 
the IV administration portion, 4 dose levels of PF-06801591 (0.5, 1, 3, and 10 mg/kg) are 
proposed to be studied, in an ascending order, to assess safety, tolerability, PK, and 
pharmacodynamics (immuno-modulatory effects) of PF-06801591 in patients with advanced 
cancer.  The proposed dosing interval is q3w for IV administration based on projected t½.
The proposed doses and dosing interval were based on the results from functional in vitro 
assays and the projected PF-06801591 PK profiles in humans from NHP data, along with 
those for 2 other anti-PD-1 antibodies, pembrolizumab and nivolumab.  
PF-06801591 showed at least similar binding affinity to human PD-1 compared to that for 
nivolumab.25 In a mixed lymphocyte reaction (MLR) assay, PF-06801591 was shown to 
accelerate T-cell proliferation and cytokine production, and the PF-06801591-elicited effects 
appeared to plateau at 10 µg/mL.  The projected serum trough concentrations for 
PF-06801591 at steady state are expected to be at 10 µg/mL or higher following the q3w 
dosing interval for all proposed dose levels, except for the 0.5 mg/kg dose.  The projected t½
of approximately 3 weeks for PF-06801591 is similar to those for pembrolizumab 
(KEYTRUDA® Prescribing Information)4 and nivolumab (OPDIVO® Prescribing 
Information).2  As the starting dose, a 0.5 mg/kg dose is not expected to produce full effect in 
terms of accelerating T-cell proliferation and cytokine production.  Accounting for 
target-mediated drug disposition at lower doses, it is expected that exposure at the 0.5 mg/kg 
dose may be dose-disproportionally lower relative to that at 1 mg/kg. Complete 
pharmacokinetic information for PF-06801591 can be found in the Investigator’s Brochure.
1.6. Subcutaneous (SC) Dose Rationale
The proposed dose of 300 mg, administered subcutaneously (SC) every 4 weeks (q4w), was 
selected with considerations of the nonclinical safety of PF-06801591, the clinical safety and 
tolerability data from the IV administration cohorts in the current study, and feasibility, in 
terms of the injection volume with the current formulation.
In cynomolgus monkeys, PF-06801591 was well tolerated following repeated IV doses for 
up to 200 mg/kg or following repeated SC doses for up to 20 mg/kg. Following SC 
administration of PF-06801591 at 300 mg q4w in humans, the systemic maximum 
concentration (Cmax) is predicted to be approximately 1% and 19% of the Cmax observed 
following administration of 200 mg/kg IV and 20 mg/kg SC, respectively, in the nonclinical 
safety studies of PF-06801591.  Similarly, the area under the concentration-time curve 
(AUC∞) following single SC administration of PF-06801591 at 300 mg, q4w is predicted to 
be approximately 8% and 99% of the AUC determined following the administration of 


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200 mg/kg IV and 20 mg/kg SC, respectively, in the nonclinical safety studies of 
PF-06801591 in cynomolgus monkeys. 
To put the proposed SC dose into perspective, assuming SC bioavailability of 60% and a 
body weight of 60 kg, the clinical systemic exposure following a 300 mg dose of 
PF-06801591 is projected to be comparable to that following a 3 mg/kg IV dose.  Available 
interim safety data from Cohorts 1, 2, and 3 (0.5, 1, and 3 mg/kg IV, respectively) will 
inform the decision to initiate SC administration at a dose level of 300 mg of PF-06801591.  
Specifically, SC administration of PF-06801591 will not begin until all patients in Part 1A 
from Cohort 3 (3 mg/kg IV) have completed safely the 21-day DLT observation period.  The 
Cmax and AUC after SC administration of 300 mg PF-06801591 are not expected to exceed 
those of the 10 mg/kg IV dose. Therefore, the cohort with SC administration at a dose level 
of 300 mg is planned to commence before or in parallel with dosing in Cohort 4 (10 mg/kg
IV).  
1.7. Rationale for Pre-treatment and On-treatment Biopsies and Expansion of Various 
Dose Level Cohorts
PF-06801591 is hypothesized to exert its anti-tumor activity by activating and enhancing 
anti-tumor T cell response.  The effect on TILs in the tumor microenvironment will provide 
important data to estimate the OBD of the PF-06801591.  In previous clinical testing of 
anti-PD-1 therapy (pembrolizumab), the presence of CD8+ T cells in the tumor invasive 
margin at baseline was predictive of clinical response.  Other tumor-related biomarkers that 
were shown to correlate with response included the number of PD-1+ and PD-L1+ cells, 
close proximity of PD-1/PD-L1 signals and diversity of the T cell clonal repertoire.53  All 
patients will be required to provide an archival biopsy sample.  Except for the first 
2 to 4 patients at each dose level, all patients in Part 1 of this study will also be required to 
provide tumor biopsy samples during screening and at Cycle 2 Day 8 (C2D8) 5 days after 
PF-06801591 treatment.  An optional biopsy sample may also be collected at disease 
progression and/or the end-of-treatment visit. Optional biopsies may also be collected from 
all Part 2 patients as clinically indicated.
The number, type, and location of TILs can present large heterogeneity among different 
tumor types and among patients.  Furthermore, it is hypothesized that immunomodulatory
effects may vary widely from patient to patient; therefore, each dose level in the IV 
administration portion in Part 1 will enroll up to approximately 9 patients following safety 
assessments in the first 2 to 4 patients, and SC administration portion Part 1 will enroll up to 
approximately 15 patients following safety assessments of the first 2 to 4 patients.  
Depending on observed safety data, additional dose levels (lower, intermediate or higher, up 
to a maximum of 20 mg/kg IV) may be introduced in order to better define the OBD. In 
Part 1B, a minimum of 2 to 5 patients with paired pre- and on-treatment biopsy samples 
available for IHC testing will be enrolled at the 1, 3, and 10 mg/kg IV and 300 mg SC dose 
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1.8. Biomarker Rationale
The objective of biomarker collections and analyses is to provide evidence of target 
engagement (TE), measure pharmacodynamic activity, and identify immunophenotypes 
associated with response to dosing with PF-06801591. This will provide data to guide dose 
selection, and allow characterization of the relationship between PF-06801591 TE, 
pharmacodynamic activity and any observed anti-tumor effects.  Furthermore, this may 
enable the identification of patients and/or tumor types most responsive to 
PF-06801591 therapy.
TE will be assessed in Part 1 only using a flow cytometry assay to measure receptor 
occupancy (RO) of PD-1 receptor expressed on peripheral blood T cells by PF-06801591.  
The relationship between RO and the PK of PF-06801591, among other analyses, will 
provide guidance for dose selection.  The goal of this analysis will be to select doses that 
result in full target engagement while exhibiting an acceptable safety profile, and potentially 
providing evidence of anti-tumor activity.
Furthermore, in Part 1 the pharmacodynamic effect of PD-1 blockade on T-cell subsets in 
peripheral blood will be investigated in all patients.  Potential effects of PF-06801591 on 
T cell activation and phenotypic markers, and relative proportions of T cell subsets
(including memory and regulatory subsets), will be assessed by flow cytometry.  
Pharmacodynamic effect of PD-1 blockade in the tumor will also be evaluated for patients 
enrolled in Part 1B, the pharmacodynamic cohorts. 
 
 
 
 
 
 
 
 
  
 
CCI
CCI


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1.9. Clinical Experience
PF-06801591 is currently being tested in 2 clinical studies. Study B8011001 a Phase 1, 
open-label, multi-center, multiple-dose, dose escalation and expansion, safety, PK, and
pharmacodynamic study of PF-06801591 in adult patients with locally advanced or 
metastatic solid tumor types with clinical evidence of response to anti PD-1 or PD-L1 agents,
who are unresponsive to currently available therapies or for whom no standard therapy is 
available.  
The second clinical study is study B7791001, a Phase 1 study to evaluate the safety, 
pharmacokinetics and pharmacodynamics of escalating doses of a vaccine based 
immunotherapy regimen (VBIR) for prostate cancer (PrCa).  Starting from Cohort 6A, 
patients with asymptomatic/minimally symptomatic castration-resistant prostate cancer who 
have not received secondary hormones will receive increasing doses of PrCa VBIR 
(PF-06753512) components, including adenovirus (AdC68), tremelimumab (PF-06753388), 
and DNA, combined with PF-06801591.
1.9.1. Clinical Experience in Study B8011001
As of a 31 January 2017 data cut off, 26 pts (ovarian cancer, n=12; sarcoma, n=6; head and 
neck cancer [SCCHN]; n=5; melanoma, n=1; small cell lung cancer, n=1; and malignant 
peritoneal neoplasm, n=1) enrolled in Phase 1 dose-escalation phase: 0.5 (n=2), 1 (n=8), 
3 (n=7), 10 (n=5) mg/kg IV, and 300 mg (n=4) SC. Maximum tolerated dose was not 
reached. Additionally, no dose-limiting toxicities were observed. All drug-related AEs were 
Grade 1 or 2, and the most frequently reported in >10% of pts include nausea (15.4%), 
fatigue (15.4%), decreased appetite (11.5%), and mucosal inflammation (11.5%).  No dose 
relationship of adverse events was observed during IV dose escalation nor were any 
significant skin toxicities observed with SC administration. Three ovarian cancer patients 
had a confirmed partial response at 0.5, 1, and 10 mg/kg IV, and 1 SCCHN patient had a 
partial response at 300 mg SC.  Three patients had stable disease lasting >24 wks.  
Preliminary PK data from Cycle 1 of treatment were available for patients receiving IV 
(n=22) or SC (n=4) doses of PF-06801591 in Part 1. PF-06801591 exhibited PK 
characteristics typical of IgG4 monoclonal antibodies (mAbs), including those approved as 
anti-PD-1 therapies. Preliminary analysis showed that mean maximum serum concentration 
(Cmax) and area under the serum concentration-time curve (AUCt) of PF-06801591 increased 
in an approximately dose-proportional manner over the dose range of 0.5 -10 mg/kg 
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following IV administration. After SC administration at 300 mg, PF-06801591 was slowly 
absorbed, with a median maximum (or peak) serum concentration (Tmax) of 182 hours. The 
mean exposure following SC administration of 300 mg PF-06801591, q4w was between the 
mean exposures observed following IV doses of 1 and 3 mg/kg, q3w. Preliminary data show 
full receptor occupancy of PD-1 was seen in all dose cohorts.
After data cut off of 31 January 2017, one drug related SAE was reported in a 72 year old 
with esophageal cancer in the 300 mg SC administration cohort.  This patient experienced 
Grade 2 pneumonitis after receiving 3 cycles of study drug. Patient's respiratory status 
improved with steroids, and study treatment was discontinued permanently.
1.9.2. Clinical Experience in Study B7791001
Study B7791001 is a study of a vaccine-based immunotherapy regimen (VBIR) for prostate 
cancer (PrCa VBIR or PF-06753512). The treatment regimen consists of:
1. Replication-deficient adenovirus C68 (AdC68) vector that expresses three selected 
prostate cancer-specific antigens;
2. Tremelimumab (an anti- cytotoxic T-lymphocyte-associated protein-4 [CTLA-4]
mAb), and
3. Plasmid deoxyribonucleic acid (DNA) booster vaccinations, encoding the same 
antigens (booster vaccinations start 4 weeks after treatment with components 1 and 
2).
In certain cohorts, PrCa VBIR was combined with PF-06801591.
The first patient treated with the PrCa VBIR regimen (minus component 3) in combination 
with PF-06801591 was a 
 who 
received the following on Study Day 1: 6 x 10
virus particles (VP) AdC68, tremelimumab 
80 mg SC, and PF-06801591 at 130 mg SC. On Study Day 29, the patient experienced 
Grade 4 myasthenia gravis (MG), Grade 4 myositis, and Grade 3 elevated liver enzymes. A 
serious adverse event (SAE) was reported and all events were considered possibly related by 
both the investigator and Pfizer to all 3 components of study treatment. Progressive 
resolution had been obtained on high dose methylprednisolone and pyridostigmine; 
anticoagulation treatment was also given, and the patient was discharged to a skilled nursing 
facility (SNF). The anticoagulation, which was administered during hospitalization, was not 
continued during his time at the SNF. The patient subsequently experienced pulmonary 
embolism on Study Day 40, which was deemed treatment-related per the Principal 
Investigator’s assessment. However, it was not deemed as treatment-related per Pfizer’s 
assessment (the Sponsor), as the anticoagulation therapy had been prematurely stopped when 
the patient was discharged from the hospital, and he was without anticoagulation in the SNF 
with a lack of activity due to his exhaustion. Furthermore, the patient had a long history of 
severe cardiac and vascular disease. In addition, the autopsy results did not reveal any acute 
sign of immune reaction or lymphocyte infiltration. The patient died due to pulmonary 
embolism on Study Day 44. 
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This patient had no documented clinical history of MG or other autoimmune disease, but 
retrospective MG autoantibody analysis revealed the existence of subclinical MG before 
entering the study, with elevated acetylcholine receptor Ab and striational Ab at baseline. In 
addition, the autopsy revealed chronic thyroiditis, adrenalitis, and myositis determined via 
autopsy, which may indicate a pre-existing general autoimmune disease.
1.9.3. Risk Benefit Assessment
Although there is limited prior clinical experience with PF-06801591 and the full extent of 
therapeutic benefit to patients with advanced or metastatic tumors is currently unknown, the 
preliminary safety and efficacy data for PF-06801591 to date have been consistent with what 
is expected for an anti-PD-1 antibody.  Drug products in the same pharmaceutical class have 
shown acceptable safety and efficacy and benefits outweighing the risks in patients with 
certain locally advanced or metastatic caners. 
Overall, the nonclinical data package and existing preliminary clinical safety and efficacy 
data for PF-06801591 support its continued clinical development in the planned first-in-
patient (FIP) study B8011001.
2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Part 1 Dose Escalation
Primary Objective(s): 
Primary Endpoint(s): 

To assess safety and tolerability of increasing dose 
levels of PF-06801591 administered IV in patients 
with locally advanced or metastatic melanoma, 
SCCHN, ovarian cancer, sarcoma, NSCLC, urothelial 
carcinoma or other solid tumor types with clinical 
evidence of response to anti PD-1 or PD-L1 agents to 
establish the MTD.

To assess safety and tolerability of PF-06801591 
administered SC in patients with locally advanced or 
metastatic melanoma, SCCHN, ovarian cancer, 
sarcoma, NSCLC, urothelial carcinoma or other solid 
tumor types with clinical evidence of response to anti 
PD-1 or PD-L1 agents.

Dose Limiting Toxicities (DLTs) at escalated doses of 
PF-06801591.

AEs as characterized by type, frequency, severity (as 
graded by National Cancer Institute Common 
Terminology Criteria for Adverse Events [NCI CTCAE] 
version 4.03), timing, seriousness, and relationship to 
study therapy PF-06801591.

Laboratory abnormalities as characterized by type, 
frequency, severity (as graded by NCI CTCAE version 
4.03), and timing.
Secondary Objective(s): 
Secondary Endpoint(s): 

To characterize the single dose and multiple dose PK 
of PF-06801591 following IV or SC administration.

PK parameters of PF-06801591: Cycle 1 and Cycle 4 
maximum drug concentration (Cmax), area under the 
concentration versus time curve (AUC) from time zero 
to the last quantifiable time point prior to the next dose 
(AUClast), and if data permit, clearance (CL), volume of 
distribution (Vd)/volume of distribution at steady state 
(Vss), accumulation ratio (Rac) when feasible, and 
terminal elimination half-life (t1/2). 

To evaluate the immunogenicity of PF-06801591 
following repeated administration.

Incidence of anti-drug antibody (ADA) and neutralizing 
antibodies (NAb) against PF-06801591.

To characterize PD-1 Receptor Occupancy (RO) in 
peripheral blood T cells following IV or SC 
PF-06801591 administration at each dose level.

PD-1 RO by PF-06801591, as assessed by measuring the 
levels of unbound (free) cell surface PD-1 on circulating 
T cells over time following PF-06801591 administration.


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•
To evaluate preliminary anti-tumor activity of
PF-06801591.
•
Objective tumor response, as assessed using the
Response Evaluation Criteria in Solid Tumor (RECIST)
version 1.1 and immune related RECIST (irRECIST)
and proportion of patients with partial response (PR) and
immune related partial response (irPR), as appropriate
>80%.
•
Time to event endpoints based on RECIST and
irRECIST, and progression free survival (PFS), duration
of stable disease (DOSD), and DOR (duration of
response).
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2.2. Part 2 Dose Expansion
Primary Objective(s): 
Primary Endpoint(s): 
•
To further characterize the safety and tolerability of 
PF-06801591 following SC administration in NSCLC 
and urothelial carcinoma.
•
AEs as characterized by type, frequency, severity (as 
graded by NCI CTCAE version 4.03), timing, 
seriousness, and relationship to study therapy 
PF-06801591 administered by SC administration.
•
Laboratory abnormalities as characterized by type, 
frequency, severity (as graded by NCI CTCAE version 
4.03), and timing.
•
To estimate clinical efficacy by overall response rate 
(ORR) of PF-06801591 following SC administration 
in NSCLC and urothelial carcinoma.
•
ORR as assessed using RECIST version 1.1 and 
irRECIST.
Secondary Objective(s): 
Secondary Endpoint(s): 
•
To further evaluate preliminary anti-tumor activity of 
PF-06801591 following SC administration.
•
Time to event endpoints by PF-06801591 administered 
by SC based on RECIST and irRECIST, including time 
to response (TTR) and time to progression (TTP) as well 
as PFS (and irPFS as appropriate), DOSD (and irDOSD 
as appropriate), and DOR (and irDOR as appropriate).
•
To evaluate overall survival (OS).
•
Median time to death, proportion of patients alive at 
6 months, 1 year, and 2 years.
•
To collect PF-06801591 drug concentration data in 
patients following SC administration for evaluation of 
population PK.
•
Trough PF-06801591 concentrations for selected cycles.
•
To evaluate the immunogenicity of PF-06801591 
following repeated SC administration.
•
Incidence of ADA and NAb against PF-06801591 
administered by SC.
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3. STUDY DESIGN
3.1. Study Overview
This is a Phase 1, open-label,
safety, PK, and pharmacodyn
locally advanced or metastati
PD-1 or PD-L1 agents.  This 
Part 2 dose expansion (see Fi
into this study.  
Figure 4.
B8011001 Study
Part 1 will enroll patients wit
cancer, sarcoma, NSCLC, uro
evidence of response to anti P
10 mg/kg PF-06801591 intra
subcutaneously (SC) every 4 
Part 1 will be further divided 
cohort). For both IV and SC 
2-4 patients per dose level. F
will enroll 2 to 5 patients per 
11 patients will be enrolled in
will be enrolled into Part 1.
August 2018
PFIZER CONFIDENTIAL
Page 75
, multi-center, multiple-dose, dose escalation an
namic study of PF-06801591 in previously treate
ic solid tumor types with clinical evidence of res
clinical trial will include 2 parts: Part 1 dose esc
igure 4). A total of approximately 140 patients w
y Schematic
th locally advanced or metastatic melanoma, SC
othelial carcinoma, or other solid tumor types w
PD-1 or PD-L1 agents. Patients will receive 0.5
avenously (IV) every 3 weeks (q3w), or 300 mg 
weeks (q4w). 
d into Part 1A (safety cohort) and Part 1B (pharm
administration portions, each safety cohort will
For IV administration portion, each pharmacodyn
dose level. For SC administration portion, up t
nto the 300 mg dose level in Part 1B. Approxim
d expansion, 
ed patients with 
sponse to anti 
calation, and 
will be enrolled 
CHN, ovarian 
with clinical 
5, 1, 3, or 
PF-06801591
macodynamic 
 enroll
namic cohort 
o approximately 
mately 40 patients 


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All patients in Part 2 will receive 300 mg PF-06801591 subcutaneously q4w. Part 2 dose 
expansion will include 2 arms: Arm 1 will enroll approximately 70 patients with NSCLC 
who progressed on or were intolerant to systemic therapy or for whom systemic therapy was 
refused or unavailable but have not previously received anti-PD-1 or anti-PD-L1.  Arm 2 will 
enroll approximately 30 patients with urothelial cancer who progressed on or were intolerant 
to systemic therapy or for whom systemic therapy was refused or unavailable but have not 
previously received anti-PD-1 or anti-PD-L1. Approximately 100 patients will be enrolled 
into Part 2.
All patients:
1. Will undergo up to 4 weeks of screening prior to study entry.
2. Receive treatment with investigational product for up to 2 years, or until one of the 
following:
a.
Disease progression by immune-related Response Evaluation Criteria in Solid 
Tumors (irRECIST, confirmed progressive disease [PD] or initial PD 
followed by rapid clinical deterioration), or
b. Unacceptable toxicity occurs, or
c.
Withdrawal of consent, or
d. Patient no longer willing to participate in trial, or
e.
Study termination. 
Any additional treatment beyond 2 years shall be discussed and approved by the 
sponsor. Patients will be allowed to stay on treatment in the case of initial 
radiological disease progression, if the investigator feels that it is in the patient’s best 
interest. For example, if a patient does not have rapid clinical deterioration after 
initial assessment demonstrating unconfirmed PD. If a patient has a confirmed CR 
(ie, 2 consecutive CR assessments at least 4 weeks apart) by irRECIST, patient may 
also discontinue treatment at the discretion of the investigator and continue follow-up 
assessments.
3. Will complete a 1 month follow-up visit after the last dose for adverse event (AE) 
collection and serious adverse event (SAE) follow-up if necessary.
4. Will undergo assessment for late irAEs up to 120 days after completion of 
PF-06801591 administration (see Section 6.4 Follow-up for Late Immune-related 
Adverse Events).


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5. After the 120-day follow-up period, the patient will be contacted by telephone every 
8 weeks for survival data collection until end of trial (2 years from last patient first 
dose [LPFD], see Section 13.2).  If the patient is seen in the clinic during the window 
of time that a scheduled telephone call is to be made to collect survival data, then the 
clinic visit may replace the survival telephone call.  After the completion of the end of 
treatment (EOT) visit subsequent anti-cancer therapy will be documented and 
recorded for patients who discontinue investigational products and continue in 
120 day safety follow-up, and subsequently during survival follow-up.
3.1.1. Part 1 Dose Escalation
Part 1 will study sequential cohorts (0.5, 1, 3, and 10 mg/kg IV, or 300 mg SC) of 
PF-06801591 in adult patients with locally advanced or metastatic melanoma, SCCHN, 
ovarian cancer, sarcoma, NSCLC, urothelial carcinoma, or other solid tumor types with 
clinical evidence of response to anti PD-1 or PD-L1 agents who are unresponsive to currently 
available therapies or for whom no standard therapy is available.  
Part 1 will be further divided into Part 1A (safety cohort) and Part 1B (pharmacodynamic 
cohort). For both IV and SC administration portions, each safety cohort will enroll
2-4 patients per dose level. A mTPI method,7 targeting a DLT rate of 27.5% will be utilized
for dose escalation. In the IV administration portion, if based on Part 1A information the 
dose level is deemed safe and well- tolerated, an additional 2 to 5 patients will enroll into the 
same dose level in Part 1B. In the SC administration portion, if based on Part 1A 
information the 300 mg dose level is deemed safe and well- tolerated, up to an additional 
11 patients (approximately) will be enrolled into Part 1B. Up to approximately 9 patients 
may be enrolled into each dose level in the IV administration portion, and up to 
approximately 15 patients may be enrolled into the 300 mg SC administration cohort 
(Part 1A and Part 1B combined). The mTPI approach would be applied across Parts 1A and 
1B to ensure that administered doses do not surpass the toxicity boundaries. Safety data from 
all patients in Parts 1A (safety cohort) and available data at cutoff from Parts 1B 
(pharmacodynamic cohort) will be used to determine the MTD. Tumor biopsies collected at 
pre and post treatment time points (screening and C2D8) are mandatory for all Part 1B 
patients.
For patients enrolled into IV administration portion, each cycle will be 3 weeks and DLT 
observation period will be 21 days. For patients enrolled into subcutaneous dosing portion, 
each cycle will be 4 weeks and DLT observation period will be 28 days. Patients will receive 
1 dose of PF-06801591 per cycle. A staggered start will be employed at all dose levels in 
both the IV and SC administration portions: a single patient will be dosed and observed for
48 hours. If no safety concerns arise during this 48-hour period, a second patient will be 
enrolled into the same dose level cohort. 


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Available safety information, provided by additional patients enrolled into each dose level 
expansion will also be taken into account for MTD determination.  If the DLT rate is 
estimated to reach >33% or more at any dose level, enrollment at that level and all higher 
levels will be temporarily stopped, and safety data will be analyzed.  The decision to move 
forward with enrollment will follow the same DLT target as described previously.  Dose 
escalation will continue until an MTD has been established or a pre-specified maximum dose 
level has been reached.
The proposed doses, schedules and PK time points may be reconsidered and amended during 
the study based on emerging safety and PK data.  Furthermore, in addition to the proposed 
dose levels, lower, intermediate, or higher dose levels may be explored (to a maximum of 
20 mg/kg IV).  For example, if DLT or clear efficacy is observed at 0.5 mg/kg IV, lower dose 
levels might be tested.  Alternatively, if the MTD has not been reached at 10 mg/kg IV, and 
tumor specific immunomodulatory effects show evidence of not being maximized, higher 
dose levels might be tested.  Higher dose levels will only be initiated if the lower dose level 
is deemed tolerable. For SC administration, a lower dose level of 150 mg maybe considered 
if toxicity boundary is exceeded per mTPI (see Section 9.2.1).
3.1.2. Part 2 Dose Expansion
Part 2 dose expansion will include 2 arms: Arm 1 will enroll approximately 70 patients with 
NSCLC who progressed on or were intolerant to systemic therapy or for whom systemic 
therapy was refused or unavailable but have not previously received anti-PD-1 or
anti-PD-L1.  Arm 2 will enroll approximately 30 patients with urothelial cancer who 
progressed on or were intolerant to systemic therapy or for whom systemic therapy was 
refused or unavailable but have not previously received anti-PD-1 or anti-PD-L1. All 
patients in Part 2 will receive 300 mg PF-06801591 subcutaneously q4w. The 300 mg SC 
dose level in Part 2 was selected based upon safety, PK, PD, and preliminary anti-tumor 
activity observed in Part 1, as well as the maximum injection volume considered feasible 
with the current formulation.
When the first 30 NSCLC patients have been enrolled and have either completed their first 
tumor assessment (at approximately 8 weeks post treatment), or have discontinued from the 
study before their first scheduled tumor assessment, preliminary assessment of safety and 
efficacy data maybe completed.  This preliminary data may provide guidance in the decision 
to the increase or decrease the sample size of each arm, to add other tumor types in a future 
amendment, or to initiate additional clinical studies.
3.1.3. Starting Dose
The initial starting dose of PF-06801591 IV (Part 1) is 0.5 mg/kg, to be given on Day 1 of
each 21-day cycle.


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3.1.4. Criteria for Dose Finding
Maximum Tolerated Dose Selection for IV Administration
An mTPI method,7 targeting a DLT rate of 27.5% and an acceptable DLT interval (22.5% to 
32.5%), will be utilized in the Part 1A dose escalation phase. The IV dose levels to be 
evaluated for the MTD following IV administration are listed in Table 2. If a high DLT rate 
is observed at the starting dose, the study may explore a lower dose than the starting dose or 
be stopped.  Cohorts of 2 to 4 patients (Part 1A) will be enrolled at each selected dose level. 
The required number of patients per dose level will be managed according to Table 3.
Table 2.
Table of Pre-Specified PF-06801591 IV Dose Levels
Dose Level
Dose
(mg/kg)
1
0.5
2
1.0
3
3.0
4
10
The mTPI method relies upon a statistical probability algorithm, calculated using all patients 
treated in the current dose level to determine one of the following dose-finding decisions: the 
subsequent dose should be escalated, maintained at the current dose, or de-escalated in the 
next cohort of 2 to 4 patients (Part 1A), or the trial should be terminated (Table 3).
In principle, all patients must be evaluated for a minimum period of 21 days.  If a patient 
withdraws from the study before Day 21 for reasons other than drug-related toxicity, another 
patient may be enrolled to replace that patient in the current cohort.  However, if a patient 
discontinues close to Day 21 for reasons other than toxicity and due to an evident non 
drug-related event, the patient may be deemed evaluable for safety if safety assessments have 
been unremarkable and the investigator and sponsor’s medical monitor both agree that the 
patient is evaluable for DLT safety observation.
1. The dose escalation Part 1 of the study will stop if any of the following criteria is met:
2. The maximum sample size has been achieved (approximately 40 patients in total);
3. 6 to 15 patients have been enrolled at a dose level that is predicted to be the MTD per 
the mTPI method; All dose levels explored appear to be overly toxic, and the MTD 
cannot be determined;
4. All pre-specified dose levels have been tested and all doses were deemed tolerable.


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Table 3.
Decision Rules for IV Administration
Number 
of 
Patients 
having 
DLT
Number of Patients Treated at a Dose Level
n=2
n=3
n=4
n=5
n=6
n=7
n=8
n=9
n=10
n=11
n=12
n=13
n=14
n=15
0
E
E
E
E
E
E
E
E
E
E
E
E
E
E
1
S
S
S
E
E
E
E
E
E
E
E
E
E
E
2
U
D
S
S
S
S
S
S
S
E
E
E
E
E
3
U
U
D
D
S
S
S
S
S
S
S
S
S
4
U
U
U
U
D
D
D
S
S
S
S
S
5
U
U
U
U
U
D
D
D
D
D
S
6
U
U
U
U
U
U
U
D
D
D
7
U
U
U
U
U
U
U
U
U
Actions to be taken:
D = De-escalate the dose; E: Escalate the dose; S: Stay at the dose.
U = Unacceptable toxicity.
The SC dose data will not be used for IV dose escalation decision and the IV MTD 
determination.  The mTPI approach as shown in Table 3, however, will be applied to ensure 
that administered SC dose does not surpass the toxicity boundaries. Subcutaneous doses may 
be de-escalated to 150 mg if the toxicity boundary is exceeded by the mTPI approach. 
Intra- patient dose reductions may also occur upon discussion with the sponsor.   
3.1.5. Dose-limiting Toxicity Definition
Previous anti-PD-1 mAbs were administered in >1000 patients and were associated in the 
clinic with inflammatory adverse reactions resulting from increased or excessive immune 
activity (immune-mediated adverse reactions), likely to be related to the mechanism of 
action.  Immune-mediated adverse reactions, which can be severe, may involve the 
gastrointestinal, skin, liver, endocrine, respiratory, renal, or other organ systems.12
Severity of AEs will be graded according to CTCAE version 4.03. For the purpose of a dose 
finding decision, any of the following drug-related AEs occurring during the first cycle of 
treatment (21 days for IV, or 28 days for SC) will be classified as DLTs following review by 
the investigators and the sponsor:

Grade 5 AE

Hematologic toxicity:

Any Grade 4 hematologic AE, with the following clarifications:

Grade 4 neutropenia lasting >5 days from initiation of granulocyte-colony stimulating 
factor.


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
Grade 4 thrombocytopenia with bleeding.

Platelet transfusion requirement or a platelet count <10,000/uL.

Non-Hematologic Toxicity

Grade 4 non-hematologic AE;

Grade 3 AE lasting >7 days despite optimal supportive care (see Appendix 8);

Grade 3 central nervous system AE regardless of duration;

Meets criteria for drug-induced liver injury (Section 8.6.2).   
The following AEs will not be adjudicated as DLTs:

Any Grade 3 endocrinopathy that is adequately controlled by hormonal replacement.

Grade 3 AE of tumor flare (defined as local pain, irritation, or rash localized at sites 
of known or suspected tumor).

Isolated Grade 3-4 laboratory abnormalities that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 
72 hours of their onset.

Grade 3 infusion reactions and allergic reactions will not be considered dose 
limiting as they are unlikely to be dose related, but all available information on these 
events will be collected.  If Grade 3 infusion reactions occur in 2 of the first 
10 patients at any dose level, or if the occurrence is 5% thereafter, a mandatory 
pre-treatment regimen for all new patients will be implemented.  The incidence of 
Grade 1 and 2 reactions will also be taken into account.  If a total rate of 
>10% all-grade infusion or allergic reactions is observed, a mandatory pre-treatment 
regimen for all new patients will be implemented.
Information regarding the DLT observation period can be found in the Criteria for Dose
Finding (Section 3.1.4).  For dose escalation, DLT observation is required for 21 days for IV 
administration, or 28 days for SC administration. However, DLT observation will continue 
for at least 120 days from first dose (or completion of 5 cycles, if still on treatment) to assess 
late immune-related dose-limiting AEs, and available data from Part 1B at data cut off will 
be taken into account for MTD determination.
3.1.5.1. Late Immune-Related Dose-Limiting Toxicities
Late immune-related DLTs are irAEs (see Appendix 8) that meet the same grading criteria as 
DLT criteria but occur after the initial 21-day DLT period for IV administration, or 28 days 
for SC administration, and during the 120-day assessment period.  Late immune-related 
DLTs will be added to the mTPI approach to reassess the dose-finding decisions (see 
Table 3).


