A Phase 3, Multinational, Randomized, Open-Label, Three Parallel-Arm Study of PF-06801591, an Anti-PD-1 Antibody, in Combination With Bacillus Calmette-Guerin (BCG Induction With or Without BCG Maintenance) Versus BCG (Induction and Maintenance) in Participants With High-Risk, BCG-Naïve Non-Muscle Invasive Bladder Cancer or PF-06801591 as a Single Agent in Participants With BCG-Unresponsive NMIBC
Phase: PHASE3
Conditions: Non-muscle Invasive Bladder Cancer
Sponsor: Pfizer

Sasanlimab (PF-06801591)
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Protocol Title: A Phase 3, Multinational, Randomized, Open-Label, Three Parallel-Arm 
Study of PF-06801591, an Anti-PD-1 antibody, in Combination With Bacillus Calmette-
Guerin (BCG Induction With or Without BCG Maintenance) Versus BCG (Induction and 
Maintenance) in Participants With High-Risk, BCG-Naïve Non-Muscle Invasive Bladder 
Cancer or PF-06801591 as a Single Agent in Participants With BCG-Unresponsive NMIBC
Protocol Number: B8011006
Amendment Number: 5
Compound Number: PF-06801591 
Study Intervention Name: sasanlimab
Study Phase: Phase 3
Short Title: CREST - Phase 3 Study of Sasanlimab (PF-06801591) in Combination With 
Bacillus Calmette-Guerin (BCG) or as a Single Agent in Participants With High-Risk Non-
Muscle Invasive Bladder Cancer
Acronym: CREST: Combination of sasanlimab and alternative BCG Regimens to Evaluate 
outcomes with Subcutaneous anti-PD-1 Treatment
Sponsor Name: Pfizer, Inc
Legal Registered Address:    66 Hudson Boulevard East, New York, NY 10001, USA
Regulatory Agency Identifier Number(s)
Registry
ID 
IND
125,681
EU CT
2023-509089-39-00
Approval Date: 17 June 2024
This document and accompanying materials contain confidential information belonging to 
Pfizer. Except as otherwise agreed to in writing, by accepting or reviewing these 
documents, 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
Amendment 5
17 June 2024
Amendment 4
10 November 2022 
Amendment 3
12 January 2022
Amendment 2
21 September 2021
Amendment 1
26 June 2020
Original protocol
15 October 2019
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and IRBs/ECs and any protocol administrative change 
letter(s).
Protocol Amendment Summary of Changes Table
Amendment 5:  17 June 2024
Overall Rationale for the Amendment:    Sponsor has revised the Cohort A study analysis 
plan for primary and key secondary study objectives. The rationale for this change is based 
on the observation that EFS events are accumulating at a much slower rate than originally 
projected, together with an increasing rate of participants dropping out from EFS 
observation. The IA2 will be removed, and the FA for EFS based on a calendar-based data 
cut-off date will be conducted.   
Description of 
Change
Brief Rationale
Section # and Name
Substantial Modifications
Update was made to 
the plan for the 
timing of the 
statistical analysis, 
including removal of 
EFS interim analysis 
2, timing of EFS  
final analysis, and 
primary completion 
date.
Update was made to support change 
to planned analysis of primary and 
key secondary objective.
Synopsis 
9.2.1 Sample Size 
Determination Cohort A
Non Substantial Modifications
Updates made to 
analysis plan for EFS 
interim analyses to 
reflect that only 
interim analysis 1 
was conducted as 
Update was made to support change 
to statistical analysis for the study 
overall.
9.5. Interim Analyses 
(Cohort A only)
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Description of 
Change
Brief Rationale
Section # and Name
originally planned, 
and interim analysis 2 
will not take place as 
originally planned.
Changed the 
multiplicity control 
testing strategy
Testing strategy updated to support 
the change to analysis plan for 
primary and key secondary study 
objectives
9.2.1 Sample Size 
Determination Cohort A
Figure 5
Updated statistical 
analysis methods for 
primary and key 
secondary objectives
and clarified that 
these analyses are 
based on investigator 
assessments
Statistical analysis methods updated 
to support overall change in analysis 
plan for primary and key secondary 
objectives and to clarify which data 
will be used for primary analyses.
9.4.1.1 Efficacy Analysis 
Cohort A
Primary estimand 
language was updated 
to align with updates 
to primary and 
secondary objectives. 
Update was made to support change 
to planned analysis of primary and 
key secondary objective.
Synopsis
3.1. BCG-Naïve Cohort 
(Cohort A)
9.1.1.1. Estimands -
Cohort A
9.4.1.1. efficacy analyses-
Cohort A
Language regarding 
types of medical 
device deficiencies to 
be reported, 
definition of device 
deficiency, and 
process for reporting 
device deficiencies
was updated.
Following update to protocol 
template. Text was implemented via 
PACL dated 04 December 2023.
8.3.9.1 Time Period for 
Detecting Medical Device 
Deficiencies
8.3.9.2. Follow-Up of 
Medical Device 
Deficiencies
8.3.9.4. Regulatory 
Reporting Requirements 
for Device Deficiencies
10.7.2 Definition of SAE, 
SADE, and Unanticipated 
Serious Adverse Device 
Effect
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Description of 
Change
Brief Rationale
Section # and Name
10.7.3 Definition of 
Device Deficiency
10.7.4 
Recording/Reporting and 
Follow-Up of AEs and/or 
SAEs and Device 
Deficiencies
Editorial updates 
made to clarify that 
SRSD should be 
reviewed and 
approved by sponsor 
and submitted to 
IRB/EC, requirement 
for health authority 
approval of protocols 
and amendments, and 
update to EU Medical 
Device Regulation 
references.
Following update to protocol 
template.
10.1.1. Regulatory and 
Ethical Considerations
Process for 
facilitating access to 
a medically qualified 
professional from 
Pfizer has been 
updated.
Following update to protocol 
template.  Text was implemented via 
PACL dated 01 February 2024.
10.1.12. Sponsor’s 
Qualified Medical 
Personnel
Editorial updates and 
clarifications were 
made.
Following update to protocol 
template.
10.1.3. Informed Consent 
Process
10.1.4 Data Protection
10.1.6. Dissemination of 
Clinical Study Data
10.1.7 10.1.7. Data 
Quality Assurance
10.1.9. Use of Medical 
Records
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Description of 
Change
Brief Rationale
Section # and Name
10.1.10. Study and Site 
Closure
Protocol amendment 
4 summary of 
changes moved from 
this Protocol 
Amendment 
Summary of Changes 
Table to Appendix 17 
and replaced in this 
table with the current 
summary of changes 
for protocol 
amendment 5.
Summary of Changes Table updated 
with changes for current amendment 
and changes for previous amendment 
moved to Appendix 17.
Protocol Amendment 
Summary of Changes 
Table
10.17. Appendix 17:
Protocol Amendment 
History
Typos, punctuation, 
and grammar were 
corrected as 
applicable.
Editorial updates
All
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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................13
LIST OF FIGURES .................................................................................................................13
1. PROTOCOL SUMMARY...................................................................................................14
1.1. Synopsis ..................................................................................................................14
1.2. Schema ....................................................................................................................25
1.3. Schedule of Activities (SoA)...................................................................................28
2. INTRODUCTION ...............................................................................................................42
2.1. Study Rationale .......................................................................................................42
2.1.1. Study Rationale for the BCG-Naive Cohort (Cohort A) ............................43
2.1.2. Study Rationale for the BCG-Unresponsive Cohort (Cohorts B1 and 
B2)....................................................................................................................44
2.2. Background .............................................................................................................46
2.2.1. Clinical Background...................................................................................46
2.2.2. Preclinical Safety and Efficacy...................................................................48
2.3. Benefit/Risk Assessment.........................................................................................48
3. OBJECTIVES, ESTIMANDS AND ENDPOINTS ............................................................50
3.1. BCG-Naïve Cohort (Cohort A)...............................................................................50
3.2. BCG-Unresponsive Cohorts (Cohorts B1 and B2) .................................................54
4. STUDY DESIGN.................................................................................................................56
4.1. Overall Design.........................................................................................................56
4.1.1. BCG-Naïve Cohort (Cohort A) ..................................................................56
4.1.2. Cohorts B1 and B2......................................................................................59
4.2. Scientific Rationale for Study Design.....................................................................61
4.3. Justification for Dose ..............................................................................................62
4.3.1. PF-06801591...............................................................................................62
4.3.2. BCG............................................................................................................63
4.4. End of Study Definition ..........................................................................................63
5. STUDY POPULATION......................................................................................................63
5.1. Inclusion Criteria.....................................................................................................63
5.2. Exclusion Criteria....................................................................................................66
5.3. Lifestyle Considerations..........................................................................................69
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5.4. Screen Failures ........................................................................................................70
6. STUDY INTERVENTION..................................................................................................70
6.1. Study Intervention(s) Administered........................................................................70
6.1.1. Medical Devices .........................................................................................72
6.1.2. Administration of the Study Intervention...................................................73
6.2. Preparation/Handling/Storage/Accountability ........................................................74
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................75
6.4. Study Intervention Compliance...............................................................................75
6.5. Concomitant Therapy..............................................................................................75
6.5.1. Other Anti-tumor/Anti-cancer or Experimental Drugs...............................75
6.5.2. Supportive Care ..........................................................................................76
6.5.3. Hematopoietic Growth Factors...................................................................76
6.5.4. Anti-Diarrhea, Anti Emetic Therapy..........................................................76
6.5.5. Anti-inflammatory and Narcotic Therapy ..................................................76
6.5.6. Corticosteroids............................................................................................76
6.5.7. Surgery........................................................................................................76
6.5.8. Radiation Therapy ......................................................................................77
6.5.9. Vaccines......................................................................................................77
6.6. Dose Modification...................................................................................................77
6.6.1. Dose Modifications for PF-06801591 ........................................................78
6.6.1.1. Hypersensitivity Types 1 and 3.................................................78
6.6.1.2. Immune-Related Adverse Events..............................................79
6.6.2. Precautions for Administration of BCG .....................................................79
6.7. Intervention after the End of the Study...................................................................79
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................80
7.1. Discontinuation of Study Intervention ....................................................................80
7.2. Participant Discontinuation/Withdrawal from the Study........................................81
7.2.1. Withdrawal of Consent...............................................................................81
7.3. Lost to Follow-up....................................................................................................82
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................82
8.1. Efficacy Assessments..............................................................................................83
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8.1.1. Clinical Assessments ..................................................................................83
8.1.1.1. Cystoscopy ................................................................................84
8.1.1.2. Cytology....................................................................................85
8.1.1.3. Imaging......................................................................................86
8.1.2. Patient Reported Outcomes (PROs) ...........................................................86
8.1.2.1. EORTC QLQ-C30.....................................................................86
8.1.2.2. EORTC QLQ-NMIBC24 ..........................................................86
8.1.2.3. EuroQol 5 Dimensions, 5-Level (EQ-5D-5L) and Visual 
Analog Scale (VAS)..........................................................................87
8.1.2.4. Patient Global Impression of Severity (PGIS) ..........................87
8.1.2.5. Patient Global Impression of Change (PGIC)...........................87
8.1.2.6. Patient Treatment Administration Burden (PTAB) ..................87
8.1.2.7. Treatment Satisfaction Questionnaire (TSQ)............................87
8.2. Safety Assessments .................................................................................................88
8.2.1. Physical Examinations................................................................................88
8.2.2. Vital Signs ..................................................................................................88
8.2.3. ECOG Performance Status .........................................................................88
8.2.4. Electrocardiograms.....................................................................................88
8.2.5. Local Site Injection Tolerability Assessment (PF-06801591 only) ...........89
8.2.6. Survival Follow-up.....................................................................................90
8.2.7. Clinical Safety Laboratory Assessments ....................................................90
8.2.8. Pregnancy Testing ......................................................................................91
8.3. Adverse Events and Serious Adverse Events..........................................................91
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......92
8.3.1.1. Reporting SAEs to Pfizer Safety...............................................92
8.3.1.2. Recording Nonserious AEs and SAEs on the eCRF.................93
8.3.2. Method of Detecting AEs and SAEs ..........................................................93
8.3.3. Follow-up of AEs and SAEs.......................................................................93
8.3.4. Regulatory Reporting Requirements for SAEs...........................................93
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational 
Exposure ..........................................................................................................94
8.3.5.1. Exposure During Pregnancy......................................................94
8.3.5.2. Exposure During Breastfeeding ................................................95
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8.3.5.3. Occupational Exposure .............................................................96
8.3.6. Cardiovascular and Death Events...............................................................96
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs..............................................................................96
8.3.8. Adverse Events of Special Interest.............................................................96
8.3.8.1. Lack of Efficacy........................................................................97
8.3.9. Medical Device Deficiencies......................................................................97
8.3.9.1. Time Period for Detecting Medical Device Deficiencies .........97
8.3.9.2. Follow-Up of Medical Device Deficiencies..............................97
8.3.9.3. Prompt Reporting of Device Deficiencies to Sponsor ..............97
8.3.9.4. Regulatory Reporting Requirements for Device 
Deficiencies .......................................................................................98
8.3.10. Medication Errors.....................................................................................98
8.4. Treatment of Overdose............................................................................................99
8.5. Pharmacokinetics ....................................................................................................99
8.6. Pharmacodynamics................................................................................................100
8.7. Genetics.................................................................................................................101
8.7.1. Specified Genetics ....................................................................................101
8.7.2. Banked Biospecimens for Genetics..........................................................101
8.8. Biomarkers ............................................................................................................101
8.8.1. Tumor Tissue Assessments.......................................................................102
8.8.2. Other Biomarker Assessments..................................................................102
8.8.2.1. Cluster of Differentiation 8 Immunohistochemistry (CD8 
IHC).................................................................................................102
8.8.2.2. Circulating Free DNA (cfDNA)..............................................102
8.8.3. Immunogenicity Assessments: Analysis of Anti-PF-06801591 
Antibodies (ADA) and Neutralizing Anti-PF-06801591 Antibodies 
(NAb).............................................................................................................102
8.8.4. Specified Gene Expression (RNA) Research ...........................................103
8.8.5. Specified Protein Research.......................................................................103
8.9. Health Economics .................................................................................................104
9. STATISTICAL CONSIDERATIONS ..............................................................................104
9.1. Estimands and Statistical Hypotheses...................................................................104
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9.1.1. Estimands..................................................................................................104
9.1.1.1. Cohort A..................................................................................104
9.1.1.2. Cohorts B1 and B2 ..................................................................107
9.2. Sample Size Determination...................................................................................107
9.2.1. Cohort A ...................................................................................................107
9.2.2. Cohorts B1 and B2....................................................................................109
9.3. Populations for Analyses.......................................................................................110
9.4. Statistical Analyses ...............................................................................................111
9.4.1. Efficacy Analyses .....................................................................................111
9.4.1.1. Cohort A..................................................................................111
9.4.1.2. Cohorts B1 and B2 ..................................................................114
9.4.2. Safety Analyses ........................................................................................114
9.4.3. Other Analyses..........................................................................................114
9.4.3.1. Patient Reported Outcomes.....................................................114
9.4.3.2. Pharmacokinetics ....................................................................115
9.4.3.3. Immunogenicity ......................................................................115
9.4.3.4. Population Pharmacokinetic Analysis or Pharmacokinetic 
(PK)/ Pharmacodynamic Modeling.................................................115
9.4.3.5. Biomarkers ..............................................................................115
9.5. Interim Analyses (Cohort A only).........................................................................115
9.5.1. External Data Monitoring Committee (EDMC).......................................116
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS........................................................................................................117
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations.............117
10.1.1. Regulatory and Ethical Considerations ..................................................117
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.......................................................................117
10.1.2. Financial Disclosure ...............................................................................118
10.1.3. Informed Consent Process ......................................................................118
10.1.4. Data Protection .......................................................................................119
10.1.5. Committees Structure .............................................................................120
10.1.6. Dissemination of Clinical Study Data ....................................................120
10.1.7. Data Quality Assurance ..........................................................................121
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10.1.8. Source Documents..................................................................................122
10.1.9. Use of Medical Records..........................................................................123
10.1.10. Study and Site Closure..........................................................................123
10.1.11. Publication Policy.................................................................................124
10.1.12. Sponsor’s Qualified Medical Personnel ...............................................125