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For any patient being treated at dose levels that are subsequently considered to exceed the 
MTD, the option to reduce their dose will be discussed between the investigator and the
sponsor’s medical monitor.  If the patient tolerated the above-MTD dose level well and is 
deriving clinical benefit, continuation of treatment at the above-MTD dose level will require 
re-consenting.
3.1.6. Maximum Tolerated Dose Definition
The MTD is defined as the highest dose with true toxicity probabilities in the equivalence 
interval (EI) where the EI is defined as 22.5%-32.5%.
In practice, the MTD will be the highest dose associated with the occurrence of DLTs 33% 
(eg, 3 of 9 evaluable patients experience a DLT during at least [90 days after the first dose])
or the first 5 treatment cycles if the patient remains on treatment.
3.1.7. Optimal Biological Dose Definition
The OBD is the lowest dose that can produce an efficacious and/or pharmacodynamic effect
that is consistent with the proposed mechanism and with an acceptable toxicity.  Examples of 
such a pharmacodynamic effect in peripheral blood may include increased expression of 
CD8+ T cell proliferation or activation markers such as Ki-67 or HLA-DR.  Increased CD8+ 
T cell infiltration into melanoma tumor tissue has been observed in patients who exhibit a 
clinical response to PD-1 blockade.52 In this study, pharmacodynamic effects that will be 
monitored to support the identification of the OBD will include, but not be limited to, change 
from baseline in Ki-67 and HLA-DR expression on peripheral blood CD8+ T cells and 
intratumoral CD8+ T cell and FoxP3+ regulatory T cell density in response to dosing with 
PF-06801591.  Note: In addition to pharmacodynamic biomarkers, preliminary anti-tumor 
activity (CR, partial response [PR]), if observed, will also be taken into consideration.
3.1.8. Recommended Phase 2 Dose (RP2D) Definition
The 300 mg SC dose has been selected for Part 2 expansion based on existing PK, 
pharmacodynamic, safety, and preliminary efficacy data (see Section 1.9.1 Clinical 
Experience in Study B8011001). If anti-tumor efficacy and safety at this dose level is 
confirmed in Part 2, 300 mg SC q4w administration will be the recommended Phase 2 dose 
(RP2D) chosen for further investigational study.
4. PATIENT SELECTION
This study can fulfill its objectives only if appropriate patients are enrolled.  The following 
eligibility criteria are designed to select patients for whom participation in the study is 
considered appropriate.  All relevant medical and non-medical conditions should be taken 
into consideration when deciding whether a particular patient is suitable for this protocol.


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4.1. Inclusion Criteria
Patient eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before patients are included in the study.
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
4.1.1. Part 1 Dose Escalation
1. Histological or cytological diagnosis of locally advanced metastatic melanoma, 
SCCHN, ovarian cancer, sarcoma, NSCLC, or urothelial carcinoma. Other solid 
tumor types with clinical evidence of response to anti PD-1 or PD-L1 agents 
(eg, mismatch repair deficient tumors, small cell lung cancer, renal cell carcinoma, 
gastric cancer, triple negative breast cancer, hepatocellular carcinoma) are required to 
be reviewed and approved by the sponsor prior to enrollment:

Patient must not be previously treated with anti PD-1 or PD-L1 agents. 

Patient should have received at least 1 prior line of therapy for recurrent or 
metastatic disease, including both standards of care and investigational therapies.  
Patient must have progressed/relapsed, be refractory, or intolerant to standard 
therapy approved for the specific tumor type.  Exception: Patients who actively 
decline chemotherapy or other standard therapies including approved anti PD-1 or 
PD-L1 agents for the treatment of advanced disease (unresectable or metastatic) 
are eligible upon documentation of their refusal.  

A mandatory archived formalin-fixed paraffin embedded (FFPE) tumor tissue 
block (preferred) must be provided. If an FFPE tumor tissue block cannot be 
provided, sites should contact sponsor for approval to submit slides. Cytological 
or fine-needle aspiration samples are not acceptable. For Part 1A or 2, if an 
archived FFPE tissue is not available, a de novo (ie, fresh) tumor sample can 
substitute and should be obtained in accordance with local institutional practice 
for tumor biopsies. For Part 1B, the archived FFPE tumor tissue sample is highly 
encouraged but can be waived if not available. 
2. At least one measurable lesion as defined by RECIST version 1.1.
3. For Part 1B expansion cohorts: patient has consented to undergo a pre-treatment and 
on-treatment biopsy.
4. Adult (male or female) aged ≥18 years.
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (see 
Appendix 6).
6. In the opinion of the investigator, patient’s current clinical status is likely to allow for
at least 8 weeks of study treatment.


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7. Adequate bone marrow function, as follows:
a.
White blood cells (WBC) ≥2,000/mm3 or ≥2.0 x 109/L;
b. Absolute neutrophil count (ANC) ≥1,500/mm3 or ≥1.5 x 109/L;
c.
Platelets ≥100,000/mm3 or ≥100 x 109/L;
d. Hemoglobin ≥9 g/dL. Limited transfusions to reach this value are allowed, after 
discussion with sponsor’s medical monitor.  There should not be a chronic need 
for transfusions in the recent past (approximately 3 months).
8. Adequate Renal Function, as follows:
a.
Serum creatinine ≤1.5 x upper limit of normal (ULN) or estimated creatinine 
clearance (CrCl) ≥40 mL/min as measured or calculated using the 
Cockcroft-Gault formula below:

Female CrCl = [(140 - age in years) x weight in kg x 0.85]/[72 x serum 
creatinine in mg/dL];

Male CrCl = [(140 - age in years) x weight in kg x 1.00]/[72 x serum 
creatinine in mg/dL];
If an estimated CrCl is believed to be inaccurate for a patient, 24-hour urine 
collection with actual assessment of CrCl is allowed.
9. Adequate Liver Function including:
a.
Total serum bilirubin ≤1.5 x ULN except patients with Gilbert syndrome who 
should have total serum bilirubin <3 x ULN;
b. Aspartate and alanine aminotransferase (AST & ALT) ≤3.0 x ULN.
10. Thyroid stimulating hormone (TSH) within normal limits (WNL) for institution; 
supplementation is acceptable to achieve a TSH WNL; in patients with abnormal 
TSH if Free T4 and Free Thyroxine Index are normal and patient is clinically 
euthyroid, patient is eligible.
11. International Normalized Ratio (INR) or activated partial prothrombin time (aPTT) 
<1.5 x ULN.
12. Negative serum or urine pregnancy test (for women of childbearing potential) at 
screening and at the baseline visit (before the patient may receive the investigational 
product).


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13. Male patients who are able to father children, and female patients of childbearing 
potential and at risk for pregnancy must agree to use 2 highly effective methods of 
contraception throughout the study and for at least 5 months after the last dose of 
assigned treatment.
14. Female patients who are not of childbearing potential as defined below, are eligible to 
be included (ie, meet at least one of the following criteria):
a.
Have undergone a documented hysterectomy and/or bilateral oophorectomy;
b. Have medically confirmed ovarian failure; or
c.
Achieved postmenopausal status, defined as follows: cessation of regular menses 
for at least 12 consecutive months with no alternative pathological or 
physiological cause; a serum follicle-stimulating hormone (FSH) level within the 
laboratory’s reference range for postmenopausal women.
15. Evidence of a personally signed and dated informed consent document indicating that 
the patient has been informed of all pertinent aspects of the study.
16. Patients who are willing and able to comply with scheduled visits, treatment plans, 
laboratory tests and other procedures.
4.1.2. Part 2 Dose Expansion
1. Either histological or cytological diagnosis of locally advanced or metastatic NSCLC
or locally advanced or metastatic urothelial carcinoma who have progressed on or 
were intolerant to standard of care systemic therapy, or for whom standard of care 
systemic therapy was refused (refusal must be documented) or unavailable. 
2. No prior treatment with anti-PD-1 or anti-PD-L1 therapy.
3. NSCLC patients whose tumor is not known to have anaplastic lymphoma kinase 
(ALK) or epidermal growth factor receptor (EGFR) mutation must not have received 
more than 1 line of prior systemic therapy and must have either:
a.
Progressed on or after platinum-containing systemic therapy, or
b. Were intolerant to standard of care systemic therapy or
c.
Refused standard of care systemic therapy (refusal must be documented). 
4. NSCLC patients whose tumor is known to be ALK or EGFR mutation positive must 
have received prior systemic therapies that only include one or more lines of ALK or 
EGFR targeting drugs and chemotherapy limited to one line of a platinum-based 
regimen, and they must have progressed on or after both types of therapies.


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5. Urothelial carcinoma patients must have received up to 2 lines of prior systemic 
therapy and either:
a.
Progressed on or after platinum-containing systemic therapy, or
b. Were intolerant to platinum-containing systemic therapy, or
c.
Had disease recurrence within 12 months of neoadjuvant or adjuvant treatment 
with platinum-containing chemotherapy, or
d. Were ineligible for platinum-containing systemic therapy, or 
e.
Refused standard of care systemic therapy (refusal must be documented). 
If patients are treatment naïve and eligible for platinum-containing systemic therapy but 
are refusing platinum chemotherapy, they must also be documented to have previous 
PD-L1 high status as defined in the following table:  
PD-L1 assay
Result 
Threshold for PD-L1 High
Dako 28-8
TC
≥5%
Dako 22C3
CPS
≥10%
Ventana SP142
IC
IC ≥5% and <10% (IC2); or,
IC ≥10% (IC3)
Ventana SP263
TC, IC, ICP
TC ≥25%; or, 
ICP >1% and IC ≥25%; or,
ICP = 1% and IC = 100%
TC: Tumor cells
CPS: Combined positive score
IC: Immune cells
ICP: Immune cells present
6. Patients must be able to provide an archived formalin-fixed paraffin embedded 
(FFPE) tumor tissue sample (block preferred). The sample must be taken within 
2 years of start of study treatment. If an FFPE tumor tissue block cannot be provided, 
sites should contact sponsor for approval to submit slides.  Cytological or fine-needle 
aspiration samples are not acceptable.  A de novo (ie, fresh) tumor sample can be 
utilized as a substitute if an archived FFPE tissue is not available, and should be 
obtained in accordance with local institutional practice for tumor biopsies. Samples 
provided should be taken from the most recently conducted available biopsy. 
7. At least one measurable lesion as defined by RECIST version 1.1.
8. Adult (male or female) aged ≥18 years.
9. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (see 
Appendix 6).


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10. In the opinion of the investigator, patient’s current clinical status is likely to allow for 
at least 8 weeks of study treatment.
11. Adequate bone marrow function, as follows:

WBC ≥2,000/mm3 or ≥2.0 x 109/L,

ANC ≥1,500/mm3 or ≥1.5 x 109/L,

Platelets ≥100,000/mm3 or ≥100 x 109/L,

Hemoglobin ≥9 g/dL.  Limited transfusions to reach this value are allowed, after 
discussion with sponsor’s medical monitor.  There should not be a chronic need 
for transfusions in the recent past (approximately 3 months).
12. Adequate Renal Function, as follows:
Serum creatinine ≤1.5 x upper limit of normal (ULN) or estimated creatinine 
clearance (CrCl) ≥30 mL/min as measured or calculated using the Chronic Kidney 
Disease Epidemiology Collaboration (CKD-EPI) method.63,64  If an estimated CrCl is 
believed to be inaccurate for a patient, 24-hour urine collection with actual 
assessment of CrCl is allowed.
13. Adequate Liver Function including:

Total serum bilirubin ≤1.5 x ULN except patients with Gilbert syndrome who 
should have total serum bilirubin <3 x ULN;

Aspartate and alanine aminotransferase (AST & ALT) ≤3.0 x ULN.
14. Thyroid stimulating hormone (TSH) within normal limits (WNL) for institution; 
supplementation is acceptable to achieve a TSH WNL; in patients with abnormal 
TSH if Free T4 and Free Thyroxine Index are normal and patient is clinically 
euthyroid, patient is eligible.
15. International Normalized Ratio (INR), activated partial prothrombin time (aPTT) or 
partial thromboplastin time (PTT) <1.5 x ULN.
16. Negative serum or urine pregnancy test (for women of childbearing potential) at 
screening and at the baseline visit (before the patient may receive the investigational 
product).
17. Male patients who are able to father children, and female patients of childbearing 
potential and at risk for pregnancy must agree to use 2 highly effective methods of 
contraception throughout the study and for at least 5 months after the last dose of 
assigned treatment.


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18. Female patients who are not of childbearing potential as defined below, are eligible to 
be included (ie, meet at least one of the following criteria):

Have undergone a documented hysterectomy and/or bilateral oophorectomy;

Have medically confirmed ovarian failure; or

Achieved postmenopausal status, defined as follows: cessation of regular menses 
for at least 12 consecutive months with no alternative pathological or 
physiological cause; a serum follicle-stimulating hormone (FSH) level within the 
laboratory’s reference range for postmenopausal women.
19. Evidence of a personally signed and dated informed consent document indicating that 
the patient has been informed of all pertinent aspects of the study.
20. 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:
4.2.1. Part 1 Dose Escalation
1. Active brain or leptomeningeal metastases.  Patients with brain metastases are eligible 
if these have been treated and magnetic resonance imaging (MRI) shows no evidence 
of progression for at least 8 weeks after treatment is complete and within 4 weeks 
prior to first dose of study drug. Patients are not eligible if they required high doses 
of systemic corticosteroids that could result in immunosuppression (>10 mg/day 
prednisone equivalents) for at least 2 weeks prior to study drug administration.
2. Ocular melanoma.
3. Active, known or suspected autoimmune disease.  Patients with vitiligo, type I 
diabetes mellitus, residual hypothyroidism due to autoimmune condition only 
requiring hormone replacement, psoriasis not requiring systemic treatment, or 
conditions not expected to recur in the absence of an external trigger are permitted to 
enroll. Diagnosis of prior immunodeficiency or organ transplant requiring 
immunosuppressive therapy or prior allogeneic bone marrow or hematopoietic stem 
cell transplant.
4. Active hepatitis B virus (HBV) or hepatitis C virus (HCV).
5. True positive test for human immunodeficiency virus (HIV) or known acquired 
immunodeficiency syndrome (AIDS).


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6. Patient is receiving chemotherapy, radioactive, or biological cancer therapy within 
4 weeks prior to the first dose of study drug (exception: palliative radiotherapy to a 
limited field is allowed after consultation with Pfizer’s medical monitor).
7. Patient has AE(s) due to cancer therapeutics administered >4 weeks earlier, which 
have not recovered to CTCAE Grade 1 (except alopecia, and except for AEs not 
constituting a safety risk by investigator judgment).
8. Patients with a history of interstitial lung disease, non-infectious pneumonitis, or 
active pulmonary tuberculosis.  Those with active lung infections requiring treatment 
are also excluded.
9. Patients with a condition requiring systemic treatment with either corticosteroids 
(>10 mg daily prednisone equivalents) or other immunosuppressive medications 
within 14 days of study drug administration.  Inhaled or topical steroids, and adrenal 
replacement doses >10 mg daily prednisone equivalents are permitted in the absence 
of active autoimmune disease.
10. History of Grade ≥3 immune-mediated AE (including AST/ALT elevations that 
where considered drug related and cytokine release syndrome) that was considered 
related to prior immune-modulatory therapy (eg, immune checkpoint inhibitors, 
co-stimulatory agents, etc.) and required immunosuppressive therapy.
11. Patients with intolerance to or who have had a severe (Grade 3) allergic or 
anaphylactic reaction to antibodies or infused therapeutic proteins.
12. Any of the following in the previous 6 months: myocardial infarction, congenital long 
QT syndrome, Torsade de Pointes, arrhythmias (including sustained ventricular 
tachyarrhythmia and ventricular fibrillation), right bundle branch block and left 
anterior hemiblock (bifascicular block), unstable angina, coronary/peripheral artery 
bypass graft, symptomatic congestive heart failure (CHF, New York Heart 
Association class III or IV), cerebrovascular accident, transient ischemic attack, or 
symptomatic pulmonary embolism or other clinical significant episode of 
thrombo-embolic disease.  Ongoing cardiac dysrhythmias of NCI CTCAE Grade 2, 
atrial fibrillation of any grade, or QTcF interval >470 msec at screening (except in 
case of right bundle branch block, these cases must be discussed with sponsor’s 
medical monitor).  Cases must be discussed in detail with sponsor’s medical monitor 
to judge eligibility.  Anticoagulation (heparin only, no vitamin-K antagonists or factor 
Xa inhibitors) will be allowed if indicated.
13. Other malignancy within 5 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, or low-grade (Gleason 6 or below) prostate cancer on surveillance without any 
plans for treatment intervention (eg, surgery, radiation, or castration) or other 
concurrent malignancy investigator feels has a very low likelihood to become 
metastatic.


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14. Pregnant female patients; breastfeeding female patients; male patients with partners 
currently pregnant; male patients able to father children and female patients of 
childbearing potential who are unwilling or unable to use 2 highly effective method(s) 
of contraception as outlined in this protocol for the duration of the study and for at 
least 5 months after the last dose of investigational product or longer based upon the 
compound’s half-life characteristics.
15. Severe acute or chronic medical or psychiatric condition, including recent (within the 
past year) or active suicidal ideation or behavior, or laboratory abnormality that may 
increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the 
judgment of the investigator, would make the patient inappropriate for entry into this 
study.
16. Concurrent enrollment in another clinical study, unless it is an observational 
(non-interventional) clinical study or the follow-up period of an interventional study.
17. 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.
4.2.2. Part 2 Dose Expansion
1. Active brain or leptomeningeal metastases.  Patients with brain metastases are eligible 
if these have been treated and magnetic resonance imaging (MRI) shows no evidence 
of progression for at least 8 weeks after treatment is complete and within 4 weeks 
prior to first dose of study drug.  Patients are not eligible if they required high doses 
of systemic corticosteroids that could result in immunosuppression (>10 mg/day 
prednisone equivalents) for at least 2 weeks prior to study drug administration.
2. Other malignancy within 5 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, or low-grade (Gleason 6 or below) prostate cancer on surveillance without any 
plans for treatment intervention (eg, surgery, radiation, or castration) or other 
concurrent malignancy investigator feels has a very low likelihood to become 
metastatic.
3. Active hepatitis B virus (HBV) or hepatitis C virus (HCV). For example, patients
with HBV surface antigen positive or HCV RNA positive will be excluded.
4. True positive test for human immunodeficiency virus (HIV) or known acquired 
immunodeficiency syndrome (AIDS).


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5. Active, known or suspected autoimmune disease.  Patients with vitiligo, type I 
diabetes mellitus, residual hypothyroidism due to autoimmune condition only 
requiring hormone replacement, psoriasis not requiring systemic treatment, or 
conditions not expected to recur in the absence of an external trigger are permitted to 
enroll. Diagnosis of prior immunodeficiency or organ transplant requiring 
immunosuppressive therapy or prior allogeneic bone marrow or hematopoietic stem 
cell transplant.
6. Patients with a history of interstitial lung disease, non-infectious pneumonitis, or 
active pulmonary tuberculosis.  Those with active lung infections requiring treatment 
are also excluded.
7. Patient has AE(s) due to cancer therapeutics administered >4 weeks earlier, which 
have not recovered to CTCAE Grade 1 (except alopecia, and except for AEs not 
constituting a safety risk by investigator judgment).
8. History of Grade ≥3 immune-mediated AE (including AST/ALT elevations that 
where considered drug related and cytokine release syndrome) that was considered 
related to prior immune-modulatory therapy (eg, immune checkpoint inhibitors, 
co-stimulatory agents, etc.) and required immunosuppressive therapy.
9. Patients with intolerance to or who have had a severe (Grade 3) allergic or 
anaphylactic reaction to antibodies or infused therapeutic proteins.
10. Patient is receiving chemotherapy, radioactive, or biological cancer therapy within 
4 weeks prior to the first dose of study drug (exception: palliative radiotherapy to a 
limited field is allowed after consultation with Pfizer’s medical monitor).
11. Patients with a condition requiring systemic treatment with either corticosteroids 
(>10 mg daily prednisone equivalents) or other immunosuppressive medications 
within 14 days of study drug administration.  Inhaled or topical steroids, and adrenal 
replacement doses >10 mg daily prednisone equivalents are permitted in the absence 
of active autoimmune disease.
12. Any of the following in the previous 6 months: myocardial infarction, congenital long 
QT syndrome, Torsade de Pointes, arrhythmias (including sustained ventricular 
tachyarrhythmia and ventricular fibrillation), right bundle branch block and left 
anterior hemiblock (bifascicular block), unstable angina, coronary/peripheral artery 
bypass graft, symptomatic congestive heart failure (CHF, New York Heart 
Association class III or IV), cerebrovascular accident, transient ischemic attack, or 
symptomatic pulmonary embolism or other clinical significant episode of 
thrombo-embolic disease.  Ongoing cardiac dysrhythmias of NCI CTCAE Grade 2, 
atrial fibrillation of any grade, or QTcF interval >470 msec at screening (except in 
case of right bundle branch block, these cases must be discussed with sponsor’s 
medical monitor).  Cases must be discussed in detail with sponsor’s medical monitor 
to judge eligibility.  Anticoagulation (heparin only, no vitamin-K antagonists or factor 
Xa inhibitors) will be allowed if indicated.


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13. Pregnant female patients; breastfeeding female patients; male patients with partners 
currently pregnant; male patients able to father children and female patients of 
childbearing potential who are unwilling or unable to use 2 highly effective method(s) 
of contraception as outlined in this protocol for the duration of the study and for at 
least 5 months after the last dose of investigational product or longer based upon the 
compound’s half-life characteristics.
14. Severe acute or chronic medical or psychiatric condition, including recent (within the 
past year) or active suicidal ideation or behavior, or laboratory abnormality that may 
increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the 
judgment of the investigator, would make the patient inappropriate for entry into this 
study.
15. Concurrent enrollment in another clinical study, unless it is an observational 
(non-interventional) clinical study or the follow-up period of an interventional study.
16. 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.
17. For South Korea only, vaccination except inactivated vaccine within 4 weeks prior to 
the enrollment on the study or during the study.
18. For South Korea only, patients with active infection requiring systemic therapy will 
be excluded.
4.3. Lifestyle Guidelines
In this study, male patients who are able to father children and female patients who are of 
childbearing potential will receive PF-06801591, which is a compound for which the 
teratogenic risk is currently unknown.  Two methods of highly effective contraception must 
be used throughout the study and continue for at least 5 months after the last dose.  The 
investigator or his/her designee, in consultation with the patient, will confirm the patient has 
selected 2 appropriate methods of contraception for the individual patient and his/her partner 
from the list of permitted contraception methods (see below) and will confirm the patient has 
been instructed in their consistent and correct use.  Patients need to affirm that they meet the 
criteria for correct use of at least 2 of the selected methods of contraception.  The investigator 
or his/her designee will discuss with the patient the need to use 2 highly effective 
contraception methods consistently and correctly according to the Schedule Of Activities and 
document such conversation in the patient’s chart.  In addition, the investigator or his/her 
designee will instruct the patient to call immediately if one or both selected contraception 
methods are discontinued or if pregnancy is known or suspected in the patient or patient’s 
partner. 


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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, implanted, or transdermal hormonal 
methods of contraception is allowed provided the patient plans to remain on the same 
treatment throughout the entire study and has been using that hormonal contraceptive 
for an adequate period of time to ensure effectiveness.
2. Correctly placed copper-containing intrauterine device.
3. Male condom or female condom used WITH a spermicide (ie, foam, gel, film, cream, 
or suppository).  For countries where spermicide is not available or condom plus 
spermicide is not accepted as highly effective contraception, this option is not 
appropriate.
4. Male sterilization with absence of sperm in the post-vasectomy ejaculate. 
5. Bilateral tubal ligation or bilateral salpingectomy or bilateral tubal occlusive 
procedure (provided that occlusion has been confirmed in accordance with the 
device’s label).
6. Female partner who meets the criteria for non-childbearing potential, defined as:

Have undergone a documented hysterectomy and/or bilateral oophorectomy;

Have medically confirmed ovarian failure; or 

Achieved postmenopausal status, defined as follows: cessation of regular menses 
for at least 12 consecutive months with no alternative pathological or 
physiological cause, and have a serum FSH level within the laboratory's reference 
range for postmenopausal women.
4.4. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the study 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 numbers, 
contact information for the investigational site, and contact details for a contact center in the 
event that the investigational site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
patient’s participation in the study. The contact number can also be used by investigational 
staff if they are seeking advice on medical questions or problems; however, it should be used 
only in the event that the established communication pathways between the investigational 


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site and the study team are not available. It is therefore intended to augment, but not replace, 
the established communication pathways between the investigational site and the study team 
for advice on medical questions or problems that may arise during the study. The contact 
number is not intended for use by the patient directly, and if a patient calls that number, he or 
she will be directed back to the investigational site.
5. STUDY TREATMENTS
For the purposes of this study, and per ICH guidelines, investigational product is defined as a 
pharmaceutical form of an active ingredient or placebo being tested or used as a reference in 
a clinical trial, including a product with a marketing authorization when used or assembled 
(formulated or packaged) in a way different from the approved form, or when used for an 
unapproved indication, or when used to gain further information about an approved use (ICH 
E6 1.33).
5.1. Allocation to Treatment
In Part 1, eligible patients will be enrolled to receive PF-06801591 in an open-label,
unblinded manner.  Patients will be registered and successively assigned to the next available 
treatment slot at a dose level decided upon after the previous cohort’s safety evaluation and 
ongoing observations of earlier enrolled patients (or to a dose of 0.5 mg/kg IV, if being 
recruited for the first cohort). In Part 2, all eligible patients will receive a SC 300 mg flat 
dose administration of PF-06801591 in an open-label unblinded manner. 
Day 1 safety laboratory test results need to be reviewed by the investigator prior to dosing at 
the beginning of each cycle for dosing confirmation and administration rate.
5.1.1. Part 1 Dose Escalation
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 
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 
forms (CRFs) and other study-related documentation or correspondence referencing that 
patient and email to the site.
No patient shall receive investigational product until the investigator or designee has received 
the following information in writing from the sponsor:

Confirmation of the patient’s enrollment;

Specification of the dose level for that patient and;

Permission to proceed with dosing the patient.
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. Treatment should begin no longer 
than 3 days from registration.


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5.1.2. Part 2 Dose Expansion
Once the patient provides their written informed consent, and screening procedures have 
been completed to confirm that they meet all inclusion and exclusion criteria, the patient 
enrollment number will be assigned through the use of an interactive response technology 
(IRT) system. The site personnel (study coordinator or specified designee) will be required 
to enter or select information including but not limited to the user’s identification (ID) and 
password, the protocol number, the patient identification number and the date of birth (if 
allowed by local authorities; if not, only the year of birth will need to be provided) of the 
patient. The site personnel will then be provided with a treatment assignment and 
dispensable unit (DU) or container number when drug is being supplied via the IRT system. 
The IRT system will provide a confirmation report containing the patient identification 
number and DU or container number assigned. The confirmation report must be stored in the 
site’s files.
There is a 24-hour-a-day, 365-days-a-year IRT helpdesk available for any questions or 
issues. The study specific IRT reference manual will provide the contact information and 
further details on the use of the IRT system.
5.2. Patient Compliance
The site will complete required dosage Preparation Record located in the study 
Investigational Product (IP) 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.
5.3. Investigational Product Supplies 
PF-06801591 will be supplied by Pfizer.
Study centers will receive a supply of Clinical Trial Material upon activation with 
instructions on how to confirm drug receipt.  Resupplies will be made during the course of 
the study based on need.  The details on drug supply will be provided in the Investigational 
Product Manual.  The study monitor should be contacted for any issues related to drug 
supplies.
5.3.1. Dosage Form(s) and Packaging
PF-06801591 50 mg/mL injection is presented as a sterile solution for IV or SC 
administration.  Each vial contains 100 mg of PF-06801591 in 2 mL of aqueous buffered 
solution, with a nominal volume of 2.25 mL, is sealed with a coated stopper and an overseal, 
and labeled according to local regulatory requirements. 


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PF-06801591 will be shipped under refrigerated conditions (2-8°C/36-46F) and should be 
stored under refrigerated conditions (2-8°C/36-46F) or as specified on the investigational 
product label. Storage conditions on the label supersede all other documents.  Protect from 
light: minimize exposure to room light and avoid direct sunlight or ultraviolet light exposure. 
Do not shake vigorously or freeze.  Avoid foaming.
5.3.2. Preparation and Dispensing
See the Dosage and Administration Instruction (DAI) located in the IP Manual for 
instructions on how to prepare the investigational product for administration.  Each vial is 
designed for single use.  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. 
Only qualified personnel who are familiar with procedures that minimize undue exposure to 
them and to the environment should undertake the preparation, handling, and safe disposal of 
biologic agents.
5.4. Administration
5.4.1. IV Administration (Part 1 Only)
PF-06801591 will be administered intravenously, with adjustment for body weight at every 
cycle.  Patient actual body weight will be used to calculate the mg/kg dose, and the calculated 
dose will be rounded off to the second decimal point.  In each cycle, patients should be 
weighed within 72 hours prior to dosing to ensure they did not experience weight loss/gain of 
>10% from the prior weight used for PF-06801591 dose preparation calculations.
The decision to recalculate PF-06801591 dose based on the weight obtained at each cycle 
may be in accordance with institutional practice; however if the patient experienced either a 
weight loss or gain of >10% compared to the weight used to calculate the most recent dose, 
the amount of PF-06801591 required for study drug preparation and administration for the 
current cycle must be recalculated using this most recent weight obtained.
PF-06801591 will be administered on an outpatient basis as an IV infusion on Day 1 of each 
21-day treatment cycle, initially over 60 minutes ±10 minutes.  The use of an infusion pump 
is the preferred method of administration to ensure accurate delivery of the investigational 
product, but gravity drips are allowed.  Refer to the Investigation Product (IP) Manual for 
infusion rate and duration.
A cycle is defined as the time from Day 1 dose to the next Day 1 dose.  If there are no 
treatment delays, IV administration cycles will be once every 21 days (+/- 2 days).  Each 
patient may receive PF-06801591 until disease progression, unacceptable toxicity, 
withdrawal of consent, or study termination. 
The dose level for Part 1 will be assigned by the sponsor. 


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5.4.2. SC Administration (Parts 1 and 2)
Qualified and trained investigator site personnel will administer PF-06801591 at a fixed dose 
of 300 mg to patients by SC injection to the abdomen. A total volume of 6 mL must be 
administered subcutaneously for a dose of 300 mg of PF-06801591. Ideally, 3 subcutaneous 
injections of 2 mL should be administered to the abdomen, although, more injections can be 
done as needed, in order to have a total volume of 6 mL.
Study drug should be administered to two or more different quadrants of the abdomen (with 
preference given to the lower quadrants when possible); 1 or 2 injections per quadrant.  The 
maximum number of injections per patient is 8 injections. Refer to Appendix 9 for details on 
administration of multiple injections to the abdomen. Study staff should refer to the IP
Manual for specific instructions on the handling and administration of study drug.
Similar to intravenous dosing, a cycle is defined as the time from Day 1 dose to the next 
Day 1 dose.  Patients will receive a single dose of PF-06801591 on Day 1 of each cycle. If 
there are no treatment delays, a cycle will be 28 days (+/- 2 days) for SC administration.  
Each patient may receive PF-06801591 until disease progression, unacceptable toxicity, 
withdrawal of consent, patient no longer willing to participate in trial, or study termination.
5.4.3. Recommended Dose Modifications
Every effort should be made to administer investigational product on the planned dose and 
schedule. 
In the event of significant toxicity, dosing may be delayed as described below.  In the event 
of multiple toxicities, dose modification should be based on the worst toxicity observed.  
Patients are to be instructed to notify investigators at the first occurrence of any adverse 
symptom.
Dose modifications may occur in one of two ways:

Within a cycle: dosing interruption until adequate recovery, if required, during a 
given treatment cycle; 

Between cycles: next cycle administration may be delayed due to persisting toxicity 
when a new cycle is due to start.
Intra-patient dose reductions are not permitted during the study unless, in discussion with the 
sponsor, a dose level is deemed beyond the determined MTD. 


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5.4.3.1. Rules For Dose Delay/Interruption/Discontinuation
Events including, but not limited to, pneumonitis, colitis, creatinine, and liver function test 
(LFT) elevation should be monitored carefully with this class of agents.  To facilitate the 
early recognition and prompt intervention in the event of clinically AEs related to study 
treatment, management algorithms have been developed for suspected pulmonary, 
gastrointestinal, liver, endocrine, skin, cardiac, renal, or other immune-related toxicities (See
Appendix 8).  For non-irAEs, please refer to the rules for dose 
delay/interruption/discontinuation below:

Withhold treatment for: creatinine, AST, ALT, or total bilirubin for drug-related 
Grade 2 elevations except if they were >ULN at baseline. 

Withhold treatment for any other Grade 3 drug-related AEs.

Resume treatment when drug-related AE recovers to Grade 0-1 except when 
creatinine, AST, ALT, or total bilirubin were >ULN at baseline.

Discontinue treatment for drug-related Grade 3-4 creatinine, AST, ALT, or total 
bilirubin elevations except if they were >ULN at baseline.

Discontinue treatment for any other Grade 4 drug-related AEs or laboratory 
abnormality, except for the following events which do not require discontinuation:

Isolated Grade 4 amylase or lipase abnormalities that are not associated with 
symptoms or clinical manifestations of pancreatitis and decrease to <Grade 
4 within 1 week of onset. 

Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with 
clinical sequelae and are corrected with supplementation/appropriate management 
within 72 hours of their onset.

Discontinue treatment for persistent Grade 2-3 drug-related AE that do not recover to 
Grade 0-1 within 12 weeks after last dose except when creatinine, AST, ALT, or total 
bilirubin were >ULN at baseline.

Discontinue treatment for any Grade 3-4 drug-related AE that recurs.

If creatinine >ULN at baseline, withhold treatment for drug-related elevation >1.5 x 
baseline and resume when ≤1.5 x baseline. Discontinue treatment with drug-related 
elevation >3 x baseline or drug-related elevation that does not recover to ≤1.5 x 
baseline within 12 weeks after last dose.

If AST, ALT, or bilirubin >ULN at baseline, withhold treatment for drug-related 
elevation >2 x baseline and resume when ≤2 x baseline. Discontinue treatment with 
drug-related elevation >3 x baseline or drug-related elevation that does not recover to 
≤2 x baseline within 12 weeks after last dose.


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
Discontinue treatment for any AE, laboratory abnormality, or intercurrent illness 
which, in the judgment of the investigator, presents a substantial clinical risk to the 
patient with continued PF-06801591 dosing.

Isolated Grade 3-4 laboratory abnormalities that are not associated with clinical 
sequelae and/or are corrected with supplementation/appropriate management within 
72 hours of their onset and may not necessarily lead to discontinuation of treatment, if 
agreed upon by the Medical Monitor and the Principal Investigator.
5.4.3.2. Infusion Reactions
Following the first administration of some antibody therapeutics, some patients experience 
fever, headache, nausea, vomiting, or hypotension.  These AEs are generally ascribed to lysis 
of cellular targets, cytokine release, or complement activation.
Clinical management of these events, and the use of pretreatments for subsequent doses, are
discussed in Appendix 7.
5.4.3.3. Hypersensitivity Types 1 and 3
Type 1 hypersensitivity or allergic (eg, shortness of breath, urticaria, anaphylaxis, 
angioedema) reactions are theoretically possible in response to any injected protein.  Immune 
complex mediated Type 3 hypersensitivity reactions are similar to the AEs of 
Type 1 reactions but are likely to be delayed from the time of administration and may include 
symptoms such as rash, urticaria, polyarthritis, myalgias, polysynovitis, fever, and, if severe, 
glomerulonephritis. 
All patients should be closely observed while receiving investigational product and 
monitoring for clinical signs of a systemic reaction will continue thereafter for clinical signs 
of allergic reactions/hypersensitivity. 
Clinical management of these events is discussed in Appendix 7. 
5.4.3.4. Extravasation
In the event of extravasation IV infusions should be stopped immediately and the investigator 
needs to be consulted immediately.  Treatment of extravasation should follow local standard 
of care. 
5.4.3.5. Immune-Related Adverse Events
While theoretically any immune checkpoint–blockade toxicity can occur at any time, certain 
toxicities have been reported earlier in the treatment course, while others develop as later 
complications. Commonly encountered irAEs include rash/dermatitis, diarrhea/colitis, 
hepatitis, and endocrinopathies. Algorithms for the clinical management of these events are 
provided in Appendix 8.


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Prior to administration of the next dose of PF-06801591, the investigator should perform a 
comprehensive review of systems with specific focus on common and serious toxicities, such 
as skin changes, diarrhea and abdominal pain, headache, fever, shortness of breath, cough, 
and neurologic changes. Routine laboratory testing, including hematologic profile, 
comprehensive metabolic panel, and TSH level, should be reviewed.  Any new symptoms or 
abnormalities in examination or laboratory test results should be evaluated prior to 
administration of the next dose of PF-06801591.
5.4.5. Dose Delays
Patients experiencing Grade 3 or 4 potentially treatment related toxicity or intolerable 
Grade 2 toxicity despite supportive care should have their treatment interrupted/delayed (see 
Section 5.4.3). Appropriate follow-up assessments should be done until adequate recovery 
(or until deemed irreversible) occurs as assessed by the Investigator.
Treatment resumption for patients recovering from treatment-related toxicity after 4 weeks of 
treatment interruption or cycle delay can be considered only if the patient is deemed to be 
deriving obvious clinical benefit per the investigator’s best medical judgment and needs to be 
agreed between the investigator and the sponsor.
If a treatment interruption continues beyond Day 21 (for IV) or Day 28 (for SC) of the 
current cycle, then the day when treatment is restarted will be counted as Day 1 of the next 
cycle. 
5.4.6. Dose Reductions
Intra-patient dose reductions are not permitted during the study unless it has been agreed 
upon following discussions with the sponsor.  For example, during Part 1, if a patient’s 
current dose level is deemed beyond the determined MTD. 
Subcutaneous doses may be de-escalated to 150 mg if the toxicity boundary is exceeded by 
the mTPI approach in Part 1.  Intra-patient dose reductions may also occur upon discussion 
with the sponsor.
5.5. Investigational Product Storage
The investigator, or an approved representative, eg, pharmacist will ensure that all 
investigational products are stored in a secured area with controlled access under required 
storage conditions and in accordance with applicable regulatory requirements.
Investigational product should be stored in its original container and in accordance with the 
label.  See the Product Specific Investigation Product Manual for storage conditions of the 
product once reconstituted and/or diluted.
Storage conditions stated in the single reference safety document (ie, Investigator’s
Brochure) will be superseded by the storage conditions stated in the labeling. 


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Site systems must be capable of measuring and documenting (eg, via a log), at a minimum, 
daily minimum and maximum temperatures for all site storage locations (as applicable, 
including frozen, refrigerated, and/or room temperature products).  This should be captured 
from the time of investigational product receipt throughout the study.  Even for continuous 
monitoring systems, a log or site procedure that ensures active daily evaluation for 
excursions should be documented.  The operation of the temperature monitoring device and 
storage unit (eg, refrigerator), as applicable, should be regularly inspected to ensure it is 
maintained in working order. 
Any excursions from the product label storage conditions should be reported upon discovery.  
The site should actively pursue options for returning the product to the storage conditions as 
described in the labeling, as soon as possible.  Deviations from the storage requirements, 
including any actions taken, must be documented and reported to the sponsor.
Once an excursion is identified, the investigational product must be quarantined and not used 
until the sponsor provides documentation of permission to use the investigational product. It 
will not be considered a protocol deviation if the sponsor approves the use of the 
investigational product after the temperature excursion.  Use of the investigational product 
prior to sponsor approval will be considered a protocol deviation.
Specific details regarding information the site should report for each excursion will be 
provided to the site.
Receipt of materials, door opening and closing, and other routine handling operations where 
the product is briefly out of the temperature range described in the labeling are not 
considered excursions.  More specific details will be provided to the sites separately.
5.6. Investigational Product Accountability
The investigator’s site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies. 
To ensure adequate records, all PF-06801591 will be accounted for in the CRF and drug 
accountability inventory forms as instructed by Pfizer.  Unless otherwise authorized by 
Pfizer, at the end of the clinical trial all drug supplies unallocated or unused must be returned 
to Pfizer or its appointed agent (eg, a contract research organization [CRO]). 
Under no circumstances should the investigator or other site personnel supply study drug to 
other investigators, patients, or clinics, or allow supplies to be used other than directed by 
this protocol without prior authorization from Pfizer.
5.6.1. Destruction of Investigational Product Supplies 
The sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site). If destruction is authorized to take place at the study site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer, and all destruction must be adequately documented.


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5.7. Concomitant Treatment(s)
Concomitant treatment considered necessary for the patient’s wellbeing may be given at 
discretion of the treating physician.
All concomitant treatments, blood products, and saline infusions, as well as non-drug 
interventions (eg, analgesic use for paracentesis) received by patients from screening until 
the end of study visit will be recorded on the CRF including the name of the procedure or 
medication, route and duration of treatment, and reason (eg, AE)).
For South Korea only, patients should not have vaccinations except an inactivated vaccine 
within 4 weeks prior to the enrollment on the study or during the study.
5.7.1. Other Anti-tumor/Anti-cancer or Experimental Drugs
Additional anticancer treatment including chemotherapy, hormonal therapy, radiotherapy
(with the exception of palliative radiation as described in Section 5.7.8), or experimental 
anticancer medications are not permitted while patients are receiving study treatment.  
Additionally, the concurrent use of herbal supplements for an anti-cancer treatment is not 
permitted. 
5.7.2. Supportive Care 
Palliative and supportive care for disease related symptoms may be administered at the 
investigator’s discretion and according to any available American Society of Clinical 
Oncology (ASCO) guidelines. 
5.7.3. Hematopoietic Growth Factors
Primary prophylactic use of granulocyte-colony stimulating factors is not permitted during 
Cycle 1, but may be used to treat treatment emergent neutropenia as indicated by the current 
ASCO guidelines.54
Erythropoietin may be used at the investigator’s discretion for the supportive treatment of 
anemia. 
5.7.4. Anti-Diarrhea, Anti Emetic Therapy
Primary prophylaxis of diarrhea, nausea, and vomiting is permitted in the first cycle.  
Primary prophylaxis in subsequent cycles is at the investigator’s discretion.  The choice of 
the prophylactic drug is up to the investigator with sponsor approval and assuming the drug 
is not included in the Concomitant Treatment(s) section, as well as the duration of treatment, 
assuming there is no known or expected drug-drug interaction.  If so, then it must be 
approved by the sponsor.


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5.7.5. Anti-inflammatory and Narcotic Therapy
Anti-inflammatory or narcotic analgesic may be offered as needed assuming there is no 
known or expected drug-drug interaction and assuming the drug is not included in the 
Concomitant Treatment(s) section. Narcotic analgesic may hide colonic perforation in case 
of colitis and should be used with caution. Anti-TNF drugs are contraindicated in case of 
perforation, sepsis, or liver insufficiency.
5.7.6. Corticosteroids
Chronic, systemic corticosteroid use (prednisone >10 mg/day or equivalents) for palliative or 
supportive purpose is not permitted.  Acute emergency and short-term administration, topical 
applications, inhaled sprays, eye drops, or local injections of corticosteroids are allowed.  If 
immune related AEs occur, immune suppressive treatment should be administered according 
to local standards or practice.
5.7.7. Surgery
Caution is advised on theoretical grounds for any surgical procedures during the study.  The 
appropriate interval of time between surgery and PF-06801591 required to minimize the risk 
of impaired wound healing and bleeding has not been determined.  Stopping PF-06801591 is 
recommended at least 7 days prior to surgery.  Postoperatively, the decision to reinitiate 
PF-06801591 treatment should be based on a clinical assessment of satisfactory wound 
healing and recovery from surgery.
5.7.8. Radiation Therapy
Palliative radiotherapy to a limited field is allowed after consultation with Pfizer’s medical 
monitor at any time during study participation, including during screening, unless clearly 
indicative of disease progression. 
6. STUDY PROCEDURES
6.1. Screening
For screening procedures see Schedule Of Activities and Section 7 assessments.
All patients will be screened within 28 days prior to study entry to confirm that they meet the 
patient selection criteria for the study.
For all patients being considered for the study and eligible for screening, informed consent 
must be obtained prior to any study-specific procedures.  The investigator (or appropriate 
delegate at the site) will obtain signed and dated informed consent from each patient in 
accordance with the procedures described in the Schedule Of Activities and Section 12.3.  A 
patient identification number will be assigned. 


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The required screening assessments, including tumor history, medical history (including 
baseline signs and symptoms) and laboratory tests are summarized in the Schedule Of 
Activities and Section 7.  Following completion of the screening assessments and 
confirmation of eligibility, patients may be enrolled.
6.2. Study Period
For treatment period procedures, see Schedule Of Activities and Section 7 Assessments.
6.3. One Month Follow-up Visit
For follow-up procedures see Schedule Of Activities and Section 7 Assessments.
At least 28 days and no more than 35 days after discontinuation of treatment, patients will 
return to undergo the assessments outlined in the Schedule Of Activities as well as a review 
of concomitant medications, vital signs, and assessment for resolution of any treatment 
related toxicity.  Patients continuing to experience toxicity at this point following 
discontinuation of treatment will continue to be followed at least every 4 weeks until 
resolution or determination, in the clinical judgment of the investigator, that no further 
improvement is expected.
In the event a patient is unable to return to the clinic for the follow-up visit, telephone contact 
with the patient to assess AEs and concomitant medications and treatment is expected.  If 
laboratory assessments are needed to follow-up unresolved AEs, retrieval of assessments 
performed at an institution local to the patient is acceptable.
6.4. Follow-up for Late Immune-related Adverse Events
Patients will undergo telephone follow-ups at 90 and 120 day (7 days) after the last dose of 
study drug to assess potential late irAEs.  If any concern arises, patient will be called in for 
an inpatient follow up visit within 5 calendar days of initial phone call.  For this inpatient 
follow-up visit, the Schedule Of Activities will be similar to the 1-month follow-up visit 
completed after EOT. 
Patients continuing to experience late immune-related toxicity at this point (up to 120 days 
after last dose of study drug) 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.
6.5. Survival Follow-up
To collect OS data, patients will be contacted by telephone every 8 weeks (7 days) post 
120 day follow up visit, until end of the trial (2 years after last patient first dose).  If the 
patient is seen in the clinic during the window of time that a scheduled telephone call is to be 
made to collect survival data, then the clinic visit may replace the survival telephone call.  
After the completion of the EOT visit subsequent anti-cancer therapy will be documented 
and recorded for patients who discontinue investigational products and continue in 120 day 
safety follow-up, and subsequently during survival follow-up.


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6.6. Patient Withdrawal
The reason for a patient’s discontinuation from treatment will be documented in the end of 
study/withdrawal CRF.  Patients will be followed for at least 120 days after the last dose of 
study drug for AEs.
Patients may withdraw from treatment at any time at their own request, or they may be 
withdrawn at the discretion of the investigator or sponsor for safety or behavioral reasons, or 
the inability of the patient to comply with the protocol-required schedule of study visits or 
procedures at a given study site. 
Reasons for withdrawal of study treatment may include:

Objective disease progression;*

Global deterioration of health status requiring discontinuation;

Unacceptable toxicity;

Pregnancy;

Significant protocol violation;

Lost to follow-up;

Patient refused further treatment;

Study terminated by sponsor;

Death.
*In the case of radiological progression but in the absence of clinical deterioration, if 
investigator deems it to be in the patient’s best interests, the patient will be allowed to stay on 
study.
Reasons for withdrawal from study follow-up may include:

Completed study follow-up;

Study terminated by sponsor;

Lost to follow-up;

Refused further follow-up;

Death.


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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 enquire 
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.
All reasonable efforts must be made to locate patients to determine and report their ongoing 
status. This includes follow-up with persons authorized by the patient as noted above. Lost 
to follow-up is defined by the inability to reach the patient after a minimum of 2 documented 
phone calls, faxes, or e-mails as well as lack of response by the patient to 1 registered mail 
letter. All attempts should be documented in the patient’s medical records. If it is 
determined that the patient has died, the site will use permissible local methods to obtain the 
date and cause of death. If the investigator’s use of a third-party representative to assist in 
the follow-up portion of the study has been included in the patient’s informed consent, then 
the investigator may use a sponsor-retained third-party representative to assist site staff with 
obtaining the patient’s contact information or other public vital status data necessary to 
complete the follow-up portion of the study. The site staff and representative will consult 
publicly available sources, such as public health registries and databases, in order to obtain 
updated contact information.  If, after all attempts, the patient remains lost to follow-up, then 
the last-known-alive date as determined by the investigator should be reported and 
documented in the patient’s medical records.
If the patient refuses further visits, the patient should continue to be followed for survival 
unless the patient withdraws consent for disclosure of future information or for further 
contact.  In this case, no further study specific evaluations should be performed, and no 
additional data should be collected.  The sponsor may retain and continue to use any data 
collected before such withdrawal of consent.
7. ASSESSMENTS
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances, outside of the control of the investigator 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, as soon as possible, the reason and any corrective and preventive 
actions taken to ensure that normal processes are adhered to.  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, 12-lead ECG, local site injection tolerability assessment (SC administration 
cohort only), laboratory assessments, including pregnancy tests and verification of 
concomitant treatments.


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7.1.1. Pregnancy Testing or Postmenopausal Status
For female patients of childbearing potential, a serum or urine pregnancy test, with 
sensitivity of at least 25 mIU/mL and assayed in a certified laboratory will be performed on 
2 occasions prior to starting study treatment: once at the start of screening and once at the 
baseline visit immediately before investigational product administration.  Following a 
negative pregnancy test result at screening, appropriate contraception must be commenced 
and another negative pregnancy test 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 treatment, at 
the 28-day Follow-Up visit, and additionally whenever 1 menstrual cycle is missed or when 
potential pregnancy is otherwise suspected.  In the case of a positive human chorionic 
gonadotropin test, the patient will be withdrawn from treatment but may remain in the study. 
If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy 
test is required. In such cases, the participant must be excluded if the serum pregnancy is 
positive. Additional pregnancy tests may also be undertaken if requested by Investigational 
Review Boards/Ethics Committees (IRBs/ECs) or if required by local regulations. In Poland
only, pregnancy tests should be performed after end of treatment on days 28, 60, 90, 120 and 
150. Pregnancy tests on days 60, 90, 120 and 150 may be collected at home by the patient.  
For female patients who achieved postmenopausal status and have not experienced their 
menses since at least 12 consecutive month, a serum FSH test must be conducted at screening 
only, in order to confirm a FSH level within the laboratory’s reference ranges for post 
menopause.
7.1.2. Adverse Events
Assessment of AEs will include the type, incidence, severity (graded by NCI CTCAE version 
4.03) timing, seriousness, and relatedness.
Adverse events that occur during the study, after the patient receives the first dose, will be 
recorded on the AE CRF page.
7.1.3. Laboratory Safety Assessment
Hematology and blood chemistry will be drawn at the time points described in the Schedule 
Of Activities and analyzed at local laboratories.
Hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), hepatitis C 
antibody (HCV Ab), and HIV serology testing should be conducted at screening.  Other tests 
may be conducted per standard practice to confirm an active hepatitis or HIV infection.


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All laboratory safety assessments conducted on Cycle 1 Day 1 (C1D1) must be completed 
prior to dosing. If baseline assessments are performed within 72 hours prior to C1D1, there 
is no need to repeat assessments on C1D1.  Assessments performed on 
Cycle 2 Day 1 (C2D1) and each subsequent cycle should be performed within 48 hours prior 
to dosing.  Investigators may have additional blood tests performed for the purpose of 
planning treatment administration, dose modification, or following AEs.  Day 1 safety 
laboratory test results need to be reviewed by the investigator prior to dosing at the beginning 
of each cycle for dosing confirmation and administration rate.
In addition, a serum sample will be collected at pre-dose C1D1.  This sample will be utilized 
as a baseline sample for cytokine measurement should cytokine release syndrome occurs.
Optional samples for cytokine analysis will be collected throughout the study, as clinically 
indicated.


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Table 4.
Laboratory Tests
Hematology
Chemistry
Coagulation
Serology
Immunology
Urinalysisa
Pregnancy Test or 
Postmeno-pausal
Status
Hematocrit
ALT
INR/PT
HBsAg, 
HBcAbb
CRP or HsCRP
(Part 1 only)
Urine dipstick 
for urine 
protein: If 
positive,
collect a spot 
urine to 
calculate 
UPCR or 
collect 24-hr 
and 
microscopic 
(Reflex 
Testing).
For female patients 
of childbearing 
potential, serum or 
urine test 
(sensitivity 
25 mIU/mL);
For female
postmenopausal 
patients who have 
not experienced 
their menses for at 
least 12 consecutive 
months. Serum FSH 
test at screening 
only, to confirm 
post menopause.
Hemoglobin
AST
aPTT or 
PTT
HCV Abb
TBNK (whole 
blood, Part 1 
only)
lactate 
dehydrogenase 
(LDH)
HIV 
serology
Cytokine
Platelets
Alkaline 
Phosphatase
WBC
Sodium
Absolute 
Neutrophils
Potassium
Lymphocytes
Magnesium
Urine dipstick 
for urine 
blood: If 
positive twice 
or as 
clinically 
indicated 
perform 
microscopic 
analysis
(Reflex 
Testing).
Monocytes
Chloride
Eosinophils
Total Calcium
Basophils
Total Bilirubinc
CBC
BUN or Urea
Creatinine
Uric Acid
Glucose 
(non-fasted)
Albumin
Phosphorous or 
Phosphate
Lipase
Amylase
TSH + reflex 
free T4 and free 
T3
ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; AST = aspartate aminotransferase; BUN = 
blood urea nitrogen; CBC = complete blood count; CRP = C-reactive protein HBsAg = hepatitis B antigen; FSH = follicle 
stimulating hormone; HBcAb = hepatitis B core antibody; HCV = hepatitis C virus; HIV = human immunodeficiency virus; 
HPV = human papilloma virus; HsCRP = high sensitivity C-reactive protein; INR = international normalized ratio; partial 
thromboplastin time = PTT; T3 = triiodothyronine; T4 = thyroxine; TBNK = T cell/B cell/natural killer cell; TSH = thyroid 
stimulating hormone; UPCR = urine protein to creatinine ratio; WBC = white blood cells;
a.
Dipstick is acceptable to perform urinalysis. Microscopic analyses if clinically indicated (eg, only after the second 
positive dipstick result for heme).  If ≥2+ protein on urine dipstick, then collect spot urine sample to calculate UPCR or 
collect 24hr urine.  
b.
In the case of apparent ongoing HBV or HCV infection, reflex serum viral load testing will be performed.
c.
For potential Hy's Law cases, in addition to repeating AST and ALT, laboratory tests should include albumin, creatine 
kinase, total bilirubin, direct and indirect bilirubin, gamma glutamyl transferase, prothrombin time (PT)/INR, alkaline 
phosphatase, total bile acids, and acetaminophen drug and/or protein adduct levels.


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7.1.4. Vital Signs and Physical Examination
Patients will have a physical examination to include weight, vital signs (temperature, sitting 
BP, sitting pulse rate after 5 minutes of rest, and pulse oximetry at rest and after exertion), 
assessment of ECOG performance status and height (height will be measured at screening
only).
See Schedule Of Activities. Abbreviated PEs should be performed as appropriate at each 
visit where complete PEs are not required.
7.1.5. (12-Lead) Electrocardiogram
Electrocardiogram machines to be utilized in this study will be supplied by a third party 
vendor. 
At screening, a single 12-lead ECG tracing (with a 10-second rhythm strip) will be obtained.
For Cycle 1 Day 1 and all subsequent specified time points (see Schedule Of Activities), 
triplicate 12-lead ECG tracings (with a 10-second rhythm strip) will be obtained.
Generally, baseline and all corresponding time point ECGs should not be collected within 
3 hours after food or beverage consumption and should be performed after the patient has 
rested quietly for at least 10 minutes in a supine position. All 12 lead ECGs should be 
confirmed by a qualified person at the institution and will be reviewed by a central 
laboratory.  ECGs on Day 1 of each cycle will be collected prior to dosing, and at the end of 
infusion or SC injection (approximately 1 hour) following administration of each dose of 
PF 06801591.  When the timing of these measurements coincides with a blood collection, the 
ECG should be obtained prior to the nominal time of the blood collection, BP, and pulse rate.
When matched with PK sampling, the ECG should preferably 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). 
At each time point (see the Schedule Of Activities and ECG manual), 3 consecutive ECGs 
will be performed at approximately 2 minutes apart to determine the mean QTcF interval; the 
average of the triplicate ECG measurements collected at each pretreatment time point on 
Day 1 of each cycle will serve as each patient’s time-controlled baseline QTc value. If the 
mean QTcF is prolonged (≥45 msec from the pre-dose baseline or is 500 msec), then the 
ECGs should be re-evaluated by a qualified person at the site for confirmation as soon as the 
finding is made, including verification that the machine reading is accurate.  If manual 
reading verifies a QTcF of ≥45 msec from the pre-dose baseline or is 500 msec, immediate 
correction for reversible causes (including electrolyte abnormalities, hypoxia and 
concomitant medications for drugs with the potential to prolong the QTcF interval) should be 
performed.  In addition, repeat ECGs should be immediately performed hourly for at least 
3 hours until the QTcF interval falls below ≥45 msec from the pre-dose baseline or is 
≤500 msec depending on the type of change originally observed.  If QTcF interval reverts to 
less than 45 msec from the pre-dose baseline or is ≤500 msec, and in the judgment of the 


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investigator(s) and sponsor is determined to be due to cause(s) other than investigational 
product, treatment may be continued with regular ECG monitoring.  If in that timeframe the 
QTcF intervals rise above ≥45 msec from the pre-dose baseline or is 500 msec the 
investigational product will be held until the QTcF interval decreases to ≤45 msec from the 
pre-dose baseline or is ≤500 msec, depending on the type of change originally observed. 
Note: If QTc values remain ≥500 msec (or ≥45 msec from the pre-dose baseline) for greater 
than 4 hours (or earlier at the discretion of the investigator); or QTc intervals get 
progressively longer, the patient should undergo continuous ECG monitoring.  A cardiologist 
should be consulted if QTc intervals do not return to less than 500 msec (or to <45 msec 
above the pre-dose baseline) after 8 hours of monitoring (or earlier at the discretion of the 
investigator).
Once the QTcF interval decreases to ≤45 msec from the pre-dose baseline or ≤500 msec,
depending on the type of change originally observed, patients may restart the investigational 
product at the next lowest dose level.  If the QTcF interval has still not decreased to 
≤45 msec from the pre-dose baseline or ≤500 msec after 2 weeks (depending on the type of 
change originally observed), or if at any time a patient has a QTcF interval >515 msec or 
becomes symptomatic, the patient will be removed from the study.  Additional triplicate 
ECGs may be performed as clinically indicated. 
Prior to concluding that an episode of QTcF interval prolongation is due to investigational 
product, thorough consideration should be given to potential precipitating factors (eg, change 
in patient clinical condition, effect of concurrent medication, electrolyte disturbance) and 
possible evaluation by specialist.
If patient experiences a cardiac or neurologic AE (specifically syncope, dizziness, seizures, 
or stroke), triplicate ECGs should be obtained at the time of the event. 
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality.  It is important that leads are placed in the 
same positions each time in order to achieve precise ECG recordings.  If a machine-read QTc 
value is prolonged, as defined above, repeat measurements may not be necessary if a 
qualified physician’s interpretation determines that the QTc values are in the acceptable 
range.
7.1.6. Local Site Injection Tolerability Assessment (SC Only)
Assessments made of the injection sites in the abdominal fat fold to monitor local tolerability 
to PF-068011591 SC injections will be performed for at least 1 hour following study drug 
administration, as per the Schedule Of Activities. If SC injections in the abdominal location 
are not possible, SC injections can be administered in a distributed manner in the thighs. SC 
injections in the upper extremities (eg, deltoid, upper and lower arm) are not permitted.  
Refer to Appendix 9 for more details.


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Site tolerability assessments should continue after each dosing day visit, only if injection site 
pain or injection site reaction (ISR) characteristics continue to persist. The assessments 
should continue at regularly scheduled visits until the symptoms resolve. The injection sites 
will be assessed for erythema, induration, ecchymosis, injection site pain, injection site 
pruritus, or other observed characteristics after study drug dosing. The diameter of the 
affected area will be measured and the condition of the injection site will be recorded on the 
SC Injection Site Assessment CRF.  Any observed abnormality at the injection site will be 
judged by the investigator to determine whether a corresponding AE should be reported. 
ISRs should be immediately photographed in color, with scaled ruler placed by the reaction, 
and these photographs should be included in the patient’s source documentation. When 
appropriate, at the discretion of the investigator, a patient with an ISR may be referred for a 
dermatological consultation and skin biopsy may be obtained for future examination of the 
ISR. The dermatology consultation is expected to take place at the dermatologist’s practice 
location, or may occur within the same institution where this study is conducted.
7.2. Pharmacokinetic Assessments
7.2.1. Blood for PK analysis of PF-06801591
Blood samples (approximate 5 mL) to provide serum for the analysis of 
PF-06801591 concentrations will be collected as outlined in the Schedule Of Activities.  The 
PK sampling schedule may be modified based on emerging PK data.
In addition to samples collected at the scheduled times, an additional blood sample should be 
collected from patients experiencing unexpected and/or serious AE’s and the date and time of 
blood sample collection and of last dosing prior to PK collection documented in the CRF.
All efforts will be made to obtain PK samples at the scheduled nominal time relative to 
dosing.  However, samples obtained within the protocol-specified time window will not be 
captured as a protocol deviation, as long as the exact time of the sample collection is noted 
on the source document and data collection tool (eg, CRF).  If a scheduled blood sample 
collection cannot be completed for any reason, the missed sample time may be re-scheduled 
with agreement of the clinical investigator, patient, and sponsor.
Sample for PK analysis will be assayed for PF-06801591 using a validated analytical method 
in compliance with Pfizer standard operating procedures.  To increase the understanding of 
the PK of PF-06801591, samples may be used for the evaluation of the bioanalytical method 
These data will not be included in the clinical 
study report. Details regarding the collection, processing, storage, and shipping of the blood 
samples will be provided in the study manual.
7.3. Biomarker and Pharmacodynamic Assessments
Biopsies and tissue samples (including but not limited to tumor, peripheral blood, and 
plasma) will be collected before and after PF-06801591 dosing for biomarker evaluation and 
pharmacodynamic assessments.
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Archived Biopsy Samples
All patients are required to provide an archival tissue sample at screening, or agree to a de 
novo tissue sample collection per institutional procedural standards. In Part 2, Patients must 
provide FFPE tissue from the most recent primary or metastatic tumor biopsy or resection 
prior to study entry, taken within 2 years of start of study treatment. 
Fresh Biopsy Samples
Fresh tumor biopsies are optional (within 28 days of first dose) for the first 2 to 4 patients in 
Part 1A at each dose level and in Part 2 if adequate archival tissue is provided at baseline, but
fresh biopsies are mandatory in Part 1B at screening (within 28 days of first study treatment 
dose) and on-treatment (on Cycle 2 Day 8 ±5 days).  Optional biopsies are encouraged at 
disease progression and/or end of treatment (assuming available tumor to biopsy) and as 
clinically indicated throughout treatment for all patients.  If biopsy is to be completed the 
same day as CT scan, it must be completed after the CT scan.  
Blood and plasma will be collected at the time points specified in the Schedule Of Activities.
  
 
 
PD-1 RO on T-cell subsets will be 
evaluated in whole blood by flow cytometry in Part 1 only. 
  