10.2. Appendix 2: Clinical Laboratory Tests ...............................................................126
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting ...................................................................128
10.3.1. Definition of AE .....................................................................................128
10.3.2. Definition of SAE...................................................................................129
10.3.3. Recording and Follow-Up of AE and/or SAE........................................131
10.3.4. Reporting of SAEs..................................................................................133
10.4. Appendix 4: Contraceptive Guidance .................................................................134
10.4.1. Male Participant Reproductive Inclusion Criteria..................................134
10.4.2. Female Participant Reproductive Inclusion Criteria...............................134
10.4.3. Woman of Childbearing Potential ..........................................................135
10.4.4. Contraception Methods     ......................................................................136
10.5. Appendix 5: Genetics..........................................................................................137
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments ......138
10.7. Appendix 7: AEs, ADEs, SAEs, USADEs and Device Deficiencies: 
Definition and Procedures for Recording, Evaluating, Follow-Up, and 
Reporting in Medical Device Studies......................................................................140
10.7.1. Definition of AE and ADE .....................................................................140
10.7.2. Definition of SAE, SADE, and Unanticipated Serious Adverse 
Device Effect .................................................................................................140
10.7.3. Definition of Device Deficiency.............................................................141
10.7.4. Recording/Reporting and Follow-Up of Device Deficiencies................141
10.8. Appendix 8: Country-specific Requirements......................................................144
10.8.1. France Contrat Unique............................................................................144
10.8.2. Japan-specific Regulatory Requirements ...............................................145
10.8.2.1. Definitions of Serious Adverse Event, Serious Adverse 
Event Caused by Medical Device, and Unanticipated Serious 
Adverse Event Caused by Medical Device .....................................145
10.9. Appendix 9: Decision Algorithm for Disease Assessment .................................146
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10.10. Appendix 10: ECOG PS....................................................................................149
10.11. Appendix 11: ECG Findings of Potential Clinical Concern .............................150
10.12. Appendix 12: Recommendations for Management of 
Allergic/Hypersensitivity Reactions, Cytokine Release Syndrome or 
Anaphylaxis.............................................................................................................152
10.13. Appendix 13: Management of Immune-related Adverse Events (irAEs).........153
10.14. Appendix 14 Management of BCG Associated Toxicity..................................162
10.15. Appendix 15 Alternative Measures During Public Emergencies......................163
10.15.1. Telehealth Visits...................................................................................163
10.15.2. Alternative Facilities for Safety Assessments ......................................163
10.15.2.1. Laboratory Testing ..............................................................163
10.15.2.2. Electrocardiograms..............................................................164
10.15.3. Study Intervention ................................................................................164
10.15.4. Home Health Visits...............................................................................165
10.15.5. Adverse Events and Serious Adverse Events.......................................166
10.15.6. Efficacy Assessments ...........................................................................166
10.15.7. Independent Oversight Committees .....................................................166
10.16. Appendix 16: Patient Reported Outcomes........................................................167
10.16.1. Patient Global Impression of Severity..................................................167
10.16.2. Patient Global Impression of Change...................................................168
10.16.3. Patient Treatment Administration Burden Questionnaire ....................169
10.16.4. Treatment Satisfaction Questionnaire (TSQ) .......................................170
10.17. Appendix 17: Protocol Amendment History.....................................................171
10.18. Appendix 18: Abbreviations .............................................................................190
11. REFERENCES ................................................................................................................195
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LIST OF TABLES
Table 1.
PF-06801591 Recommended Treatment Modifications for Drug-
Related Toxicity (Excluding Immune-Related AEs)................................78
Table 2.
Possible Clinical Outcomes for Participants with or without CIS at 
Randomization and EFS Evaluation.......................................................106
Table 3.
Outcome and Event Dates for EFS.........................................................106
Table 4.
Sample Size and Exact 95% CIs for CR Rate – BCG Unresponsive 
CIS Cohort B1 ........................................................................................109
Table 5.
Protocol Specified Laboratory Tests ......................................................127
LIST OF FIGURES
Figure 1.
B8011006: Study Schematic – Cohort A..................................................25
Figure 2.
B8011006 Study Schematic - Cohorts B1 and B2....................................27
Figure 3.
B8011006: Study Schematic Cohort A.....................................................59
Figure 4.
B8011006 Study Schematic Cohorts B1 and B2......................................60
Figure 5.
Testing Strategy......................................................................................109
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1. PROTOCOL SUMMARY
1.1. Synopsis
Protocol Title: A Phase 3, Multinational, Randomized, Open-Label, Three Parallel-Arm 
Study of PF-06801591, an Anti-PD-1 antibody, in Combination With Bacillus Calmette-
Guerin (BCG Induction With or Without BCG Maintenance) Versus BCG (Induction and 
Maintenance) in Participants With High-Risk, BCG-Naïve Non-Muscle Invasive Bladder 
Cancer or PF-06801591 as a Single Agent in Participants With BCG-Unresponsive NMIBC
Short Title: CREST - Phase 3 Study of Sasanlimab (PF-06801591) in Combination With 
Bacillus Calmette-Guerin (BCG) or as a Single Agent in Participants With High-Risk Non-
Muscle Invasive Bladder Cancer
Rationale:
Overall, incidence and mortality for bladder cancer (BC) has changed very little over the past 
20 years.1  Vaccination using BCG was the first Food and Drug Administration (FDA) 
approved immunotherapy indication in the 1980s and for patients with high-risk non-muscle 
invasive bladder cancer (NMIBC) after transurethral resection of the bladder tumor 
(TURBT), induction with BCG followed by maintenance still represents the standard of care 
(SOC).7  While treatment with BCG has been shown to reduce the risk of tumor recurrence, 
approximately 40% of patients with NMIBC will eventually have disease recurrence or 
progression despite BCG therapy;32 thus, alternative treatments are urgently required to 
improve the outcome.33
Increased programmed death – ligand (PD-L) 1 expression was observed in bladder cancer 
cells in response to BCG treatment both in vitro and in vivo preclinical models and the 
combination of BCG and anti-PD-L1 agent induced an antitumor immune response.2 In 
addition, the combination showed higher tumor growth inhibition and prolonged survival as 
compared to either agent alone.  
Sasanlimab (PF-06801591) is a humanized, monoclonal antibody (mAb) specific for human 
programmed death – 1 (PD-1) that blocks the interaction between PD-1 and PD-L1/PD-L2.  
PF-06801591 administered at 300 mg subcutaneous (SC) every 4 weeks has been evaluated 
in the Phase 1 Study B8011001 in participants with advanced solid tumors. The clinical 
safety data available to date suggest an acceptable safety profile, aligned with other anti-PD-
1/PD-L1 agents, and also preliminary evidence of clinical efficacy aligned with other 
anti-PD-1/PD-L1 agents in patients with advanced urothelial cancer (UC).
The role of PD-L1 expression level as a predictive factor of response to BCG therapy in 
patients with high-risk NMIBC was recently suggested in a retrospective evaluation 
suggesting that higher PD-L1 expression level is associated with failure of BCG 
treatment.3 Supportive of this hypothesis, pembrolizumab showed promising activity in 
Keynote-057, a Phase 2 study in participants with high-risk NMIBC unresponsive to 
BCG. In an analysis of 101 participants with carcinoma in situ (CIS), a complete response 
(CR) rate of 41% (95% confidence interval [CI]: 30.7, 51.1) was reported with a median 
duration of CR of 16.2 months (95% CI: 6.7, 36.2). The most common (>5%) treatment-
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related adverse events (AEs) included diarrhea (11%), fatigue (11%), pruritis (11%), 
hypothyroidism (7.0%), maculopapular rash (6%), rash, hyperthyroidism, and nausea (each 
5%), which was consistent with the known adverse event (AE) profile of pembrolizumab in 
the advanced disease setting.4
Rationale for Cohort A
A Phase 1 study of pembrolizumab in combination with BCG in participants with high-grade 
NMIBC persisting or recurring following at least 2 courses of intravesical therapy or 1 course 
of BCG (induction and maintenance), showed that the combination regimen of 
pembrolizumab (at 100 mg and 200 mg fixed doses) and BCG was well tolerated.6 Fatigue, 
dysuria, spasm, urgency, sensitivity and frequency were the most frequently reported AEs, 
with all AEs reported as Grade 1 or 2.6 Of the first 9 participants enrolled, 7 participants 
(78%) had no evidence of disease in the bladder at 19 weeks. These data suggest an 
improved clinical activity over each of the agents alone, considering BCG alone is expected 
to have minimal or no clinical activity in the treatment setting and pembrolizumab showed a 
CR rate 41% in a similar population.4
To treat patients with NMIBC appropriately, treatment considerations include the European 
Organisation for Research and Treatment of Cancer (EORTC) risk table scores of recurrence 
and progression.7  For patients with high-risk NMIBC, the current standard of care is TURBT 
followed by intravesical BCG.7  The standard schedule for BCG is induction (once weekly 
for 6 weeks) followed by maintenance for a minimum of 1 year.  Full-dose BCG 
maintenance, administered once per week for 3 weeks, starting at 3 months after the first 
BCG dose of induction course (ie, 6 weeks after completion of induction BCG), and at 6 
months, and then every 6 months, as used in the Southwest Oncology Group (SWOG) 8507 
and European Organization for Research and Treatment of Cancer (EORTC) 30911 and 
30962 trials,8,11 is the most appropriate maintenance schedule.  Indeed, addition of 
maintenance to induction treatment with BCG according to the administration schedule 
described in the study is currently recommended in the European Association of Urology 
(EAU) and National Comprehensive Cancer Network (NCCN) guidelines7,9 because it has 
proven to reduce both progression and recurrence of the disease.10
The optimal duration of BCG maintenance therapy has been investigated in the European 
Organization for Research and Treatment of Cancer Genito-Urinary (EORTC-GU) Study 
30962.11  In this study, full dose BCG maintenance for 3 years was associated with a 
reduction in recurrence (hazard ratio [HR] = 1.61, 95% CI: 1.13-2.30, p = 0.009) in high-risk 
participants as compared with 1 year of BCG maintenance; however, there were no 
differences in progression or survival.11  For this reason, the benefit of the 2 additional years 
of maintenance should be weighed against its additional costs, inconveniences, and 
tolerability.  Therefore, the study design for Cohort A of B8011006 includes a BCG 
maintenance duration of up to 2 years (Arm A: BCG plus PF-06801591, Arm C: BCG 
alone).  Considering the expected improved clinical activity of the PF-06801591 plus BCG 
combination regimen, investigation of PF-06801591 plus BCG induction only, is justified 
(Arm B).
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Based on preclinical and clinical data, an intervention in BCG-naïve participants with high-
risk NMIBC, with PF-06801591 in combination with BCG induction therapy (with or 
without maintenance therapy) may provide a greater benefit with longer event-free survival 
and reduction in the rate of subsequent cystectomy as compared to SOC BCG treatment. In 
addition, PF-06801591 is administered subcutaneously (SC) every 4 weeks which is expected 
to reduce burden for the participants and for the healthcare system. 
Rationale for Cohorts B1 and B2
BCG treatment fails in approximately 40% of patients with high-risk NMIBC32 and limited 
therapeutic options are available for those with BCG-unresponsive disease after adequate 
BCG therapy (defined as a minimum of 5 out of 6 doses of an induction course followed by 
either 2 out of 6 doses of a re-induction course, or 2 of 3 doses of a maintenance course). 12  
Patients with BCG-unresponsive disease are unlikely to respond to further BCG therapy, 
which is associated with an increased risk of progression, and radical cystectomy is therefore 
the standard and preferred option according to the treatment guidelines.13,14 Radical 
cystectomy is considered curative for some patients, but it is associated with significant 
morbidity and mortality.15 The overall 90-day complication rates are up to 28-64% 16,17 and 
the majority of early complications following radical cystectomy include gastrointestinal 
(29%), infection (25%), intestinal obstruction (23%), wound-related complications (15%) 
and deep vein thrombosis (4.7%); late complications include gastrointestinal bowel 
obstruction, urinary tract infection, deterioration in renal function, calculi formation, voiding 
dysfunction and metabolic complications.15, 17
Non-surgical treatment options for patients with BCG-unresponsive NMIBC are currently 
limited. Valrubicin is approved by the US but response rates are low (18-21%) and not 
durable.18, 19  A recent meta-analysis reported data from 42 studies in 2254 patients with 
NMIBC treated after BCG failure with 24 different treatments, including approved and 
investigational agents. The median CR rates in the treatment of CIS-containing tumors were 
26%, 17%, and 8% at 6, 12, and 24 months, respectively.20 In the studies that enrolled 
patients with papillary disease without CIS the median recurrence-free rates were 67%, 44%, 
and 10% at 6, 12, and 24 months, respectively.20 Similar results were reported from another 
meta-analysis that included 4 randomized-controlled studies and 24 single-arm studies that 
evaluated different bladder-sparing treatment options: the pooled 12-month response rates 
were 24% (95% CI: 16-32%) for trials with two or more prior BCG courses and 36% (95% 
CI: 25-47%) for those with one or more prior BCG courses.21 Even considering the 
heterogeneity of the patient population, the different definitions of BCG failure, and the 
different study designs, these results define the high unmet need for new treatment options 
treatments to improve clinical outcomes in patients with NMIBC that recurs after initial BCG 
treatment.
Based on the results of the Keynote-057 study4, pembrolizumab has been recently approved 
by the FDA for the treatment of patients with BCG-unresponsive CIS who are ineligible for 
or decline to undergo radical cystectomy.22  In this study after a median duration of follow-up 
of 36.4 months (IQR 32.0 - 40.7),  the CR rate was 41% (95% CI, 30.7-51.1) with a median 
duration of CR of 16.2 months (95% CI, 6.7 – 36.2).4 In addition, atezolizumab has shown 
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signs of clinical efficacy in patients with BCG-unresponsive CIS [CR rate at 3 months was 
41.1% (95% CI, 29.7-53.2)]53 and in patients with BCG-unresponsive papillary disease [EFS 
rate at 18 months was 45% (95% CI, 34-57)].54
PF-06801591 300 mg SC Q4W showed a safety and efficacy profile aligned to the other anti-
PD-1/PD-L1 agents in patients with advanced UC and NSCLC23 and PF-06801591 600 mg 
SC every 6 weeks (Q6W) showed a safety profile consistent with the B8011001 study and 
with the safety profiles of other PD-1 agents (data summarized in IB).  Both dosing regimens 
offer the convenience of subcutaneous administration. Indeed, real world evidence of 
oncology biologics show that subcutaneous administration reduces healthcare resource 
utilization and associated costs by saving time in drug preparation and administration 
compared to intravenous (IV) therapy. SC administration also reduces time spent in the 
infusion chair and in caregiver assistance, while patients report better quality of life and 
preference for SC therapy over IV therapy.24 In addition, the Q6W dosing frequency of 
PF-06801591, which will be evaluated in Cohort B2, explores an extended dosing interval 
for PF-06801591 to further reduce the burden for the participants, their caregivers and the 
healthcare system.
In summary, an unmet need exists for new innovative bladder-sparing treatment options for 
patients with BCG-unresponsive NMIBC that delay disease recurrence, progression, and 
radical cystectomy. PF-06801591 may provide greater clinical benefit with higher CR rate, 
durable responses and longer event-free survival relative to currently approved intravesical 
chemotherapies (valrubicin). Furthermore, the subcutaneous administration route and the 
lower frequency of dosing associated with the longer dosing interval are expected to reduce 
burden for the participants and for the healthcare system while maintaining a safety and 
efficacy profile aligned to other anti-PD-1/PD-L1 agents administered intravenously 
(pembrolizumab).  
Cohorts B1 and B2 of B8011006 will include patients with BCG-unresponsive NMIBC.  
Cohort B1 will include participants with CIS (with or without Ta/T1 papillary disease) and 
Cohort B2 will include participants with high-grade Ta/T1 papillary disease only.
As of 31 August 2022, enrollment in Cohorts B1 and B2 was closed by the sponsor for 
business strategy reasons.  This decision was not made due to any safety concerns, new 
emerging data, or regulatory interaction.  Participants that have already been enrolled into 
Cohorts B1 and B2 may continue treatment and study procedures and assessments per the 
Cohorts B1 and B2 SoA.
Due to the decision to close enrollment in Cohorts B1 and B2, the Cohort B1 and B2 study 
objectives are no longer required.  
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Objectives, Estimands and Endpoints
Cohort A
Primary Objectives
Primary Endpoints
To demonstrate that PF-06801591 + 
BCG (induction and maintenance) is 
superior to BCG (induction and 
maintenance) in prolonging event-free 
survival (EFS) in participants with high-risk 
NMIBC.
EFS as assessed by the investigator
Key Secondary Objectives
Key Secondary Endpoints
To demonstrate that PF-06801591 + 
BCG (induction) is superior to BCG 
(induction and maintenance) in prolonging 
EFS in participants with high-risk NMIBC
EFS as assessed by the investigator
To demonstrate that PF-06801591 + 
BCG (induction and maintenance) is 
superior to BCG (induction and 
maintenance) in prolonging overall survival 
(OS) in participants with high-risk NMIBC.
OS
To demonstrate that PF06801591 + BCG 
(induction) is superior to BCG (induction 
and maintenance) in prolonging OS in 
participants with high-risk NMIBC.
OS
Secondary Objectives
Secondary Endpoints
To estimate the complete response (CR) 
rate of PF-06801591 + BCG (induction and 
maintenance or induction) and BCG 
(induction and maintenance) in participants 
with CIS at randomization.
CR as assessed by the investigator (in 
participants with CIS at randomization)
To evaluate the duration of CR of 
PF06801591 + BCG (induction and 
maintenance or induction) and BCG 
(induction and maintenance) in participants 
with CIS at randomization.
Duration of CR for participants with CR 
as assessed by the investigator (in 
participants with CIS at randomization)
To evaluate the time to recurrence of low 
grade disease of PF-06801591 + BCG 
(induction and maintenance or induction) 
and BCG (induction and maintenance) in 
participants with high-risk NMIBC.
Time to recurrence of low-grade disease 
as assessed by the investigator 
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Cohort A
To evaluate the time to cystectomy of 
PF06801591 + BCG (induction and 
maintenance or induction) and BCG 
(induction and maintenance) in participants 
with high-risk NMIBC.
Time to cystectomy
To evaluate the disease-specific survival 
(DSS) of PF-06801591 + BCG (induction 
and maintenance or induction) and BCG 
(induction and maintenance) in participants 
with high-risk NMIBC.
DSS as assessed by the investigator
To evaluate the overall safety profile of 
PF06801591+BCG (induction and 
maintenance or induction) and BCG 
(induction and maintenance) in participants 
with high-risk NMIBC.
AEs as characterized by type, severity (as 
graded by National Cancer Institute 
Common Terminology Criteria for Adverse 
Events [NCI CTCAE] v5.0), timing, 
seriousness, and relationship to study 
therapy. Laboratory abnormalities as 
characterized by type, severity (as graded 
by NCI CTCAE v5.0), and timing
To assess the effects of PF06801591 + 
BCG (induction and maintenance or
induction) and BCG (induction and 
maintenance) on patient-reported health-
related quality of life in participants with 
high-risk NMIBC.
Health-related quality of life as measured 
by: 1) EORTC QLQ-C30 (European 
Organization for Treatment of Cancer 
Quality of Life Questionnaire), 2) EORTC 
QLQ-NMIBC24, 3) PTAB (Patient 
Treatment Administration Burden 
Questionnaire)
To characterize the PK of PF06801591 + 
BCG (induction and maintenance or
induction).
Ctrough of PF-06801591 when in 
combination with BCG (induction and 
maintenance or induction). Arms A and B 
only. 
To evaluate the immunogenicity of 
PF06801591 + BCG (induction and 
maintenance or induction).
ADAs; NAbs of PF-06801591 when in 
combination with BCG (induction and 
maintenance or induction). Arms A and B 
only. 
To evaluate PD-L1 expression in pre-
treatment tumor tissue that may aid in the 
identification of a participant subpopulation 
most likely to benefit from treatment with 
Tumor sample biomarker status based on 
PD-L1 expression (high or low)
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Cohort A
PF06801591 + BCG (induction and 
maintenance or induction).
Cohorts B1 and B2
Primary Objectives
Primary Endpoints
To estimate the CR rate of PF-06801591 
in participants with BCG-unresponsive CIS 
(Cohort B1 only)
CR as assessed by the BICR
To evaluate the EFS of PF-06801591 in 
participants with BCG-unresponsive 
NMIBC (Cohort B2 only)
EFS as assessed by the investigator
Secondary Objectives
Secondary Endpoints
To evaluate the duration of CR of PF-
06801591 in participants with BCG-
unresponsive CIS (Cohort B1 only).
Duration of CR for participants with CR 
as assessed by the BICR
To estimate the CR rate of PF-06801591 
at 12 months in participants with BCG-
unresponsive CIS (Cohort B1 only)
CR at 12 months as assessed by the BICR
To evaluate the EFS of PF-06801591 in 
participants with BCG-unresponsive CIS 
(Cohort B1 only)

EFS as assessed by the investigator
To evaluate the time to cystectomy of 
PF-06801591 in participants with BCG-
unresponsive NMIBC (Cohorts B1 and B2).
Time to cystectomy
To evaluate OS in participants with 
BCG-unresponsive NMIBC treated with 
PF-06801591 (Cohorts B1 and B2).
OS
To evaluate the overall safety of PF-
06801591 in participants with BCG-
unresponsive NMIBC (Cohorts B1 and B2).
AEs as characterized by type, severity (as 
graded by National Cancer Institute 
Common Terminology Criteria for Adverse 
Events [NCI CTCAE] v5.0), timing, 
seriousness, and relationship to study 
therapy. Laboratory abnormalities as 
characterized by type, severity (as graded 
by NCI CTCAE v5.0), and timing
To assess the effects of PF-06801591 on 
patient-reported health-related quality of life 
Health-related quality of life as measured 
by: 1) EORTC QLQ-C30 (European 
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Cohorts B1 and B2
in participants with BCG-unresponsive 
NMIBC (Cohorts B1 and B2).
Organization for Treatment of Cancer 
Quality of Life Questionnaire), 2) EORTC 
QLQ-NMIBC24, 3) PTAB (Patient 
Treatment Administration Burden 
Questionnaire) 
To evaluate PD-L1 expression in 
pretreatment tumor tissue that may aid in 
the identification of a subpopulation of 
participants with BCG unresponsive 
NMIBC most likely to benefit from PF-
06801591 (Cohorts B1 and B2).
PD-L1 expression
To characterize the PK and 
immunogenicity of PF06801591 single 
agent in participants with BCG-
unresponsive NMIBC (Cohorts B1 and B2).
Ctrough, Cmax (Cohort B2 only), ADAs and 
NAbs following PF-06801591 single agent. 
Estimands are defined below for the primary and key secondary endpoints of the study.
Table 2 (Section 9.1.1) defines the possible clinical outcomes for the EFS evaluation. The 
clinical definitions of recurrence of high-grade disease, progressive disease, persistence of 
CIS, recurrence of low-grade disease and CR are included in Section 10.9. For Cohort A, in 
participants with CIS at randomization “persistence of CIS” is defined as persistence of CIS 
after induction or, if re-induction is administered, after re-induction. Persistence of CIS after 
induction with CR after re-induction is not considered persistence of CIS. For Cohort B1, 
persistence of CIS is defined as persistence of CIS at the 12 week disease assessment. The 
censoring and event date options to be considered for the EFS analyses are presented in 
Table 3 (Section 9.1.1).
Cohort A
Primary Estimand (event-free survival [EFS] for Arm A vs Arm C) and Key Secondary 
Estimand (EFS for Arm B vs Arm C): treatment effect, estimated based on data from all 
randomized participants, of each experimental arm (Arm A and Arm B) on EFS compared to 
Arm C from randomization to the earliest of recurrence of high-grade disease, progression of 
disease, persistence of CIS, or death regardless of tolerability, duration of study treatment, or 
initiation of subsequent anti-cancer therapy. The date of the event (event as defined in 
Table 2) is the date of disease assessment documenting recurrence of high-grade disease, 
progression of disease, persistence of CIS (applicable only to participants with CIS at 
randomization), or death, whichever occurs earlier. The date of persistence of CIS is the 
earliest date when persistence of CIS is observed, if CR is not observed after re-induction.
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
Variable: EFS defined as the time from randomization until recurrence of high-grade 
disease, progression of disease, persistence of CIS, or death due to any cause, whichever 
occurs first.

Censoring: See Table 3. 

Population-level summary measure: hazard ratio for EFS including all randomized 
participants.
Supportive Estimand 1 (EFS): treatment effect, estimated based on data from all randomized 
participants, of each experimental arm (Arm A and Arm B) on EFS compared to Arm C from 
randomization to the earliest of recurrence of high-grade disease, progression of disease,
persistence of CIS, or death, regardless of tolerability, duration of study treatment, initiation 
of subsequent anti-cancer therapy. The date of the event (event as defined in Table 2) is the 
date of disease assessment documenting recurrence of high-grade disease, progression of 
disease, date of randomization for participants with persistent CIS (applicable only to 
participants with CIS at randomization), or death, whichever occurs earlier.

Variable: EFS defined as the time from randomization until recurrence of high-grade 
disease, progression of disease, persistence of CIS, or death due to any cause, whichever 
occurs first.

Censoring: See Table 3.

Population-level summary measure: hazard ratio for EFS including all randomized 
participants. 
Supportive Estimand 2 (EFS): treatment effect of each experimental arm (Arm A and Arm B) 
on EFS compared to Arm C from randomization to the earliest of recurrence of high-grade 
disease, progression of disease, persistence of CIS, or death regardless of tolerability, 
duration of study treatment, or initiation of subsequent anti-cancer therapy.  Data from 
randomized participants who do not meet per-protocol criteria as defined below are excluded. 
The date of the event (event as defined in Table 2) is the date of disease assessment 
documenting recurrence of high-grade disease, progression of disease, persistence of CIS 
(applicable only to participants with CIS at randomization), or death, whichever occurs 
earlier. The date of persistence of CIS is the earliest date when persistence of CIS is 
observed, if CR is not observed after re-induction.

Variable: EFS defined as the time from randomization until recurrence of high-grade 
disease, progression of disease, persistence of CIS, or death due to any cause, whichever 
occurs first.

Censoring: See Table 3. 
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
Population-level summary measure: hazard ratio for EFS excluding randomized 
participants who did not receive at least 1 dose of study drug, did not meet inclusion 
criteria 2 or 3, or met exclusion criteria 1 or 2.
Key Secondary Estimand (overall survival [OS]): Treatment effect, estimated based on data 
from all randomized participants, of each experimental arm (Arm A and Arm B) on OS 
compared to Arm C regardless of tolerability, duration of study treatment, initiation of 
subsequent anti-cancer therapy or participant’s request to discontinue study procedures. 

Variable: OS 

Censoring: data for participants not known to have died are censored at the time of last 
contact. 

Population-level summary measure: hazard ratio for OS, including all randomized 
participants.
Overall Design:
This is a Phase 3, multicenter, multinational, randomized, open label, parallel, 3-arm study to 
evaluate PF-06801591 in combination with BCG vs BCG in participants with high-risk, 
BCG-naïve non-muscle invasive bladder cancer (Cohort A). The study will also evaluate PF-
06801591 as a single agent in participants with BCG unresponsive, NMIBC in 2 separate 
non-randomized cohorts (Cohorts B1 and B2).
Randomization (1:1:1) in Cohort A will occur via interactive response technology (IRT) 
within approximately 28 days of start of screening.  Randomization will be stratified by the 
presence of CIS (yes vs no) and geography (United States [US] vs Western Europe and 
Canada vs rest of world [ROW]). Registration into Cohorts B1 and B2 will occur via 
interactive response technology (IRT) within approximately 28 days of start of screening. For 
Cohort B1, diagnosis of CIS alone or with concomitant recurrent Ta/T1 disease and absence 
of muscle-invasive bladder cancer and extravesical disease must be confirmed by the BICR 
prior to registration.
In order to conduct a preliminary assessment of the safety profile of PF-06801591 plus BCG 
regimen, a review of safety data will be performed by an external data monitoring committee 
(EDMC) approximately 6 weeks after 20 participants have been randomized in each of the 3 
arms and have received at least one dose of study treatment.  The enrollment will continue 
during EDMC review.  The EDMC will convene to monitor safety in the study (Cohort A 
only) approximately every 6 months thereafter.  The EDMC will also review cumulative 
safety data during the study conduct as well as review the futility interim analysis (IA) data 
for EFS from Cohort A.  
Based on protocol amendment 5, the IA2 will be removed, and the FA for EFS based on a 
calendar-based data cut-off date will be conducted. Randomization to Cohort A was 
completed on 16 November 2021 and the EFS FA data cut-off date will be set to allow for 
approximately 3 years of follow-up after last randomized participant.   
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Based on the blinded observed EFS event accrual rate, approximately 261 EFS events are 
expected to have occurred across the three study arms by the EFS FA data cut-off date.  
Disclosure Statement:
Cohort A is a Parallel Treatment study with 3 arms that have No masking.  
Number of Participants:
Cohort A: Approximately 999 participants (including a minimum of 250 participants with 
CIS) will be randomized to one of 3 treatment arms (A, B, and C) in this Cohort, each arm 
will have approximately 333 randomized participants. As of 16 November 2021, enrollment 
to Cohort A has completed with 1056 participants randomized.    
Intervention Groups and Duration:
Cohort A

Arm A: PF-06801591 + BCG (induction and maintenance period)

Arm B: PF-06801591 + BCG (induction period only)

Arm C: BCG only (induction and maintenance period)
BCG Dosing (intravesical instillation):

Induction period: one dose every week (QW) for 6 consecutive weeks (QWx6)

Re-Induction period: Following first induction period, participants with CIS at 
randomization who have persistent disease and participants with recurrence of high grade 
Ta disease may receive re-induction (QWx6) 

Maintenance period: (Arm A and Arm C): Doses on D1, D8, D15 during Cycles C4, C7, 
C13, C19 and C25. For participants that have a re-induction period, the maintenance 
period will begin at C7D1.
PF-06801591 Dosing (subcutaneous injection): 
Once every 4 weeks 300 mg up to Cycle 25 (cycle = 4 weeks).
All participants will enter the safety follow-up period at end of treatment (EOT). Concurrent 
to the safety follow-up, participants with no recurrence of high-grade disease, progression of 
disease, or persistence of CIS before EOT, will continue disease assessment through the 
disease follow-up period (assessments every 12 weeks for 2 years after randomization and 
every 24 weeks thereafter until recurrence of high grade disease or progression of disease, 
withdrawal of consent for further participation in the study, lost to follow-up, or death).  
After recurrence of high-grade disease, persistence of CIS, or progression of disease 
participants will be followed for survival via telephone calls every 12 weeks until the earliest 
of withdrawal of consent, lost to follow-up, death, study termination by the sponsor, or end 
of study (5 years from last participant randomized).
Data Monitoring Committee: Yes
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1.2. Schema
Figure 1.
B8011006: Study Schematic – Cohort A
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Cohorts B1 and B2: 