The primary objective of these analyses will be to confirm target occupancy,
 
Table 5 summarizes representative assays to be used and the source of the samples.  Refer to 
the SCHEDULE OF ACTIVITIES for details pertaining to specific days of sample collection 
and to the Lab Manual for details of sample preparation, storage, and shipment.
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Table 5.
Sampling and Assays for Biomarkers
Biomarker
Matrix
Assay
PD-1 Receptor Occupancy     
(Part 1 Only)
Whole Blood
Flow Cytometry
7.4. Tumor Response Assessments
Tumor assessments will include all known or suspected disease sites.  Radiographic 
assessments obtained per the patient’s standard of care prior to enrollment into the study do 
not need to be repeated and are acceptable to be used as baseline evaluation, if, (1) obtained 
within 28 days before C1D1, (2) performed using the method requirements (ie, RECIST v. 
1.1 ), (3) the same technique/modality can be used to follow identified lesions throughout the 
trial for a given patient, and (4) appropriate documentation indicating that these radiographic 
tumor assessments were performed as standard of care is available in the patient’s source 
notes. Radiographic images may potentially be collected for central review.
Acceptable imaging may include CT, MRI (with contrast at minimum) of the chest, abdomen 
and pelvis, or other radiographic disease sites as clinically indicated. Brain MRI or CT scans 
will be performed at baseline and on-study for patients with known or suspected brain 
metastases or if disease is suspected or has been previously documented as appropriate to 
follow disease.  Baseline central nervous system (CNS) imaging is not required with the 
exception of symptomatic patients to rule out CNS metastases.  FDG-PET may be performed 
for further characterization of tumors, but any CT scans performed concurrently with PET 
must be of diagnostic quality with contrast in order to be used for tumor assessments. Bone 
scans should be performed at baseline and on-study for patients with known or suspected 
bone metastases not well-visualized on other imaging or if disease is suspected or has been 
previously documented as appropriate to follow disease. 
The same imaging technique used to characterize each identified and reported lesion at 
baseline will be employed in the following tumor assessments whenever possible.
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Anti-tumor activity will be assessed through radiological tumor assessments conducted at 
baseline, during treatment as specified in the Schedule Of Activities, whenever disease 
progression is suspected (eg, symptomatic deterioration), and at the time of withdrawal from 
treatment, if not done in the previous 3 weeks, after end of treatment for patients who did not 
end treatment due to disease progression, death, or withdrawal of consent, a tumor 
assessment will be performed every 12 weeks until disease progression by irRECIST,
initiation of a new anti-cancer treatment, or end of trial (2 years after LPFD, see
Section 13.2), whichever is first. Note: If a patient is classified as having PD during an on-
treatment tumor assessment, then confirmation of PD by a second scan in the absence of 
rapid clinical deterioration is required per irRECIST.
CT or MRI scans to be done every 6 weeks (5 days) for patients on IV administration
portion and every 8 weeks (5 days) for Parts 1 and 2 SC administration portion from the 
start of study entry (defined as C1D1) until disease progression by immune-related RECIST 
(irRECIST), death, withdraw consent, or subsequent administration of an anti-chemotherapy 
agent.  CT or MRI scans may be assessed every 12 weeks (±5 days) for patients who 1) have 
remained on treatment for ≥24 weeks, and 2) have no confirmed progression by irRECIST 
within the last 6 months, and 3) have demonstrated stability of disease. Tumor assessments 
should be fixed according to the calendar, regardless of treatment delays.  
Confirmation of response (complete response [CR]/partial response [PR]) with a second 
consecutive scan at least 4 weeks later is preferred.  Tumor assessments should be repeated at
the End of Treatment visit if more than 6 weeks (IV) or 8 weeks (SC) have passed since the 
last evaluation.  CT or MRI scans should be completed before tumor biopsy samples are 
collected.  If a patient is classified as having progressive disease (PD) at a post-baseline 
tumor assessment, then confirmation of PD by a second consecutive scan at least 4 weeks 
later in the absence of rapid clinical deterioration is required.  After End of Treatment for 
patients who did not end treatment due to disease progression, death, or withdrawal of 
consent, a tumor assessment will be performed every 12 weeks (1 week), until disease 
progression by irRECIST, or initiation of a new anti-cancer treatment, or end of trial (2 years 
after LPFD, see Section 13.2), whichever is first.
If imaging is used in disease assessment, the same imaging technique used to characterize 
each identified and reported lesion at baseline will be employed in post-baseline disease 
assessments whenever possible.
Disease response assessments will be based upon disease-specific response criteria: RECIST 
v 1.1 (Appendix 3) and irRECIST (Appendix 4).
7.5. CA-125 Tumor Marker Assessment (Ovarian Cancer Only)
Serum CA-125 is the standard for tumor markers in the evaluation of pelvic masses, 
particularly epithelial ovarian cancers. During treatment for ovarian cancer, CA-125 is a 
helpful indicator of disease activity and can be used to follow response to therapy and detect 
an early recurrence.55,56 The first measurement for CA-125 must be collected within 2 weeks 
before treatment is started, during the screening period.  Subsequent CA-125 levels will be 
measured on Day 1 of each cycle before treatment, at End of Treatment, and at Follow-up 


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visit 28 days after last dose administration.  There is no need to repeat on C1D1, if the 
baseline (screening) assessment was performed within 72 hours prior to that day.
7.6. Immunogenicity Evaluations
Blood samples (approximately 10 mL) to provide serum for detection of anti-drug antibody
(ADA) and neutralizing antibodies (Nab) against PF-06801591 will be collected into 
appropriately labeled tubes at times specified in the Schedule Of Activities.  Additional 
instructions for sample collection, processing, storage, and shipping will be provided in the 
lab manual. A companion blood sample for the determination of PF-06801591 concentration 
will be collected in conjunction with the ADA sample collection to facilitate immunogenicity 
assessment.
The ADA samples will be analyzed using a validated assay in compliance with Pfizer 
standard operating procedures.  The sample analysis will follow a tiered approach of 
screening, confirmation, and titer determination.  Samples tested positive for ADA will be 
further analyzed for NAb using a validated assay in compliance with Pfizer standard 
operating procedures. 
As part of understanding the immunogenicity of the study drug, samples may be used for 
additional characterization of an observed immunogenicity response and/or evaluation of the 
bioanalytical method.  These data 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.
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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 will be reported as described in the following 
sections. 
For all AEs, the investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as an SAE 
requiring immediate notification to Pfizer or its designated representative.  For all AEs, 
sufficient information should be obtained by the investigator to determine the causality of the 
AE.  The investigator is required to assess causality.  For adverse events that the investigator 
deems immune-related, that specific causality and whether an immunosuppressive therapy 
(eg, corticosteroids, other immunosuppressant drugs) is indicated, will be recorded on the 
CRF.  For any adverse event, regardless of investigator determined causality, if the 
management requires administration of an immunosuppressive therapy, the use will be 
documented on a specific case report form that will record generic drug name, stop and start 
dates (duration), dose, units, route, frequency of administration, and response to medication.
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 150 calendar days after the last 
administration of the investigational product or until administration of subsequent anti-cancer 
therapy whichever comes first.  Death must be reported as an SAE if it occurs within 
150 calendar days after last administration of the investigational product, irrespective of any 
intervening treatment. SAEs occurring to a patient after the active reporting period has ended 
should be reported to the sponsor if the investigator becomes aware of them.  At a minimum, 
all SAEs that the investigator believes have at least a reasonable possibility of being related 
to investigational product are to be reported to the sponsor.
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If an SAE occurs after informed consent is signed and before study drug is administered, this 
information will be reported on an SAE Form and will be recorded in the safety database.
AEs (serious and non-serious) should be recorded on the CRF from the time the patient has 
taken at least 1 dose of investigational product through the patient’s last visit.  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.  Additional, immune-related AEs 
will be collected with a follow-up phone call at 90 and 120 days after last dose administration 
date to collect post-treatment related AE information.
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.  
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;


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
Medication error;

Occupational exposure;

Worsening of signs and symptoms of the malignancy under study should be reported 
as AEs in the appropriate section of the CRF.  Disease progression assessed by 
measurement of malignant lesions on radiographs or other methods should not be 
reported as AEs.
8.4. Medication Errors
Medication errors may result, in this study, from the administration or consumption of the 
wrong product, by the wrong patient, at the wrong time, or at the wrong dosage strength.  
Such medication errors occurring to a study participant are to be captured on the medication 
error CRF, which is a specific version of the AE page, and on the SAE form when 
appropriate.  In the event of medication dosing error, the sponsor should be notified 
immediately.
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:

Medication errors involving patient exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating patient.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is captured on the medication error version of the AE page 
and, if applicable, any associated AEs are captured on an AE CRF page. 
8.5. Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be reported as 
an AE are as follows: 

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 AE by the investigator or sponsor.


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Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
reporting as an AE.
8.6. Serious Adverse Events
An 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 an SAE unless the outcome is fatal within the 
safety reporting period.  Hospitalization due to signs and symptoms of disease 
progression should not be reported as an SAE.  If the malignancy has a fatal outcome 
during the study or within the safety reporting period, then the event leading to death 
must be recorded as an AE and as an SAE with CTCAE Grade 5 (see the section on 
Severity Assessment).
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the patient or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.
8.6.1. Protocol-Specified Serious Adverse Events
There are no protocol-specified SAEs in this study.  All SAEs will be reported by the 
investigator as described in previous sections and will be handled as SAEs in the safety 
database (see the section on Serious Adverse Event Reporting Requirements).
8.6.2. Potential Cases of Drug-Induced Liver Injury 
Abnormal values of AST and/or ALT levels concurrent with abnormal elevations in total 
bilirubin level that meet the criteria outlined below in the absence of other causes of liver 


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injury are considered potential cases of drug-induced liver injury (potential Hy’s law cases) 
and should always be considered important medical events. 
The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the patient’s individual baseline values and underlying conditions.  Patients who 
present with the following laboratory abnormalities should be evaluated further to 
definitively determine the etiology of the abnormal laboratory values:

Patients with AST or ALT and total bilirubin baseline values within the normal range 
who subsequently present with AST or ALT values ≥3 X ULN concurrent with a total 
bilirubin value ≥2 × ULN with no evidence of hemolysis and an alkaline phosphatase 
value ≤2 × ULN or not available.

For patients with pre-existing ALT OR AST OR total bilirubin values above the 
ULN, the following threshold values should be used in the definition mentioned 
above:

For patients with pre-existing AST or ALT baseline values above the normal 
range, AST or ALT value ≥2 times the baseline values and ≥3 × ULN, or 
≥8 × ULN (whichever is smaller).
Concurrent with:

For patients with pre-existing values of total bilirubin above the normal range: Total 
bilirubin level increased from baseline by an amount of at least 1 × ULN or if the 
value reaches ≥3 × ULN (whichever is smaller).
The patient should return to the investigational site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment.  The possibility of hepatic 
neoplasia (primary or secondary) should be considered. 
In addition to repeating measurements of AST and ALT, laboratory tests should include 
albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, gamma-glutamyl 
transferase, PT/INR, and alkaline phosphatase.  A detailed history, including relevant 
information, such as review of ethanol, acetaminophen, recreational drug, and supplement 
consumption, family history, occupational exposure, sexual history, travel history, history of 
contact with a jaundiced person, surgery, blood transfusion, history of liver or allergic 
disease, and work exposure, should be collected.  Further testing for acute hepatitis A, B, or 
C infection and liver imaging (eg, biliary tract) may be warranted.  All cases confirmed on 
repeat testing as meeting the laboratory criteria defined above, with no other cause for LFT 
abnormalities identified at the time, should be considered potential Hy’s law cases 
irrespective of availability of all the results of the investigations performed to determine 
etiology of the abnormal LFTs.  Such potential Hy’s law cases should be reported as SAEs.


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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 of an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit should be assessed for medical 
importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same-day surgeries (as outpatient/same day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
AE is not in itself an SAE.  Examples include: 

Admission for treatment of a pre-existing condition not associated with the 
development of a new AE or with a worsening of the pre-existing condition (eg, for 
workup of persistent pre-treatment laboratory abnormality);

Social admission (eg, patient has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual patient;

Admission exclusively for the administration of blood products.


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Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as AEs.  However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE.  For example, an acute appendicitis 
that begins during the AE reporting period should be reported as the AE, and the resulting 
appendectomy should be recorded as treatment of the AE.
8.8. Severity Assessment
Adverse events will be assessed in accordance with NCI CTCAE version 4.03, see Table 6.
Table 6.
CTCAE Criteria for Adverse Events
Grade
Clinical Description of Severity
0
No Change from normal or reference range (This grade is not included in the 
Version 4.03 CTCAE document but may be used in certain circumstances.)
1
MILD adverse event
2
MODERATE adverse event
3
SEVERE adverse event
4
LIFE-THREATENING consequences; urgent intervention indicated
5
DEATH RELATED TO adverse event
CTCAE = Common Terminology Criteria for Adverse Events
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
the patient’s usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs listed above.
8.9. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious); the investigator must record the causal relationship in the CRF, as appropriate, 
and report such an assessment in accordance with the SAE reporting requirements if 
applicable. An investigator’s causality assessment is the determination of whether there 
exists a reasonable possibility that the investigational product caused or contributed to an 
AE; generally the facts (evidence) or arguments to suggest a causal relationship should be 
provided.  If the investigator does not know whether or not the investigational product caused 
the event, then the event will be handled as “related to investigational product” for reporting 
purposes, as defined by the sponsor (see the section on Reporting Requirements).  If the 
investigator's causality assessment is “unknown but not related to investigational product,”
this should be clearly documented on study records.  In addition, if the investigator 
determines that an SAE is associated with study procedures, the investigator must record this 
causal relationship in the source documents and CRF, as appropriate, and report such an 
assessment in accordance with the SAE reporting requirements, if applicable.


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


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Additional information about pregnancy outcomes that are reported as SAEs follows: 

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the investigational product.
Additional information regarding the EDP may be requested by the investigator.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays).  In the case of paternal exposure, the 
investigator will provide the study patient with the Pregnant Partner Release of Information 
Form to deliver to his partner.  The investigator must document in the source documents that 
the patient was given the Pregnant Partner Release of Information Form to provide to his 
partner.
8.11. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to the drug safety unit within 24 hours of the 
investigator’s awareness, using the SAE report form, regardless of whether there is an 
associated AE/SAE.  Since the information does not pertain to a patient enrolled in the study, 
the information is not reported on a CRF; however, a copy of the completed SAE report form 
is maintained in the investigator site file.
8.12. Withdrawal Due to Adverse Events (See Also the Section 6.6 Patient Withdrawal)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted earlier, and recorded on the appropriate AE CRF 
page.
When a patient withdraws because of an SAE, the SAE must be reported in accordance with 
the reporting requirements defined below.
8.13. Eliciting Adverse Event Information
The investigator is to report all directly observed AEs and all AEs spontaneously reported by 
the study patient.  In addition, each study patient will be questioned about AEs.
8.14. Reporting Requirements
Each AE is to be assessed to determine if it meets the criteria for SAEs.  If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate.


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8.14.1. Serious Adverse Event Reporting Requirements
If an SAE occurs, Pfizer is to be notified within 24 hours of investigator awareness of the 
event.  In particular, if the SAE is fatal or life-threatening, notification to Pfizer must be 
made immediately, irrespective of the extent of available AE information.  This time frame 
also applies to additional new information (follow-up) on previously forwarded SAE reports 
as well as to the initial and follow-up reporting of EDP, exposure via breastfeeding, and 
occupational exposure cases. 
In the rare event that the investigator does not become aware of the occurrence of an SAE 
immediately (eg, if an outpatient study patient initially seeks treatment elsewhere), the 
investigator is to report the event within 24 hours after learning of it and document the time 
of his or her first awareness of the AE.
For all SAEs, the investigator is obligated to pursue and provide information to Pfizer in 
accordance with the time frames for reporting specified above.  In addition, an investigator 
may be requested by Pfizer to obtain specific additional follow-up information in an 
expedited fashion.  This information collected for SAEs is more detailed than that captured 
on the AE CRF.  In general, this will include a description of the AE in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality.  Information on other possible causes of the event, such as concomitant 
medications, vaccines, and/or illnesses, must be provided.  In the case of a patient death, a 
summary of available autopsy findings must be submitted as soon as possible to Pfizer or its 
designated representative. 
8.14.2. Non-Serious Adverse Event Reporting Requirements
All AEs will be reported on the AE page(s) of the CRF.  It should be noted that the form for 
collection of SAE information is not the same as the AE CRF.  Where the same data are 
collected, the forms must be completed in a consistent manner.  For example, the same AE 
term should be used on both forms.  AEs should be reported using concise medical 
terminology on the CRFs as well as on the form for collection of SAE information.
8.14.3. Medical Device Complaint Reporting Requirements
Not applicable.
8.14.4. Sponsor’s Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in a statistical analysis plan (SAP), which will be maintained by the 
sponsor.  This document may modify the plans outlined in the protocol; however, any major 
modifications of the primary endpoint definition and/or its analysis will also be reflected in a 
protocol amendment.


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9.1. Analysis Sets 
9.1.1. Safety Analysis Set
The safety analysis set includes all enrolled patients who receive at least one dose of study 
treatment.
9.1.2. Full Analysis Set
The full analysis set includes all enrolled patients.
9.1.3. Per-protocol Analysis Set (evaluable for MTD)
The per protocol analysis set includes all enrolled patients who received at least one dose of 
study treatment and who did not have major treatment deviations during the Cycle 1.  For the 
IV administration of PF-06801591, patients with major treatment deviations in the 21-day 
DLT observation period are not evaluable for the MTD assessment and will be replaced as 
needed to permit MTD estimation. 
For the SC administration of PF-06801591, patients with major treatment deviations in the 
28-day observation period will not be evaluable for DLT. 
Major treatment deviations include:

Administration of <50% of the planned dose of PF-06801591, provided that the 
reduction is not due to toxicity attributable to PF-06801591.

Administration of >150% of the planned dose of PF-06801591. 
9.1.4. PK Analysis Sets
The PK parameter analysis population is defined as all enrolled patients treated who have 
sufficient information to estimate at least one of the PK parameters of interest.
The PK concentration population is defined as all patients who receive PF-06801591, have 
no protocol deviations affecting the PK assessment, and have at least one post-dose 
concentration measurement.
9.1.5. Biomarker Analysis Set
The biomarker analysis set includes all enrolled patients with at least one of the 
pharmacodynamic/biomarker parameters evaluated at pre- and/or post-dose.
9.1.6. Immunogenicity analysis set
The immunogenicity analysis set is defined as patients who receive at least 1 dose of study 
treatment and have at least 1 ADA or NAb sample collected.


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9.2. Statistical Methods and Properties
A primary study objective is to establish the MTD, defined as the dose that yields 
approximately 27.5% probability of DLT and considers equivalent doses that yield 
probability of DLT in the interval (equivalence interval) 22.5% to 32.5%.  The 27.5% target, 
the symmetry of the equivalence interval and its upper limit <33% were chosen based on 
safety considerations. The prior distribution of DLT is set as a beta (0.5, 0.5), and the 
threshold probability for early termination and dose exclusion is set to 0.95. Doses with an 
incidence of DLT >33% (eg, 4 out of 10) will not be declared the MTD but will be allowed 
by the mTPI method.7
9.2.1. Dose Escalation/De-Escalation and MTD Estimation (Part 1)
Part 1 dose escalation phase of this study employs an mTPI design to estimate the MTD with 
the IV administration of PF-06801591.  The mTPI design employs a simple beta-binomial 
model with prior a conjugated prior beta (0.5, 0.5).  Decision rules are based on calculating 
the unit probability mass (UPM) of 3 intervals corresponding to underdosing, proper dosing, 
and overdosing in terms of dose limiting toxicity. A proper dosing interval is centered at the 
target toxicity rate (pT) of 27.5% with 5% uncertainty (0.225 < pT <0.325).  The under 
dosing interval is (0, 0.225), and the overdosing interval is (0.325, 1).  The 3 dosing intervals 
are associated with 3 different dose escalation decisions.  The underdosing interval 
corresponds to a dose escalation (E), overdosing corresponds to a dose de-escalation, and 
proper-dosing corresponds to staying at the same current dose. Given an interval and a 
probability distribution, the UPM of that interval is defined as the probability of the interval 
divided by the length of the interval. The mTPI design calculates the UPMs for the 3 dosing 
intervals, and the one with the largest UPM implies the corresponding dose-finding decision. 
That decision provides the dose level to be used for future patients. For example, if the 
underdosing interval has the largest UPM, decision E (to escalate) will be executed, and the 
next cohort of patients will be treated at the next-higher dose level.  Under the mTPI design, 
a trial is terminated when either the lowest dose is above the MTD or a pre-specified 
maximum sample size of (for Part 1, n=60) is reached. 
The following table shows the probability of escalating to the next dose level for a range of 
underlying true DLT rates.  For example, for a cohort size of n=3 and for a DLT that occurs 
in 10% of patients, there is a greater than 90% probability of escalating.  Conversely, for a 
DLT that occurs with a rate of 70%, the probability of escalating is 3%.  It is assumed that 
dose escalation occurs with either 0/3 or 1/6 patients with DLTs.
Probability of Escalating Dose
True underlying DLT rate
10%
20%
30%
40%
50%
60%
70%
80%
90%
Probability of escalating dose
0.91
0.71
0.49
0.31
0.17
0.08
0.03
0.009
0.001


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9.2.2. Dose Expansion (Part 2: 300 mg of SC PF-06801591)
Part 2 (N=100) of this study is intended to further characterize the safety, efficacy, PK, PD, 
and immunogenicity profiles of 300 mg of SC PF-06801591 in anti-PD-1 or anti-PD-L1 
treatment naïve patients with NSCLC (N=70) and urothelial carcinoma (N=30) who have 
progressed on or were intolerant to systemic therapy or for whom systemic therapy was 
refused or unavailable.  
Summary statistics will be provided for trough PF-06801591 concentrations, safety 
endpoints, immunogenicity, pharmacodynamic/biomarkers, and efficacy data.
When the first 30 NSCLC patients have been enrolled and have either completed their first 
tumor assessment (at approximately 8 weeks post treatment), or have discontinued from the 
study before their first scheduled tumor assessment, preliminary assessment of safety and 
efficacy data maybe completed.  This preliminary data may provide guidance in the decision 
to the increase or decrease size of each arm, to add other tumor types in a future amendment, 
or to initiate additional clinical studies.
9.3. Sample Size Determination
The exact sample size for the dose escalation design in Part 1 cannot be specified in advance 
due to the dynamic features of mTPI. For the first dose level (0.5 mg/kg IV), in the absence 
of actual DLTs, a total of 2 patients will be enrolled: 2 patients in Part 1A and no patient in 
Part 1B.  For subsequent dose levels it is anticipated that approximately 2 to 4 patients will 
be enrolled in Part 1A and approximately 2 to 5 patients in Part 1B with available pre- and 
on-treatment biopsies for IHC testing and up to 9 patients at dose levels 1, 3, and 10 mg/kg 
administered by IV in Part 1.  A single cohort with SC administration at a dose level of 
300 mg of PF-06801591 will be opened for enrollment shortly after the cohort at a dose level 
of 3 mg/kg IV in Part 1A will have completed enrollment and the 21-day DLT observation 
period. This cohort at a dose level of 300 mg SC will seek 2 to 4 patients in Part 1A, up to 
11 patients in Part 1B with available pre- and on-treatment biopsies for IHC testing, and up 
to 15 patients in Part 1. The actual Part 1 sample size may be smaller, depending on the 
underlying dose toxicity profile, and the number of dose levels studied.
Part 2 of the study will enroll approximately 70 patients with NSCLC who progressed on or 
were intolerant to systemic therapy or for whom systemic therapy was refused or unavailable.  
but are treatment naïve for anti-PD-1 or anti-PD-L1.  NSCLC was selected for historical 
comparability to prior large anti-PD-1 studies and dosing of 300 mg SC in Part 2 has been 
selected based on safety, PK, available biomarker data and preliminary anti-tumor activity 
from Part 1.  There is no hypothesis testing in Part 2.  Estimation approach is used to 
characterize the precision of response data.  The estimation of ORR using N=70 is described 
as follows.  Suppose that the ORR estimate is 19% in Part 2 with N=70, then the 80% and 
90% confidence intervals of the true ORR will be (13.4, 25.2%) and (12.2, 27.3%) 
respectively.  Note that an ORR of 19% was observed in a clinical trial for nivolumab in 
previously treated NSCLC patients. In Part 2, approximately 30 urothelial cancer patients 
will also be enrolled; the sample size is based on clinical considerations of expanding the 
safety database.


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9.4. Efficacy Analysis
In this first-in-patient study, anti-tumor activity is a secondary objective in Part 1 dose 
escalation. Overall response rate (ORR) are primary objectives in Part 2 dose expansion.  
Other efficacy endpoints are secondary objectives in Part 2. 
In Part 1 of the study, tumor response will be presented in the form of patient data listings 
that include, but are not limited to, tumor type, starting dose, tumor response at each visit, 
and best overall response.  In addition, disease progression date, death date, date of first 
response, and last tumor assessment date, and date of last contact will be listed. Summary 
tables may be generated by dose level, if deemed necessary. 
In Part 2 of the study, the following analyses will be performed: 
1. Approximately 8 weeks after the first 30 NSCLC patients have enrolled, a data 
snapshot will be taken for an early data assessment. Descriptive statistics (frequency 
and percentage) for tumor response (CR, PR, PD, stable disease [SD] etc.) from the 
first tumor assessment; ORR, the proportion of patients who achieved unconfirmed 
CR or PR, and the 95% confidence interval for ORR; DCR (disease control rate), the 
proportion of patients who achieved unconfirmed CR or PR or SD, and the 95% 
confidence interval for the DCR will be presented. If tumor response data are 
collected based on both RECIST 1.1 and irRECIST, separate presentations will be 
generated for each response criterion. In this data snapshot, some patients may have 
gone through their second tumor assessment as of the data snapshot, however only 
data through the first tumor assessment will be used for this analysis.  The above 
described analyses may be repeated, if deemed necessary, when the first 40 or 
45 NSCLC patients are enrolled and have gone through their first tumor assessment. 
This preliminary data may provide guidance in the decision to the increase or 
decrease the sample size of each arm, to add other tumor types in a future
amendment, or to initiate additional clinical studies.
2. In the early data assessment, a Bayesian approach will be used to calculate the 
posterior probability that the true ORR is greater than or equal to the minimal 
expected ORR. For example, the minimal expected ORR if all patients received only 
one tumor assessment is approximately 10% but may be adjusted based on how many 
patients had assessments beyond 8 weeks and the PD-L1 status of patients which will 
be tested at baseline.  A beta prior (0.235, 1) is chosen, where the parameter beta is 
set to be 1, and parameter alpha 0.235 was calculated from a reference product 
pembrolizumab on NSCLC patients where a 19% ORR was observed. For example, 
if 4 responders are observed out of the first 30 patients as of the first tumor 
assessments, the posterior probability that the true ORR is greater than a minimal 
expected ORR of 10% is approximately 70%.


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3. When all 70 NSCLC patients and 30 urothelial cancer patients are enrolled and have 
completed their scheduled tumor assessments, another snapshot will be taken. 
Descriptive statistics (frequency and percentage) will be presented for each tumor 
type (NSCLC or urothelial cancer) for the following endpoints:

Tumor response (CR, PR, PD, SD etc.) at each assessment; 

Best overall response up to week 16 (ie, across the first two tumor assessments 
plus the next consecutive tumor assessment when a confirmatory scan is needed); 

Best overall response across all assessments; 

ORR, the proportion of patients who achieved CR or PR, by week 16 and the 95% 
confidence interval for ORR; 

DCR (disease control rate), the proportion of patients who achieved CR or PR or 
SD, by week 16 and the 95% confidence interval for the DCR.  
If tumor response data are collected based on both RECIST 1.1 and irRECIST, 
separate presentations will be generated for each response criterion. 
Time to event data (overall survival [OS], progression-free survival [PFS], time to
response [TTR], time to progression [TTP], DOR, and duration of stable disease
[DOSD]) will be analyzed by the Kaplan-Meier approach for each tumor type. 
The analyses may be separated and performed at two separate time points if the 
70 NSCLC and 30 urothelial cancer patients do not complete enrollment at 
approximately the same time.
4. A final analysis will be performed at the end of the study, which will be 2 years from 
LPFD. 
Detailed analyses for these efficacy endpoints will be described in the Statistical Analysis 
Plan (SAP). 
9.5. Analysis of Pharmacokinetics and Pharmacodynamics
9.5.1. PF-06801591 Pharmacokinetic Analysis
The concentration-time data of PF-06801591 will be summarized by descriptive statistics (n, 
mean, and standard deviation, coefficient of variation, median, minimum, maximum, and 
geometric mean) according to dosing cohort and time for each part of the study.  In addition, 
the concentration-time data from Part 2 will also be summarized by descriptive statistics 
according to tumor type.


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For patients enrolled in Part 1 of the study, the individual concentration-time data of 
PF-06801591 during Cycle 1 and Cycle 4 will be analyzed separately by non-compartmental 
methods to estimate the PK parameters.  The PK parameters estimated will include Cmax, 
Tmax, and AUClast. If data permit or if considered appropriate, t1/2, CL, volume of distribution 
(Vd)/ volume of distribution at steady state (Vss), and accumulation ratio (Rac, when 
feasible) will also be estimated for Cycle 1 and Cycle 4.  The PK parameters will be 
summarized descriptively by dose level and cycle.
Additionally, for Part 1, dose-normalized AUClast and Cmax will be plotted against dose (using 
a logarithmic scale) by cycle.  These plots will include individual patient values and the 
geometric means for each dose.  These plots will be used to help understand the relationship 
between the PK parameters and dose.
For patients enrolled in Part 2 of the study, trough PF-06801591 concentrations will be 
summarized descriptively by cycle and tumor type.
9.5.3. Population Pharmacokinetic Analysis or Pharmacokinetic (PK)/
Pharmacodynamic Modeling 
Pharmacokinetic and pharmacodynamic data from this study may be analyzed using 
modeling approaches and may also be pooled with data from other studies to investigate any 
association between PF-06801591 exposure and biomarkers or significant safety endpoints.  
The results of these analyses, if performed, may be reported separately.
9.6. Safety Analysis
Summaries and analyses of safety parameters will include all patients in the Safety Analysis 
Set.
9.6.1. Analysis of the Primary Endpoint in Part 1
Dose-limiting toxicity is the primary endpoint for Part 1 dose escalation component of the 
study.  The occurrence of DLTs observed in the dosing cohorts will be used to estimate the 
MTD as described in the Section 3.1.  AEs constituting DLTs will be listed per dose level.
CCI


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9.6.2. Analysis of Secondary Safety Endpoints
Adverse Events
Adverse Events as characterized by type, frequency, severity, timing, seriousness, and 
relationship to study therapy PF-06801591 will be tabulated. 
Adverse Events will be graded by the investigator according to the NCI CTCAE 
version 4.03, and coded using the Medical Dictionary for Regulatory Activities.  The focus 
of AE summaries will be on treatment emergent AEs, those with initial onset or increasing in 
severity after the first dose of study treatment.  The number and percentage of patients who 
experienced any AE, SAE, treatment-related AE, and treatment related SAE will be 
summarized according to worst toxicity grades.  The summaries will present AEs both on the 
entire study period and by cycle (Cycle 1 and Cycles beyond 1). 
Laboratory Test Abnormalities
Laboratory abnormalities as characterized by type, frequency, severity (as graded by NCI 
CTCAE version 4.03), and timing will be summarized by treatment group.  Baseline 
corrected QTcF interval at the maximum plasma concentration at steady state at the MTD 
will be tabulated by treatment group. Central assessment of the QTcF interval would be 
considered primary but listings will be produced for the local (study site) assessment as well.
The number and percentage of patients who experienced laboratory test abnormalities will be 
summarized according to worst toxicity grade observed for each laboratory assay.  The 
analyses will summarize laboratory tests both on the entire study period and by cycle 
(Cycle 1 and Cycles beyond 1).  Shift tables will be provided to examine the distribution of 
laboratory toxicities.
For laboratory tests without CTCAE grade definitions, results will be categorized as normal, 
abnormal, or not done. 
9.6.3. Electrocardiogram
The analysis of ECG results will be based on patients in the Safety Analysis Set with baseline 
and on-treatment ECG data.
ECG measurements (an average of the triplicate measurements) will be used for the 
statistical analysis and all data presentations.  Any data obtained from ECGs repeated for 
safety reasons after the nominal time-points will not be averaged along with the preceding 
triplicates.  Interval measurements from repeated ECGs will be included in the outlier 
analysis (categorical analysis) as individual values obtained at unscheduled time points.