PF-06801591 as a single agent
PF-06801591 Dosing (subcutaneous injection): 
Cohort B1: Once every 4 weeks 300 mg up to Cycle 25 (cycle = 4 weeks).
Cohort B2: Once every 6 weeks 600 mg up to Cycle 17 (cycle = 6 weeks).
As noted in Figure 2, participants in Cohort B1 with persistence of CIS at the 12 week 
disease assessment may continue on PF-06801591 for an additional 3 cycles (until the 24 
week disease assessment).  This may only occur after the investigator and participant discuss 
the option of cystectomy, and the participant re-consents to 3 additional cycles of PF-
06801591 instead of cystectomy.  Participants with persistence of CIS at or after the 24 week 
disease assessment will enter the post-treatment follow-up period for safety visits.
All participants will enter the safety follow-up period at end of treatment (EOT). 
Data Monitoring Committee: No
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Figure 2.
B8011006 Study Schematic - Cohorts B1 and B2
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1.3. Schedule of Activities (SoA)
Screening and Induction Period – Cohort A 
Screening
Induction Period 
Notes
Cycle 1
Cycle 2
Cycle 3 Cycle = 4 weeks
D -28 to
D -1
D1
D8
D15
D22
D1
D8
D1
Visit Window (Days)
±0
±3
±3
±3
±3
±3
±3
Informed Consent 
X
Informed consent may be obtained more than 28 days prior to 
randomization. All screening procedures must be completed within 28 days 
of randomization.
The Consent for future research will be signed as applicable. 
Participants must sign consent prior to any trial-specific procedure.  See 
Section 10.1.3.
Tumor and Medical 
History
X
See Section 8 for details.
Physical Examination
X
X
X
X
Physical examinations should be performed according to clinical practice.   
Any abnormalities should be recorded as AEs.  See Section 8.2.1.
Weight
X
X
X
X
Vital Signs 
X
X
X
X
BP and pulse rate will be performed.  Any clinically significant 
abnormalities should be recorded as AEs.  See Section 8.2.2.
ECOG PS
X
X
X
X
Refer to Section 8.2.3. and Section 10.10.
12-Lead ECG
X
X
X
As clinically 
indicated
Single 12-lead ECG will be collected prior to dosing of PF-06801591. See 
Section 8.2.4 for details.
Adverse Events
X
See Section 8.3 and Section 10.3.
Concomitant Therapy
X
See Section 6.5.
Contraception Check
X
X
X
Must be performed D1 of each cycle.  See Section 10.4 for details. 
Chest X-Ray/ Laboratory 
Assessment/ Skin Test to 
Exclude Tuberculosis
X
As clinically indicated
Active tuberculosis is to be excluded per local guidelines or the applicable 
BCG product label prior to randomization.  If tuberculosis is excluded by 
chest x-ray, the chest x-ray is not required to be repeated at screening if 
performed within 90 days prior to randomization.  Methods of ruling out 
tuberculosis other than those specified in the protocol are permitted, if they 
are local standard practice.
Laboratory
Hematology
X
X
X
X
See Section 10.2 for the list of the tests. 
Blood Chemistry
X
X
X
X
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Screening
Induction Period 
Notes
Cycle 1
Cycle 2
Cycle 3 Cycle = 4 weeks
D -28 to
D -1
D1
D8
D15
D22
D1
D8
D1
Visit Window (Days)
±0
±3
±3
±3
±3
±3
±3
Coagulation
X
X
Not necessary to repeat on C1D1 if performed within 7 days prior to C1D1 
as part of Screening. Laboratory tests may be performed up to 3 days prior to 
the scheduled clinic visit, so that results will be available for review before 
study treatment administration, including C1D1. See Section 8.2.7 for 
requirements on minimum labs to be reviewed prior to dosing.
Urinalysis
X
X
X
X
Collect sample before BCG administration.  Not necessary to repeat on 
C1D1 if performed within 7 days prior to C1D1 as part of Screening. 
See Section 10.2 for the list of the tests. 
Pregnancy Test
X
X
X
X
A negative highly sensitive test is required prior to study treatment dosing 
on Day 1 of all cycles.  Results must be available for review prior to dosing.  
See Section 8.2.8 and Section 10.4.  Pregnancy testing after C1D1 per local 
guidelines. 
FSH
X
For female postmenopausal participants under the age of 60 and not using 
hormonal contraception or HRT, a serum FSH test is required at screening 
only, to confirm postmenopausal status. FSH is not required for participants 
not meeting these criteria.  See Section 10.2 and Section 10.4.
Hepatitis B and C
X
HBV surface antigen and anti-HCV antibody tests.  If HBV surface antigen 
or anti-HCV antibody test is positive, reflex testing must be carried out, as 
detailed in Table 5
ACTH & Thyroid 
Function Test
X
X
X
X
Not necessary to repeat on C1D1 if performed within 7 days prior to C1D1 
as part of Screening. 
Randomization
X
Participants will receive assigned treatment within 3 days after 
randomization.
BCG Administration 
(All Arms)
X
X
X
X
X
X
Follow calendar days for dosing, not the schedule cycles.  See Section 6.1.2
for details. On days when BCG and PF-06801591 are both administered,  
BCG is administered first.
PF-06801591 
Administration
(Arms A & B)
X
X
X
Administer subcutaneously. See Section 6.1.2.
Disease Assessments
CT or MRI
X
As clinically indicated
CT/MRI/Urogram of the abdomen and pelvis/urinary tract.  Imaging 
performed with contrast agents unless contraindicated for medical reasons.  
As clinically indicated to confirm and/or rule out distant metastasis.  See 
Section 8.1.1.3 for additional details. 
Cystoscopy, with or 
without Biopsy 
X
Cystoscopy is required during screening.  Same equipment and methods by 
the same study staff should be used for the duration of the study whenever 
possible.  See Section 8.1.1.1.
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Screening
Induction Period 
Notes
Cycle 1
Cycle 2
Cycle 3 Cycle = 4 weeks
D -28 to
D -1
D1
D8
D15
D22
D1
D8
D1
Visit Window (Days)
±0
±3
±3
±3
±3
±3
±3
Cytology
X
Urine cytology; ±7 days allowed for on-treatment assessment.  Same 
equipment and methods by the same study staff should be used for the 
duration of the study whenever possible. See Section 8.1.1.2.
Patient Reported Outcomes (PROs)
EORTC-QLQ-C30,
EORTC NMIBC24
X
X
X
X
All PROs will be completed prior to clinical assessments and procedures 
and/treatment administration, with the exception of the PTAB, which will be 
completed immediately after treatment administration.  Laboratory 
assessments may be done prior to PROs if laboratory assessments are done 
on a date prior to the rest of the study visit.  
PROs will be administered in following order: EORTC QLQ-C30, 
EORTC NMIBC24, EQ-5D-5L, PGIS, PGIC, TSQ, PTAB.
See Section 8.1.2.
EQ-5D-5L
X
X
X
PGIS
X
X
X
X
PGIC
X
X
TSQ
X
PTAB
X
X
Immunogenicity, Pharmacokinetic, Pharmacodynamic, Biomarker Analyses
Immunogenicity
X
X
Collected pre-dose at each time point for Anti-PF-06801591 Antibody 
(ADA/NAb) measurement.    See Section 8.8.3. Arms A and B only.
Pharmacokinetics
X
X
Collected pre-dose at each time point for PK analysis of PF-06801591. All 
efforts should be made to obtain PK samples within 2 hours prior to PF-
06801591 dosing. See Section 8.5. Arms A and B only.
Tumor Tissue Sample 
from Most Recent TURBT
X
See Section 8.8.1.
Whole Blood Biomarkers
X
X
X
See Section 8.8.
Plasma and Serum 
Biomarker Sample
X
X
X
See Section 8.8.
Banked Biospecimen 
X
See Section 8.7.2.
AE: adverse event, ACTH: adrenocorticotropic hormone, ADA: anti-drug antibodies; BCG: Bacillus Calmette Guérin, BP: blood pressure; CT: computed tomography, ECG: 
electrocardiogram, ECOG PS: Eastern Cooperative Oncology Group Performance Status, EORTC-QLQ-C30: European Organisation for Research and Treatment of Cancer 
Quality of Life Questionnaire–30 (items), FSH: follicle-stimulating hormone, HRT: hormone replacement therapy, MRI: magnetic resonance imaging, NAb: neutralizing 
antibodies; NMIBC: non-muscle invasive bladder cancer, PGIC: Patient Global Impression of Change; PGIS: Patient Global Impression of Severity; PK: pharmacokinetics, 
PTAB: Patient Treatment Administration Burden; TSQ: Treatment Satisfaction Questionnaire; TURBT: transurethral resection of bladder tumor
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Maintenance Period – Cohort A 
Maintenance Period: Cycles 4 to 25 (Cycle = 4 Weeks) for participants without re-induction
BCG Re-induction Period for Participants Who Receive BCG Re-induction: Cycles 4-6 ; Maintenance Period: Cycles 7 to 25
C4D1
C5D1
C6D1
C7D1
C8D1
C9D1
C10D1
C11D1
C12D1
C13D1
C14D1
C15D1 
thru 
C25D1
Notes
Visit Window (Days)
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
Physical Examination
X
X
X
X
X
X
X
X
X
X
X
X
Physical examinations should be performed 
according to clinical practice. Any clinically 
significant abnormalities should be recorded 
as AEs. See Section 8.2.1.
Weight
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs 
X
X
X
X
X
X
X
X
X
X
X
X
BP and pulse rate will be performed. Any 
clinically significant abnormalities should be 
recorded as AEs. See Section 8.2.2.
Contraception Check
X
X
X
X
X
X
X
X
X
X
X
X
Must be performed D1 of each cycle. See 
Section 10.4 for details.
ECOG PS
X
X
X
X
X
X
X
X
X
X
X
X
See Section 8.2.3 and Section 10.10.
Concomitant Therapy
X
See Section 6.5.
Adverse Events
X
See Section 8.3 and Section 10.3.
12-Lead ECG
X
X
X
As clinically indicated
Prior to dosing. See Section 8.2.4.
Completed on Day 1 of Cycles 4, 5, and 6 
only. For all other cycles in maintenance, 
ECG will be completed as clinically 
indicated. 
Chest X-Ray
As clinically indicated
Laboratory
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
See Section 10.2 for the list of the tests. 
Laboratory tests may be performed up to 3 
days prior to the scheduled clinic visit, so that 
results will be available for review before 
study treatment administration. See 
Section 8.2.7 for requirements on minimum 
labs to be reviewed prior to dosing.
Blood Chemistry
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation
X
X
X
X*
*Completed on Day 1 of Cycles 15, 18, 21, 
24.
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Maintenance Period: Cycles 4 to 25 (Cycle = 4 Weeks) for participants without re-induction
BCG Re-induction Period for Participants Who Receive BCG Re-induction: Cycles 4-6 ; Maintenance Period: Cycles 7 to 25
C4D1
C5D1
C6D1
C7D1
C8D1
C9D1
C10D1
C11D1
C12D1
C13D1
C14D1
C15D1 
thru 
C25D1
Notes
Visit Window (Days)
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
Urinalysis
X
X*
X
X
X**
Collect sample prior to each BCG 
administration as indicated, including:
*during the re-induction, as applicable 
(Cycles 4 and 5) 
**during Cycles 19 and 25. 
As clinically indicated during other cycles. 
See Section 10.2 for the list of the tests. 
Pregnancy Test
X
X
X
X
X
X
X
X
X
X
X
X
A negative highly sensitive test is required 
prior to study intervention dosing on Day 1 of 
all cycles. Results must be available for 
review prior to dosing. See Section 8.2.8 and 
Section 10.4. Pregnancy testing per local 
guidelines.
ACTH & Thyroid 
Function Test
X
X
X
X* 
*Completed on Day 1 of Cycles 15, 18, 21, 
24, 25.
BCG Administration 
(Arms A & C)
X*#
X*
X#
X#
X#
Follow calendar cycle for dosing, not the 
schedule. See Section 6.1.2 for details. On 
days when BCG and PF-06801591 are both 
administered, BCG is administered first. 
*Re-induction period: See Section 4.1 for 
participants who may meet criteria for re-
induction. Suggested instillations on C4D1, 
C4D8, C4D15, C4D22, C5D1, and C5D8.  
Maintenance will then begin on C7D1. If 
TURBT is performed, BCG re-induction 
schedule should be modified according to the 
product label.
#Maintenance BCG schedule: D1, D8, D15 of 
Cycles 4, 7, 13, 19, and 25.
PF-06801591 
Administration (Arms 
A & B)
X
X
X
X
X
X
X
X
X
X
X
X
Administer subcutaneously Q4W up to 
Cycle 25. See Section 6.1.2.
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Maintenance Period: Cycles 4 to 25 (Cycle = 4 Weeks) for participants without re-induction
BCG Re-induction Period for Participants Who Receive BCG Re-induction: Cycles 4-6 ; Maintenance Period: Cycles 7 to 25
C4D1
C5D1
C6D1
C7D1
C8D1
C9D1
C10D1
C11D1
C12D1
C13D1
C14D1
C15D1 
thru 
C25D1
Notes
Visit Window (Days)
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
Disease Assessments
CT or MRI
As clinically indicated
CT/MRI/Urogram of the abdomen and 
pelvis/urinary tract. Imaging performed with 
contrast agents unless contraindicated for 
medical reasons. As clinically indicated to 
confirm and/or rule out distant metastasis. See 
Section 8.1.1.3.
Cystoscopy with or 
without Biopsy
X
X
X
X
X*
Participants with CIS at randomization who 
do not achieve a CR within 6 months of 
initiating study intervention will discontinue 
study treatment and enter the post-treatment 
follow-up period. Cystoscopy with or without 
tumor biopsy; ±7 days allowed for on-
treatment assessment. Same equipment and 
methods by the same study staff should be 
used for the duration of the study whenever 
possible.  See Section 8.1.1.1.
* Completed every 12 weeks.
Cytology
X
X
X
X
X*
Urine cytology; ±7 days allowed for on-
treatment assessment. Same equipment and 
methods by the same study staff should be 
used for the duration of the study whenever 
possible.  See Section 8.1.1.2.
*Completed every 12 weeks.
Patient Reported Outcomes (PROs)
EORTC-QLQ-C30,
EORTC NMIBC24, 
X
X
X
X
X
X
X*
All PROs will be completed prior to clinical 
assessments and procedures and treatment 
administration, with the exception of the 
PTAB, which will be completed immediately 
after treatment administration. Laboratory 
assessments may be done prior to PROs if 
laboratory assessments are done on a date 
prior to the rest of the study visit. See 
EQ-5D-5L
X
X
X
X
X
X
X*
PGIS
X
X
X
X
X
X
X*
PGIC
X
X
X
X
X
X
X*
TSQ
X
X
X
X*
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Maintenance Period: Cycles 4 to 25 (Cycle = 4 Weeks) for participants without re-induction
BCG Re-induction Period for Participants Who Receive BCG Re-induction: Cycles 4-6 ; Maintenance Period: Cycles 7 to 25
C4D1
C5D1
C6D1
C7D1
C8D1
C9D1
C10D1
C11D1
C12D1
C13D1
C14D1
C15D1 
thru 
C25D1
Notes
Visit Window (Days)
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
PTAB
X
X
X
X*
Section 8.1.2. 
PROs will be administered in the following 
order: EORTC QLQ-C30, 
EORTC NMIBC24, EQ-5D-5L, PGIS, PGIC, 
TSQ, PTAB.
*Completed on Day 1 of Cycles 19 and 25.
Immunogenicity, Pharmacokinetic, and Pharmacodynamic Biospecimen
Immunogenicity
X
X
X
X
X
Collected pre-dose at each time point for 
Anti-PF-06801591 Antibody (ADA/NAb) 
measurement. See Section 8.8.3. Arms A and 
B only.
Pharmacokinetics 
X
X
X
X
X
Collected pre-dose at each time point for PK 
analysis of PF-06801591. All efforts should 
be made to obtain PK samples within 2 hours 
prior to PF-06801591 dosing. See Section 8.5. 
Arms A and B only. 
Whole blood 
biomarkers
X
X
X
X
X
See Section 8.8.
Plasma and Serum 
Biomarker Sample 
X
X
X
X
X
See Section 8.8.
AE: adverse event, ACTH: adrenocorticotropic hormone, ADA: anti-drug antibodies; BCG: Bacillus Calmette Guérin, BP: blood pressure; CIS: carcinoma in situ; CT: computed 
tomography, ECG: electrocardiogram, ECOG PS: Eastern Cooperative Oncology Group Performance Status, EORTC-QLQ-C30: European Organisation for Research and 
Treatment of Cancer Quality of Life Questionnaire–30 (items); EOT: end of treatment; MRI: magnetic resonance imaging, NAb: neutralizing antibodies; NMIBC: non-muscle 
invasive bladder cancer, PGIC: Patient Global Impression of Change; PGIS: Patient Global Impression of Severity; PK: pharmacokinetics, PTAB: Patient Treatment 
Administration Burden; Q4W: every 4 weeks; TSQ: Treatment Satisfaction Questionnaire
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End of Treatment Visit and Follow-Up Period – Cohort A 
EOT*
Post-Treatment Period 
*EOT: End of Treatment visit will take place within 7 days of the last dose of PF-06801591 or 
BCG (whichever is later) or decision to discontinue both drugs. This includes participants that 
complete the full 25 cycles of treatment as well as participants that discontinue treatment early.
**Safety Follow-Up: All participants enter safety follow-up period at EOT. Visits at 30, 60, 
and 90 days post-EOT.
***Disease Follow-Up: Participants with no recurrence of high-grade disease, disease 
progression, or persistence of CIS before EOT will be assessed Q12W for 2 years after 
randomization and Q24W thereafter until recurrence of high-grade disease or disease 
progression, consent withdrawal, lost to follow-up, or death. Timing of disease assessment is 
fixed according to the calendar, starting with randomization and should not be adjusted.
****Survival Follow-Up: Q12W until consent withdrawal, lost to follow-up, death, or end of 
study (5 yrs from last participant randomized).  Sponsor may request that sites complete 
additional survival follow-up to facilitate planned analyses as needed.
Safety
Follow-Up**
Disease
Follow-Up***
Survival 
Follow-Up****
Visit Window (Days)
+7
±7
±7
±7
Physical Examination
X
X
Physical examinations should be performed according to clinical practice. Any abnormalities 
should be recorded as adverse events.  
See Section 8.2.1.
Weight
X
X
Vital Signs 
X
X
BP and pulse rate will be performed. Any abnormalities should be recorded as AEs. 
See Section 8.2.2.
Contraception check
X
X
ECOG PS
X
AEs
X
X
Treatment-related SAEs will be reported during the disease follow-up and survival follow-up. 
See Section 8.3 and Section 10.3.
Concomitant Therapy
X
X
See Section 6.5.
Laboratory
Hematology
X
X
See Section 10.2 for the list of the tests. Laboratory tests may be performed up to 3 days prior to 
the scheduled clinic visit, so that results will be available for review before study treatment 
administration. See Section 8.2.7 for requirements on minimum labs to be reviewed prior to 
dosing.
Blood Chemistry
X
X
Coagulation
X
Urinalysis
X
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EOT*
Post-Treatment Period 
*EOT: End of Treatment visit will take place within 7 days of the last dose of PF-06801591 or 
BCG (whichever is later) or decision to discontinue both drugs. This includes participants that 
complete the full 25 cycles of treatment as well as participants that discontinue treatment early.
**Safety Follow-Up: All participants enter safety follow-up period at EOT. Visits at 30, 60, 
and 90 days post-EOT.
***Disease Follow-Up: Participants with no recurrence of high-grade disease, disease 
progression, or persistence of CIS before EOT will be assessed Q12W for 2 years after 
randomization and Q24W thereafter until recurrence of high-grade disease or disease 
progression, consent withdrawal, lost to follow-up, or death. Timing of disease assessment is 
fixed according to the calendar, starting with randomization and should not be adjusted.
****Survival Follow-Up: Q12W until consent withdrawal, lost to follow-up, death, or end of 
study (5 yrs from last participant randomized).  Sponsor may request that sites complete 
additional survival follow-up to facilitate planned analyses as needed.
Safety
Follow-Up**
Disease
Follow-Up***
Survival 
Follow-Up****
Visit Window (Days)
+7
±7
±7
±7
Pregnancy Test
X
X
Required 30 days (±7 days) after last dose. At Day 90 and Day 180 after EOT, pregnancy status 
should be discussed (may be done by telephone, unless the participant is visiting the site for 
other reasons) and pregnancy test can be conducted as necessary. See Section 8.2.8, 
Section 10.2, and Section 10.4.
Disease Assessments
CT or MRI
As clinically indicated  
CT/MRI/Urogram of the abdomen and pelvis/urinary tract. Imaging performed with contrast 
agents unless contraindicated for medical reasons. As clinically indicated to confirm and/or rule 
out distant metastasis. See Section 8.1.1.3 for additional details.
Cystoscopy with or 
without Biopsy and 
Cytology
X
Q12W for 2 years after randomization and Q24W thereafter until recurrence of high-grade 
disease or disease progression, consent withdrawal, lost to follow-up, or death.
Same equipment and methods by the same study staff should be used for the duration of the 
study whenever possible.  Disease assessment will include urine cytology and cystoscopy with 
or without tumor biopsy according to the modalities described in Section 8.1.1.1 and 
Section 8.1.1.2. 
Patient Reported Outcomes (PROs)
EORTC-QLQ-C30,
EORTC NMIBC24, 
X
X
X
All PROs will be completed prior to assessments with the exception of the PTAB, which will 
be completed immediately after treatment administration.  Laboratory assessments may be done 
prior to PROs if laboratory assessments are done on a date prior to the rest of the study visit. If 
the EOT and last treatment visits are not on the same day, the PTAB assessment does not need 
to be completed. 
EQ-5D-5L
X
X
PGIS
X
X
PGIC
X
X
TSQ
X
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EOT*
Post-Treatment Period 
*EOT: End of Treatment visit will take place within 7 days of the last dose of PF-06801591 or 
BCG (whichever is later) or decision to discontinue both drugs. This includes participants that 
complete the full 25 cycles of treatment as well as participants that discontinue treatment early.
**Safety Follow-Up: All participants enter safety follow-up period at EOT. Visits at 30, 60, 
and 90 days post-EOT.
***Disease Follow-Up: Participants with no recurrence of high-grade disease, disease 
progression, or persistence of CIS before EOT will be assessed Q12W for 2 years after 
randomization and Q24W thereafter until recurrence of high-grade disease or disease 
progression, consent withdrawal, lost to follow-up, or death. Timing of disease assessment is 
fixed according to the calendar, starting with randomization and should not be adjusted.
****Survival Follow-Up: Q12W until consent withdrawal, lost to follow-up, death, or end of 
study (5 yrs from last participant randomized).  Sponsor may request that sites complete 
additional survival follow-up to facilitate planned analyses as needed.
Safety
Follow-Up**
Disease
Follow-Up***
Survival 
Follow-Up****
Visit Window (Days)
+7
±7
±7
±7
PTAB
X
PROs will be administered in following order: EORTC QLQ-C30, EORTC NMIBC24, 
EQ-5D-5L, PGIS, PGIC, TSQ, PTAB.
See Section 8.1.2.
Survival
Subsequent Anti-cancer 
Therapy
X
X
X
X
Start date and other details of anti-cancer therapy (including cystectomy) subsequent to the 
study treatment will be recorded.
Survival Follow-up
X
Visit is a phone call Q12W. See Section 8.2.6.
Immunogenicity and Pharmacodynamic Biospecimen
Pharmacokinetics
X
Collect the last PK sample at EOT. If EOT is done on the same date as the last dose of PF-
06801591, all efforts should be made to obtain PK samples within 2 hours prior to PF-
06801591 dosing. Arms A and B only. See Section 8.5.
Immunogenicity
X
Collect the last immunogenicity sample at EOT. See Section 8.8.3. Arms A and B only.
AE: adverse event, ADA: anti-drug antibodies; BP: blood pressure; CT: computed tomography, ECG: electrocardiogram, EORTC-QLQ-C30: European Organisation for Research 
and Treatment of Cancer Quality of Life Questionnaire–30 (items); EOT: end of treatment; MRI: magnetic resonance imaging, NAb: neutralizing antibodies; NMIBC: non-muscle 
invasive bladder cancer, PGIC: Patient Global Impression of Change; PGIS: Patient Global Impression of Severity; PK: pharmacokinetics, PTAB: Patient Treatment 
Administration Burden; SAE: serious adverse event; TSQ: Treatment Satisfaction Questionnaire
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Screening and Treatment Period – Cohorts B1 and B2
Screening
Treatment Period
Notes
Cycles 1-25 (Cohort B1)
Cycles 1-17 (Cohort B2)
Cohort B1: Cycle = 4 weeks
Cohort B2: Cycle = 6 weeks
D -28 to
D -1
D1
Visit Window 
(Days)
±0   (C1)
±7  
C2-25 [Cohort B1]
C2-C17 [Cohort B2]
Informed Consent 
X
X
Informed consent may be obtained more than 28 days prior to start of study treatment. All screening procedures must be 
completed within 28 days of registration.
The Consent for continuation of treatment at 12 weeks for those participants in Cohort B1 with persistent CIS and Consent 
for future research will be signed as applicable. 
Participants must sign consent prior to any trial-specific procedure.  See Section 10.1.3.
Tumor and Medical 
History
X
Detailed information about prior BCG usage, response to prior BCG, and details regarding disease persistence or recurrence 
will be collected in the CRF. Reasons for subject ineligibility or refusal of radical cystectomy will also be collected.
See Section 8 for details.
Physical 
Examination
X
X
Physical examinations should be performed according to clinical practice.   Any abnormalities should be recorded as AEs.  
See Section 8.2.1.
Weight
X
X
Vital Signs 
X
X
BP and pulse rate will be performed.  Any clinically significant abnormalities should be recorded in the eCRF as AEs.  See 
Section 8.2.2.
ECOG PS
X
X
See Section 8.2.3. and Section 10.10.
12-Lead ECG
X
X
Single 12-lead ECG will be collected prior to dosing of PF-06801591 on day 1 of cycles 1, 2, 4, 5, 6.  After cycle 6, ECGs 
will only be required as clinically indicated. See Section 8.2.4 for details.
AEs
X
See Section 8.3 and Section 10.3.
Concomitant 
Therapy
X
See Section 6.5.
Contraception 
Check
X
Must be performed on D1 of each cycle.  See Section 10.4 for details. 
Laboratory
Hematology
X
X
See Section 10.2.
Not necessary to repeat on C1D1 if performed within 7 days prior to C1D1 as part of Screening. Laboratory tests may be 
performed up to 3 days prior to the scheduled clinic visit, so that results will be available for review before study intervention 