PF-06801591
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QT intervals will be corrected
[default correction], Bazett’s,
interval will be calculated usi
Data will be summarized and
study arm and dose.  Individu
study arm time and dose.  Th
for the following analyses of 
conclusions.  Descriptive stat
maximum) will be used to su
baseline in corrected QT afte
and by treatment, the maximu
maximum post-baseline inter
for the maximum change from
interval. 
Shift tables will be provided 
correction methods will be us
provided for ECG abnormalit
Patients experiencing clinical
(including frequency and perc
The effect of drug concentrat
graphically.  Additional conc
be pooled with other study re
models.
Changes from baseline for th
interval, and QRS interval wi
The number (%) of patients w
from baseline in the followin
Safety QTc
Absolute Value
Absolute Change
In addition, the number of pa
be summarized.
August 2018
PFIZER CONFIDENTIAL
Page 135
d for HR (QTc) using standard correction factor
, and possibly a study specific factor, as appropr
ing the Fridericia formula, as follows:
d listed for QT, HR, response rate (RR), PR, QR
ual QT` (all evaluated corrections) intervals will
he most appropriate correction factor will be sele
f central tendency and outliers and used for the st
tistics (n, mean, median, standard deviation, min
ummarize the absolute corrected QT interval and
r treatment by study arm dose and time point.  F
um change from baseline will be calculated as w
rval across time points.  Categorical analysis wil
m baseline in corrected QT and the maximum po
for baseline vs worst on treatment corrected QT
sed) using maximum CTCAE Grade.  Shift table
ty at baseline vs. on treatment (yes, no, not done
lly-relevant morphological ECG changes will be
centage).
tions on corrected QT change from baseline will
centration-corrected QT analyses may be perform
esults and/or explored further with PK/pharmaco
he ECG parameters QT interval, heart rate, QTc 
ill be summarized by treatment and visit.
with maximum post dose QTc values and maxim
ng categories will be tabulated by treatment: 
Borderline (msec)
Prolong
450 - <480

30-<60

atients with corrected and uncorrected QT values
rs (ie, Fridericia’s 
riate).  QTcF 
RS, QTcF and by 
l be listed by 
ected and used 
tudy 
nimum, and 
d changes from 
For each patient 
well as the 
ll be conducted 
ost-baseline QT 
T (1 or more 
es will also be 
e: (n, %).  
e summarized 
l be explored 
med.  Data may 
odynamic
interval, PR 
mum increases 
ged (msec)
480
60
s 500 msec will 


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If more than one ECG is collected at a nominal time post dose (eg, triplicate ECGs), the 
mean of the replicate measurements will be used to represent a single observation at that time 
point.  If any of the 3 individual ECG tracings has a QTc value 500 msec, but the mean of 
the triplicates is not 500 msec, the data from the patient’s individual tracing will be 
described in a safety section of the study report in order to place the 500 msec value in 
appropriate clinical context.  However, values from individual tracings within triplicate 
measurements that are 500 msec will not be included in the categorical analysis unless the 
average from the triplicate measurements is also 500 msec.  Changes from baseline will be 
defined as the change between QTc post dose from the time-matched average baseline 
triplicates on Day 0, or the average of the pre-dose triplicate values on Day 1.
In addition, an attempt will be made to explore and characterize the relationship between 
plasma concentration and QT interval length using a PK/ pharmacodynamic modeling 
approach.  If a PK/pharmacodynamic relationship is found, the impact of patient factors 
(covariates) on the relationship will be examined.
9.7. Analysis of Other Endpoints
9.7.1. Analysis of Anti-Drug Antibody for PF-06801591
Summary of number of patients and incidence of developed ADA against PF-06801591 will 
be tabulated by dose level cohort.  For patients with positive ADA or NAb, the magnitude 
(titre), time of onset, and duration of ADA or NAb response will also be described, if data 
permit. Subgroup analysis may be performed to assess the PK or pharmacodynamics 
response if data warrant. 
9.8. Data Safety Monitoring Committee 
An external Data Safety Monitoring Committee will not be established for the study.  For the 
purpose of this protocol, Pfizer procedures for periodic safety review will be applied by an 
internal safety review team with medical and statistical capabilities to review individual and 
summary data collected in the safety and clinical databases.  Procedures include:

Surveillance for SAEs according to regulatory guidelines;

Discussions between the investigators and the sponsor of AEs and laboratory tests 
alterations seen at each dose level in an on-going manner at regular teleconferences 
and/or meetings to determine the safety profile and risk/benefit ratio and decide if 
further enrollment is appropriate.
Part 2: When approximately 30 patients have had the opportunity for a Week 8 tumor 
assessment, a preliminary analysis will be performed to evaluate safety and efficacy and to 
explore the possibility of extending the protocol to additional tumor types or to maintain the 
current study design.


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10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer or its agent will conduct periodic monitoring visits during study conduct to ensure that 
the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs are accurate.  The 
investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification.  This 
verification may also occur after study completion.
During study conduct and/or after study completion, the study site may be subject to review 
by the institutional review board (IRB)/ethics committee (EC), and/or to quality assurance 
audits performed by Pfizer, or companies working with or on behalf of Pfizer, and/or to 
inspection by appropriate regulatory authorities.
The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study. Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the study site for the inspection and will allow Pfizer or its agent, 
whenever feasible, to be present during the inspection. The investigator will promptly 
provide copies of the inspection findings to Pfizer or its agent.  Before response submission 
to the regulatory authorities, the investigator will provide Pfizer or its agents with an 
opportunity to review and comment on responses to any such findings.
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included patient.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true.  Any corrections to entries made in the CRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry. 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.


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In some cases, the CRF, or part of the CRF, may also serve as source documents.  In these 
cases, a document should be available at the investigative site as well as at Pfizer and clearly 
identify those data that will be recorded in the CRF, and for which the CRF will stand as the 
source document.
11.2. Record Retention
To enable evaluations and/or audits from regulatory authorities or Pfizer, the investigator 
agrees to keep records, including the identity of all participating patients (sufficient 
information to link records, eg, CRFs and hospital records), all original signed informed 
consent documents, copies of all CRFs, safety reporting forms, source documents, and 
detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, and telephone call reports).  The records should 
be retained by the investigator according to ICH guidelines, according to local regulations, or 
as specified in the clinical study agreement (CSA), whichever is longer.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer.
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board/Ethics Committee 
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, 
eg, recruitment advertisements, if applicable, from the IRB/EC.  All correspondence with the 
IRB/EC should be retained in the investigator file.  Copies of IRB/EC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the patients.  In 
that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as well as 
the general principles set forth in the International Ethical Guidelines for Biomedical 
Research Involving Human Subjects (Council for International Organizations of Medical 
Sciences 2002), Guidelines for GCP (ICH 1996), and the Declaration of Helsinki (World 
Medical Association 1996 and 2008). 


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In addition, the study will be conducted in accordance with the protocol, the ICH guideline 
on GCP, and applicable local regulatory requirements and laws.
12.3. Patient Information and Consent
All parties will ensure protection of patient personal data and will not include patient names 
or other identifiable data in any reports, publications, or other disclosures, except where 
required by law.
When study data are compiled for transfer to Pfizer and other authorized parties, patient 
names, addresses, and other identifiable data will be replaced by a numerical code consisting 
of a numbering system provided by Pfizer in order to de-identify study patients.  The study 
site will maintain a confidential list of patients who participated in the study, linking each 
patient’s numerical code to his or her actual identity.  In case of data transfer, Pfizer will 
maintain high standards of confidentiality and protection of patients’ personal data consistent 
with applicable privacy laws.
The informed consent documents must be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements, including applicable privacy laws.
The informed consent documents used during the informed consent process must be 
reviewed and approved by the sponsor, approved by the IRB/EC before use, and available for 
inspection.
The investigator must ensure that each study patient is fully informed about the nature and 
objectives of the study and possible risks associated with participation. 
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each patient before any study-specific activity is performed.  The investigator 
will retain the original of each patient's signed consent document.
12.4. Patient Recruitment
Advertisements approved by IRBs/ECs and investigator databases may be used as 
recruitment procedures.
Pfizer will have an opportunity to review and approve the content of any study recruitment 
materials directed to potential study patients before such materials are used.
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
competent authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, Pfizer should be informed immediately. 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study patients against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.


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13. DEFINITION OF END OF TRIAL
13.1. End of Trial in a Member State 
End of trial in a Member State of the EU is defined as the time at which it is deemed that a 
sufficient number of patients have been recruited and completed the study as stated in the 
regulatory application (ie, clinical trial application [CTA]) and ethics application in the 
Member State.  Poor recruitment (recruiting less than the anticipated number in the CTA) by 
a Member State is not a reason for premature termination but is considered a normal 
conclusion to the study in that Member State.
End of trial is defined as 2 years after last patient first dose (LPFD).
13.2. End of Trial in All Other Participating Countries
End of trial in all other participating countries is defined as 2 years after last patient first dose
(LPFD).
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, or investigational product safety problems, or at the 
discretion of Pfizer.  In addition, Pfizer retains the right to discontinue development of 
PF-06801591 at any time.
If a study is prematurely terminated or discontinued, Pfizer will promptly notify the 
investigator.  After notification, the investigator must contact all participating patients and 
the hospital pharmacy (if applicable) within a time period set by Pfizer. As directed by 
Pfizer, all study materials must be collected and all CRFs completed to the greatest extent 
possible.
15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations. 
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer sponsored 
interventional studies (conducted in patients) that evaluate the safety and/or efficacy of a 
Pfizer product, regardless of the geographical location in which the study is conducted.  US 
Basic Results are submitted for posting within 1 year of the primary completion date for 
studies in adult populations or within 6 months of the primary completion date for studies in 
pediatric populations.


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Primary completion date is defined as the date that the final patient was examined or received 
an intervention for the purposes of final collection of data for the primary outcome, whether 
the clinical study concluded according to the pre-specified protocol or was terminated.
EudraCT
Pfizer posts EU Basic Results on EudraCT for all Pfizer-sponsored interventional studies that 
are in scope of EU requirements.  EU Basic Results are submitted for posting within 1 year 
of the primary completion date for studies in adult populations or within 6 months of the 
primary completion date for studies in pediatric populations.
www.pfizer.com
Pfizer posts Public Disclosure Synopses (clinical study report synopses in which any data 
that could be used to identify individual patients has been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the US Basic Results document is 
posted to www.clinicaltrials.gov.
15.2. Publications by Investigators
Pfizer supports the exercise of academic freedom and has no objection to publication by 
principal investigator of the results of the study based on information collected or generated 
by principal investigator, whether or not the results are favorable to the Pfizer product.  
However, to ensure against inadvertent disclosure of confidential information or unprotected 
inventions, the investigator will provide Pfizer an opportunity to review any proposed 
publication or other type of disclosure of the results of the study (collectively, “Publication”) 
before it is submitted or otherwise disclosed.
The investigator will provide any publication to Pfizer at least 30 days before they are 
submitted for publication or otherwise disclosed.  If any patent action is required to protect 
intellectual property rights, the investigator agrees to delay the disclosure for a period not to 
exceed an additional 60 days.
The investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study- or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results.
If the study is part of a multicenter study, the investigator agrees that the first publication is 
to be a joint publication covering all study sites, and that any subsequent publications by the 
principal investigator will reference that primary publication.  However, if a joint manuscript 
has not been submitted for publication within 12 months of completion or termination of the 
study at all participating sites, the investigator is free to publish separately, subject to the 
other requirements of this section.


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For all publications relating to the study, Institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the CSA between Pfizer and the 
institution.  In this section entitled Publications by Investigators, the defined terms shall have 
the meanings given to them in the CSA.
If there is any conflict between the CSA and any Attachments to it, the terms of the CSA 
control.  If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study patients, and the CSA will control as to all other 
issues.


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63.
Oken M, Creech R, Tormey D et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol 1982; 5:649-655.
64.
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, 3rd, Feldman HI, et al. A 
new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150(9):604-
12.


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Appendix 1.
Abbreviations
Abbreviation
Term
Ab
antibody
AdC68
adenovirus C38
ADA
anti-Drug Antibody
AE
adverse event
AIDS
acquired immunodeficiency syndrome 
Ag
antigen
ALK
anaplastic lymphoma kinase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ANOVA
analysis of variance
aPTT
activated partial thromboplastin time
ASCO
American Society of Clinical Oncology
ASCT
autologous stem cell transplant
AST
aspartate aminotransferase
AUC
area under the curve
AUCt
area under the serum concentration-time curve
AUC∞
area under the concentration-time curve
BCG
bacillus calmette-guérin
BP
blood pressure
BUN
blood urea nitrogen
C
cycle
C2D8
cycle 2 day 8
CAR
chimeric antigen receptor
CCL
chemokine (C-C motif) ligand
CD
cluster of differentiation
CHF
congestive heart failure
cHL
classic Hodgkin lymphoma
CI
confidence interval
CKD-EPI
chronic kidney disease epidemiology collaboration 
CL
clearance
Cmax
maximum drug concentration
CNS
central nervous system
CR
complete response
CrCl
creatinine clearance
CRF
case report form
CRO
contract research organization
CRP
C-reactive protein
CSA
clinical study agreement
CT
computed tomography
CTA
clinical trial application
CTCAE
Common Terminology Criteria for Adverse Events


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Abbreviation
Term
CTLA-4
cytotoxic T-lymphocyte-associated protein-4
D
day
DAI
dosage and administration instructions
DCR
disease control rate
DLT
dose-limiting toxicity
DNA
deoxyribonucleic acid
DOR
duration of response
DOSD
duration of stable disease
DR
D related
DU
dispensable unit
EC
ethics committee
EC50
half maximal effective concentration
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EDP
exposure during pregnancy
EGFR
epidermal growth factor receptor
EI
equivalence interval
EOT
end of treatment
ESMO
European Society for Medical Oncology
EU
European Union
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration (United States)
FDG-PET
fluordeoxyglucose-positron emission tomography
FFPE
formalin-fixed paraffin embedded
FIP
first in patient
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
GM-CSF
granulocyte-macrophage colony-stimulating factor 
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HNSTD
highest non-severely toxic dose 
HR
Hazard ratio
ICH
International Conference on Harmonization
ICOS
inducible T cell co-simulator 
ID
Identification
IFN-γ
interferon-gamma
Ig
Immunoglobulin
CCI
CCI


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Abbreviation
Term
IL
Interleukin
IND
investigational new drug application
INR
international normalized ratio
IP
investigation product
irAE
immune-related adverse event
IRB
institutional review board
irRECIST
immune-related Response Evaluation Criteria in Solid Tumors
IRT
interactive response technology
ISR
injection site reaction
IV
Intravenous
JAK/STAT
janus kinase/signal transducer and activator of transcription
K2EDTA
dipotassium ethylene diamine tetraacetic acid
LFT
liver function test
LPFD
last patient first dose
LPLV
last patient last visit
mAb
monoclonal antibody
MAPA
magnesium ammonium phospholineate-palmitoleate anhydride
MCC
merkel cell carcinoma
MCP-1
monocyte chemoattractant protein-1
MG
myasthenia gravis
MIP
macrophage inflammatory protein
MLR
mixed lymphocyte reaction
MRI
magnetic resonance imaging
mRNA
messenger ribonucleic acid
MTD
maximum tolerated dose
mTPI
modified toxicity probability interval
NA
not available
NAb
neutralizing antibodies
NCI 
National Cancer Institute 
NCCN
National Comprehensive Cancer Network 
NHP
non-human primates
NMIBC
non- muscle invasive bladder cancer
NOAEL
no observed adverse effect level
NSCLC
non-small-cell lung cancer
ORR
objective response rate
OS
overall survival
PBMC
peripheral blood mononuclear cell
PD
progressive disease
PD-1
programmed cell death protein-1
PD-L
programmed death ligand
PET
positron emission tomography
CCI
CCI


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Abbreviation
Term
PGE2
prostaglandin E2
PFS
progression-free survival
PK
Pharmacokinetics
PR
partial response
PrCa
prostate cancer
PT
prothrombin time
PTT
partial thromboplastin time
q2w/q3w/q4w
every 2 weeks/every 3 weeks/every 4 weeks
QT
time between the start of the Q wave and the end of the T wave
Rac
accumulation ratio
RCC
renal cell carcinoma
RECIST
response evaluation criteria in solid tumors
irRECIST
immune related Response Evaluation Criteria in Solid Tumors
RO
receptor occupancy
RP2D
recommended Phase 2 dose
RR
response rate
SAE
serious adverse event
SAP
Statistical Analysis Plan
SC
Subcutaneous
SCCHN
squamous cell carcinoma of the head and neck
SD
stable disease
SEB
staphylococcal enterotoxin B
SNF
skilled nursing facility
SOA
schedule of activities
SOCS1
suppressor of cytokine signaling 1
SPD
sum of the products of the greatest diameters
SRSD
single reference safety document
t1/2
half-life
TBNK
T cell/B cell/natural killer cell
TE
target engagement
TGFβ
transforming growth factor beta
TH
T helper cell
TIL
tumor-infiltrating lymphocytes
TIMP1
tissue inhibitor of metalloproteinase 1
Tmax
maximum (or peak) serum concentration
TNF
tumor necrosis factor
Treg
regulatory T-cell
TPS
Tumor proportion score
TSH
thyroid stimulating hormone
TTP
time to progression
TTR
time to response
CCI
CCI


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Abbreviation
Term
ULN
upper limit of normal
UPM
unit probability mass
US
United States
Vd
volume of distribution
VBIR
vaccine based immunotherapy regimen
VP
virus particles
Vss
volume of distribution at steady state
WBC
white blood cell
WHO
World Health Organization
WNL
within normal limits


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Appendix 2.
Detailed Dose Escalation/De-Escalation Scheme for mTPI design 
Escalation/De-escalation algorithms for total number of patients treated at the current 
dose level (current and previous cohorts)

With 2 patients treated at current dose level
0 DLT > escalate
1 DLT > remain at the same dose
2 DLTs > de-escalate and consider current dose as intolerable

With 3 patients treated at current dose level
0 DLT > escalate
1 DLT > remain at the same dose
2 DLTs > de-escalate 
3 DLTs > de-escalate and consider current dose as intolerable

With 4 patients treated at current dose level
0 DLT > escalate
1-2 DLTs > remain at the same dose
3-4 DLTs > de-escalate and consider current dose as intolerable

With 5 patients treated at current dose level
0-1 DLT > escalate
2 DLTs > remain at the same dose
3 DLTs > de-escalate
4-5 DLTs > de-escalate and consider current dose as intolerable

With 6 patients treated at current dose level
0-1 DLT > escalate
2 DLTs > remain at the same dose
3 DLTs > de-escalate 
4-6 DLTs > de-escalate and consider current dose as intolerable

With 7 patients treated at current dose level
0-1 DLT > escalate
2-3 DLTs > remain at the same dose
4-7 DLTs > de-escalate and consider current dose as intolerable

With 8 patients treated at current dose level
0-1 DLT > escalate
2-3 DLTs > remain at the same dose
4 DLTs > de-escalate
5-8 DLTs > de-escalate and consider current dose as intolerable


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
With 9 patients treated at current dose level
0-1 DLT > escalate
2-3 DLTs > remain at the same dose
4 DLTs > de-escalate (mTPI suggests “remain at the same dose”)
5-9 DLTs > de-escalate and consider current dose as intolerable

With 10 patients treated at current dose level
0-1 DLT > escalate
2-3 DLTs > remain at the same dose
4 DLTs > de-escalate (mTPI suggests “remain at the same dose”)
5 DLTs > de-escalate
6-10 DLTs > de-escalate and consider current dose as intolerable

With 11 patients treated at current dose level
0-2 DLT > escalate
3-4 DLTs > remain at the same dose
5 DLTs > de-escalate (mTPI suggests “remain at the same dose”)
6-11 DLTs > de-escalate and consider current dose as intolerable

With 12 patients treated at current dose level
0-2 DLTs > escalate
3-4 DLTs > remain at the same dose
5 DLTs > de-escalate (mTPI suggest “remain at the same dose”)
6-12 DLTs > de-escalate and consider current dose as intolerable

With 13 patients treated at current dose level
0-2 DLTs > escalate
3-4 DLTs > remain at the same dose
5 DLTs > de-escalate (mTPI suggest “remain at the same dose”)
6 DLTs > de-escalate
7-13 DLTs > de-escalate and consider current dose as intolerable

With 14 patients treated at current dose level
0-2 DLTs > escalate
3-4 DLTs > remain at the same dose
5-6 DLTs > de-escalate (mTPI suggest “remain at the same dose”)
7-14 DLTs > de-escalate and consider current dose as intolerable

With 15 patients treated at current dose level
0-2 DLTs > escalate
3-4-5 DLTs > remain at the same dose
6 DLTs > de-escalate (mTPI suggest “remain at the same dose”)
7-15 DLTs > de-escalate and consider current dose as intolerable


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Appendix 3. RECIST (Response Evaluation Criteria In Solid Tumors) version 
1.1 Guidelines
Adapted from Eisenhauer E.A., et al.57
CATEGORIZING LESIONS AT BASELINE
Measurable Lesions 
Lesions that can be accurately measured in at least one dimension.

Lesions with longest diameter twice the slice thickness and at least 10 mm or greater 
when assessed by CT or MRI (slice thickness 5-8 mm).

Lesions with longest diameter at least 20 mm when assessed by Chest X-ray.

Superficial lesions with longest diameter 10 mm or greater when assessed by caliper.

Malignant lymph nodes with the short axis 15 mm or greater when assessed by CT.
NOTE: The shortest axis is used as the diameter for malignant lymph nodes, longest 
axis for all other measurable lesions. 
Non-measurable disease 
Non-measurable disease includes lesions too small to be considered measurable (including 
nodes with short axis between 10 and 14.9 mm) and truly non-measurable disease such as
pleural or pericardial effusions, ascites, inflammatory breast disease, leptomeningeal disease, 
lymphangitic involvement of skin or lung, clinical lesions that cannot be accurately measured 
with calipers, abdominal masses identified by physical exam that are not measurable by 
reproducible imaging techniques.

Bone disease: Bone disease is non-measurable with the exception of soft tissue 
components that can be evaluated by CT or MRI and meet the definition of 
measurability at baseline.

Previous local treatment: A previously irradiated lesion (or lesion subjected to other 
local treatment) is non-measurable unless it has progressed since completion of 
treatment.
Normal sites

Cystic lesions: Simple cysts should not be considered as malignant lesions and should 
not be recorded either as target or non-target disease.  Cystic lesions thought to 
represent cystic metastases can be measurable lesions, if they meet the specific 
definition above. If non-cystic lesions are also present, these are preferred as target 
lesions.


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
Normal nodes: Nodes with short axis <10 mm are considered normal and should not 
be recorded or followed either as measurable or non-measurable disease.
RECORDING TUMOR ASSESSMENTS
All sites of disease must be assessed at baseline.  Baseline assessments should be done as 
close as possible prior to study start. For an adequate baseline assessment, all required scans 
must be done within 28 days prior to treatment and all disease must be documented 
appropriately. If baseline assessment is inadequate, subsequent statuses generally should be 
indeterminate.
Target lesions
All measurable lesions up to a maximum of 2 lesions per organ, 5 lesions in total, 
representative of all involved organs, should be identified as target lesions at baseline. 
Target lesions should be selected on the basis of size (longest lesions) and suitability for 
accurate repeated measurements.  Record the longest diameter for each lesion, except in the 
case of pathological lymph nodes for which the short axis should be recorded.  The sum of 
the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions 
at baseline will be the basis for comparison to assessments performed on study. 

If two target lesions coalesce the measurement of the coalesced mass is used.  If a 
large target lesion splits, the sum of the parts is used.

Measurements for target lesions that become small should continue to be recorded.  If 
a target lesion becomes too small to measure, 0 mm should be recorded if the lesion is 
considered to have disappeared; otherwise a default value of 5 mm should be 
recorded.
NOTE: When nodal lesions decrease to <10 mm (normal), the actual measurement 
should still be recorded.
Non-target disease 
All non-measurable disease is non-target. All measurable lesions not identified as target 
lesions are also included as non-target disease.  Measurements are not required but rather 
assessments will be expressed as ABSENT, INDETERMINATE, PRESENT/NOT 
INCREASED, INCREASED.  Multiple non-target lesions in one organ may be recorded as a 
single item on the CRF (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: 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: 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: 20% increase in the sum of diameters of target measurable 
lesions above the smallest sum observed (over baseline if no decrease in the sum is 
observed during therapy), with a minimum absolute increase of 5 mm.

Indeterminate: Progression has not been documented, and:

one or more target measurable lesions have not been assessed.

or assessment methods used were inconsistent with those used at baseline.

or one or more target lesions cannot be measured accurately (eg, poorly visible 
unless due to being too small to measure).

or one or more target lesions were excised or irradiated and have not reappeared 
or increased.
Non-target disease

CR: Disappearance of all non-target lesions and normalization of tumor marker 
levels. All lymph nodes must be ‘normal’ in size (<10 mm short axis).

Non-CR/Non-PD: Persistence of any non-target lesions and/or tumor marker level 
above the normal limits.

PD: Unequivocal progression of pre-existing lesions. Generally the overall tumor 
burden must increase sufficiently to merit discontinuation of therapy.  In the presence 
of SD or PR in target disease, progression due to unequivocal increase in non-target 
disease should be rare.


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
Indeterminate: Progression has not been determined and one or more non-target sites 
were not assessed or assessment methods were inconsistent with those used at 
baseline.
New Lesions 
The appearance of any new unequivocal malignant lesion indicates PD.  If a new lesion is 
equivocal, for example due to its small size, continued assessment will clarify the etiology.  
If repeat assessments confirm the lesion, then progression should be recorded on the date of 
the initial assessment.  A lesion identified in an area not previously scanned will be 
considered a new lesion.
Supplemental Investigations

If CR determination depends on a residual lesion that decreased in size but did not 
disappear completely, it is recommended the residual lesion be investigated with 
biopsy or fine needle aspirate.  If no disease is identified, objective status is CR.

If progression determination depends on a lesion with an increase possibly due to 
necrosis, the lesion may be investigated with biopsy or fine needle aspirate to clarify 
status.
Subjective progression
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 7.
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 8 will be used:
Table 8.
Objective Response Status at each Evaluation for Patients 
with Non-Target Disease Only
Non-target Disease
New Lesions
Objective status
CR
No
CR
Non-CR/Non-PD
No
Non-CR/Non-PD
Indeterminate
No
Indeterminate
Unequivocal progression
Yes or No
PD
Any
Yes
PD


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Appendix 4.
Immune-related RECIST (irRECIST)
Increasing clinical experience indicates that traditional response criteria may not be sufficient 
to fully characterize activity in this new era of targeted therapies and/or biologics. 
This is particularly true for immunotherapeutic agents such as anti-cytotoxic T 
lymphocyte-associated protein-4 (CTLA-4) and anti PD-1/anti-PD-L1 antibodies which exert 
the antitumor activity by augmenting activation and proliferation of T cells, thus leading to 
tumor infiltration by T cells and tumor regression rather than direct cytotoxic effects.1,58,59
Clinical observations of patients with advanced melanoma treated with ipilimumab, for 
example, suggested that conventional response assessment criteria such as Response 
Evaluation Criteria in Solid Tumors (RECIST) and WHO criteria are not sufficient to fully 
characterize patterns of tumor response to immunotherapy because tumors treated with 
immunotherapeutic agents may show additional response patterns that are not described in 
these conventional criteria.
Furthermore, the conventional tumor assessment criteria (RECIST and WHO criteria) have 
been reported as not capturing the existence of a subset of patients who have an OS similar to 
those who have experienced CR or PR but were flagged as PD by WHO criteria.60,61,62
On these grounds, a tumor assessment system has been developed that incorporates these 
delayed or flare type responses into the RECIST v1.1 (irRECIST).
For irRECIST, only target and measurable lesions are taken into account.  In contrast to 
RECIST v1.1, irRECIST: 

Requires confirmation of both progression and response by imaging at least 4 weeks 
from the date first documented; and 

Does not necessarily score the appearance of new lesions as PD if the sum of lesion 
diameters of target lesions (minimum of 10 mm longest diameter per non-nodal lesion 
and 15 mm shortest diameter per nodal lesion, maximum of 5 target lesions, 
maximum of 2 per organ) and measurable new lesions does not increase by 20%. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported target lesion(s) at baseline and throughout the trial. 
irRECIST is defined as follows: 

Overall immune related complete response (irCR): Complete disappearance of all 
lesions (whether measurable or not) and no new lesions.  All measurable lymph nodes 
also must have a reduction in short axis to <10 mm. 

Overall immune-related partial response (irPR): Sum of the diameters (longest for 
non-nodal lesions, shortest for nodal lesions) of target and new measurable lesions 
decreases 30%. 


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
Overall immune related stable disease (irSD): Sum of the diameters (longest for 
non-nodal lesions, shortest for nodal lesions) of target and new measurable lesions is 
neither irCR, irPR, (compared to baseline) nor immune related progressive disease 
(irPD, compared to nadir). 

Overall irPD: Sum of the diameters (longest for non-nodal lesions, shortest for nodal 
lesions) of target and new measurable lesions increases 20% (compared to nadir)
with a minimum absolute increase of 5 mm, confirmed by a repeat, consecutive 
observation at least 4 weeks from the date first documented. 
New measurable lesions: Incorporated into tumor burden (ie, added to the target lesion 
measurements). A lymph node has to be ≥15 mm in short axis to be a measurable new lesion 
and its short axis measurement is included in the sum. Up to 2 new lesions per organ and up 
to 5 new lesions in total can be added to the measurements at each assessment time point.
New non measurable lesions: Do not define progression but preclude irCR.


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Appendix 5. Overall Response Derived from Changes in Index, Non-index, and New 
Lesions
Overall responses derived from changes in index, non-index, and new lesions are outlined in
Table 9.
Table 9.
Overall Response Derived from Changes in Index, Non-index, and New 
Lesions
Measurable response
Non-measurable response
Overall response using 
irRECISTb
Index and New 
Measurable Lesions 
(Tumor Burden)a
Non-Index Lesions
Measurable Lesions
Decrease 100%
Absent
Absent
irCR
Decrease 100%
Stable
Any
irPR
Decrease 100%
Unequivocal progression
Any
irPR
Decrease 30%
Absent/stable
Any
irPR
Decrease 30%
Unequivocal progression
Any
irPR
Decrease <30% and 
increase <20%
Absent/stable
Any
irSD
Decrease <30% and 
increase <20%
Unequivocal progression
Any
irSD
Increase 20%
Any
Any
irPD
a.
Decrease assessed relative to baseline.
b.
Response (irCR and irPR) and progression (irPD) must be confirmed by a second, consecutive 
assessment at least 4 weeks apart.


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Appendix 6. ECOG Performance Status
Grade
ECOG Performance Status
0
Fully active, able to carry on all pre-disease performance without restriction.
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, eg, light house work, office work.
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities.  Up and about more than 50% of waking hours.
3
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours.
4
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed 
or chair.
5
Dead
Source: Oken M et al. 1982.63


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Appendix 7. Recommendations for Management of Infusion Related Reactions 
Including Allergic/Hypersensitivity Reactions, Cytokine Release Syndrome or 
Anaphylaxis
Following the first infusion of some monoclonal antibody therapeutics, some patients 
experience fever, headache, nausea, vomiting or hypotension.  These AEs are generally 
ascribed to lysis of cellular targets, cytokine release, or complement activation.
Type 1 hypersensitivity or allergic (eg, shortness of breath, urticaria, anaphylaxis, 
angioedema) reactions are theoretically possible in response to any injected protein.  Immune 
complex mediated Type 3 hypersensitivity reactions are similar to the AEs of 
Type 1 reactions but are likely to be delayed from the time of infusion and may include 
symptoms such as rash, urticaria, polyarthritis, myalgias, polysynovitis, fever, and, if severe, 
glomerulonephritis. 
All patients should be closely observed while receiving investigational product infusions.
Monitoring for clinical signs of a systemic reaction should continue thereafter for clinical 
signs of allergic reactions/hypersensitivity.
Infusion reactions
If chills and fever (>100.4F/38.0C) or hypotension occur, the infusion should be 
interrupted.  Patients should be treated symptomatically according to best medical and 
nursing practice and the infusion should be restarted at 50% of the original rate. 
If infusion reactions, characterized by fever and chills, and less commonly hypotension, are 
experienced either by an individual patient or in other patients, pretreatment medication may 
be administered prior to subsequent doses to reduce the incidence and severity.  The 
following pretreatment regimen is suggested, although a different regimen based on local 
standard of care is permitted:

Patients should be pretreated with acetaminophen and diphenhydramine (or other 
antihistamine) approximately 0.5 to 2 hours before each PF-06801591 administration.  
Pretreatment medications will not be supplied by Pfizer.  Suggested starting doses are 
650 to 1000 mg acetaminophen and 50 mg diphenhydramine (or equivalent of other 
antihistamine) IV or oral.  Two (2) additional doses of acetaminophen may be 
administered approximately every 4-6 hours after the initial pretreatment or as 
needed.
Hypersensitivity reactions:
In the case of a hypersensitivity reaction, the patient will be treated symptomatically, with 
supportive care and further monitoring until the end of the study.  Study infusions may be 
stopped.