administration, including C1D1. See Section 8.2.7 for requirements on minimum labs to be reviewed prior to dosing.  
Coagulation testing should be done on day 1 of cycles 3, 6, 9, 12, 15, 18, 21, and 24 (up to cycle 17 for Cohort B2)
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Screening
Treatment Period
Notes
Cycles 1-25 (Cohort B1)
Cycles 1-17 (Cohort B2)
Cohort B1: Cycle = 4 weeks
Cohort B2: Cycle = 6 weeks
D -28 to
D -1
D1
Visit Window 
(Days)
±0   (C1)
±7  
C2-25 [Cohort B1]
C2-C17 [Cohort B2]
Blood Chemistry
X
X
Coagulation
X
X
Urinalysis
X
X
Not necessary to repeat on C1D1 if performed within 7 days prior to C1D1 as part of Screening. Urinalysis should be 
collected on day 1 of cycles 1, 2, 3, 4, 5, 7, and 13 (Cohorts B1 and B2), and 19 and 25 (Cohort B1), and as clinically 
indicated.  
See Section 10.2. 
Pregnancy Test
X
X
A negative highly sensitive test is required prior to study intervention dosing on Day 1 of all cycles.  Results must be 
available for review prior to dosing.  See Section 8.2.8 and Section 10.4.  Pregnancy testing after C1D1 per local guidelines. 
FSH
X
For female postmenopausal participants under the age of 60 and not using hormonal contraception or HRT, a serum FSH test 
is required at screening only, to confirm postmenopausal status. FSH is not required for participants not meeting these 
criteria.  See Section 10.2 and Section 10.4.
Hepatitis B and C
X
HBS Ag and HCV Ab tests.  If HBS Ag or HCV Ab  test is positive, reflex testing must be carried out, as detailed in Section 
10.2 Table 5. 
ACTH & Thyroid 
Function Test
X
X
Not necessary to repeat on C1D1 if performed within 7 days prior to C1D1 as part of Screening. ACTH and Thyroid Function 
Test should be done at cycles 1, 2, 3, 6, 9, 12, 15, 18, 21, 24, 25 (up to cycle 17 for Cohort B2) and as clinically indicated.  
See Section 10.2 Table 5.
PF-06801591 
Administration
X
Administer subcutaneously. See Section 6.1.2.
Disease Assessments
CT or MRI
X
X
CT/MRI/Urogram of the abdomen and pelvis/urinary tract.  Imaging performed with contrast agents unless contraindicated 
for medical reasons. For Cohort B1, screening imaging must be reviewed by the BICR prior to registration. The same method 
should be used for the duration of the study. For Cohort B1, imaging should be performed every 24 weeks for 2 years after 
initiation of study intervention until persistence of CIS, recurrence of high-grade disease or disease progression, consent 
withdrawal, lost to follow-up, EOT, or death. Additional imaging may be performed as clinically indicated to confirm and/or 
rule out distant metastasis. For Cohort B2, imaging is done as clinically indicated. See Section 8.1.1.3  and Appendix 9 for 
additional details. 
Cystoscopy, With or 
Without Biopsy 
X
X
Cystoscopy should be performed for disease assessment on day 1 of cycles 4, 7, 10, 14, 16, 19, 22, 25 for Cohort B1 and day 
1 of cycles 3, 5, 7, 9, 11, 13, 15 and 17 for Cohort B2. At most disease assessments, biopsy may or may not be required, 
depending on outcome of cystoscopy and cytology.  Same equipment and methods by the same study staff should be used for 
the duration of the study whenever possible.  See Section 8.1.1.1 and Appendix 9.
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Screening
Treatment Period
Notes
Cycles 1-25 (Cohort B1)
Cycles 1-17 (Cohort B2)
Cohort B1: Cycle = 4 weeks
Cohort B2: Cycle = 6 weeks
D -28 to
D -1
D1
Visit Window 
(Days)
±0   (C1)
±7  
C2-25 [Cohort B1]
C2-C17 [Cohort B2]
Cytology
X
X
For Cohort B1, screening cytology must be reviewed by the BICR prior to registration.  Urine cytology should be performed 
for disease assessment on day 1 of cycles 4, 7, 10, 14, 16, 19, 22, 25 for Cohort B1 and day 1 of cycles 3, 5, 7, 9, 11, 13, 15 
and 17 for Cohort B2.    Same equipment and methods by the same study staff should be used for the duration of the study 
whenever possible. See Section 8.1.1.2.
Tumor Tissue
Tumor Tissue 
Sample from Most 
Recent TURBT 
X
See Section 8.8.1. For Cohort B1 tumor tissue sample must be reviewed by the BICR prior to registration.
AE: adverse event, ACTH: adrenocorticotropic hormone, BP: blood pressure; CT: computed tomography, ECG: electrocardiogram, ECOG PS: Eastern Cooperative Oncology Group 
Performance Status, FSH: follicle-stimulating hormone, HRT: hormone replacement therapy, MRI: magnetic resonance imaging, NMIBC: non-muscle invasive bladder cancer, 
TURBT: transurethral resection of bladder tumor
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End of Treatment Visit and Follow-Up Period – Cohorts B1 and B2 
EOT*
Post-Treatment Period *EOT: End of Treatment visit will take place within 7 days of the last dose of PF-06801591 or decision to discontinue 
PF-06801591. This includes participants that complete the full 25 cycles (Cohort B1) or 17 cycles (Cohort B2) of 
treatment as well as participants that discontinue treatment early.
**Safety Follow-Up: All participants enter safety follow-up period at EOT. Visits at 30, 60, and 90 days post-EOT.
Safety
Follow-Up**
Visit Window 
(Days)
+7
±7
Physical 
Examination
X
X
Physical examinations should be performed according to clinical practice. Any abnormalities should be recorded in the 
eCRF as adverse events.  
See Section 8.2.1.
Weight
X
X
Vital Signs 
X
X
BP and pulse rate will be performed. Any abnormalities should be recorded in the eCRF as AEs. 
See Section 8.2.2.
Contraception 
Check
X
X
See Section 10.4.
ECOG PS
X
See Section 10.10.
AEs
X
X
Treatment-related SAEs will be reported during the disease follow-up and survival follow-up. See Section 8.3 and 
Section 10.3.
Concomitant 
Therapy
X
X
See Section 6.5.
Hematology
X
X
See Section 10.2. Laboratory tests may be performed up to 3 days prior to the scheduled clinic visit, so that results will be 
available for review before study intervention administration. See Section 8.2.7 for requirements on minimum labs to be 
reviewed prior to dosing.
Blood Chemistry
X
X
Coagulation
X
Urinalysis
X
Pregnancy Test
X
X
Required 30 days (±7 days) after last dose. At Day 90 and Day 180 after EOT, pregnancy status should be discussed (may 
be done by telephone, unless the participant is visiting the site for other reasons) and pregnancy test can be conducted as 
necessary. See Section 8.2.8, Section 10.2, and Section 10.4.
AE: adverse event, BP: blood pressure; CT: computed tomography, ECG: electrocardiogram,  EOT: end of treatment; MRI: magnetic resonance imaging, NMIBC: non-muscle 
invasive bladder cancer, SAE: serious adverse event
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2. INTRODUCTION
PF-06801591 is a humanized, hinge region stabilized immunoglobulin G4 (IgG) monoclonal 
antibody (mAb) specific for human PD-1 that can selectively bind to human PD-1 and block 
the interaction between PD-1 and PD-L1/PD-L2.  Extensive preclinical and clinical research 
have demonstrated that anti-PD-1/PD-L1 agents are efficacious in several tumor types and 
these agents have been utilized in clinical practice since 2014, when anti-PD-1 agent 
pembrolizumab was approved by the US FDA for treatment of advanced melanoma. Anti-
PD-1/PD-L1 agents have also demonstrated clinical activity in the treatment of advanced UC 
with 5 drugs (nivolumab, atezolizumab, pembrolizumab, durvalumab, and avelumab) 
currently approved for this indication.25,26,27,28,29
UC includes tumors originating from the urothelial cells lining the bladder, renal pelvis, 
ureter, and urethra.9 Of these, BC accounts for more than 90% of UC,9 and is the tenth most 
prevalent cancer worldwide, with approximately 500,000 new cases diagnosed and 200,000 
deaths attributed to this disease each year.30 Approximately 75% of cases of BC are non-
muscle invasive bladder cancer (NMIBC) and the current standard of care (SOC) for patients 
with high-risk NMIBC is transurethral resection of the bladder tumor (TURBT) followed by 
intravesical instillation of Bacillus Calmette-Guerin (BCG).7 Whilst treatment with BCG has 
been shown to reduce the risk of tumor recurrence, BCG therapy will eventually fail in 
approximately 40% of patients with NMIBC resulting in recurrence or progression to more 
advanced disease; thus, alternative treatments are urgently required to improve the 
outcome.7,32,33
2.1. Study Rationale
Overall, incidence and mortality for bladder cancer (BC) has changed very little over the past 
20 years.1  Vaccination using BCG was the first Food and Drug Administration (FDA) 
approved immunotherapy indication in the 1980s and for patients with high-risk non-muscle 
invasive bladder cancer (NMIBC) after transurethral resection of the bladder tumor 
(TURBT), induction with BCG followed by maintenance still represents the standard of care 
(SOC).7  While treatment with BCG has been shown to reduce the risk of tumor recurrence, 
approximately 40% of patients with NMIBC will eventually have disease recurrence or 
progression despite BCG therapy;32 thus, alternative treatments are urgently required to 
improve the outcome.33
Increased programmed death – ligand (PD-L) 1 expression was observed in bladder cancer 
cells in response to BCG treatment both in vitro and in vivo preclinical models and the 
combination of BCG and anti-PD-L1 agent induced an antitumor immune response.2 In 
addition, the combination showed higher tumor growth inhibition and prolonged survival as 
compared to either agent alone.  
Sasanlimab (PF-06801591) is a humanized, monoclonal antibody (mAb) specific for human 
programmed death – 1 (PD-1) that blocks the interaction between PD-1 and PD-L1/PD-L2.  
PF-06801591 administered at 300 mg subcutaneous (SC) every 4 weeks has been evaluated 
in the Phase 1 Study B8011001 in participants with advanced solid tumors and at 600 mg SC 
every 6 weeks in patients with advanced malignancies in study B8011007. The clinical safety 
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data available to date suggest an acceptable safety profile, aligned with other anti-PD-1/PD-
L1 agents, and also preliminary evidence of clinical efficacy aligned with other 
anti-PD-1/PD-L1 agents in patients with advanced urothelial cancer (UC).
The role of PD-L1 expression level as a predictive factor of response to BCG therapy in 
patients with high-risk NMIBC was recently suggested in a retrospective evaluation 
suggesting that higher PD-L1 expression level is associated with failure of BCG 
treatment.3 Supportive of this hypothesis, pembrolizumab showed promising activity in 
Keynote-057, a Phase 2 study in participants with high-risk NMIBC unresponsive to 
BCG. In an analysis of 101 participants with carcinoma in situ (CIS), a complete response 
(CR) rate of 41% (95% confidence interval [CI]: 30.7, 51.1) was reported with a median 
duration of CR of 16.2 months (95% CI: 6.7, 36.2). The most common (>5%) treatment-
related adverse events (AEs) included diarrhea (11%), fatigue (11%), pruritis (11%), 
hypothyroidism (7.0%), maculopapular rash (6%), rash, hyperthyroidism, and nausea (each 
5%), which was consistent with the known adverse event (AE) profile of pembrolizumab in 
the advanced disease setting.4
2.1.1. Study Rationale for the BCG-Naive Cohort (Cohort A)
A Phase 1 study of pembrolizumab in combination with BCG in participants with high-grade 
NMIBC persisting or recurring following at least 2 courses of intravesical therapy or 1 course 
of BCG (induction and maintenance), showed that the combination regimen of 
pembrolizumab (at 100 mg and 200 mg fixed doses) and BCG was well tolerated.6 Fatigue, 
dysuria, spasm, urgency, sensitivity and frequency were the most frequently reported AEs, 
with all AEs reported as Grade 1 or 2.6 Of the first 9 participants enrolled, 7 participants 
(78%) had no evidence of disease in the bladder at 19 weeks. These data suggest an 
improved clinical activity over each of the agents alone, considering BCG alone is expected 
to have minimal or no clinical activity in the treatment setting and pembrolizumab showed a 
CR rate 41% in a similar population.4
To treat patients with NMIBC appropriately, treatment considerations include the European 
Organisation for Research and Treatment of Cancer (EORTC) risk table scores of recurrence 
and progression.7  For patients with high-risk NMIBC, the current standard of care is TURBT 
followed by intravesical BCG.7  The standard schedule for BCG is induction (once weekly 
for 6 weeks) followed by maintenance for a minimum of 1 year.  Full-dose BCG 
maintenance, administered once per week for 3 weeks, starting at 3 months after the first 
BCG dose of induction course (ie, 6 weeks after completion of induction BCG), and at 6 
months, and then every 6 months, as used in the Southwest Oncology Group (SWOG) 8507 
and European Organization for Research and Treatment of Cancer (EORTC) 30911 and 
30962 trials,8,11 is the most appropriate maintenance schedule.  Indeed, addition of 
maintenance to induction treatment with BCG according to the administration schedule 
described in the study is currently recommended in the European Association of Urology 
(EAU) and National Comprehensive Cancer Network (NCCN) guidelines7,9 because it has 
proven to reduce both progression and recurrence of the disease.10
The optimal duration of BCG maintenance therapy has been investigated in the European 
Organization for Research and Treatment of Cancer Genito-Urinary (EORTC-GU) Study 
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30962.11  In this study, full dose BCG maintenance for 3 years was associated with a 
reduction in recurrence (hazard ratio [HR] = 1.61, 95% CI: 1.13-2.30, p = 0.009) in high-risk 
participants as compared with 1 year of BCG maintenance; however, there were no 
differences in progression or survival.11  For this reason, the benefit of the 2 additional years 
of maintenance should be weighed against its additional costs, inconveniences, and 
tolerability.  Therefore, the study design for Cohort A of B8011006 includes a BCG 
maintenance duration of up to 2 years (Arm A: BCG plus PF-06801591, Arm C: BCG 
alone).  Considering the expected improved clinical activity of the PF-06801591 plus BCG 
combination regimen, investigation of PF-06801591 plus BCG induction only, is justified 
(Arm B).
Based on preclinical and clinical data, an intervention in BCG-naïve participants with high-
risk NMIBC, with PF-06801591 in combination with BCG induction therapy (with or 
without maintenance therapy) may provide a greater benefit with longer event-free survival 
and reduction in the rate of subsequent cystectomy as compared to SOC BCG treatment. In 
addition, PF-06801591 is administered subcutaneously (SC) every 4 weeks which is expected 
to reduce burden for the participants and for the healthcare system.
2.1.2. Study Rationale for the BCG-Unresponsive Cohort (Cohorts B1 and B2)
BCG treatment fails in approximately 40% of patients with high-risk NMIBC 32 and limited 
therapeutic options are available for those with BCG-unresponsive disease after adequate 
BCG therapy defined as a minimum of 5 out of 6 doses of an induction course followed by 
either 2 out of 6 doses of a re-induction course, or 2 of 3 doses of a maintenance course.12
Currently, a shortage of BCG supply is ongoing globally, and recommendations aimed to 
optimize the administration of BCG and prioritize its use in patients with high-risk NMIBC 
have been issued by several organizations such as the AUA and have been included in the 
most recent version of the NCCN guidelines.9  Some of the proposed BCG schedule 
modifications consist of a reduction in the dose of BCG intravesical instillations. 
Specifically, the AUA and the NCCN guidelines recommend prioritizing use of full dose 
BCG for induction and either do not administer maintenance therapy or split the BCG dose to 
1/3 or 1/2.9,13  The EORTC 30962 study assessed the impact of a reduced dose of BCG (1/3 
vs full dose in both induction and maintenance) on treatment outcomes in patients with high-
risk NMIBC. No difference in progression or survival rate between 1/3 and full dose BCG 
was reported even if 1/3 BCG dose was associated with a 5-year disease-free rate of 58.5% 
as compared to 61.7% for BCG full dose (HR = 1.15;  95% CI: 0.98–1.35; p = 0.045).11
Considering these results, the persisting shortage of BCG supplies, and based on the NCCN 
and AUA treatment recommendations, administration of a reduced dose (1/3 or 1/2) during 
the prior maintenance course is considered as adequate prior BCG therapy. Administration of 
full dose BCG during the prior induction BCG course will be required.
Patients with BCG-unresponsive disease are unlikely to respond to further BCG therapy, 
which is associated with an increased risk of progression, and radical cystectomy is therefore 
the standard and preferred option according to the treatment guidelines.13,14 Radical 
cystectomy is considered curative for some patients, but it is associated with significant 
morbidity and mortality.15 The overall 90-day complication rates are up to 28%-64% 16,17 and 
the majority of early complications following radical cystectomy include gastrointestinal 
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(29%), infection (25%), intestinal obstruction (23%), wound-related complications (15%), 
and deep vein thrombosis (4.7%); late complications include gastrointestinal bowel 
obstruction, urinary tract infection, deterioration in renal function, calculi formation, voiding 
dysfunction, and metabolic complications.15, 17
Non-surgical treatment options for patients with BCG-unresponsive NMIBC are currently 
limited. Valrubicin is approved by the US but response rates are low (18%-21%) and not 
durable.,18, 19 A recent meta-analysis reported data from 42 studies in 2254 patients with 
NMIBC treated after BCG failure with 24 different treatments, including approved and 
investigational agents. The median CR rates in the treatment of CIS-containing tumors were 
26%, 17%, and 8% at 6, 12, and 24 months, respectively.20 In the studies that enrolled 
patients with papillary disease without CIS the median recurrence-free rates were 67%, 44%, 
and 10% at 6, 12, and 24 months, respectively.20 Similar results were reported from another 
meta-analysis that included 4 randomized-controlled studies and 24 single-arm studies that 
evaluated different bladder-sparing treatment options: the pooled 12-month response rates 
were 24% (95% CI: 16-32%) for trials with 2 or more prior BCG courses and 36% (95% CI: 
25-47%) for those with 1 or more prior BCG courses.21 Even considering the heterogeneity 
of the patients population, the different definitions of BCG failure, and the different study 
designs, these results define the high unmet need for new treatment options treatments to 
improve clinical outcomes in patients with NMIBC that recurs after initial BCG treatment.
Based on the results of the Keynote-057 study4, pembrolizumab has been recently approved 
by the FDA for the treatment of patients with BCG-unresponsive CIS who are ineligible for 
or decline to undergo radical cystectomy.22 In the Keynote-057 study, after a median duration 
of follow-up of 36.4 months (IQR 32.0 – 40.7), the CR rate was 41% (95% CI, 30.7-51.1) 
with a median duration of CR of 16.2 months (95% CI, 6.7 – 36.2).4 In addition, 
atezolizumab has shown signs on clinical efficacy in patients with BCG-unresponsive CIS 
[CR rate at 3 months was 41.1% (95% CI, 29.7-53.2)]53 and in patients with BCG-
unresponsive papillary disease [EFS rate at 18 months was 45% (95% CI, 34-57)].54
PF-06801591 300 mg SC Q4W showed a safety and efficacy profile aligned to the other anti-
PD-1/PD-L1 agents in patients with advanced UC and NSCLC23 and PF-06801591 600 mg 
SC Q6W showed a safety profile consistent with the B8011001 study and with the safety 
profiles of other PD-1 agents (data summarized in IB).  Both dosing regimens offer the 
convenience of subcutaneous administration. Indeed, real world evidence of oncology 
biologics show that subcutaneous administration reduces healthcare resource utilization and 
associated costs by saving time in drug preparation and administration compared to 
intravenous (IV) therapy. SC administration also reduces time spent in the infusion chair and 
in caregiver assistance, while patients report better quality of life and preference for SC 
therapy over IV therapy.24 In addition, the Q6W dosing frequency of PF-06801591, which 
will be evaluated in Cohort B2, explores an extended dosing interval for PF-06801591 to 
further reduce the burden for the participants, their caregivers and the healthcare system.
In summary, an unmet need exists for new innovative bladder-sparing treatment options for 
patients with BCG-unresponsive NMIBC that delay disease recurrence, progression and 
radical cystectomy. PF-06801591 may provide greater clinical benefit with higher CR rate, 
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durable responses and longer event-free survival relative to currently approved intravesical 
chemotherapies (valrubicin) and subcutaneous administration is expected to reduce burden 
for the participants and for the healthcare system while maintaining a safety and efficacy 
profile aligned to other anti-PD-1/PD-L1 agents administered intravenously 
(pembrolizumab). 
Cohorts B1 and B2 of B8011006 will include participants with BCG-unresponsive NMIBC.  
Cohort B1 will include participants with CIS (with or without Ta/T1 papillary disease) and 
Cohort B2 will include participants with high-grade Ta/T1 papillary disease only.
As of 31 August 2022, enrollment in Cohorts B1 and B2 was closed by the sponsor for 
business strategy reasons.   Participants that have already been enrolled into Cohorts B1 and 
B2 may continue treatment and study procedures and assessments per the Schedule of 
Activities per the Cohorts B1 and B2 SoA.
2.2. Background
2.2.1. Clinical Background
Study B8011001
Early data on pharmacokinetics (PK), safety, and efficacy of PF-06801591 are available from 
B8011001, an ongoing Phase 1, open-label, dose escalation and expansion study in 
participants with locally advanced or metastatic melanoma, squamous cell carcinoma of the 
head and neck (SCCHN), ovarian cancer, sarcoma, non-small cell lung cancer (NSCLC), 
urothelial carcinoma (UC) or other solid tumors.  The study was divided into a dose 
escalation phase, and a dose expansion phase.  The dose escalation phase evaluated 4 pre-
specified intravenous (IV) dose levels (0.5, 1, 3, and 10 milligram/kilogram (mg/kg) 
administered every 3 weeks [Q3W]), and 1 SC dose level (300 mg administered every 4 
weeks [Q4W]). In the dose expansion phase of the study, 1 SC dose level (300 mg Q4W) 
was explored. No dose limiting toxicities (DLTs) were observed and no maximum tolerated 
dose (MTD) was identified during the dose escalation phase of the study. 
During the dose expansion phase 106 participants (68 participants with NSCLC and 38 
participants with UC) were evaluated, who were anti-PD-1/anti-PD-L1 treatment-naïve and 
who had progressive disease (PD) on or were intolerant to systemic therapy or for whom 
SOC systemic therapy was refused or unavailable.  Participants with UC could have received 
up to 2 lines of prior systemic therapies for locally advanced or metastatic disease. The 
eligible participants had adequate renal, bone marrow, liver, and cardiac function, with 
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. All participants 
received 300 mg of PF-06801591 SC every 4 weeks.
Safety during the dose expansion phase: Of 106 participants exposed to 1 or more 300 mg 
SC injections of study drug, 103 participants (97.2%) experienced at least one treatment-
emergent AE (TEAE) while on the study. The most common AEs (experienced by ≥10% of 
participants) were anemia (n = 24, 22.6%) followed by disease progression (n = 20, 18.9%), 
dyspnea (n = 14, 13.2%), decreased appetite (n = 13, 12.3%), asthenia, fatigue, and amylase 
increased (n = 12 each , 11.3%), and aspartate aminotransferase increased, hyperthyroidism, 
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and pruritis (n = 11 each, 10.4%).  A total of 60 participants (56.6%) had a least one 
treatment-related AE (TRAE) while on study. The most common TRAEs (experienced by 
>5% of participants) were hyperthyroidism (n = 11, 10.4%), lipase increased and pruritis (n = 
7 each, 6.6%), and amylase increased, hypothyroidism, and anemia (n = 6 each, 5.7%). Ten 
participants had maximum Grade 3 TRAEs and 2 had maximum Grade 4 TRAE. Grade 3 
TRAEs were lipase increased, amylase increased (n = 2 each, 1.9%), blood alkaline 
phosphatase increased, decreased appetite, hypermagnesemia, pneumonitis, ageusia, 
anosmia, and jaundice (n = 1 each, 0.9%). There were 3 Grade 4 TRAEs of lipase increased, 
white blood cell count decreased, and neutrophil count decreased (n = 1 each, 0.9%). One 
Grade 5 treatment-related arrhythmia was reported (n = 1, 0.9%).  
Serious Adverse Events (SAEs): Across both phases of the B8011001 study, there were 122 
SAEs reported in 78 participants and 7 treatment-related SAEs reported: pneumonitis (n = 3), 
death (n = 2), arrythmia and cognitive disorder (n = 1 each).  In the dose expansion phase, a 
fatal AE of arrhythmia occurred in a 
-year old 
 subject approximately 47 days after 
starting treatment with SC PF-06801591 for UC. Medical history included 
 
 The subject was hospitalized at an institution outside 
the study site due to third degree heart block. Details of the hospital admission were only 
verbally reported due to refusal of the treating institution to release further information. 
Elevated levels of troponin, transaminases and creatinine were reported by the treating 
hospital although serious electrolyte abnormalities, infection, or ischemic heart disease were 
reportedly excluded. The subject received a pacemaker implant on Day 13 of the 
hospitalization, and unspecified complications were reported. One day later, the subject died. 
The reason for death was unclear, and no autopsy was performed. The Investigator 
considered the event was possibly related to PF-06801591. The Sponsor considered the event 
unrelated to PF-06801591 as there is insufficient information regarding the clinical course of 
events to support a causal relationship and that complications successive to pacemaker 
placement may provide an alternative explanation for the event.
Efficacy during the dose expansion phase: The objective response rate (ORR) in the UC 
cohort was 21.1% (n=8 confirmed partial response [PR], 95% CI: 9.6, 37.3%), consistent 
with historical data reported for other anti-PD-1 treatments in similar therapeutic setting. In 
the NSCLC cohort the ORR was 19.1% (n=13 confirmed PR, 95% CI: 10.6, 30.5%). This 
efficacy profile also is aligned with the one reported for other anti-PD-1 treatments in similar 
therapeutic setting.34,35,36
Summary of Clinical Pharmacology: PF-06801591 demonstrated PK characteristics typical 
of IgG4 monoclonal antibodies. Over the Q3W IV dose range of 0.5 -10 mg/kg evaluated in 
Study B8011001, increases in PF-06801591 exposures (Cmax, Ctrough and AUC) were linear 
and dose proportional. Following 300 mg Q4W SC dosing, median Tmax was approximately 8 
days, t1/2 was approximately 13 days, and steady-state was reached by Cycle 4 (week 12) 
with approximately 2-fold accumulation. Steady-state concentrations following 300 mg SC 
Q4W fell within the concentration range observed following the 1 mg/kg and 3 mg/kg Q3W 
IV doses. Population PK-derived clearance was 0.158 L/day with no evidence of variance 
over time. Incidence of anti-PF-06801591 antibody formation was low (<10%) across both 
IV and SC dosing regimens.
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Study B8011007
The feasibility of increasing time between PF-06801591 SC administration from Q4W to 
Q6W to further improve dosing convenience for patients, their caregivers, and the healthcare 
system, is being investigated in Study B8011007. This study consists of 2 parts: Phase 1b 
(dose escalation and dose expansion) for participants with advanced malignancies, and a 
Phase 2 in participants with NSCLC. PF-06801591 monotherapy is administered in both 
phases as either 300 mg SC Q4W or 600 mg SC Q6W. As of 01 July 2021, 144 participants 
have been treated: 57 with 300 mg SC Q4W (n = 16 in the Phase 1b and n = 41 in the Phase 
2) and 87 with 600 mg SC Q6W (n = 7 in the Phase 1b and n = 80 in the Phase 2).  In Phase 
1 of the study, dose escalation has been completed and currently dose expansion is ongoing. 
No DLT has been reported so far and both treatment regimens were well tolerated. The Phase 
2 completed enrollment, and safety and efficacy evaluations are ongoing. As of the data cut-
off date (01 July 2021), in Phase 2 300 mg SC Q4W cohort (n = 41), 35 (85.4%) of the 41 
participants reported TEAEs. The most commonly reported TEAEs in ≥10% participants 
were: dyspnea, decreased appetite, and anemia in 7 (17.1%) participants, asthenia in 6 
(14.6%) participants, and chest pain in 5 (12.2%) participants. In Phase 2 600 mg SC Q6W 
cohort (n = 80), 59 (73.8%) participants reported TEAEs. The most commonly reported 
TEAE in ≥10% participants was dyspnea in 9 (11.3%) participants.   No increase in 
frequency of TEAEs was observed in the 600 mg SC Q6W cohorts relative to the 300 mg 
Q4W cohorts. Further detailed information is summarized in the IB.  Based on preliminary 
analyses, the overall safety profiles across the two treatment regimens were similar and the 
safety profile in this B8011007 study (both treatment regimens) is consistent with that 
observed in Study B8011001, and with the safety profiles of other PD-1 agents. No new 
safety signals have been identified.  Although efficacy data was immature at data cut off, 
currently no clinically meaningful differences have been observed between the two dosing 
regimens and there is no expectation that the 600 mg SC Q6W regimen will result in 
unexpected safety concerns or a compromise in efficacy.
2.2.2. Preclinical Safety and Efficacy
Detailed information about the preclinical data for PF-06801591 may be found in the 
Investigator’s Brochure.37
2.3. Benefit/Risk Assessment
The benefit risk relationship has been carefully considered in the planning of this study. 
PF-06801591 administered at 300 mg SC every 4 weeks has been evaluated in the Phase 1 
study B8011001 in participants with advanced solid tumors and 600 mg SC every 6 weeks in 
the Phase 1/2 study B8011007 in patients with advanced malignancies as described in 
Section 2.2.1. The clinical safety data available to date with single agent PF-06801591 
suggest an acceptable safety profile with most of the observed AEs in line with those 
expected in participants with advanced solid tumors or with similar class effects of mAbs 
blocking the PD-1/PD-L1 axis. Immune-related AEs (irAEs) have been identified as 
important risks for PF-06801591 and risk mitigation measures have been implemented in all 
ongoing clinical studies, including this study. These measures include guidelines for 
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treatment interruption and discontinuation in case of toxicities, and guidelines for steroid 
treatment implementation. In the same study PF-06801591 has shown preliminary evidence 
of clinical activity aligned to other anti-PD-1/PD-L1 single agents in participants with 
advanced UC.
Additionally, a Phase 1 study of pembrolizumab in combination with BCG in participants 
with high-grade NMIBC persisting or recurring following at least 2 courses of intravesical 
therapy or one course of BCG (induction and maintenance) showed that the combination was 
well tolerated and preliminary evidences of clinical activity were observed (Section 2.1).
Intravesical BCG administration is currently SOC for the patient population eligible for this 
study. Bladder irritability symptoms are commonly expected. Most of the adverse reactions 
from BCG instillation, such as urinary frequency, burning, mild malaise, and low-grade 
fever, are a result of the immune stimulation by BCG that is required to effectively eradicate 
cancer cells.38  The rarely occurring systemic BCG infections are almost invariably 
associated with systemic absorption of BCG.  By excluding patients with active tuberculosis, 
withholding BCG when participants have cystitis, previous high fever, or most importantly, 
traumatic catheterization, systemic absorption of BCG can be avoided, and systemic 
reactions can be nearly eliminated.39
The safety profile of BCG is distinct from that of PF-06801591 with limited overlapping 
toxicities so exacerbation of the toxicities related to both agents is not expected when 
administered in combination. In order to conduct a preliminary assessment of the safety 
profile of PF-06801591 plus BCG regimen, a review of safety data will be performed by an 
external data monitoring committee (EDMC) approximately 6 weeks after 20 participants in 
each of the 3 treatment arms have been randomized and received at least one dose of study 
treatment (Section 4.1). The enrollment will continue during EDMC review.  The EDMC 
will convene to monitor safety in the study (Cohort A only) approximately every 6 months 
thereafter. The EDMC will also review cumulative safety data during the study conduct as 
well as review the futility interim analysis data from Cohort A for EFS (see Section 9.5.1).
Based on the manageable safety profiles of PF-06801591 and BCG and the anticipated 
enhanced anti-tumor activity described in Section 2.1, the benefit-risk assessment of PF-
06801591 given in combination with BCG (induction and maintenance or induction only) is 
expected to be favorable and it is considered appropriate to proceed with the proposed 
clinical investigation in participants with high-risk NMIBC.
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of PF-06801591 may be found in the SRSD, which is the 
Investigator’s Brochure (IB) for PF-06801591.37 For additional information about BCG refer 
to the current local product label. TICE USPI40 will serve as SRSD for additional safety 
reporting that is required by the health authority in Japan.      
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3. OBJECTIVES, ESTIMANDS AND ENDPOINTS
3.1. BCG-Naïve Cohort (Cohort A)
Objectives
Endpoints
Primary
To demonstrate that PF-06801591 + 
BCG (induction and maintenance) is 
superior to BCG (induction and 
maintenance) in prolonging event-free 
survival (EFS) in participants with high-
risk NMIBC.
EFS as assessed by the investigator
Key Secondary 
To demonstrate that PF-06801591 + 
BCG (induction) is superior to BCG 
(induction and maintenance) in 
prolonging EFS in participants with high-
risk NMIBC.
EFS as assessed by the investigator
To demonstrate that PF-06801591 + 
BCG (induction and maintenance) is 
superior to BCG (induction and 
maintenance) in prolonging overall 
survival (OS) in participants with high-
risk NMIBC.
OS
To demonstrate that PF-06801591 + 
BCG (induction) is superior to BCG 
(induction and maintenance) in 
prolonging OS in participants with high-
risk NMIBC.
OS
Secondary
To estimate the complete response (CR) 
rate of PF-06801591 + BCG (induction 
and maintenance or induction) and BCG 
(induction and maintenance) in 
participants with CIS at randomization.
CR as assessed by the investigator (in 
participants with CIS at randomization)
To evaluate the duration of CR of PF-
06801591 + BCG (induction and 
maintenance or induction) and BCG 
(induction and maintenance) in 
participants with CIS at randomization 
Duration of CR for participants with CR 
as assessed by the investigator (in 
participants with CIS at randomization)
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Objectives
Endpoints
To evaluate the time to recurrence of 
low-grade disease of PF-06801591 + 
BCG (induction and maintenance or
induction) and BCG (induction and 
maintenance) in participants with high-
risk NMIBC.
Time to recurrence of low-grade disease 
as assessed by the investigator
To evaluate the time to cystectomy of 
PF-06801591 + BCG (induction and 
maintenance or induction) and BCG 
(induction and maintenance) in 
participants with high-risk NMIBC.
Time to cystectomy
To evaluate the disease-specific survival 
(DSS) of PF-06801591 + BCG (induction 
and maintenance or induction) and BCG 
(induction and maintenance) in 
participants with high-risk NMIBC.
DSS as assessed by the investigator
To evaluate the overall safety profile of 
PF-06801591+BCG (induction and 
maintenance or induction) and BCG 
(induction and maintenance) in 
participants with high-risk NMIBC.
AEs as characterized by type, severity 
(as graded by National Cancer Institute 
Common Terminology Criteria for 
Adverse Events [NCI CTCAE] v5.0), 
timing, seriousness, and relationship to 
study therapy. Laboratory abnormalities 
as characterized by type, severity (as 
graded by NCI CTCAE v5.0), and timing
To assess the effects of PF-
06801591+BCG (induction and 
maintenance or induction) and BCG 
(induction and maintenance) on patient-
reported health-related quality of life in 
participants with high-risk NMIBC. 
Health-related quality of life as measured 
by: 1) EORTC QLQ-C30 (European 
Organization for Treatment of Cancer 
Quality of Life Questionnaire), 
2) EORTC QLQ-NMIBC24, 3) PTAB 
(Patient Treatment Administration 
Burden Questionnaire)
To characterize the PK of PF-
06801591+BCG (induction and 
maintenance or induction).
Ctrough of PF-06801591 when in 
combination with BCG (induction and 
maintenance or induction); Arms A and 
B only.
To evaluate the immunogenicity of PF-
06801591+BCG (induction and 
maintenance or induction).
ADAs; NAbs of PF-06801591 when in 
combination with BCG (induction and 
maintenance or induction); Arms A and 
B only.
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Objectives
Endpoints
To evaluate PD-L1 expression in pre-
treatment tumor tissue that may aid in the 
identification of a participant 
subpopulation most likely to benefit from 
treatment with PF-06801591 + BCG 
(induction and maintenance or
induction).
Tumor sample biomarker status based on 
PD-L1 expression (high or low)
Tertiary/Exploratory
To assess the effects of PF-
06801591+BCG (induction and 
maintenance or induction) and BCG 
(induction and maintenance) on patient 
reported outcomes (PROs) in participants 
with high-risk NMIBC.
Health state utilities as measured by the 
Euro Qol 5 Dimension (EQ5D-5L) & 
VAS 
Overall assessment of disease severity as 
measured by the Patient Global 
Impression of Severity (PGIS)
Overall assessment of change as 
measured by the Patient Global 
Impression of Change (PGIC)
Patient satisfaction as measured by the 
Treatment Satisfaction Questionnaire 
(TSQ)
To explore the predictive and 
pharmacodynamic characteristics of 
peripheral blood and additional tumor 
tissue biomarkers that may be relevant to 
the mechanism of action of, or resistance 
to, treatment with PF-06801591 + BCG 
(induction and maintenance or
induction), including but not limited to 
biomarkers related to antitumor immune 
response or target modulation.
Peripheral blood and additional tumor 
tissue biomarkers consisting of the levels 
of cells, deoxyribonucleic acid (DNA), 
ribonucleic acid (RNA), or proteins that 
may be related to antitumor immune 
response or disease progression.
Estimands
This section defines the estimands associated with the primary and key secondary endpoints 
of Cohort A of the study.  
Table 2 (Section 9.1.1) defines the possible clinical outcomes for the EFS evaluation. The 
clinical definitions of recurrence of high-grade disease, progressive disease, persistence of 
CIS, recurrence of low-grade disease and CR are included in Section 10.9. In participants 
with CIS at randomization “persistence of CIS” is defined as persistence of CIS after 
induction or, if re-induction is administered, after re-induction. Persistence of CIS after 
induction with CR after re-induction is not considered persistence of CIS. The censoring and 
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event date options to be considered for the EFS analyses are presented in Table 3
(Section 9.1.1).
Primary Estimand (EFS for Arm A vs Arm C) and Key Secondary Estimand (EFS for Arm B 
vs Arm C): treatment effect, estimated based on data from all randomized participants, of 
each experimental arm (Arm A and Arm B) on EFS compared to Arm C from randomization 
to the earliest of recurrence of high-grade disease, progression of disease, persistence of CIS, 
or death regardless of tolerability, duration of study treatment, or initiation of subsequent 
anti-cancer therapy.  The date of the event (event as defined in Table 2) is the date of disease 
assessment documenting recurrence of high-grade disease, progression of disease,
persistence of CIS (applicable only to participants with CIS at randomization), or death, 
whichever occurs earlier. The date of persistence of CIS is the earliest date when persistence 
of CIS is observed, if CR is not observed after re-induction.