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Guidelines for the management of hypersensitivity reactions are as follows: 
1. NCI-CTCAE Grade 1 allergic reaction or cytokine release syndrome:
a.
Monitor for worsening condition.  If the reaction worsens, stop the infusion.  Use
premedication for subsequent infusions, as described above. 
2. NCI-CTCAE Grade 2 allergic reaction or cytokine release syndrome:
a.
Stop PF-06801591 infusion.
b. Administer bronchodilators, oxygen, acetaminophen, etc. as medically indicated.
c.
Resume infusion at 50% of previous rate once reaction has decreased to 
Grade 1 in severity.  Monitor closely for any worsening.  If the reaction recurs, 
stop infusion.  Institute premedication for subsequent infusions as described 
above.
3. NCI-CTCAE Grade 3 or Grade 4 allergic reaction or cytokine release syndrome or 
anaphylaxis:
- Grade 3 anaphylaxis (hypersensitivity reaction) consists of symptomatic 
bronchospasm requiring parenteral medications with or without urticaria, 
allergy-related edema/angioedema, or hypotension.
- Grade 4 anaphylaxis (hypersensitivity reaction) is a life-threatening event requiring 
urgent intervention.
a.
Stop the PF-06801591 infusion immediately and disconnect infusion tubing from 
the patient.
b. Administer epinephrine, bronchodilators, antihistamines, glucocorticoids, 
intravenous fluids, vasopressor agents, oxygen, etc. as medically indicated.
c.
Telephone sponsor or designated representative to report an SAE as per
Section 8.6.
d. For a NCI-CTCAE Grade 3 or 4 hypersensitivity reaction, discontinue study 
treatment.
4. Re-treatment following Grade 1 or Grade 2 allergic reactions or cytokine release 
syndrome:
a.
Once the PF-06801591 infusion rate has been decreased due to an allergic 
reaction or cytokine release syndrome, it will remain decreased for all subsequent 
infusions.


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b. If the patient has a second reaction at the lower infusion rate, the infusion should 
be stopped and the patient should receive no further PF-06801591.
c.
If the patient experiences a Grade 3 or 4 allergic reaction, cytokine release 
syndrome, or anaphylaxis at any time, the patient should receive no further 
PF-06801591.
d. If there are questions concerning whether an observed reaction is consistent with 
an allergic reaction, cytokine release syndrome, or anaphylaxis, the medical 
monitor should be contacted immediately to assist with grading the reaction.
Sampling for PK, pharmacodynamics and ADA should continue as long as the sampling does 
not interfere with the medical treatment of the patient.
In cases of suspected cytokine release syndrome, a serum sample should be provided for 
cytokine release assay analysis by the central lab so as long as the sampling does not interfere 
with the medical treatment of the patient.
Detailed guidance on treatment, dose interruptions and potential retreatment is provided in 
the DAI.


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Page 167
Appendix 8. Management of Immune-related Adverse Events (irAEs)
Gastrointestinal irAEs
Severity of Diarrhea/Colitis
(NCI-CTCAE v4)
Initial Management
Follow-up Management
Grade 1
Diarrhea: <4 stools/day over
Baseline
Colitis: asymptomatic
-Continue study treatment.
-Symptomatic treatment
(eg, loperamide).
-Close monitoring for worsening 
symptoms.
-Educate patient to
report worsening
immediately.
-If worsens:
Treat as Grade 2, 3 or 4.
Grade 2
Diarrhea: 4 to 6 stools per day over
Baseline; IV fluids indicated <24
hours; not interfering with ADL
Colitis: abdominal pain; blood in
stool
-Withhold study treatment.
-Symptomatic treatment.
-If improves to Grade ≤1:
Resume study treatment.
-If persists >5-7 days or recurs:
Treat as Grade 3 or 4.
Grade 3 to 4
Diarrhea (Grade 3): ≥7 stools per day
over Baseline; incontinence; IV fluids
≥24 h; interfering with ADL
Colitis (Grade 3): severe abdominal
pain, medical intervention indicated,
peritoneal signs
Grade 4: life-threatening, perforation
-Withhold for Grade
3.
-Permanently discontinue 
study treatment for Grade 4 or 
recurrent Grade 3.
-1.0 to 2.0 mg/kg/day 
prednisone IV or 
equivalent.
-Add prophylactic 
antibiotics for
opportunistic infections.
-Consider lower endoscopy.
-If improves:
-Continue steroids until Grade
≤1, then taper over at least 1 
month; resume study treatment
following steroids taper (for 
initial Grade 3).
-If worsens, persists >3 to 5 
days, or recurs after
improvement:
-Add infliximab 5mg/kg (if no 
contraindication).
-Note: infliximab should not be
used in cases of perforation or 
sepsis.


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Page 168
Dermatological irAEs
Grade of
Rash (NCI-
CTCAE v4)
Initial Management
Follow-up Management
Grade 1 to 2
Covering ≤30% body surface area
-Continue study treatment.  
-Symptomatic therapy (for 
example, antihistamines, 
topical steroids).
-If persists >1 to 2 weeks or recurs: 
-Withhold study treatment.
-Consider skin biopsy.
-Consider 0.5-1.0 mg/kg/day 
prednisone or equivalent. Once
improving, taper steroids over at 
least 1 month, consider prophylactic 
antibiotics for opportunistic
infections, and resume study 
treatment following steroids taper.
-If worsens: Treat as Grade 3 to 4.
Grade 3 to 4
Grade 3: Covering >30% 
body surface area;
Grade 4: Life
threatening 
consequences
-Withhold study 
treatment for Grade 3.
-Permanently discontinue for
Grade 4 or recurrent Grade 3.
-Consider skin biopsy.
-Dermatology consult.
-1.0 to 2.0 mg/kg/day 
prednisone or equivalent.
-Add prophylactic antibiotics 
for opportunistic infections.
-If improves to Grade ≤1:
-Taper steroids over at least 1 month; 
resume study treatment following
steroids taper (for initial Grade 3).


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Pulmonary irAEs
Grade of Pneumonitis
(NCI-CTCAE v4)
Initial Management
Follow-up Management
Grade 1
Radiographic changes only
-Consider withholding  study 
treatment.
-Monitor for symptoms
every 2 to 3 days.
-Consider Pulmonary and
Infectious Disease 
consults.
-Re-assess at least
every 3 weeks.
-If worsens: Treat as Grade 2
or Grade 3 to 4.
Grade 2
Mild to moderate new symptoms
-Withhold study treatment.
-Pulmonary and Infectious 
Disease consults.
-Monitor symptoms 
daily; consider 
hospitalization.
-1.0 to 2.0 mg/kg/day 
prednisone or equivalent.
-Add prophylactic 
antibiotics for opportunistic 
infections.
-Consider bronchoscopy, 
lung biopsy.
-Re-assess every 
1 to 3 days If
improves:
-When symptoms return to
Grade ≤1, taper steroids over at 
least 1 month, and then resume  
study treatment following
steroids taper.
-If not improving after 2 weeks 
or worsening: Treat as Grade 3
to 4.
Grade 3 to 4
Grade 3: Severe new symptoms;
New/worsening hypoxia;
Grade 4: Life-threatening
-Permanently
discontinue study 
treatment.
-Hospitalize.
-Pulmonary and 
Infectious Disease 
consults.
-1.0 to 2.0 mg/kg/day 
prednisone or equivalent.
-Add prophylactic antibiotics 
for opportunistic infections.
-Consider bronchoscopy, lung
biopsy.
-If improves to Grade ≤1:
-Taper steroids over at least 1 
month.
-If not improving after 48 hours
or worsening: Add additional
immunosuppression (for
example, infliximab, 
cyclophosphamide, IV
immunoglobulin, or 
mycophenolate mofetil).


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Hepatic irAEs
Grade of Liver
Test Elevation
(NCI-CTCAE v4)
Initial Management
Follow-up Management
Grade 1
Grade 1 AST or ALT >
ULN to 3.0 x ULN 
and/or Total bilirubin >
ULN to
1.5 x ULN
-Continue study treatment.
-Continue liver function monitoring.
-If worsens: Treat as Grade 2 or 3 - 4.
Grade 2
AST or ALT >3.0 to
≤5 x ULN and/or
total bilirubin >1.5 to 
≤3 x ULN
-Withhold study treatment.
-Increase frequency of monitoring
to every 3 days.
-If returns to Grade ≤1:
-Resume routine monitoring; 
resume study treatment.
-If elevation persists > 5 to 7 days or 
worsens: 
-Treat as Grade 3 to 4.
Grade 3 to 4
AST or ALT >5 x
ULN and/or total
bilirubin >3 x ULN
-Permanently discontinue study 
treatment.
-Increase frequency of
monitoring to every 1 to 2 days.
-1.0 to 2.0 mg/kg/day prednisone or
equivalent.
-Add prophylactic antibiotics for
opportunistic infections.
-Consult 
gastroenterologist/hepatologist.
-Consider obtaining MRI/CT scan of 
liver and liver biopsy if clinically 
warranted.
-If returns to Grade ≤1:
-Taper steroids over at least 1 month.
-If does not improve in >3 to 5 days,
worsens or rebounds:
-Add mycophenolate mofetil 1 gram 
(g) twice daily.
-If no response within an additional 3
to 5 days, consider other 
immunosuppressants per local
guidelines.


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Page 171
Renal irAEs
Grade of Creatinine 
Increased (NCI-CTCAE v4)
Initial Management
Follow-up
Management
Grade 1
Creatinine increased > ULN to 1.5
x ULN
-Continue study treatment.
-Continue renal function
monitoring.
-If worsens: Treat as Grade
2 to 3 or 4.
Grade 2 to 3
Creatinine increased >1.5 and ≤6 x
ULN
-Withhold study treatment.
-Increase frequency of monitoring to
every 3 days.
-1.0 to 2.0 mg/kg/day prednisone or 
equivalent.
-Add prophylactic antibiotics for
opportunistic infections.
-Consider renal biopsy.
-If returns to Grade ≤1:
-Taper steroids over at least 
1 month, and resume study 
treatment following
steroids taper.
-If worsens:
-Treat as Grade 4.
Grade 4
Creatinine increased >6 x ULN
-Permanently discontinue study treatment.
-Monitor creatinine daily.
-1.0 to 2.0 mg/kg/day prednisone or 
equivalent.
-Add prophylactic antibiotics for
opportunistic infections Consider renal 
biopsy.
-Nephrology consult.
-If returns to Grade ≤1:
Taper steroids over at least 
1 month.


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Page 172
Cardiac irAEs
Myocarditis
Initial Management
Follow-up
Management
New onset of cardiac signs or 
symptoms and / or new laboratory
cardiac biomarker elevations (eg,
troponin, CK-MB, BNP) or 
cardiac imaging abnormalities
suggestive of myocarditis.
-Withhold study treatment.
-Hospitalize.
-In the presence of life threatening cardiac 
decompensation, consider transfer to a 
facility experienced in advanced heart 
failure and arrhythmia management.
-Consult cardiologist to establish etiology
and rule-out immune-mediated
myocarditis.
-Guideline based supportive treatment as
per cardiology consult.*
-Consider myocardial biopsy if
recommended per cardiology consult.
-If symptoms improve
and immune-mediated
etiology is ruled out, re-
start study treatment.
-If symptoms do not 
improve/worsen, viral 
myocarditis is excluded, 
and immune-mediated
etiology is suspected or 
confirmed following
cardiology consult, 
manage as immune-
mediated myocarditis.
Immune-mediated myocarditis
-Permanently discontinue study treatment.
-Guideline based supportive treatment as
appropriate as per cardiology consult.*
1.0 to 2.0 mg/kg/day prednisone or 
equivalent.
-Add prophylactic antibiotics for
opportunistic infections.
-Once improving, taper
steroids over at least 1 
month.
If no improvement or 
worsening, consider 
additional 
immunosuppressants
(eg, azathioprine,
cyclosporine A).
*Local guidelines, or eg. ESC or AHA guidelines
ESC guidelines website: https://www.escardio.org/Guidelines/Clinical-Practice-
Guidelines AHA guidelines website:
http://professional.heart.org/professional/GuidelinesStatements/searchresults.jsp?q=&y=&t=1001


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Page 173
Endocrine irAEs
Endocrine Disorder
Initial Management
Follow-up
Management
Grade 1 or Grade 2 
endocrinopathies
(hypothyroidism,
hyperthyroidism,
adrenal insufficiency,
type I diabetes mellitus)
-Continue study treatment.
-Endocrinology consult if needed.
-Start thyroid hormone replacement 
therapy (for hypothyroidism),
anti-thyroid treatment (for 
hyperthyroidism), corticosteroids (for
adrenal insufficiency) or insulin (for 
Type I diabetes mellitus) as appropriate.
-Rule-out secondary endocrinopathies (ie,
hypopituitarism / hypophysitis).
-Continue hormone 
replacement/suppression
and monitoring of 
endocrine function as 
appropriate.
Grade 3 or Grade 4 
endocrinopathies
(hypothyroidism,
hyperthyroidism,
adrenal insufficiency,
type I diabetes mellitus)
-Withhold study treatment.
-Consider hospitalization.
-Endocrinology consult.
-Start thyroid hormone replacement 
therapy (for hypothyroidism),
anti-thyroid treatment (for 
hyperthyroidism), corticosteroids (for
adrenal insufficiency) or insulin (for type
I diabetes mellitus) as appropriate.
-Rule-out secondary endocrinopathies (ie,
hypopituitarism / hypophysitis).
-Resume study treatment 
once symptoms and/or
laboratory tests improve to
Grade ≤1 (with or without
hormone
replacement/suppression).
-Continue hormone 
replacement/suppression
and monitoring of 
endocrine function as 
appropriate.
Hypopituitarism/ 
Hypophysitis
(secondary
endocrinopathies)
-If secondary thyroid and/or adrenal 
insufficiency is confirmed (ie, subnormal
serum FT4 with inappropriately low TSH
and/or low serum cortisol with
inappropriately low ACTH) :

-Refer to endocrinologist for dynamic 
testing as indicated and measurement
of other hormones (FSH, LH,
GH/IGF-1, PRL,
testosterone in men, estrogens in 
women).

-Hormone replacement/suppressive 
therapy as appropriate.


-Perform pituitary MRI and visual 
field examination as indicated.
-If hypophysitis is confirmed:

-Continue study treatment if 
mild symptoms with normal 
MRI. Repeat the MRI in 1 
month.

-Resume study treatment 
once symptoms and
hormone tests improve to
Grade ≤1 (with or without
hormone replacement).
-In addition, for
hypophysitis with
abnormal MRI, resume
study treatment only once
shrinkage of the pituitary
gland on MRI/CT scan is 
documented.
-Continue hormone 
replacement/suppression 
therapy as appropriate.


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Page 174
Endocrine irAEs
Endocrine Disorder
Initial Management
Follow-up
Management

-Withhold study treatment if moderate,
severe or life-threatening symptoms of 
hypophysitis and/or abnormal MRI.
Consider hospitalization. Initiate 
corticosteroids (1 to 2 mg/kg/day 
prednisone or equivalent) followed by
corticosteroids taper during at least 1 
month.

-Add prophylactic antibiotics for
opportunistic infections.


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Page 175
Other irAEs (not described above)
Grade of other
irAEs (NCI-
CTCAE v4)
Initial Management
Follow-up Management
Grade 2 or Grade 3 clinical
signs or symptoms
suggestive of a potential
irAE
-Withhold study treatment pending
clinical investigation.
-If irAE is ruled out, manage as
appropriate according to the 
diagnosis and consider re-
starting study treatment
-If irAE is confirmed, treat as
Grade 2 or 3 irAE.
Grade 2 irAE  or first 
occurrence of Grade 3 irAE
-Withhold study treatment.
-1.0 to 2.0 mg/kg/day prednisone  
or equivalent.
-Add prophylactic antibiotics 
for opportunistic infections.
-Specialty consult as appropriate.
-If improves to Grade ≤1:
-Taper steroids over at least 1
month and resume study 
treatment following steroids 
taper.
Recurrence of same Grade 3 
irAEs
-Permanently discontinue  study 
treatment.
-1.0  to 2.0 mg/kg/day prednisone or 
equivalent.
-Add prophylactic antibiotics for 
opportunistic infections.
-Specialty consult as appropriate.
-If improves to Grade ≤1:
Taper steroids over at least 1 
month.
Grade 4
-Permanently discontinue study 
treatment.
-1.0  to 2.0 mg/kg/day prednisone  or 
equivalent and/or other 
immunosuppressant as needed
-Add prophylactic antibiotics for 
opportunistic infections.
-Specialty consult.
-If improves to Grade ≤1:
Taper steroids over at least 1 
month.
Requirement for 10 mg per 
day or greater prednisone 
or equivalent for more than 
12 weeks for reasons other 
than hormonal replacement 
for adrenal insufficiency
Persistent Grade 2 or 3 irAE 
lasting 12 weeks or longer
- Permanently discontinue study 
treatment.
-Specialty consult.
Abbreviations: ACTH=adrenocorticotropic hormone; ADL=activities of daily living; ALT=alanine aminotransferase;
AST=aspartate aminotransferase; BNP=B-type natriuretic peptide; CK-MB=creatine kinase MB; CT= computed
tomography; FSH=follicle-stimulating hormone; GH=growth hormone; IGF-1=insulin-like growth factor 1; irAE=immune-
related adverse event; IV=intravenous; LH=luteinizing hormone; MRI=magnetic resonance imaging; NCI-
CTCAE=National Cancer Institute-Common Terminology Criteria for Adverse Events; PRL=prolactin; T4=thyroxine; 
TSH=thyroid-stimulating hormone; ULN=upper limit of normal.


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PFIZER CONFIDENTIAL
Page 176
Appendix 9. Subcutaneous Injection Site Location Diagram
Injection site locations include a maximum of 8 unique administration sites distributed across 
4 abdominal quadrants with a possibility of up to 2 injection locations per quadrant.  
Location 1 is proximal to the umbilicus and Location 2 is distal to the umbilicus.
Administer the required number of injections in the following order:
1. Lower Left Quadrant Location 1
2. Lower Right Quadrant Location 1
3. Lower Left Quadrant Location 2
4. Lower Right Quadrant Location 2
5. Upper Right Quadrant Location 1
6. Upper Left Quadrant Location 1
7. Upper Right Quadrant Location 2
8. Upper Left Quadrant Location 2
Injections to the abdomen are preferred.  If SC injections in the abdominal location are not 
possible, SC injections can be administered in a distributed manner in the thighs.  SC 
injections in the upper extremities (eg, deltoid, upper and lower arm) are not permitted.
Track the patient’s injection site(s) sequentially on this diagram with a red pen and mark the 
injection sites on the patient’s abdomen according to your clinic’s standard practice.
Record the location, time of each injection and any injection site reactions in the patient’s 
source records and study CRF. Complete one CRF per injection.
Upper Left
Lower Left
Lower Right
Upper Right
1
1
1
1
2
2
2
2

SAP_001.pdf: 
Protocol B8011001 (PF-06801591) Statistical Analysis Plan Amendment 2
PFIZERCONFIDENTIAL
Page 1
Protocol B8011001
A Phase 1, Open-Label, Dose Escalation and Expansion Study of PF-06801591 in 
Patients with Locally Advanced or Metastatic Melanoma, Squamous Cell Head and 
Neck Cancer, Ovarian Carcinoma, Sarcoma, Non-Small Cell Lung Cancer, Urothelial 
Carcinoma or other Solid Tumors
Statistical Analysis
Plan (SAP)
Version:
Amendment 2
Author:
(Early Clinical Development Statistics, Cambridge, MA, USA)
Date:
24-AUG-2020
PPD


Protocol B8011001 (PF-06801591) Statistical Analysis Plan Amendment 2
PFIZERCONFIDENTIAL
Page 2
TABLE OF CONTENTS
LIST OF TABLES .................................................................................................................... 4
LIST OF FIGURES................................................................................................................... 4
1. VERSION HISTORY ........................................................................................................... 5
2. INTRODUCTION................................................................................................................. 6
2.1. Study Objectives....................................................................................................... 6
2.2. Study Design............................................................................................................. 8
2.2.1. MTD Determination (Part 1)........................................................................ 9
2.2.2. Part 2 Dose Expansion............................................................................... 11
3. ENDPOINTS AND COVARIATES: DEFINITIONS AND CONVENTIONS................. 11
3.1. Primary Endpoint(s) ............................................................................................... 11
3.2. Secondary Endpoint(s) ........................................................................................... 12
4. ANALYSIS SETS............................................................................................................... 14
4.1. Full Analysis Set..................................................................................................... 14
4.2. Safety Analysis Set................................................................................................. 14
4.3. ‘PER PROTOCOL’ Analysis Set........................................................................... 14
4.4. PK Analysis Set...................................................................................................... 15
4.4.1. PK Concentration Set................................................................................. 15
4.4.2. PK Parameter Set ....................................................................................... 15
4.5. PD Biomarker Analysis Set.................................................................................... 15
4.6. Modified Intent-to-Treat Set................................................................................... 15
4.7. Immunogenicity Analysis Set................................................................................. 15
4.8. Treatment Misallocations ....................................................................................... 15
4.9. Protocol Deviations ................................................................................................ 15
5. GENERAL METHODOLOGY AND CONVENTIONS ................................................... 16
5.1. Statistical Hypotheses............................................................................................. 16
5.2. Statistical Decision Rules ....................................................................................... 16
5.2.1. Part 1 (MTD Finding) ................................................................................ 16
5.2.2. Part 2 (Dose Expansion) ............................................................................ 16
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Page 3
5.2.3. Sample Size Determination........................................................................ 17
5.3. General Methods..................................................................................................... 17
5.3.1. Analyses for Time to Event Data............................................................... 18
5.3.2. Analyses for Binary Data........................................................................... 18
5.3.3. Analyses for Continuous Data ................................................................... 18
5.4. Methods to Manage Missing Data.......................................................................... 18
5.4.1. Missing Dates............................................................................................. 18
5.4.2. Efficacy Analysis ....................................................................................... 18
5.4.3. Pharmacokinetics ....................................................................................... 19
5.5. Statistical Considerations of COVID-19 Impacted Data........................................ 20
6. ANALYSES AND SUMMARIES ..................................................................................... 20
6.1. Standard Analyses .................................................................................................. 21
6.2. Analysis of Primary Endpoint ................................................................................ 23
6.2.1. DLT (Part 1)............................................................................................... 23
6.2.2. Safety Endpoints (Part 1 and Part 2).......................................................... 24
6.2.3. ORR (Part 2) .............................................................................................. 24
6.3. Analysis for Secondary Endpoints.......................................................................... 25
6.3.1. Efficacy Endpoints Analysis...................................................................... 25
6.3.2. Pharmacokinetics Analyses........................................................................ 27
6.3.3. Immunogenicity Assessment ..................................................................... 29
6.3.4. RO of PD-1 by PF-06801591 in Circulating T Cells................................. 29
6.5. Population PK and PK/PD Modeling ..................................................................... 29
6.6. ECG and Vital Sign Data Analysis......................................................................... 30
7. INTERIM ANALYSES ...................................................................................................... 31
8. REFERENCES.................................................................................................................... 33
9. APPENDICES..................................................................................................................... 34
9.1. Details of Definitions of Endpoints ........................................................................ 34
9.2. Time to Event Data Analysis Censoring Rules ...................................................... 37
9.3. Categorical Classes for ECG and Vital Signs......................................................... 39
9.4. RECIST 1.1 Tumor Assessment Criteria ............................................................... 41
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Protocol B8011001 (PF-06801591) Statistical Analysis Plan Amendment 2
PFIZERCONFIDENTIAL
Page 4
9.5. Immune-related RECIST (irRECIST) Tumor Assessment Criteria....................... 48
LIST OF TABLES
Table 1.
Decision Rules ......................................................................................... 10
LIST OF FIGURES
Figure 1
B8011001 Study Schematic....................................................................... 8


Protocol B8011001 (PF-06801591) Statistical Analysis Plan Amendment 2
PFIZERCONFIDENTIAL
Page 5
1. VERSION HISTORY
Amendment 
2
Section
Update
5.5
A new section is added to address the analysis 
strategies on data that is impacted by the 
COVID-19 pandemic. 
Appendix 
9.2 
Removed the PFS window. The statistical 
programming standard for this study is 
switching from Pfizer Data Standard (PDS) to 
CaPS (CDISC and Pfizer Standard), to be 
consistent with the late stage studies of the 
program (B8011006 and B8011007) that are 
being conducted at the time of this SAP 
amendment. In CaPS, the PFS window is no 
longer required. Table 9.2.1 and 9.2.2 are 
updated to be consistent with CaPS 
requirements. 
Amendment 
1
Section
Update
All 
Texts taken directly from the protocol are 
made italicized
2.1
Objectives are updated and reformatted per 
protocol amendment 3
2.2 
Study design is updated per protocol 
amendment 3
3
Endpoints are updated per protocol 
amendment 3
4
Analysis sets are updated per protocol 
amendment 3
5.2.2.
Statistical decision rules are updated for Part 2 
per protocol amendment 3
5.3
General statistical methods are updated with 
additional details for programming personnel
6
Details about unconfirmed and confirmed 
tumor response and progression for RECIST 
1.1 and irRECIST added.
6.1
Cycle delay is updated; Cycle skip is added
6.3.1
Editorial changes were made to the efficacy 
endpoints analyses
7
Informal data monitoring is added 
9.6
All lymphoma response assessment is removed 
per protocol amendment 3


Protocol B8011001 (PF-06801591) Statistical Analysis Plan Amendment 2
PFIZERCONFIDENTIAL
Page 6
2. INTRODUCTION
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in study B8011001. 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. This SAP amendment is based on the protocol amendment 3 
dated June 3, 2017. 
Note: in this document any text taken directly from the protocol is italicized.
2.1. Study Objectives
Part 1 (Dose-Escalation) Primary Objective
•
To assess safety and tolerability of increasing dose levels of PF-06801591 in patients with 
locally advanced or metastatic melanoma, SCCHN, ovarian carcinoma, sarcoma, NSCLC, 
urothelial carcinoma or other solid tumor types with clinical evidence of response to anti 
PD-1 or PD-L1 agents to establish the MTD.
•
To assess safety and tolerability of PF-06801591 administered SC in patients with locally 
advanced or metastatic melanoma, SCCHN, ovarian cancer, sarcoma, NSCLC, urothelial 
carcinoma or other solid tumor types with clinical evidence of response to anti PD-1 or PD-
L1 agents.
Part 1 (Dose-Escalation) Secondary Objective
•
To characterize the single-dose and multiple-dose PK of PF-06801591 following IV or SC 
administration.
•
To evaluate the immunogenicity of PF-06801591 following repeated administration.
•
To characterize PD-1 receptor occupancy (RO) in peripheral blood T cells following IV or 
SC PF-06801591 administration at each dose level.
•
To evaluate preliminary anti-tumor activity of PF-06801591.
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Protocol B8011001 (PF-06801591) Statistical Analysis Plan Amendment 2
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Page 7
Part 2 (Dose-Expansion) Primary Objective
•
To further characterize the safety and tolerability of PF-06801591 following SC 
administration in NSCLC and urothelial carcinoma.
•
To estimate clinical efficacy by overall response rate (ORR) of PF-06801591 following SC 
administration in NSCLC and urothelial carcinoma.
Part 2 (Dose-Expansion) Secondary Objective
•
To further evaluate preliminary anti-tumor activity of PF-06801591 following SC 
administration.
•
To evaluate overall survival (OS).
•
To collect PF-06801591 drug concentration data in patients following SC administration for 
evaluation of population PK.
•
To evaluate the immunogenicity of PF-06801591 following repeated SC administration.
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2.2. Study Design
This is a Phase 1, open-label, multi-center, multiple-dose, dose escalation and expansion, safety,
PK, and PD study of PF-06801591 in previously treated patients with locally advanced or
metastatic solid tumor types with clinical evidence of response to anti PD-1 or PD-L1 agents.  This
clinical trial will include 2 parts: Part 1 dose escalation and Part 2 dose expansion (Figure 1). A 
total of approximately 140 patients will be enrolled into this study. 
Figure 1
B8011001 Study Schematic
Part 1 will enroll patients with locally advanced or metastatic melanoma, SCCHN, ovarian cancer, 
sarcoma, NSCLC, urothelial carcinoma, or other solid tumor types with clinical evidence of 
response to anti PD-1 or PD-L1 agents. Patients will receive 0.5, 1, 3, or 10 mg/kg 
PF-06801591 intravenously (IV) every 3 weeks (q3w), or 300 mg PF-06801591 subcutaneously 
every 4 weeks (q4w). The Part 1 dose escalation phase will enroll approximately 8 to 15 patients 
per dose level. 
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Part 1 will be further divided into Part 1A (safety cohort) 
. 
For both IV and SC administration portions, each safety cohort will enroll 2-4 patients per dose 
level. 
 
 
All patients in Part 2 will receive 300 mg PF-06801591 SC q4w. Part 2 dose expansion will 
include 2 arms: Arm 1 will enroll approximately 60 patients with NSCLC who progressed on or 
were intolerant to systemic therapy or for whom systemic therapy was refused or unavailable but 
have not previously received anti-PD-1 or anti-PD-L1.  Arm 2 will enroll approximately 40 
patients with urothelial carcinoma who progressed on or were intolerant to systemic therapy or for 
whom systemic therapy was refused or unavailable but have not previously received anti-PD-1 or 
anti-PD-L1. Approximately 100 patients will be enrolled into Part 2.
2.2.1. MTD Determination (Part 1)
Part 1 will study sequential cohorts (0.5, 1, 3, and 10 mg/kg, or 300 mg SC) of PF-06801591 in 
adult patients with locally advanced or metastatic melanoma, SCCHN, ovarian cancer, sarcoma, 
NSCLC, urothelial carcinoma, or other solid tumor types with clinical evidence of response to anti 
PD-1 or PD-L1 agents who are unresponsive to currently available therapies or for whom no
standard therapy is available.  An mTPI method, targeting a dose limiting toxicity (DLT) rate of
27.5% will be utilized for dose escalation. In the IV administration portion, if based on Part 1A 
information the dose level is deemed safe and well- tolerated, an additional 2 to 5 patients will 
enroll into the same dose level in Part 1B.  In the SC administration portion, if based on Part 1A 
information the 300 mg dose level is deemed safe and well- tolerated, up to an additional 
11 patients (approximately) will be enrolled into Part 1B.  Up to approximately 9 patients may be 
enrolled into each dose level in the IV administration portion, and up to approximately 15 patients 
may be enrolled into the 300 mg SC administration cohort (Part 1A and Part 1B combined).  The 
mTPI approach would be applied across Parts 1A and 1B to ensure that administered doses do not 
surpass the toxicity boundaries.  Safety data from all patients in Parts 1A (safety cohort) 
 
 will be used to determine the 
MTD.  The dose finding decision will be based on 1-cycle (21-day) DLT observation for patients 
enrolled into IV administration portion and 1-cycle (28-day) DLT observation for patients enrolled 
into subcutaneous dosing portion.  A staggered start will be employed at all dose levels.  A single
patient will be dosed and observed for 48 hours. If no safety concerns arise during this 48-hour 
period, a second patient will be enrolled into the same dose level cohort.
Late immune-related DLTs are irAEs that meet the same grading criteria as DLT criteria but occur 
after the initial 21-day DLT period for IV administration, or 28 days for SC administration, and 
during the 120-day assessment period.  Late immune-related DLTs will be added to the mTPI 
approach to reassess the dose-finding decisions. 
Safety information, provided by additional patients enrolled into each dose level expansion will
also be taken into account for MTD determination. If the DLT rate is estimated to reach >33% or
more at any dose level, enrollment at that level and all higher levels will be temporarily stopped,
and safety data will be analyzed. The decision to move forward with enrollment will follow the 
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same DLT target as described previously. Dose escalation will continue until an MTD has been 
established or a prespecified maximum dose level has been reached.
The mTPI method relies upon a statistical probability algorithm, calculated using all patients 
treated in the current dose level to determine one of the following dose-finding decisions: the
subsequent dose should be escalated, maintained at the current dose, or de-escalated in the next
cohort of 2 to 4 patients, or the trial should be terminated (see Table 1).
In principle, all patients must be evaluated for a minimum period of 21 days (q3w dosing interval)
or 28 days for the subcutaneous cohort. If a patient withdraws from the study before Day 21 (or 28 
days for the subcutaneous cohort) for reasons other than drug- related toxicity, another patient may
be enrolled to replace that patient in the current cohort. However, if a patient discontinues close to 
Day 21 (or 28 days for the subcutaneous cohort) for reasons other than toxicity and due to an 
evident nondrug-related event, the patient may be deemed evaluable for safety if safety assessments
have been unremarkable and the investigator and sponsor’s medical monitor both agree that the 
patient is evaluable for DLT safety observation.
Table 1.
Decision Rules
The dose escalation Part 1 of the study will stop if any of the following criteria is met:
1. The maximum sample size has been achieved (approximately 40 patients in total);
2. 6 to 15 patients have been enrolled at a dose level that is predicted to be the MTD per the 
mTPI method;
3. All dose levels explored appear to be overly toxic, and the MTD cannot be determined;
4. All candidate dose levels have been tested and deemed safe.
Number 
of 
Patients 
having 
DLT
Number of Patients Treated at a Dose Level
n=2
n=3
n=4
n=5
n=6
n=7
n=8
n=9
n=10
n=11
n=12
n=13
n=14
n=15
0
E
E
E
E
E
E
E
E
E
E
E
E
E
E
1
S
S
S
E
E
E
E
E
E
E
E
E
E
E
2
U
D
S
S
S
S
S
S
S
E
E
E
E
E
3
U
U
D
D
S
S
S
S
S
S
S
S
S
4
U
U
U
U
D
D
D
S
S
S
S
S
5
U
U
U
U
U
D
D
D
D
D
S
6
U
U
U
U
U
U
U
D
D
D
7
U
U
U
U
U
U
U
U
U
Actions to be taken:
D = De-escalate the dose; E: Escalate the dose; S: Stay at the dose.
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2.2.2. Part 2 Dose Expansion
Part 2 dose expansion will include 2 arms: Arm 1 will enroll approximately 60 patients with 
NSCLC who progressed on or were intolerant to systemic therapy or for whom systemic therapy 
was refused or unavailable but have not previously received anti-PD-1 or anti-PD-L1.  Arm 2 will 
enroll approximately 40 patients with urothelial carcinoma who progressed on or were intolerant 
to systemic therapy or for whom systemic therapy was refused or unavailable but have not 
previously received anti-PD-1 or anti-PD-L1.  All patients in Part 2 will receive 300 mg 
PF-06801591 SC q4w.  The 300 mg SC dose level in Part 2 was selected based upon safety, PK, 
PD, and preliminary anti-tumor activity observed in Part 1, as well as the maximum injection 
volume considered feasible with the current formulation.
After the first 30 NSCLC patients have been enrolled and have either completed their first tumor 
assessment (at approximately 8 weeks post treatment), or have discontinued from the study before 
their first scheduled tumor assessment, preliminary assessment of safety and efficacy data maybe 
completed.  This preliminary data may provide guidance in the decision to the increase or 
decrease the sample size of each arm, to add other tumor types in a future amendment, or to 
initiate additional clinical studies. The specific details for this data look are described in Section 7. 
3. ENDPOINTS AND COVARIATES: DEFINITIONS AND CONVENTIONS
3.1. Primary Endpoint(s)
Part 1:

DLTs at escalated doses of PF-06801591.The specific definition of DLT is provided in the 
study protocol. 

Adverse Events (AEs) as characterized by type, frequency, severity (as graded by National 
Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] version
4.03), timing, seriousness, and relationship to study therapy PF-06801591.

Laboratory abnormalities as characterized by type, frequency, severity (as graded by NCI
CTCAE version 4.03), and timing.
Part 2:

AEs as characterized by type, frequency, severity (as graded by NCI CTCAE version 4.03), 
timing, seriousness and relationship to study therapy PF-06801591 administered by SC 
administration.

Laboratory abnormalities as characterized by type, frequency, severity (as graded by NCI
CTCAE version 4.03) and timing.

ORR as assessed using RECIST version 1.1 and irRECIST. ORR is defined as the 
proportion of patients who achieved completed response (CR) or partial response (PR) per 
RECIST 1.1, or irRECIST.


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3.2. Secondary Endpoint(s)
Part 1:

PK parameters of PF-06801591: Cycle 1 and Cycle 4 Cmax, area under the concentration
versus time curve (AUC) from time zero to the last quantifiable time point prior to the next
dose (AUClast), and if data permit, CL, Vd, volume of distribution at steady state (Vss), 
accumulation ratio (Rac) when feasible, and terminal elimination t1/2.

Incidence of anti-drug antibodies (ADA) and neutralizing antibodies (NAb) against PF-
06801591.

PD-1 receptor occupancy (RO) by PF-06801591, as assessed by measuring the levels of 
unbound (free) cell surface PD-1 on circulating T cells over time following PF-06801591 
administration.

Objective tumor response, as assessed using the Response Evaluation Criteria in Solid
Tumor (RECIST) version 1.1 and immune-related RECIST (irRECIST); and proportion of 
subjects with PR (and irPR, as appropriate).

Time-to-event endpoints based on RECIST and irRECIST and PFS (and irPFS as
appropriate), Duration of stable disease (DOSD, or irDOSD as appropriate), and Duration
of response (DOR, or irDOR as appropriate).

PFS is defined as the time from treatment start date to date of first documentation of 
progression or death due to any cause. 

Duration of stable disease is defined from the start of the treatment until the criteria for 
progression are met, taking as reference the smallest tumor measurements recorded 
since the treatment started, including the baseline measurements. This endpoint is 
applicable to the subset of patients who achieved a best overall response of stable 
disease (SD), those patients whose best overall response is not SD will be excluded 
from this endpoint analysis. A minimum of 6 weeks (with a - 5 days window, which is 
essentially a minimum of 35 days) interval of two assessments is required for this 
endpoint. 

Duration of response is defined as the time from start date (which is the date of first 
documentation of PR or CR) to date of first documentation of objective progression or 
death. DOR is only applicable to those patients with an objective response. 


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Part 2:
•
Time to event endpoints by PF-06801591 administered by SC based on RECIST and 
irRECIST, including time to response (TTR) and time to progression (TTP) as well as PFS 
(and irPFS as appropriate), DOSD (and irDOSD as appropriate), and DOR (and irDOR as 
appropriate). Time to response is defined as the time from the study treatment date to the 
first documentation of PR or CR. Time to progression is the time from start date to date of 
first documentation of objective progression.
•
Median time to death, proportion of patients alive at 6 months, 1 year, and 2 years. Time to 
death (i.e. overall survival) is the time from treatment start date to date of death due to any 
cause. 
•
Trough PF-06801591 concentrations for selected cycles.
•
Incidence of ADA and NAb against PF-06801591 administered by SC.
Detailed descriptions of Endpoints are provided in Appendice 9.1, 9.4, and 9.5.
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4. ANALYSIS SETS
4.1. Full Analysis Set
The full analysis set includes all enrolled patients. This is equivalent to the ITT (intent-to- treat) 
population.
4.2. Safety Analysis Set
The safety analysis set includes all enrolled patients who receive at least one dose of study
medication.
4.3. ‘PER PROTOCOL’ Analysis Set
The per protocol analysis set includes all enrolled patients who received at least one dose of study 
treatment and who did not have major treatment deviations during the Cycle 1.  For the IV 
administration of PF-06801591, patients with major treatment deviations in the 21-day DLT 
observation period are not evaluable for the MTD assessment and will be replaced as needed to 
permit MTD estimation. 
For the SC administration of PF-06801591, patients with major treatment deviations in the 28-day 
observation period will not be evaluable for DLT. 
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Major treatment deviations include:

Administration of <50% of the planned dose of PF-06801591, provided that the reduction is 
not due to toxicity attributable to PF-06801591.

Administration of >150% of the planned dose of PF-06801591.
4.4. PK Analysis Set
4.4.1. PK Concentration Set
The PK concentration population is defined as all patients who receive PF-06801591, have no
protocol deviations affecting the PK assessment, and have at least 1 post-dose concentration 
measurement.
4.4.2. PK Parameter Set
The PK parameter analysis population is defined as all enrolled patients treated who have
sufficient information to estimate at least 1 of the PK parameters of interest.
4.5. PD Biomarker Analysis Set
The biomarker analysis set includes all enrolled patients with at least one of the 
pharmacodynamic/biomarker parameters evaluated at pre- and/or post-dose.
4.6. Modified Intent-to-Treat Set
The modified intent-to-treat (mITT) population is defined as all the randomized subjects who have 
received at least 1 dose of study medication, have measurable disease baseline assessment (within
28 days prior to study entry) and at least 1 post baseline assessment or disease progression, global 
deterioration of health status, or death.  The mITT population will be used for anti-tumor
assessment.
4.7. Immunogenicity Analysis Set 
The immunogenicity analysis set is defined as patients who receive at least 1 dose of study treatment 
and have at least 1 ADA or NAb sample collected.
4.8. Treatment Misallocations
Subjects who receive the wrong initial dose for whatever reason will be analyzed according to the 
initial dose actually received.  Subjects who receive the wrong dose after the initial dose will be 
analyzed according to the initial dose received.
4.9. Protocol Deviations
The determination of protocol deviations (PDs) and important protocol deviations (IPDs) will
follow Pfizer standard operating procedures. A full list of PDs, IPDs, and IPDs that are excluded 
from Per-protocol analysis will be determined prior to the database release and be included in the
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5. GENERAL METHODOLOGY AND CONVENTIONS
This is an open-label dose escalation study and no interim analysis or blinding is planned for this 
study.  
5.1. Statistical Hypotheses
There are no statistical hypotheses. 
5.2. Statistical Decision Rules
5.2.1. Part 1 (MTD Finding)
Part 1 dose escalation phase of this study employs an mTPI design to estimate the MTD. The mTPI
design employs a simple beta-binomial model with prior a conjugated prior beta (0.5, 0.5).  
Decision rules are based on calculating the unit probability mass (UPM) of 3 intervals
corresponding to underdosing, proper dosing, and overdosing in terms of dose limiting toxicity.  A 
proper dosing interval is centered at the target toxicity rate (pT) of 27.5% with 5% uncertainty
(0.225 < pT <0.325). The under dosing interval is (0, 0.225), and the overdosing interval is 
(0.325, 1). The 3 dosing intervals are associated with 3 different dose escalation decisions. The 
underdosing interval corresponds to a dose escalation (E), overdosing corresponds to a dose de-
escalation, and proper-dosing corresponds to staying at the same current dose. Given an interval 
and a probability distribution, the UPM of that interval is defined as the probability of the interval 
divided by the length of the interval. The mTPI design calculates the UPMs for the 3 dosing
intervals, and the one with the largest UPM implies the corresponding dose-finding decision. That
decision provides the dose level to be used for future patients.  For example, if the underdosing 
interval has the largest UPM, decision E (to escalate) will be executed, and the next cohort of
patients will be treated at the next-higher dose level. Under the mTPI design, a trial is terminated
when either the lowest dose is above the MTD or a pre-specified maximum sample size for Part 1
(approximately 40) is reached.
The following table shows the probability of escalating to the next dose level for a range of 
underlying true DLT rates.  For example, for a cohort size of n=3 and for a DLT that occurs in 
10% of patients, there is a greater than 90% probability of escalating. Conversely, for a DLT that 
occurs with a rate of 70%, the probability of escalating is 3%. It is assumed that dose escalation 
occurs with either 0/3 or 1/6 patients with DLTs.
Probability of Escalating Dose
True underlying DLT rate
10%
20%
30%
40%
50%
60%
70%
80%
90%
Probability of escalating
0.91
0.71
0.49
0.31
0.17
0.08
0.03
0.009
0.001
5.2.2. Part 2 (Dose Expansion)
Part 2 (N=100) of this study is intended to further characterize the safety, efficacy, PK, PD, and 
immunogenicity profiles of 300 mg of SC PF-06801591 in anti-PD-1 or anti-PD-L1 treatment 
naïve patients with NSCLC (N=60) and urothelial carcinoma (N=40) who have progressed on or 
were intolerant to systemic therapy or for whom systemic therapy was refused or unavailable.  


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Summary statistics will be provided for trough PF-06801591 concentrations, safety endpoints, 
immunogenicity, pharmacodynamic/biomarkers, and efficacy data.
When the first 30 NSCLC patients have been enrolled and have either completed their first tumor 
assessment (at approximately 8 weeks post treatment), or have discontinued from the study before 
their first scheduled tumor assessment, preliminary assessment of safety and efficacy data may be 
completed.  This preliminary data may provide guidance in the decision to increase or decrease 
the size of each arm, to add other tumor types in a future amendment, or to initiate additional 
clinical studies.
5.2.3. Sample Size Determination
The exact sample size for the dose escalation design in Part 1 cannot be specified in advance due 
to the dynamic features of mTPI.  For the first dose level (0.5 mg/kg IV), in the absence of actual 
DLTs, a total of 2 patients will be enrolled: 2 patients in Part 1A and no patient in Part 1B.  For 
subsequent dose levels it is anticipated that approximately 2 to 4 patients will be enrolled in Part 
1A and approximately 2 to 5 patients in Part 1B with available pre- and on-treatment biopsies for 
IHC testing and up to 9 patients at dose levels 1, 3, and 10 mg/kg administered by IV in Part 1.  A 
single cohort with SC administration at a dose level of 300 mg of PF-06801591 will be opened for 
enrollment shortly after the cohort at a dose level of 3 mg/kg IV in Part 1A will have completed 
enrollment and the 21-day DLT observation period.  This cohort at a dose level of 300 mg SC will 
seek 2 to 4 patients in Part 1A, up to 11 patients in Part 1B with available pre- and on-treatment 
biopsies for IHC testing, and up to 15 patients in Part 1.  The actual Part 1 sample size may be 
smaller, depending on the underlying dose toxicity profile, and the number of dose levels studied.
Part 2 of the study will enroll approximately 60 patients with NSCLC who progressed on or were 
intolerant to systemic therapy or for whom systemic therapy was refused or unavailable and are 
treatment naïve for anti-PD-1 or anti-PD-L1.  NSCLC was selected for historical comparability to 
prior large anti-PD-1 studies and dosing of 300 mg SC in Part 2 has been selected based on safety, 
PK, available biomarker data and preliminary anti-tumor activity from Part 1.  There is no 
hypothesis testing in Part 2.  Estimation approach is used to characterize the precision of response 
data.  The estimation of ORR using N=60 is described as follows.  Suppose that the ORR estimate 
is 19% in Part 2 with N=60, then the 80% and 90% confidence intervals of the true ORR will be 
(13.3, 26.3%) and (12.1, 28.6%) respectively.  Note that an ORR of 19% was observed in a clinical 
trial for nivolumab in previously treated NSCLC patients.  In Part 2, approximately 40 urothelial 
cancer patients will also be enrolled, the sample size is based on clinical considerations of 
expanding the safety database.
5.3. General Methods
Whilst every effort has been made to pre-specify all analyses in this statistical analysis plan, if any
additional exploratory analyses be found to be necessary, the analyses and the reasons for them 
will be detailed in the clinical study report (CSR).
Unless otherwise specified, the baseline value is defined as the value collected at the time closest 
to, but prior to, the start of study drug administration in the first cycle. All data will be categorized


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based on the scheduled visit at which it was collected. These visit designators are predefined 
values that appear as part of the visit tab in the eCRF.
5.3.1. Analyses for Time to Event Data
Time to event endpoints in this study include progression-free survival (PFS), duration of response 
(DOR), duration of stable disease (DoSD), time to response (TTR), time to progression (TTP), and 
overall survival (OS). When appropriate and data permits, the immune-response version of these 
endpoints based on irRECIST will also be explored. The specific definitions of these endpoints are 
provided in Section 3. These endpoints will be summarized using the Kaplan-Meier method2 and 
displayed graphically when appropriate. Median event times and 2-sided 95% confidence 
intervals for each time-to-event endpoint (Brookmeyer and Crowley, 1982)3 will be provided.
5.3.2. Analyses for Binary Data
Binary endpoints in this study include ORR, complete response (CR), partial response (PR) based 
on RECIST 1.1. When appropriate and data permits, the immune-response version of these 
endpoints based on irRECIST will also be explored. If deemed necessary disease control rate (i.e. 
DCR, which is defined as the proportion of patients that achieved CR, or PR, or stable disease) 
may also be calculated for Part 2. Descriptive statistics along with the corresponding 2-sided 95%
confidence intervals using an exact method will be provided for these endpoints.
5.3.3. Analyses for Continuous Data
Descriptive statistics, such as the mean, standard deviation, coefficient of variation, median,
minimum, and maximum values, will be provided for continuous endpoints.
5.4. Methods to Manage Missing Data
5.4.1. Missing Dates
In compliance with Pfizer standards, if the day of the month is missing for any date used in a 
calculation, the 1st of the month will be used to replace the missing date unless the calculation
results in a negative time duration (eg, date of onset cannot be prior to day one date). In this case,
the date resulting in 0 time duration will be used. Pfizer standards are also used if both month and 
day are missing (Jan 1 unless negative time duration).  This excludes the pharmacokinetic, ECG, 
and pharmacodynamic analyses, which will only use the actual date collected or if date not 
available deem the data missing.
5.4.2. Efficacy Analysis
For the time-to-event endpoints, the missing data handling method will be censoring. Censoring 
rules for time-to-event endpoints are detailed in Appendix 9.2.


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5.4.3. Pharmacokinetics
Concentrations below the limit of quantification
In all data presentations (except listings), concentrations below the limit of quantification (BLQ)
will be set to zero.  (In listings BLQ values will be reported as “<LLQ”, where LLQ (i.e. lower 
limit of quantification) will be replaced with the value for the LLQ).
Deviations, missing concentrations and anomalous values
Patients who experience events that may affect their PK (eg, incomplete dosing) may be excluded 
from the PK analysis.
In summary tables and plots of median profiles, statistics will be calculated with concentrations set 
to missing if one of the following cases is true:
1. A concentration has been reported as ND (ie, not done) or NS (ie, no sample),
2. A deviation in sampling time is of sufficient concern or a concentration has been flagged 
anomalous by the pharmacokineticist.
Note that summary statistics will not be presented at a particular time point if more than 50% of the
data are missing.
An anomalous concentration value is one that, after verification of bioanalytical validity, is grossly
inconsistent with other concentration data from the same individual or from other subjects. For 
example, a BLQ concentration that is between quantifiable values from the same dose is 
considered as anomalous. Anomalous concentration values may be excluded from PK analysis at
the discretion of the PK analyst.
Pharmacokinetic parameters
Actual PK sampling times will be used in the derivation of PK parameters. If a PK parameter
cannot be derived from a subject’s concentration data, the parameter will be coded as NC (ie, not
calculated). (Note that NC values will not be generated beyond the day that a subject
discontinues).
In summary tables, statistics will not be presented for a particular treatment group if more than 
50% of the data are NC. For statistical analyses, PK parameters coded as NC will also be set to 
missing.
If an individual subject has a known biased estimate of a PK parameter, 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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5.5. Statistical Considerations of COVID-19 Impacted Data
In March 2020, prior to the database release for this study, the World Health Organization 
(WHO) announced a global pandemic of the virus SARS-CoV-2 and the resulting disease 
COVID-19. During the conduct of this trial, if any participant’s data is impacted by this 
pandemic, the following considerations will be given in the data analyses:
a.
Death caused by COVID-19 is still considered as an “event” in the analysis of PFS (Parts 1 
and 2) and OS (Part 2). If deemed necessary, a sensitivity analysis may be performed where 
COVID-19 driven death is censored at the death date. 
b. If a scheduled tumor radiographic scan is delayed out of the Schedule of Activity allowable 
window, or is missing (i.e. participant skipped a scheduled tumor radiographic scan) due to 
any reasons related to the pandemic, this delay or missingness does not alter the censoring 
rules for PFS or TTP. A censoring reason of “COVID-19” may be added to the PFS or TTP 
summary if the specific reason of tumor scan delay or missing can be attributed to COVID-
19. If deemed necessary, a sensitivity analysis may be performed where participants would 
be censored on the date of COVID-19 diagnosis. 
In the confirmed ORR analysis, as described in Section 6, if a response can’t be confirmed 
by a subsequent tumor scan because of the pandemic (i.e. the subsequent tumor scan wasn’t 
performed), then the initial response will be considered as unconfirmed. This is a 
conservative approach. No sensitivity analysis will be performed. 
c.
Any COVID-19 related symptoms are to captured as adverse events in the case report form. 
Those adverse events will be summarized in the same manner as other adverse events. If a 
label of COVID-19 can be identified in the investigator provided adverse event term, then a 
separate AE listing may be provided for just the COVID-19 related events. 
d. If identifiable, the COVID-19 related data points, including missing data where the reason 
of missing is identified as COVID-19 related (site closure hence data could not captured; 
participants skipped a visit because of concern over the pandemic), protocol deviations 
driven by COVID-19, safety events caused by COVID-19 may be separately listed. 
6. ANALYSES AND SUMMARIES
For efficacy related endpoints in this study, as both RECIST 1.1 and irRECIST will be used for 
tumor assessments, and there are different requirements in these criteria in terms of confirming 
tumor response or progression, the following analysis plan will be implemented: 
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Endpoint
Part 1
Part 2
RECIST 1.1
irRECIST
RECIST 1.1
irRECIST
ORR (or irORR)
Unconfirmed
Both
Both
Both
PFS (or irPFS)
Unconfirmed
Both
Unconfirmed*
Both
DOR (or irDOR)
Unconfirmed
Both
Both
Both
DOSD (or irDOSD)
Unconfirmed
Both
Both
Both
TTP
Unconfirmed
Both
Unconfirmed*
Both
TTR
Unconfirmed
Both
Both
Both
Note: “Both” in the above table represents both unconfirmed and confirmed tumor assessments. 
*: Confirmation for progressed disease is not applicable in RECIST 1.1
In the “unconfirmed” analyses (i.e. tumor response or progression without confirmation required), 
all tumor assessments data will be included for analyses. Specifically, regardless if a patient’s 
tumor response or progression is subsequently confirmed or not, the patient data will all be 
included in the “unconfirmed” analyses. This is a more comprehensive analysis where tumor 
confirmation is not required and not taken into account. For example in the ORR analysis, if a 
patient achieved CR or PR, regardless it is subsequently confirmed or not, the patient will be 
included in the numerator.  
In the “confirmed” analyses (i.e. tumor response or progression with confirmation required), only 
those tumor assessments data that’s subsequently confirmed by a consecutive tumor scan will be 
considered as a “success” or “event” and be included for analyses as appropriate. For example, in 
the ORR analysis, a patient will only be counted in the numerator (the “success”) if the tumor 
response (CR or PR) is subsequently confirmed. If a patient’s tumor response is not subsequently 
confirmed, the patient will still be included in the denominator (the population set) but will not be 
included in the numerator (the “success”). In the PFS analysis, only a PD that’s subsequently 
confirmed will be considered as an “event”. 
6.1. Standard Analyses
Study Conduct and Patient Disposition
An accounting of the study patients will be tabulated. The subject evaluation groups will be listed.  
The Full Analysis Set will be used.
Subject discontinuation from treatment and study will be tabulated and listed separately with their 
reason for discontinuation.  The Safety Analysis Set will be used.
Baseline Characteristics
Baseline characteristics such as demographics, prior medication, medical history, ECOG
performance status, and primary diagnosis will be tabulated and listed. For ECOG performance
status a shift table (worst post-baseline vs baseline may be produced). The Safety Analysis Set 
will be used.


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Treatment Administration/Compliance
Listings and tables by dose level will be provided. Cycle length is 21 days (+/- 2 days) for IV 
infusion and 28 days (+/- 2 days) for subcutaneous administration. Day 1 of a cycle is the first 
date of dose within that cycle. The safety analysis set will be used.
Dose modifications may occur in the following ways:

Cycle delay—Day 1 of current cycle starts later than 21 (+2) days from Day 1 of the
previous cycle (only applies to cycle 2 and above). For subcutaneous administration, 28
(+2) days, rather than 21 (+2) days, will be used in determining cycle delay. For example,
after cycle 1 ended for a patient in Part 2, a new cycle didn’t start until 28 (+2) days after 
(but before 56 days after) cycle 1 day 1, the newly started cycle will be considered as cycle 
2, and cycle 2 is considered delayed. 

Cycle skip – Day 1 of current cycle starts later than 42 (+4) days from Day 1 of the 
previous cycle (only applies to cycle 2 and above). For subcutaneous administration, 56
(+4) days, rather than 42 (+4) days, will be used in determining cycle skip. For example, 
After cycle 1 ended for a patient in Part 2, a new cycle didn’t start until 56 (+4) days after 
cycle 1 day 1, the newly started cycle will be considered as cycle 3, and cycle 2 is 
considered skipped for this patient. 

Dose reduction— a decrease in the administered total daily dose (non-zero) compared to 
the planned total daily dose upon enrollment. If in the CRF the prescribed dose unit is
mg/kg, but the actual dose is in mg the actual dose mg/kg should be calculated considering 
the body weight of the patient at that visit. Intrapatient dose reductions are not permitted 
during the study unless, in discussion with the sponsor, a dose level is deemed beyond the
determined MTD.
The following will be summarized by subject for overall and each dose level:

Number of subjects per dose level;

Median and range of number of cycles started per subject;

Number (%) of subjects starting a cycle (1, 2, 3…);

Number (%) of subjects with cycle delays and cycle skips;

Number (%) of dose interruptions (include both known and unknown dates);

Number (%) of subjects with dose reductions;

Number (%) of each reason (drug related AE vs AE vs. Other) for cycle delays, dose
interruptions and dose reductions;


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
Time on treatment (median, range).
The following will be summarized by cycle received for overall and each dose level:

Total number of cycles started;

Number of cycles started per subject (median, range);

Number of cycles before 1st delay (median, range);

Number of cycles before 1st reduction (median, range);

Number of cycles before 1st interruption (median, range);

Number of cycles before 1st dose skip (median, range).
The following will be summarized for cumulative dose by dose level and cycle:

Summary statistics (mean, median, standard deviation and range) of cumulative dose and 
percent of starting dose (compared to Day 1 dose of each cycle).
Listings by subject (ordered by dose level): start date and stop date of each dosing period within 
each cycle (including records with 0 mg), administered total daily dose for each period, any missed 
doses with unknown dates (Y/N), number of missed doses with unknown dates, reason for any
dosing changes.
Listings by subject and each cycle (ordered by dose level): cycle length, total planned dose,
administered total dose, percentage of planned dose, dose delay (yes/no), dose reduction (yes/no),
and dose interruption (yes/no).
Prior, Concomitant, and Further Therapies
Prior, concomitant, and further therapies (drug and non-drug treatments) will be coded by the
World Health Organization (WHO) medical dictionary. Listings of prior, concomitant, and
further therapies will be provided separately.
6.2. Analysis of Primary Endpoint
6.2.1. DLT (Part 1)
Dose Limiting Toxicity is the primary endpoint of the dose escalation phase of the study, which 
will be summarized by dose level using the Per Protocol Analysis Set for patients in the dose 
escalation portion of the study.  A listing of the DLTs will also be provided. If necessary, a 
summary and listing of the DLT by malignancy may be provided using the Per Protocol Analysis
Set for patients in the MTD expansion portion of the study.


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6.2.2. Safety Endpoints (Part 1 and Part 2) 
In safety data tabulations, only data collected during the on-treatment period, defined as on or after 
the first dose of study treatment, and before the last dose of study treatment + 28 days, or the start 
of any other anti-cancer therapy, whichever is earlier, will be included. In safety data listings, all 
collected data will be listed. 
Adverse Events
Adverse Events (AEs) will be graded by the investigator according to the CTCAE version 4.03 and 
coded using the MedDRA.4   The focus of AE summaries will be on Treatment Emergent Adverse 
Events, those with initial onset or increasing in severity after the first dose of study medication. 
The number and percentage of patients who experienced any AE, serious AE (SAE), treatment 
related AE, and treatment related SAE will be summarized according to worst toxicity grades.  The 
summaries will present AEs both on the entire study period and by cycle (Cycle 1 and Cycles 
beyond 1) for overall and each dose.  The Safety Analysis Set will be used.  Part 1 and Part 2 data 
will be summarized separately and will also be pooled together for analysis. Pfizer standard on 
safety data reporting will be followed.
Laboratory Tests Abnormalities
The number and percentage of patients who experienced laboratory test abnormalities will be 
summarized according to worst toxicity grade observed for each laboratory test for overall and 
each dose.  The analyses will summarize laboratory tests both in the entire study period and by 
cycle (Cycle 1 and Cycles beyond 1). Shift tables will be provided to examine the distribution of 
laboratory abnormalities. The Safety Analysis Set will be used.
For laboratory tests without CTC grade definitions, results will be categorized as normal, abnormal 
high/low or not done.
6.2.3. ORR (Part 2) 
ORR, as assessed using RECIST version 1.1 and irRECIST, is a primary efficacy endpoint for Part 
2. The following analyses will be performed in the mITT population by tumor type (NSCLC or 
urothelial carcinoma) and pooled: 
1. ORR by visit, separately for RECIST 1.1 and irRECIST: investigator provided tumor 
response CR, PR, and CR+PR will be presented by descriptive statistics (frequency and 
percentage) and 95% confidence interval. 
2. Best overall response of CR, PR, and CR+PR, separately for RECIST 1.1 and irRECIST. 
This will include best overall response derivation without confirmation and with 
confirmation. Descriptive statistics (frequency and percentage) and 95% confidence 
interval will be provided. 


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6.3. Analysis for Secondary Endpoints
6.3.1. Efficacy Endpoints Analysis
Except ORR for Part 2, efficacy is a secondary objective.  The efficacy analysis will be performed 
in the mITT population. Part 1 and Part 2 data will be summarized separately, and may also be 
pooled together for analysis if deemed necessary.  Efficacy data assessed by RECIST will be 
analyzed separately from those assessed by irRECIST.
Tumor response data in Part 1, Part 2 and across the two Parts may be summarized with descriptive 
statistics (frequency and percentage) in the following groups by visit and then best overall response 
across all visits:

Overall summary for all doses and all tumor types;

By tumor type regardless of dose;

By dose regardless of tumor type;

By dose and tumor type if data permit.
Summary tables of best overall response rate, PFS, OS, DOSD, and DOR may be provided by the 
groups aforementioned when deemed necessary (e.g. if there are ≥5 patients in a specific group). 
Efficacy listings (tumor measurements listings and tumor response listings) will be provided that 
include the investigator provided tumor measurement data, tumor response, best overall response, 
first CR/PR date, last date with CR or PR, most recent date without progression, progression date, 
death date, and last tumor assessment date, etc. 
Swimmer plot for individual clinical response and time on treatment, waterfall plot for individual 
tumor size percent change from baseline, and spider plot for individual tumor size percent change 
from baseline over time will be presented for RECIST and irRECIST separately.


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The following table provides an overview of the efficacy analysis.
Endpoint
Analysis Set
Statistical 
Method
Model/ Covariates/
Strata
Missing Data
Overall response
mITT
Exact CI
See aforementioned
summary descriptions 
on data pooling
across dose and
tumor type
Observed case
Overall Survival
ITT
Kaplan-Meier
See aforementioned
summary descriptions 
on data pooling
across dose and
tumor type
Censored at
last visit
Progression Free
Survival (PFS)
mITT
Kaplan-Meier
See aforementioned
summary descriptions 
on data pooling 3721
across dose and
tumor type
Censored per
Appendix 9.2
Time to 
Progression (TTP)
and Time to 
Response (TTR)
mITT
Kaplan-Meier
See aforementioned
summary descriptions 
on data pooling
across dose and
tumor type
Censored per
Appendix 9.2


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Endpoint
Analysis Set
Statistical 
Method
Model/ Covariates/
Strata
Missing Data
Duration of
Response (DOR)
mITT
Kaplan-Meier
See aformentioned
summary descriptions 
on data pooling
across dose and
tumor type
Censored per
Appendix 9.2
Duration of Stable
Disease (DOSD)
mITT
Kaplan-Meier
See aformentioned
summary descriptions 
on data pooling
across dose and
tumor type
Censored per
Appendix 9.2
6.3.2. Pharmacokinetics Analyses
The concentration-time data of PF-06801591 will be summarized by descriptive statistics (n, 
mean, standard deviation, coefficient of variation, median, minimum, maximum, and geometric 
mean) according to dosing cohort and time for each part of the study.  In addition, the 
concentration-time data from Part 2 will also be summarized by descriptive statistics according to 
tumor type.
The actual time of sample collection will be used in PK parameter calculation.  In the event that 
the actual sampling time is not available, the nominal time may be used if there is no evidence 
that the actual sampling time deviates substantially from the nominal time.
Presentation of PF-06801591 concentration-time data
The concentration-time data of PF-06801591 will be presented as below:

a listing of all concentrations by cohort, subject ID and nominal time.  The concentration 
listing will also include the actual times. Deviations from the nominal time will be given
in a separate listing.

a summary of concentrations by cohort and nominal time, where the set of statistics will 
include n, mean, standard deviation, median, coefficient of variation (cv), minimum, 
maximum and the number of concentrations above the lower limit of quantification.

for the concentration-time data after the 1st and 4th dose, median concentration-time plots
(on both linear and semi-log scales) against nominal time postdose by cohort (all cohorts 
on the same plot per scale, based on the summary of concentrations by cohort and time 
postdose).

for the concentration-time data after the 1st and 4th dose, mean concentration-time plots 
(on both linear and semi-log scales) against nominal time postdose by cohort (all cohorts
on the same plot per scale, based on the summary of concentrations by cohort and time 
postdose).