Variable: EFS defined as the time from randomization until recurrence of high-grade 
disease, progression of disease, persistence of CIS or death due to any cause, whichever 
occurs first.

Censoring: see Table 3. 

Population-level summary measure: hazard ratio for EFS including all randomized 
participants.
Supportive Estimand 1 (EFS): treatment effect, estimated based on data from all randomized 
participants, of each experimental arm (Arm A and Arm B) on EFS compared to Arm C from 
randomization to the earliest of recurrence of high-grade disease, progression of disease,
persistence of CIS, or death, regardless of tolerability, duration of study treatment or  
initiation of subsequent anti-cancer therapy. The date of the event (event as defined in 
Table 2) is the date of disease assessment documenting recurrence of high-grade disease, 
progression of disease, date of randomization for participants with persistent CIS (applicable 
only to participants with CIS at randomization), or death, whichever occurs earlier.

Variable: EFS defined as the time from randomization until recurrence of high-grade 
disease, progression of disease, persistence of CIS, or death due to any cause, whichever 
occurs first.

Censoring: see Table 3

Population-level summary measure: hazard ratio for EFS including all randomized 
participants. 
Supportive Estimand 2 (EFS): treatment effect of each experimental arm (Arm A and Arm B) 
on EFS compared to Arm C from randomization to the earliest of recurrence of high-grade 
disease, progression of disease, persistence of CIS, or death regardless of tolerability, 
duration of study treatment, or initiation of subsequent anti-cancer therapy. Data from 
randomized participants who do not meet per-protocol criteria as defined below are excluded. 
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The date of the event (event as defined in Table 2) is the date of disease assessment 
documenting recurrence of high-grade disease, progression of disease, persistence of CIS 
(applicable only to participants with CIS at randomization), or death, whichever occurs 
earlier. The date of persistence of CIS is the earliest date when persistence of CIS is 
observed, if CR is not observed after re-induction.

Variable: EFS defined as the time from randomization until recurrence of high-grade 
disease, progression of disease, persistence of CIS, or death due to any cause, whichever 
occurs first.

Censoring: see Table 3

Population-level summary measure: hazard ratio for EFS excluding randomized 
participants who did not receive at least 1 dose of study drug, did not meet inclusion 
criteria 2 or 3, or met exclusion criteria 1 or 2.
Key Secondary Estimand (OS): treatment effect, estimated based on data from all 
randomized participants, of each experimental arm (Arm A and Arm B) on OS compared to 
Arm C regardless of tolerability, duration of study treatment, initiation of subsequent anti-
cancer therapy or participant’s request to discontinue study procedures. 

Variable: OS

Censoring: data for participants not known to have died are censored at the time of last 
contact. 

Population-level summary measure: hazard ratio for OS, including all randomized 
participants.
3.2. BCG-Unresponsive Cohorts (Cohorts B1 and B2)
Due to the decision to close enrollment in Cohorts B1 and B2, the Cohort B1 and B2 study 
objectives are no longer required.  
Primary Objectives
Primary Endpoints
To estimate the CR rate of PF-06801591 
in participants with BCG-unresponsive CIS 
(Cohort B1 only)
CR as assessed by the BICR
To evaluate the EFS of PF-06801591 in 
participants with BCG-unresponsive 
NMIBC (Cohort B2 only)
EFS as assessed by the investigator
Secondary Objectives
Secondary Endpoints
To evaluate the duration of CR of PF-
06801591 in participants with BCG-
unresponsive CIS (Cohort B1 only).
Duration of CR for participants with CR 
as assessed by the BICR 
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To estimate the CR rate of PF-06801591 
at 12 months in participants with BCG-
unresponsive CIS (Cohort B1 only)
CR at 12 months as assessed by the 
BICR 
To evaluate the EFS of PF-06801591 in 
participants with BCG unresponsive CIS 
(Cohort B1 only)

EFS as assessed by the investigator
To evaluate the time to cystectomy of PF-
06801591 in participants with BCG-
unresponsive NMIBC (Cohorts B1 and B2).
Time to cystectomy
To evaluate OS of PF-06801591 in 
participants with BCG-unresponsive 
NMIBC treated with PF-06801591 (Cohorts 
B1 and B2).
OS
To evaluate the overall safety of PF-
06801591 in participants with BCG-
unresponsive NMIBC (Cohorts B1 and B2).
AEs as characterized by type, severity (as 
graded by NCI CTCAE v5.0, timing, 
seriousness, and relationship to study 
therapy. Laboratory abnormalities as 
characterized by type, severity (as graded 
by NCI CTCAE v5.0), and timing
To assess the effects of PF-06801591 on 
patient-reported health-related quality of life 
in participants with BCG-unresponsive 
NMIBC (Cohorts B1 and B2).
Health-related quality of life as measured 
by: 1) EORTC QLQ-C30 , 2) EORTC 
QLQ-NMIBC24, 3) PTAB 
To evaluate PD-L1 expression in 
pretreatment tumor tissue that may aid in 
the identification of a subpopulation of 
participants with BCG unresponsive 
NMIBC most likely to benefit from PF-
06801591 (Cohorts B1 and B2).
PD-L1 expression
To characterize the PK and 
immunogenicity of PF06801591 single 
agent in participants with BCG-
unresponsive NMIBC (Cohorts B1 and B2).
Ctrough, Cmax (Cohort B2 only), ADAs and 
NAbs following PF-06801591 single agent. 
Tertiary/Exploratory
To assess the effects of PF-06801591 on 
patient reported outcomes (PROs) in 
participants with BCG unresponsive 
NMIBC (Cohorts B1 and B2).
Health state utilities as measured by the 
EQ5D-5L & VAS 
Overall assessment of disease severity as 
measured by the PGIS
Overall assessment of change as 
measured by the PGIC
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Patient satisfaction as measured by the 
TSQ
To explore the predictive and 
pharmacodynamic characteristics of 
peripheral blood and additional tumor 
tissue biomarkers that may be relevant to 
the mechanism of action of, or resistance 
to, treatment with PF-06801591, including 
but not limited to biomarkers related to 
antitumor immune response or target 
modulation (Cohorts B1 and B2).
Peripheral blood and additional tumor 
tissue biomarkers consisting of the levels 
of cells, deoxyribonucleic acid (DNA), 
ribonucleic acid (RNA), or proteins that 
may be related to antitumor immune 
response or disease progression.
Table 2 (Section 9.1.1) defines the possible clinical outcomes for the EFS evaluation. The 
clinical definitions of recurrence of high-grade disease, progressive disease, persistence of 
CIS, recurrence of low-grade disease and CR are included in Section 10.9. The censoring and 
event date options to be considered for the EFS analyses are presented in Table 3 (replacing 
date of randomization with the date of first dose) (Section 9.1.1). 
4. STUDY DESIGN
4.1. Overall Design
This is a Phase 3, multicenter, multinational, randomized, open-label, parallel, 3-arm study to 
evaluate PF-06801591 in combination with BCG vs BCG in participants with high-risk, 
BCG-naïve NMIBC (Cohort A). The study will also evaluate PF-06801591 as a single agent 
in participants with BCG-unresponsive, non-muscle invasive bladder cancer in 2 separate 
non-randomized cohorts (Cohorts B1 and B2). Cohort B1 will enroll participants with BCG-
unresponsive CIS alone or with concomitant recurrent Ta/T1 disease. Cohort B2 will enroll 
participants with BCG-unresponsive recurrent high-grade Ta/T1 disease. The study will be 
conducted in conformance with Good Clinical Practices (GCPs).  
4.1.1. BCG-Naïve Cohort (Cohort A) 
A total of approximately 999 participants with BCG naïve, high-risk, NMIBC (including a 
minimum of 250 participants with CIS) will be randomized in a 1:1:1 ratio to one of 3 
treatment arms below. As of 16 November 2021, enrollment to Cohort A has completed with 
1056 participants randomized.    

Arm A: PF-06801591 + BCG (induction and maintenance period)

Arm B: PF-06801591 + BCG (induction period only)

Arm C: BCG only (induction and maintenance period)
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BCG Dosing:

Induction period: one dose every week via intravesical instillation for 6 consecutive 
weeks (QWx6: Cycle [C]1Day [D]1, C1D8, C1D15, C1D22, C2D1, C2D8)

Re-Induction period: Following first induction period, participants with CIS at 
randomization who have persistent disease and participants with recurrence of 
high- grade Ta disease may receive re-induction with one dose every week via 
intravesical instillation for up to 6 consecutive weeks.  Suggested schedule is C4D1, 
C4D8, C4D15, C4D22, C5D1, C5D8.  Maintenance will then begin on C7D1.  If 
TURBT is performed, schedule for BCG re-induction should be modified according 
to the product label. 

Maintenance period: (Arm A and Arm C): Doses on D1, D8, D15 during Cycles C4, 
C7, C13, C19 and C25. For participants that have a re-induction period, the 
maintenance period will begin at C7D1.  
PF-06801591 Dosing
Once every 4 weeks (Q4W) 300 mg SC up to Cycle 25.
Randomization will be stratified by the presence of CIS (yes vs no) and geography (US vs 
Western Europe and Canada vs ROW).
The study was initially designed with two primary objectives: 1) to demonstrate that PF-
06801591 given in combination with BCG (induction and maintenance) is superior to BCG 
alone (induction and maintenance) in prolonging EFS in participants with high-risk NMIBC 
and 2) to demonstrate that PF-06801591 given in combination with BCG (induction only) is 
superior to BCG alone (induction and maintenance) in prolonging EFS in participants with 
high-risk NMIBC.
The study was initially designed with two key secondary objectives: 1) to demonstrate that 
PF-06801591 + BCG (induction and maintenance) is superior to BCG (induction and 
maintenance) in prolonging OS in participants with high-risk NMIBC and 2) to demonstrate 
that PF-06801591 + BCG (induction) is superior to BCG (induction and maintenance) in 
prolonging OS in participants with high-risk NMIBC.
As of Amendment 5, the study will have one primary objective (to demonstrate that PF-
06801591 given in combination with BCG [induction and maintenance] is superior to BCG 
alone [induction and maintenance] in prolonging EFS in participants with high-risk NMIBC. 
The objective to demonstrate that PF-06801591 given in combination with BCG (induction 
only) is superior to BCG alone (induction and maintenance) in prolonging EFS in 
participants with high-risk NMIBC will be considered a key secondary objective.
In order to conduct a preliminary assessment that the safety profile of PF-06801591 plus 
BCG regimen remains aligned with that expected from each agent separately, a review of 
safety data will be performed by an external data monitoring committee (EDMC) 
approximately 6 weeks after 20 participants in each of the 3 arms have been randomized and 
received at least one dose of study treatment.  The EDMC will convene to monitor safety in 
the study (Cohort A only) approximately every 6 months thereafter.  The EDMC will also 
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review cumulative safety data during the study conduct as well as review the futility interim 
analysis  (IA) data for EFS (see Section 9.5.1).  
Participants who meet the following criteria will enter the post-treatment follow-up period 
for safety visits.

Progression of NMIBC

Recurrence (T1 [stage of cancer in which the cancer cells are only growing in the most 
superficial layer of tissues and have not grown into deeper tissues.  In bladder cancer, T1 
is defined as an invasion into the lamina propria without invasion into the muscularis 
propria], high-grade Ta [non-invasive papillary carcinoma], and/or CIS). Participants 
with high-grade Ta recurrence at 3 months after initiating study intervention following 
first induction period may receive re-induction.  Following re-induction if recurrence of 
high-grade Ta disease occurs at 6 months of initiating study intervention, participants will 
discontinue study treatment and enter the post-treatment follow-up period.

Participants with CIS at randomization that is not responding within 6 months of 
initiating study intervention, following induction or re-induction (persistence of CIS).

Participants who complete or those who permanently discontinue study intervention 
early.  
All participants will enter the safety follow-up period at EOT. Visits will occur 30 days, 60 
days, and 90 days after EOT.  Concurrent to the safety follow-up, participants with no 
recurrence of high-grade disease, progression of disease, or persistence of CIS before EOT, 
will also continue disease assessment after EOT through the disease follow-up period and 
will be assessed every 12 weeks for 2 years after randomization and every 24 weeks 
thereafter until recurrence of high-grade disease or progression of disease, withdrawal of 
consent for further participation in the study, lost to follow-up, or death. 
All participants after recurrence of high-grade disease, persistence of CIS, or progression of 
disease will be followed via telephone visits every 12 weeks for survival until the earliest of 
withdrawal of consent for further participation in the study, lost to follow-up, death, study 
termination by the sponsor, or end of study (5 years from last participant randomized). 
The study design for Cohort A is illustrated in Figure 3
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Figure 3.
B8011006: Study Schematic Cohort A
4.1.2. Cohorts B1 and B2
Approximately 160 participants with BCG-unresponsive high-risk NMIBC (including a 
minimum of 110 participants with CIS) will be enrolled to receive PF-06801591 as a single 
agent.  For Cohort B1, diagnosis of CIS alone or with concomitant recurrent Ta/T1 disease 
and absence of muscle-invasive bladder cancer and extravesical disease must be confirmed 
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by the BICR prior to registration. Participants discontinuing from Arm C of Cohort A will 
not be eligible to enroll into Cohorts B1 or B2. 
As of 31 August 2022, enrollment in Cohorts B1 and B2 was closed by the sponsor for 
business strategy reasons.   Participants that have already been enrolled into Cohorts B1 and 
B2 may continue treatment and study procedures and assessments per the Cohorts B1 and B2
SoA.
Figure 4.
B8011006 Study Schematic Cohorts B1 and B2
PF-06801591 Dosing
Cohort B1: Once every 4 weeks (Q4W) 300 mg SC up to Cycle 25.
Cohort B2: Once every 6 weeks (Q6W) 600 mg SC up to Cycle 17.
Due to the decision to close enrollment in Cohorts B1 and B2, the Cohort B1 and B2 study 
objectives are no longer required.  
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As noted in Figure 4, participants in Cohort B1 with persistence of CIS at the 12 week 
disease assessment may continue on PF-06801591 for an additional 3 cycles (until the 24 
week disease assessment). This may only occur after the investigator and participant discuss 
the option of cystectomy, and the participant re-consents to 3 additional cycles of PF-
06801591 instead of cystectomy.  Participants with persistence of CIS at the 24 week disease 
assessment will enter the post-treatment follow-up period for safety visits. Participants with 
recurrence of high-grade Ta, T1 or CIS disease at or after the 12 week disease assessment 
will enter the post-treatment follow-up period for safety visits. Continuation of treatment for 
1 additional cycle while waiting for confirmation of recurrence of high-grade Ta, T1 or CIS 
disease by the BICR will be allowed at the discretion of the investigator. If the 12 week 
disease assessment is “Not Evaluable” per the BICR, the assessment with a non-evaluable 
result should be repeated as soon as possible.
For Cohort B2, participants with recurrence of high-grade Ta, T1 or CIS disease at or after 
the 12 week disease assessment will enter the post-treatment follow-up period for safety 
visits.  
Participants who meet the following criteria will enter the post-treatment follow-up period 
for safety visits.