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For drug concentration summary statistics, median and mean plots by sampling time, the
nominal PK sampling time will be used; for individual subject plots by time, the actual PK
sampling time will be used, with the pre-dose time set to zero.
Calculation of PF-06801591 PK parameters
For patients enrolled in Part 1 of the study, the individual concentration-time data of PF-
06801591 during Cycle 1 and Cycle 4 will be analyzed separately by non-compartmental
methods to estimate the PK parameters. The PK parameters estimated will include Cmax, Tmax,
and AUClast (AUCtau at steady state).  If data permit or if considered appropriate, t1/2, CL (or CL/F 
for SC cohort), Vd (or Vd/F for SC cohort; Vss at steady state), and accumulation ratio (Rac) 
will also be estimated for Cycle 1 and Cycle 4.  For IV cohorts in Part 1, individual Cycle 6 pre-
dose concentrations will be used in lieu of Cycle 5 pre-dose concentrations while calculating 
Cycle 4 PK parameters. The PK parameters will be summarized descriptively by dose level and 
cycle.
Additionally, for Part 1, dose-normalized AUClast and Cmax will be plotted against dose (using a
logarithmic scale) by cycle.  These plots will include individual patient values and the geometric
means for each dose. These plots will be used to help understand the relationship between the
PK parameters and dose.
For patients enrolled in Part 2 of the study, trough concentrations of PF-06801591 will be
summarized descriptively by cycle and by tumor type.
PK parameters will be calculated using standard non-compartmental methods:
Parameter 
State
Method of Determination
AUCtau
sd, ss 
Linear/Log trapezoidal method 
AUClast 
sd,ss 
Linear/Log trapezoidal method 
AUCinf a
sd 
AUClast + (Clast*/kel), where Clast* is the 
predicted serum concentration at the last 
quantifiable time 
point estimated from the log-linear 
regression analysis.
Cmax 
sd, ss 
Observed directly from data 
Tmax 
sd, ss 
Observed directly from data as time of first 
occurrence
CL and CL/F
sd, ss 
Dose/AUCinf for sda 
Dose/AUCtau for ss
Vd/F
sd, ss
Dose/AUCinf for sd
Dose/(AUCτ / kel) for ss
Vss a
sd, ss 
CL * MRT, where MRT is the mean 


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residence time adjusted for the duration of
infusion
t½a
sd
Loge(2)/kel, where kel is the terminal phase 
rate constant calculated by a linear
regression of the log-linear concentration 
time
curve.
a if data permit.
6.3.3. Immunogenicity Assessment
For the immunogenicity data, the percentage of patients with positive ADAs and neutralizing 
antibodies will be summarized by overall, tumor type, and dose within tumor type as data permit.  
For patients with positive ADAs, the magnitude (titer), time of onset, and duration of ADA 
response will also be described, if data permit.  In addition, efforts will be made if data permit, as 
appropriate, to examine possible correlations of the ADA response with clinical data on the PK, 
safety and/or efficacy.
6.3.4. RO of PD-1 by PF-06801591 in Circulating T Cells
Descriptive statistics of PD-1 receptor occupancy by PF-06801591 evaluated from the percentage 
of free (ie unbound) PD-1 on the surface of circulating T cells will be summarized by overall, 
tumor type, and dose within tumor type as data permit.
6.5. Population PK and PK/PD Modeling
Pharmacokinetic and PD data from this study may be analyzed using modeling approaches and 
may also be pooled with data from other studies to investigate any association between PF-
06801591 exposure and biomarkers or significant safety endpoints. The results of these analyses,
if performed, may be reported separately.
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6.6. ECG and Vital Sign Data Analysis
The analysis of ECG results will be based on patients in the Safety Analysis Set with baseline 
and on-treatment ECG data, and will follow the ICH E14 guidance on the clinical evaluation of 
QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs.5
ECG measurements (an average of the triplicate measurements) will be used for the statistical 
analysis and all data presentations. Any data obtained from ECGs repeated for safety reasons 
after the nominal time-points will not be averaged along with the preceding triplicates.
Interval measurements from repeated ECGs will be included in the outlier analysis categorical 
analysis) as individual values obtained at unscheduled time points.
QT intervals will be corrected for HR (QTc) using standard correction factors [ie, Fridericia’s 
(default correction), Bazett’s, and possibly a study specific factor, as appropriate]. QTcF
interval will be calculated using the Friderica formula, as follows:
QTcF QT
3 RR
Data will be summarized and listed for QT, HR, response rate (RR), PR, QRS, QTcF (and/or
QTcB if deemed appropriate by overall, and dose. Individual QT` (all evaluated corrections)
intervals will be listed by study arm time and dose.  The most appropriate correction factor will 
be selected and used for the following analyses of central tendency and outliers and used for the 
study conclusions.  Descriptive statistics (n, mean, median, standard deviation, minimum, and
maximum) will be used to summarize the absolute corrected QT interval and changes from 
baseline in corrected QT after treatment by study arm dose and time point. For each patient and 
by treatment, the maximum change from baseline will be calculated as well as the maximum
post-baseline interval across time points.  Categorical analysis will be conducted for the
maximum change from baseline in corrected QT and the maximum post- baseline QT interval.
Shift tables will be provided for baseline vs worst on treatment corrected QT (one or more 
correction methods will be used) using maximum CTCAE version 4.03 Grade. Shift tables will 
also be provided for ECG abnormality at baseline vs. on treatment (yes, no, not done: (n, %).
Patients experiencing clinically-relevant morphological ECG changes will be summarized
(including frequency and percentage).
The effect of drug concentrations on corrected QT change from baseline may be explored
graphically.  Additional concentration-corrected QT analyses may be performed.  Data may be 
pooled with other study results and/or explored further with PK/PD models.
Changes from baseline for the ECG parameters QT interval, heart rate (HR), QTc interval, PR 
interval and QRS interval will be summarized by treatment and visit. Categorical data analysis
will follow Appendix 9.3.


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If more than one ECG is collected at a nominal time post dose (for example, triplicate ECGs),
the mean of the replicate measurements will be used to represent a single observation at that
time point.  If any of the three individual ECG tracings has a QTc value ≥500 msec, but the
mean of the triplicates is not ≥500 msec, the data from the subject’s individual tracing will be
described in a safety section of the study report in order to place the ≥500 msec value in
appropriate clinical context. However, values from individual tracings within triplicate
measurements that are ≥500 msec will not be included in the categorical analysis unless the
average from the triplicate measurements is also ≥500 msec. Changes from baseline will be
defined as the change between QTc post dose from the time-matched average of the pre-dose
triplicate values on Day 1.
In addition, an attempt will be made to explore and characterize the relationship between plasma
concentration and QT interval length using a PK/PD modeling approach. If a PK/PD
relationship is found, the impact of subject factors (covariates) on the relationship will be 
examined.
7. INTERIM ANALYSES
There is no formal interim analysis planned in this study. In Part 2, a Bayesian approach will be 
used aiming to detect early sign of efficacy. The following analyses will be performed: 
1. Approximately 8 weeks after the first 30 NSCLC patients have enrolled, a data snapshot 
will be taken for an early data assessment. Descriptive statistics (frequency and 
percentage) for tumor response (CR, PR, PD, stable disease [SD] etc.) from the first 
tumor assessment; ORR, the proportion of patients who achieved unconfirmed CR or 
PR, and the 95% confidence interval for ORR; DCR (disease control rate), the 
proportion of patients who achieved unconfirmed CR or PR or SD, and the 95% 
confidence interval for the DCR will be presented. If tumor response data are collected 
based on both RECIST 1.1 and irRECIST, separate presentations will be generated for 
each response criterion.  In this data snapshot, some patients may have gone through 
their second tumor assessment as of the data snapshot, however only data through the 
first tumor assessment will be used for this analysis.  The above described analyses may 
be repeated, if deemed necessary, when the first 40 or 45 NSCLC patients are enrolled 
and have gone through their first tumor assessment.  This preliminary data may provide 
guidance in the decision to the increase or decrease the sample size of each arm, to add 
other tumor types in a future amendment, or to initiate additional clinical studies.
2. In the early data assessment, a Bayesian approach will be used to calculate the posterior 
probability that the true ORR is greater than or equal to the minimal expected ORR.  For 
example, the minimal expected ORR if all patients received only one tumor assessment 
is approximately 10% but may be adjusted based on how many patients had assessments 
beyond 8 weeks and the PD-L1 status of patients which will be tested at baseline.  A 
beta prior (0.235, 1) is chosen, where the parameter beta is set to be 1, and parameter 
alpha 0.235 was calculated from a reference product pembrolizumab on NSCLC patients 
where a 19% ORR was observed.  For example, if 4 responders are observed out of the 
first 30 patients as of the first tumor assessments, the posterior probability that the true 
ORR is greater than a minimal expected ORR of 10% is approximately 70%.


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A final analysis will be performed when all 60 NSCLC patients and 40 urothelial cancer 
patients are enrolled and have completed their scheduled tumor assessments.  
This is an open label study, the Pfizer study team will review safety, immunogenicity, 
pharmacodynamics, 
 and other data throughout the study.
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8. REFERENCES
1.
B8011011 Protocol Amendment 1, Dec. 10, 2015; Protocol Amendment 2, July 21, 2016; 
Protocol Amendment 3, June 3, 2017
2.
Kaplan EL, Meier P. Nonparametric estimation from incomplete observations.  J Am Stat 
Assoc 1958; 53:457-481.
3.
Brookmeyer R, Crowley JJ. A confidence interval for the median survival time.
Biometrics 1982; 38:29-41.
4.
NCI Common Terminology Criteria for Adverse Events v4.03 (CTCAE).
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf.
5.
ICH E14 - The clinical evaluation of QT/QTc interval prolongation and proarrhythmic
potential for non-antiarrhythmic drugs. CHMP/ICH/2/04.
6.
E.A. Eisenhauer, P. Therasseb, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. Dancey,
S. Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. 
Lacombe, J. Verweij: New response evaluation criteria in solid tumours: Revised RECIST
guideline (version 1.1). European Journal of Cancer 45 (2009) 228-247.
7.
Nishino M, Gargano M, Suda M, Ramaiya NH, Hodi FS. Optimizing immune-related
tumor response assessment: does reducing the number of lesions impact response
assessment in melanoma patients treated with ipilimumab?  J Immunother Cancer
2014;2:17.
8.
Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant
lymphoma. J Clin Oncol 2007; 25: 579-86. Responses must last for at least 4 weeks off
treatment.
9.
Guha M:The new era of immune checkpoint inhibitors; Pharm J Volume 293, 18 NOV
2014, No 7837/8 online URL 200671127.


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9. APPENDICES
9.1. Details of Definitions of Endpoints
DLT Definitions
Previous anti-PD1 mAbs were administered in >1000 patients and were associated in the clinic 
with inflammatory adverse reactions resulting from increased or excessive immune activity
(immune-mediated adverse reactions), likely to be related to the mechanism of action. Immune-
mediated adverse reactions, which can be severe, may involve the gastrointestinal, skin, liver, 
endocrine, respiratory, renal or other organ systems.9
Severity of AEs will be graded according to CTCAE version 4.03.  For the purpose of a dose 
finding decision, any of the following drug-related AEs occurring during the first cycle of
treatment (21 days, or 28 days for subcutaneous administration) will be classified as DLTs 
following review by the investigators and the sponsor:

Grade 5 AE.

Hematologic toxicity:

Any Grade 4 hematologic AE, with the following clarifications.

Grade 4 neutropenia lasting >5 days from initiation of granulocyte-colony
stimulating factor.

Grade 4 thrombocytopenia with bleeding.

Platelet transfusion requirement or a platelet count <10,000/uL.

Non-Hematologic Toxicity:

Grade 4 non-hematologic AE.

Grade 3 AE lasting >7 days despite optimal supportive care.

Grade 3 central nervous system AE regardless of duration.

Concurrent aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 
>3X upper limit of normal (ULN) and total bilirubin >2X ULN (potential Hy’s law 
case see section Potential Cases of Drug-Induced Liver Injury).
The following AEs will not be adjudicated as DLTs:

Any Grade 3 endocrinopathy that is adequately controlled by hormonal replacement.


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
Grade 3 AE of tumor flare (defined as local pain, irritation, or rash localized at sites of
known or suspected tumor).

Isolated Grade 3-4 laboratory abnormalities that are not associated with clinical sequelae
and are corrected with supplementation/appropriate management within 72 hours of their
onset.

Grade ≥3 infusion reactions and allergic reactions will not be considered dose limiting 
as they are unlikely to be dose related, but all available information on these events will 
be collected. If Grade ≥3 infusion reactions occur in 2 of the first 10 patients at any
dose level, or if the occurrence is ≥5% thereafter, a mandatory pre- treatment regimen 
for all new patients will be implemented. The incidence of Grade 1 and 2 reactions will 
also be taken into account. If a total rate of >10% all-grade infusion or allergic reactions 
is observed, a mandatory pre-treatment regimen for all new patients will be 
implemented.
Information regarding the DLT observation period can be found in the Criteria for Dose Finding 
(See protocol Section 3.1.4).  For dose escalation, DLT observation is required for 21 days for 
IV infusion and 28 days for subcutaneous administration. However, DLT observation will 
continue for at least 120 days from first dose (or completion of 5 cycles, if still on treatment) to 
assess late immune-related dose-limiting AEs, and will be taken into account for MTD 
determination.
Late immune-related DLTs
Late immune-related DLTs are irAEs (see protocol Appendix 9) that meet the same grading
criteria as DLT criteria but occur after the initial 21-Day DLT period for IV or 28-day DLT 
period for SC and during the first 120-day assessment period.  Late immune-related DLTs will
be added to the mTPI approach to reassess the dose-finding decisions.
For any patient being treated at dose levels that are subsequently considered to exceed the MTD,
the option to reduce their dose will be discussed between the investigator and the sponsor’s
medical monitor. If the patient tolerated the above-MTD dose level well and is deriving clinical
benefit, continuation of treatment at the above-MTD dose level will require re-consenting.
Maximum tolerated dose (MTD)
The maximum tolerated dose (MTD) is defined as the highest dose with true toxicity 
probabilities in the equivalence interval (EI) where the EI is defined as [22.5%-32.5%].
In practice, the MTD will be the highest dose associated with the occurrence of DLTs 33% (eg, 
3 of 9 evaluable patients experience a DLT during at least [90 days after the first dose]) or the
first 5 treatment cycles if the patient remains on treatment.


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Recommended Phase 2 Dose (RP2D) Definition
The recommended Phase 2 dose (RP2D) is the dose chosen for further study combining the
MTD and OBD, based on Phase 1 study results, from the primary and secondary endpoints of
the study.  If the MTD proves to be clinically feasible for long-term administration in a
reasonable number of patients, then this dose usually becomes the RP2D.
Further experience
with the MTD may result in a RP2D lower than the MTD.  Next to safety assessment, careful
consideration will be given to immunomodulatory effects, PK information, and preliminary anti-
tumor activity. If an OBD can be determined, this will be a key factor in the determination of
the RP2D.


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9.2. Time to Event Data Analysis Censoring Rules
Table 9.2.1: Progression Free Survival and Duration of Response
Situation
Date of Progression/Censoring1
Outcome
Inadequate baseline assessment
First dosing date in Cycle 1
Censored
No on-study assessments
First dosing date in Cycle 1
Censored
Alive over the course of the study 
and no progression
Date of last objective tumor 
assessment
Censored
Progression or death documented 
on or between scheduled tumor 
assessments
Date of first objective tumor 
assessment showing objective 
progression or death date
Progressed/Death
(Event)
Treatment discontinuation for 
undocumented progression
Date of last objective tumor 
assessment
Censored
Treatment discontinuation due 
to toxicity or other reason
Date of last objective tumor 
assessment
Censored
Progression/Death prior to 
second planned tumor 
Date of death
Progressed/Death 
(Event)
Death or progression after 2 or 
more missed tumor assessments
Date of last objective tumor 
assessment prior to the event
Censored
1.
For date of censorship, if a tumor assessment takes place over a number of days (eg, superficial lesions one 
day, scans another), the last date is used as the assessment date.
2.
The first two reasons (Inadequate baseline assessment; No on-study assessments) are not applicable for 
Duration of Response, as that endpoint is only for the subset of responders. 
Table 9.2.2: Time to Progression
Situation
Date of Progression/Censoring1
Outcome
Inadequate baseline assessment
First dosing date in Cycle 1
Censored
No on-study assessments
First dosing date in Cycle 1
Censored
Alive over the course of the study
and no progressionProgression
Date of last objective tumor 
assessment
Censored
Progression Documented on or
between scheduled tumor 
assessments
Date of first objective tumor 
assessment showing objective 
progression
Progressed (Event)
Treatment discontinuation for 
undocumented progression
Date of last objective tumor 
assessment
Censored


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Situation
Date of Progression/Censoring1
Outcome
Treatment discontinuation due 
to toxicity or other reason
Date of last objective tumor
assessment
Censored
New anticancer treatment
prior to documented
progression
Date of last objective tumor 
assessment prior to new anticancer
treatment
Censored
Death prior to first planned
tumor assessment
Start date (C1D1)
Censored
Death without objective
progression
Date of last objective tumor 
assessment prior to death
Censored
Progression after 2 or more 
missed tumor assessments
Date of last objective tumor 
assessment prior to the event
Censored
3.
For censoring date, if a tumor assessment takes place over a number of days (eg, superficial lesions one day,
scans another), the last date is used as the assessment date.


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9.3. Categorical Classes for ECG and Vital Signs
Categories for QTcB and QTcF
QTcB/QTcF
(ms)
max. ≤450
450< max. ≤480
480< max.≤500
max. >500
QTcB/QTcF
(ms) increase
from baseline
max. <30
30≤max. <60
max. ≥60
Categories for PR and QRS
PR (ms)
max ≥300
PR (ms)
increase from
baseline
Baseline
>200 and
max. ≥25%
increase
Baseline ≤200
and max. ≥50%
increase
QRS (ms)
max ≥200
QRS (ms)
Baseline
Baseline ≤100
increase from
>100 and
and max. ≥50%
baseline
max. ≥25%
increase
increase


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Categories for Vital Signs
Systolic BP (mm Hg)
min. <90
Systolic BP (mm Hg)
change from baseline
max. decrease
≥30
max. increase
≥30
Diastolic BP (mm Hg)
min. <50
Diastolic BP (mm Hg) 
change from baseline
max. decrease
≥20
max. increase
≥20
Supine pulse rate (bpm)
min. <40
max. >120
Measurements that fulfil these criteria are to be listed in the study report.


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9.4. RECIST 1.1 Tumor Assessment Criteria
Adapted from E.A. Eisenhauer, P. Therasseb, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. 
Dancey, S. Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. 
Lacombe, J. Verweij: New response evaluation criteria in solid tumours: Revised RECIST
guideline (version 1.1). European Journal of Cancer 45 (2009) 228–247.6
At baseline, individual tumor lesions will be categorized by the investigator as either measurable
or not, according to the criteria summarized below:
Measurable Lesions
Lesions that can be accurately measured in at least one dimension (longest diameter in the plane 
of measurement is to be recorded) with a minimum size of:

10 mm for lesions other than lymph nodes and assessed by CT scan (CT scan slice
thickness no greater than 5 mm).

10 mm for lesions assessed clinically by caliper measurement (lesions which cannot be 
accurately measured with calipers should be recorded as non-measurable).

20 mm for lesions assessed by chest X-ray.

15 mm in short axis for lymph nodes when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).
Non-measurable Lesions
Non-measurable lesions include small lesions (longest diameter <10 mm or pathological lymph 
nodes with a 10 but <15 mm short axis) as well as truly non-measurable lesions. Truly non-
measurable lesions include: leptomeningeal disease, ascites, pleural or pericardial effusion, 
inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal masses 
identified by physical exam and not measurable by reproducible imaging techniques.


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Nodes that have a short axis <10 mm are considered non-pathological and should not be
recorded or followed.
Special Considerations Regarding Specific Lesions
Bone lesions:

Bone scan, PET scan or plain films are not considered adequate imaging techniques to
measure bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions.

Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue
components, that can be evaluated by cross sectional imaging techniques such as CT or
MRI can be considered as measurable lesions if the soft tissue component meets the 
definition of measurability described above.

Blastic bone lesions are non-measurable.
Cystic lesions:

Lesions that meet the criteria for radiographically defined simple cysts should not be
considered as malignant lesions (neither measurable nor non-measurable) since they are, 
by definition, simple cysts.

‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions.
Lesions with prior local treatment:

Tumor lesions situated in a previously irradiated area, or in an area subjected to other
loco-regional therapy, are usually not considered measurable unless there has been
demonstrated progression in the lesion.
Solitary lesions:
If a measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology/histology.


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Recording Tumor Measurements
All measurable lesions up to a maximum of 2 lesions per organ and up to 5 in total and 
representative of all involved organs should be identified as target lesions and measured and 
recorded at baseline and at the stipulated intervals during treatment.  Target lesions should be 
selected on the basis of their size (lesions with the longest diameters) and their suitability for 
accurate repetitive measurements (either by imaging techniques or clinically).
The longest diameter will be recorded for each target lesion. The sum of the longest diameter of 
all target lesions will be calculated and recorded as the baseline sum diameter to be used as 
reference to further characterize the objective tumor response of the measurable dimension of 
the disease during treatment.
One exception to the above described approach is related to pathological lymph nodes. 
Pathological lymph nodes are defined as measurable lesions and may be identified as target 
lesions if the criterion of a short axis of 15 mm by CT scan is met. Only the short axis of
these nodes will contribute to the baseline sum.  Nodal size is normally reported as two 
dimensions in the plane in which the image is obtained (for CT scan this is almost always the 
axial plane; for MRI the plane of acquisition may be axial, sagittal or coronal). The smaller of 
these measures is the short axis.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. The baseline sum 
diameters will be used as reference to further characterize any objective tumor regression in the 
measurable dimension of the disease.
All other lesions (or sites of disease) should be identified as non-target lesions and should also 
be recorded at baseline. Measurements are not required and these lesions should be followed as 
‘present’, ‘absent’, or in rare cases ‘unequivocal progression’.  In addition, it is possible to
record multiple non-target lesions involving the same organ as a single item on the case record
form (eg, ‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver metastases’).
Definition of Tumor Response
Target Lesions
Response in target lesions is defined as follows:
Complete Response (CR): disappearance of all target lesions.

Partial Response (PR): at least a 30% decrease in the sum of diameters of target
lesions, taking as reference the baseline sum diameters.


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
Progressive Disease (PD): at least a 20% increase in the sum of diameters of target
lesions, taking as reference the smallest sum on study (this includes the baseline sum if 
that is the smallest on study).  In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm.  The appearance of one or more 
new lesions is also considered a sign of progression.

Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study.
When nodal disease is included in the sum of target lesions and the nodes decrease to ‘normal’ 
size (<10 mm), they may still have a measurement reported on scans.  This measurement should 
be recorded even though the nodes are normal in order not to overstate progression should it be 
based on increase in size of the nodes.  As noted earlier, this means that patients with CR may 
not have a total sum of ‘zero’ on the CRF.
Non-Target Lesions
While some non-target lesions may actually be measurable, they need not be measured and
instead should be assessed only qualitatively at the time points specified in the protocol.
Response in non-target lesions is defined as follows:

Complete Response (CR): Disappearance of all non-target lesions and normalization of 
tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm short 
axis).

Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance 
of tumor marker level above the normal limits.

Progressive Disease (PD): Unequivocal progression of existing non-target lesions.
(Note: the appearance of one or more new lesions is also considered progression).
Cytology, histology
These techniques can be used to differentiate between PR and CR in rare cases if required by 
protocol (for example, residual lesions in germ cell tumors).  When effusions are known to be a 
potential adverse effect of treatment (eg, taxane compounds or angiogenesis inhibitors), the
cytological confirmation of the neoplastic origin of any effusion that appears or worsens during 
treatment can be considered if the measurable tumor has met criteria for response or stable
disease in order to differentiate between response or stable disease and progressive disease.
For patients having effusions or ascites, only cases having cytological proof of malignancy
should be recorded on the CRF. Effusions that have not been evaluated using cytology or were 
found to be non-malignant should not be recorded on the CRF.


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New Lesions
The appearance of new malignant lesions indicates PD.  New lesion should be unequivocal (eg, 
not attributable to differences in imaging technique, or change in imaging modality or findings 
not attributable to tumor).  If a new lesion is equivocal, for example due to its small size, 
continued therapy and follow-up assessment will clarify the etiology of the disease. If repeat
scans confirm there is definitely a new lesion, then progression should be declared using the date 
of the initial scan.
The use of FDG-PET is sometimes reasonable to complement a CT scan assessment of a PD
(particularly for possible ‘new’ disease). New lesions on the basis of FDG-PET imaging can be 
identified according to the following algorithm:

Negative FDG-PET at baseline, with a positive FDG-PET at follow-up.

No FDG-PET at baseline and a positive FDG-PET at follow- up: if the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.
If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional 
follow-up CT scans are needed to determine if there is truly progression occurring at that site (if 
so, the date of PD will be the date of the initial abnormal FDG-PET scan).
If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT that is 
not progressing on the basis of the anatomic images, this is not PD.
Determination of Overall Response by the RECIST 1.1 Criteria
When both target and non-target lesions are present, individual assessments will be recorded
separately. The overall assessment of response will involve all parameters as depicted in the
following table.
Table 10.4.1: Response Evaluation Criteria in Solid Tumors by RECIST 1.1
Target 
lesions
Non-target
lesions
New
Lesions
Overall
response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not
all evaluated
No
PR
SD
Non-PD or
not all evaluated
No
SD
Not all
evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD


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Target 
lesions
Non-target
lesions
New
Lesions
Overall
response
Any
Any
Yes
PD
CR = complete response, PR = partial response, SD = stable disease,
PD = progressive disease, and NE = inevaluable.
Best overall response
The best overall response is defined according to the tumor response along the study. Complete 
or partial responses may be claimed only if the criteria for each are met at a following time point 
as specified in the protocol (generally 4 weeks later). In this circumstance, the best overall 
response can be interpreted as the following table.
Table 10.4.2 Best Overall Response When Confirmation of CR and PR Required
Overall
response
First time
point
Overall
response
Subsequent 
time point
BEST overall response
CR
CR
CR
CR
PR
SD, PD or PRa
CR
SD
SD provided minimum criteria for
SD duration met, otherwise, PD
CR
PD
SD provided minimum criteria for
SD duration met, otherwise, PD
CR
NE
SD provided minimum criteria for
SD duration met, otherwise NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD provided minimum criteria for
SD duration met, otherwise, PD
PR
NE
SD provided minimum criteria for
SD duration met, otherwise NE
NE
NE
NE
CR = complete response, PR = partial response, SD = stable disease, 
PD = progressive disease, and NE = inevaluable.
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease
meeting PR criteria relative to baseline, makes the disease PD at that point (since disease must have
reappeared after CR). Best response would depend on whether minimum duration for SD was met.
However, sometimes ‘CR’ may be claimed when subsequent scans suggest small lesions were likely
still present and in fact the patient had PR, not CR at the first time point. Under these circumstances,
the original CR should be changed to PR and the best response is PR.


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Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
‘symptomatic deterioration’.  Every effort should be made to document objective progression 
even after discontinuation of treatment. Symptomatic deterioration is not a descriptor of an 
objective response: it is a reason for stopping study therapy.  The objective response status of 
such patients is to be determined by evaluation of target and non-target lesions.
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of CR depends upon this determination, it is recommended that the 
residual lesion be investigated (fine needle aspirate/biopsy) before assigning a status of 
complete response. FDG-PET may be used to upgrade a response to a CR in a manner similar 
to a biopsy in cases where a residual radiographic abnormality is thought to represent fibrosis or
scarring. The use of FDG-PET in this circumstance should be prospectively described in the 
protocol and supported by disease specific medical literature for the indication.  However, it 
must be acknowledged that both approaches may lead to false positive CR due to limitations of 
FDG-PET and biopsy resolution/sensitivity.


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9.5. Immune-related RECIST (irRECIST) Tumor Assessment Criteria
Increasing clinical experience indicates that traditional response criteria may not be sufficient to 
fully characterize activity in this new era of targeted therapies and/or biologics.
This is particularly true for immunotherapeutic agents such as anti-cytotoxic T lymphocyte-
associated protein 4 (CTLA4) and anti PD-1/anti-PD-L1 antibodies which exert the antitumor 
activity by augmenting activation and proliferation of T cells, thus leading totumor infiltration 
by T cells and tumor regression rather than direct cytotoxic effects. Clinical observations of 
patients with advanced melanoma treated with ipilimumab, for example, suggested that 
conventional response assessment criteria such as Response Evaluation Criteria in Solid Tumors 
(RECIST) and WHO criteria are not sufficient to fully characterize patterns of tumor response 
to immunotherapy because tumors treated with immunotherapeutic agents may show additional 
response patterns that are not described in these conventional criteria.
Furthermore, the conventional tumor assessment criteria (RECIST and WHO criteria) have been 
reported as not capturing the existence of a subset of patients who have an OS similar to those 
who have experienced CR or PR but were flagged as PD by WHO criteria.
On these grounds, a tumor assessment system has been developed that incorporates these
delayed or flare type responses into the RECIST v1.1 (irRECIST).7
For irRECIST, only target and measurable lesions are taken into account. In contrast to
RECIST v1.1, irRECIST:

Requires confirmation of both progression and response by imaging at least 4 weeks
from the date first documented, and

Does not necessarily score the appearance of new lesions as progressive disease if the
sum of lesion diameters of target lesions (minimum of 10 mm longest diameter per non-
nodal lesion and 15 mm shortest diameter per nodal lesion, maximum of 5 target lesions, 
maximum of 2 per organ) and measurable new lesions does not increase by ≥20%.
The same method of assessment and the same technique should be used to characterize each
identified and reported target lesion(s) at baseline and throughout the trial.
irRECIST is defined as follows:

Overall immune related complete response (irCR): Complete disappearance of all 
lesions (whether measurable or not) and no new lesions. All measurable lymph nodes
also must have a reduction in short axis to <10 mm.

Overall immune-related partial response (irPR): Sum of the diameters (longest for non-
nodal lesions, shortest for nodal lesions) of target and new measurable lesions decreases
≥30%.


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
Overall immune related stable disease (irSD): Sum of the diameters (longest for non-
nodal lesions, shortest for nodal lesions) of target and new measurable lesions is
neither irCR, irPR, (compared to baseline) or immune related progressive disease
(irPD, compared to nadir).

Overall immune related progressive disease (irPD): Sum of the diameters (longest for
non-nodal lesions, shortest for nodal lesions) of target and new measurable lesions
increases ≥20% (compared to nadir) with a minimum absolute increase of 5 mm, 
confirmed by a repeat, consecutive observation at least 4 weeks from the date first
documented.
New measurable lesions: Incorporated into tumor burden (ie, added to the target lesion 
measurements). A lymph node has to be ≥15 mm in short axis to be a measurable new lesion 
and its short axis measurement is included in the sum.  Up to 2 new lesions per organ and up to 
5 new lesions in total can be added to the measurements.
New non measurable lesions: Do not define progression but preclude irCR.