Progression of NMIBC.

Recurrence (T1, high-grade Ta, and/or CIS). 

Persistence of CIS (for those participants in Cohort B1): Participants with CIS that are 
not responding at or after the 12 or 24 week disease assessment.

Participants who complete or those who permanently discontinue study intervention 
early.  
All participants will enter the safety follow-up period at EOT. Visits will occur 30 days, 60 
days, and 90 days after EOT.  
The study design for Cohorts B1 and B2 is illustrated in Figure 4.
4.2. Scientific Rationale for Study Design
Refer to Section 2.1 for the Study Rationale.
The efficacy endpoints selected for this study (EFS, OS, CR [for participant with CIS at 
randomization], time to cystectomy, and disease-specific survival [DSS]) are accepted by the 
regulatory agencies for validation of clinical efficacy in oncology clinical trials in similar 
therapeutic setting. Similarly, safety evaluations for oncology intervention(s) are typically 
characterized using National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE) criteria. 
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Patients with NMIBC have a 5-year survival rate of approximately 80%;11 therefore, health-
related quality of life (HRQoL) and management of symptoms and the associated treatment 
burden are important considerations.  The PRO instruments were selected for this trial in 
order to study the impact of treatment on patient health-related quality of life (EORTC QLQ-
C30 and EORTC QLQ-NMIBC24 [24 items]), health state utilities (Euro Qol 5 Dimension 
[EQ-5D-5L]), burden of treatment administration (Patient Treatment Administration Burden 
[PTAB]), overall change in disease (Patient Global Impression of Change, [PGIC]), overall 
disease severity (Patient Global Impression of Severity [PGIS]), and satisfaction with the 
treatment (Treatment Satisfaction Questionnaire [TSQ]). 
Banked Biospecimens will be collected for exploratory 
pharmacogenomic/genomic/biomarker analyses and retained in the Biospecimen Banking 
System (BBS), which makes it possible to better understand the study intervention’s 
mechanism of action and to seek explanations for differences in, for example, exposure, 
tolerability, safety, and/or efficacy not anticipated prior to the beginning of the study.
4.3. Justification for Dose
4.3.1. PF-06801591
During the dose escalation phase of the Phase 1 study B8011001, an MTD was not 
determined and DLTs were not observed.  The proposed dose of 300 mg SC Q4W was 
selected with considerations of the nonclinical safety of PF-06801591, the clinical safety and 
tolerability data from the IV and SC administration cohorts in study B8011001, together with 
the feasibility, in terms of the injection volume with the current formulation.37  The safety,  
efficacy, PK, and immunogenicity data from study B8011001 are described in Section 2.2.1.   
PF-06801591 600 mg will be also investigated SC Q6W in Cohort B2. The 600 mg Q6W 
dosing regimen is currently being investigated in Study B8011007 and was chosen to 1) 
maintain a similar minimum exposure (Ctrough ss) to the 300 mg Q4W dosing regimen and 2) 
to accommodate the SC presentation (as pre-filled syringe) that is currently formulated for 
300 mg injection increments. Data from Study B8011001 were combined with preliminary 
PK data from Study B8011007 to model expected exposures following PF-06801591 dosing 
regimens with longer, Q6W, dosing interval. PF-06801591 600 mg Q6W SC was chosen to 
be investigated in Cohort B2 of this B8011006 study, based on similar model-predicted 
steady-state Ctrough (approximately 3% higher relative to 300 mg Q4W SC). While the 
predicted steady-state average concentrations over the dosing interval (Cave, ss = AUCτ ss/τ) 
and Cmax ss are expected to be respectively 36% and 59% higher following the 600 mg Q6W 
SC relative to 300 mg Q4W SC dosing regimens, those higher exposures are still well below 
those observed following the highest, 10 mg/kg Q3W dose level tested in humans in Study 
B8011001, where no DLTs were observed.  Additionally, dose-exposure data from Study 
B8011001 suggest relatively flat exposure-response relationships for safety of PF-06801591.
Based on the last PK/ADA data cut-off in study B8011007 (31 May 2021) there was no 
apparent difference in ADA incidence between the 300 mg Q4W (7.7%, n = 39) and 600 mg 
Q6W (1.3%, n = 77) dose groups.
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Therefore, there is no expectation that the 600 mg Q6W regimen will result in unexpected 
safety concerns.
4.3.2. BCG
The intravesical instillation dose for BCG is 1 therapeutic dose per the product label for the 
strain given (this is often 1 vial, but please refer to the applicable BCG strain product label).  
Please see locally approved label for dose justification.40  Justification for BCG regimen is 
provided in Section 2.1.
4.4. End of Study Definition
A participant is considered to have completed the study if he/she has completed all phases of 
the study including the last visit or the last scheduled procedure shown in the SoA.
The end of the study is defined as 5-years after randomization of the last participant into 
Cohort A.  
5. STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. The Sponsor must review and 
approve certain eligibility criteria prior to registration/randomization into the study.
5.1. Inclusion Criteria
Participants are eligible to be included in the study only if all the following criteria apply.  
The following criteria apply to all Cohorts ie, A, B1, and B2 unless otherwise noted:
Age
1. Participant must be ≥18 years of age, at the time of signing the informed consent 
(except in Japan, where participants must be ≥20 years).
Type of Participant and Disease Characteristics
2. Histological confirmed diagnosis of high-risk, non-muscle invasive transitional cell 
carcinoma (TCC) of the urothelium of the urinary bladder (tumors of mixed 
transitional/non-transitional cell histology are allowed, but TCC must be the 
predominant histology) defined as any of the following per World Health 
Organization grading system.41, 42, 43
a.
T1 tumor;
b. High-grade Ta tumor;
c.
Carcinoma in situ (CIS);
3. Complete resection of all Ta/T1 papillary disease (including participants with 
concurrent CIS), with most recent positive TURBT occurring within 12 weeks prior 
to randomization for participants in Cohort A, or within 12 weeks prior to initiation of 
study intervention for participants in Cohorts B1 and B2 . A second TURBT must 
have been performed if indicated according to the current locally applicable 
guidelines, ie, American Urological Association, European Association of Urology. 
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4. Availability of the tumor tissue from the most recent TURBT for the assessment of 
the PD-L1 expression. If a second TURBT was performed, as indicated according to 
the current locally applicable guidelines, the tumor tissue from the TURBT procedure 
that supports the primary diagnosis for study eligibility should be the tumor tissue 
used for the PD-L1 expression testing. 
5. ECOG Performance Status (PS) ≤ 2. 
6. Adequate Bone Marrow Function (without hematopoietic growth factor or transfusion 
support within 14 days prior to study randomization for participants in Cohort A, or 
within 14 days prior to initiation of study intervention for participants in Cohorts B1 
and B2), including:
a.
Absolute neutrophil count (ANC) ≥1,500/mm3 or ≥1.5 x 109/L;
b. Platelets ≥100,000/mm3 or 100 x 109/L;
c.
Hemoglobin  ≥9 g/dL (≥5.6 mmol/L).
7. Adequate renal function defined by an estimated creatinine clearance ≥30 mL/min 
according to the Cockcroft Gault formula or by 24-hour urine collection for creatinine 
clearance, or according to local institutional standard method.
8. Adequate liver function, including:
a.
Total serum bilirubin ≤1.5 × the upper limit of normal range (ULN). 
Participants with Gilbert syndrome who should have total serum bilirubin <3 
x ULN; 
b. Aspartate and alanine aminotransferase (AST and ALT) ≤ 2.5 × ULN.
9. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and 
other procedures.
Sex
10. Male or Female
Contraceptive use by men or women should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies
Male Participants:
Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 6 months after the last dose of study treatment: 

Refrain from donating sperm
PLUS either:

Be abstinent from heterosexual or homosexual intercourse as their preferred and usual 
lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent 
OR

Must agree to use contraception/barrier as detailed below 
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Agree to use a male condom and should also be advised of the benefit for a female 
partner to use a highly effective method of contraception as a condom may break or 
leak when having sexual intercourse with a woman of childbearing potential who is 
not currently pregnant.
Female Participants: 
A female participant is eligible to participate if she is not pregnant or breast-feeding, and at 
least one of the following conditions applies:

Is not a woman of childbearing potential; (WOCBP) refer to Section 10.4 for definition.
OR

Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate 
of <1% per year), with low user dependency, as described in Section 10.4 during the 
intervention period and for at least 6 months after the last dose of study treatment. The 
investigator should evaluate the effectiveness of the contraceptive method in relationship 
to the first dose of study treatment.

A WOCBP must have a negative highly sensitive (at least 25 IU/Ml) pregnancy test 
(urine or serum as required by local regulations) within 24 hours before the first dose of 
study treatment.

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 from 
participation if the serum pregnancy result is positive.

Additional requirements for pregnancy testing during and after study treatment are 
located in Section 10.2.

The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy.
Informed Consent
11. Capable of giving signed informed consent as described in Section 10.1.3 which 
includes compliance with the requirements and restrictions listed in the informed 
consent document (ICD) and in this protocol
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Type of Participant and Disease Characteristics (BCG-Unresponsive Cohorts B1 and 
B2 only)
12. Histological confirmed diagnosis of BCG-unresponsive high-risk, non-muscle 
invasive TCC of the urothelium of the urinary bladder defined as any of the 
following:
a) Cohort B1: persistent or recurrent CIS alone or with concomitant recurrent Ta/T1 
disease within 12 months of completion of adequate BCG therapy. Stage and 
grade must be confirmed by the BICR prior to registration;
b) Cohort B2: recurrent high-grade Ta/T1 disease within 6 months of completion of 
adequate BCG therapy;
c) Cohort B2: T1 high-grade disease at the first evaluation following an adequate (at 
least 5 of 6 doses) induction BCG course.  It is not required that the participant 
receive BCG maintenance or a second induction course of BCG per inclusion 
criterion 13. 
13. Have received adequate BCG therapy defined as at least one of the following:
a) At least 5 of 6 doses of an initial induction course plus at least 2 of 3 doses of 
maintenance therapy;
b) At least 5 of 6 doses of an initial induction course plus at least 2 of 6 doses of a 
second induction course. 
Note: The 2 courses described in “a” and “b” should have been administered within a 
12 months period (ie the second course started within 12 months from the start of the 
first course). 
Note: Additional doses or courses of BCG above the minimum 5 + 2 described in “a” 
and “b” are allowed, and these do not have to be within the 12 month period.
Note: The BCG dose administered in maintenance courses may be 1/2 or 1/3 dose in 
the event of a BCG shortage, according to NCCN and AUA treatment guidelines.
Note: Prior BCG courses must have been comprised ONLY of one or more of the 
following strains: TICE, RIVM, TOKYO172, IMURON-VAC or Verity BCG (BCG-
1), D2PB302, Danish (SSI).  
14. Have refused or are ineligible for radical cystectomy. 
5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply. The following 
criteria apply to Cohorts A, B1, and B2 unless otherwise noted:
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Medical Conditions
1. Evidence of muscle-invasive, locally advanced or metastatic urothelial cancer or 
concurrent extravesical, non-muscle invasive TCC of the urothelium. For Cohort 
B1, absence of muscle-invasive and extravesical disease must be confirmed by the 
BICR prior to registration.
2. Active or prior autoimmune disease that might deteriorate when receiving an 
immunostimulatory agent.  Participants with diabetes type I, vitiligo, psoriasis, or 
hypo or hyperthyroid disease not requiring immunosuppressive treatment are 
eligible.
3. Severe active infections including pulmonary tuberculosis requiring systemic 
therapeutic oral or IV antibiotics within 2 weeks prior to randomization for 
participants in Cohort A, or within 2 weeks prior to initiation of study intervention 
for participants in Cohorts B1 and B2. Patients receiving prophylactic antibiotics 
(e.g., for prevention of a urinary tract infection) are eligible.
4. Other malignancy within 5 years prior to randomization for participants in Cohort 
A, or within 5 years prior to initiation of study intervention for participants in 
Cohorts B1 and B2, 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 
the investigator feels has a very low likelihood to become metastatic after 
discussion with the sponsor.
5. Clinically significant multiple or severe drug allergies, intolerance to topical 
corticosteroids, or severe post-treatment hypersensitivity reactions (including, but 
not limited to, erythema multiforme major, linear immunoglobulin A (IgA) 
dermatosis, toxic epidermal necrolysis, and exfoliative dermatitis.
6. Current unstable liver or biliary disease per investigator assessment defined by the 
presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, 
oesophageal or gastric varices, persistent jaundice, or cirrhosis.  NOTE: Stable 
chronic liver disease (including Gilbert's syndrome, asymptomatic gallstones, and 
chronic stable hepatitis B or C -eg, presence of hepatitis B surface antigen (HBsAg) 
or positive hepatitis C antibody test result at screening or within 3 months prior to 
randomization for participants in Cohort A, or within 3 months prior to initiation of 
study intervention for participants in Cohorts B1 and B2) is acceptable if the 
participant otherwise meets entry criteria.
Prior/Concomitant Therapy
7. Cohort A: Intravesical BCG therapy within 2 years prior to randomization. Cohorts 
B1 and B2: Any systemic or intravesical chemotherapy or immunotherapy from the 
time of most recent positive TURBT to initiation of study intervention (single-dose 
intravesical chemotherapy as part of the most recent positive TURBT according to 
the current locally applicable guidelines is allowed). Prior intravesical 
chemotherapy for NMIBC is allowed in all Cohorts.
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8. Prior immunotherapy with anti PD-1, anti PD-L1, anti PD-L2, or anti cytotoxic T-
lymphocyte-associated antigen-4 (CTLA-4) antibody.
9. Prior treatment with immunostimulatory agents including interleukin (IL)-2, IL-15, 
interferon (INF)-.
10. Prior radiation therapy to the bladder.
11. Treatment with systemic anti-cancer therapy including investigational agents within 
4 weeks prior to randomization for participants in Cohort A, or within 4 weeks 
prior to initiation of study intervention for participants in Cohorts B1 and B2.
12. Vaccination with live attenuated vaccines within 4 weeks prior to randomization for 
participants in Cohort A, or within 4 weeks prior to initiation of study intervention 
for participants in Cohorts B1 and B2 is prohibited; however, inactivated vaccines 
are permitted.
13. 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.
Prior/Concurrent Clinical Study Experience
14. Participation in other studies involving investigational drug(s) within 4 weeks prior 
to randomization for participants in Cohort A, or within 4 weeks prior to initiation 
of study intervention for participants in Cohorts B1 and B2. 
Diagnostic assessments
15. Cohort A: Known or documented absolute and/or relative contraindication of 
adjuvant intravesical BCG treatment:
a.
Prior BCG sepsis or systemic infection (including current urinary tract 
infection)
b. Total bladder incontinence defined as use more than 6 pads in 24 hours
c.
Adverse experience to previous BCG instillation that resulted in treatment 
discontinuation or precludes re-treatment.
16. Clinically significant (ie, active) cardiovascular disease including the following: 
cerebral vascular accident/stroke (<6 months prior to randomization for participants 
in Cohort A, or <6 months prior to initiation of study intervention for participants 
in Cohorts B1 and B2); myocardial infarction (<6 months prior to randomization 
for participants in Cohort A, or <6 months prior to initiation of study intervention 
for participants in Cohorts B1 and B2); unstable angina; congestive heart failure 
(≥New York Heart Association Classification Class II); or serious cardiac 
arrhythmia (uncontrolled, clinically significant) requiring medication.
17. Q-T interval corrected for heart rate (QTc) >450 msec for male participants or QTc 
>470 msec for female participants or QTc >480 msec in participants with right 
bundle branch block
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Other Exclusions
18. Major surgery within 2 weeks prior to randomization for participants in Cohort A, 
or within 2 weeks prior to initiation of study intervention for participants in Cohorts 
B1 and B2.
19. Prior organ transplantation or allogenic stem cell transplantation.
20. Known history of: immune-mediated colitis, inflammatory bowel disease, 
pneumonitis, or pulmonary fibrosis.
21. 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).
22. Patients with intolerance to or who have had a severe (Grade ≥3) allergic or 
anaphylactic reaction to antibodies or infused therapeutic proteins. 
23. Pregnant female patients; breastfeeding female patients; male patients able to father 
children and female patients of childbearing potential who are unwilling or unable 
to use a highly effective method(s) of contraception as outlined in this protocol for 
the duration of the study treatment and for at least 6 months after the last dose of 
PF-06801591 (Arm A and Arm B only).
24. 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 study intervention 
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.
25. Investigator 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, including their family members, directly 
involved in the conduct of the study.
26. Cohorts B1 and B2: Prior participation in Cohort A.
5.3. Lifestyle Considerations
The investigator or his or her designee, in consultation with the participant, will confirm that 
the participant has selected an appropriate method of contraception for the individual 
participant and his or her partners from the permitted list of contraception methods (see 
Section 10.4, Section 10.4.4) and will confirm that the participant has been instructed in its 
consistent and correct use.  At time points indicated in the SoA (Section 1.3), the investigator 
or designee will inform the participant of the need to use highly effective contraception 
consistently and correctly and document the conversation and the participant’s affirmation in 
the participant’s chart (participants need to affirm their consistent and correct use of at least 1 
of the selected methods of contraception; as for female participants using a highly effective 
method that is user dependent, this contraception method must be used  together with a 
second effective method of contraception, as described in Section 10.4. In addition, the 
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investigator or designee will instruct the participant to call immediately if the selected 
contraception method is discontinued or if pregnancy is known or suspected in the participant 
or partner.
5.4. Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomly assigned to study treatment. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet 
the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any serious adverse event (SAE).
Individuals who do not meet the criteria for participation in Cohorts A, B1 or B2 of this study 
(screen failure) may be rescreened. Rescreened participants should be assigned a new 
participant number as for the initial screening.
6. STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
In this study, PF-06801591 is an investigational medicinal product (IMP).  The IMP will be 
provided in prefilled syringe (PFS) for SC injection.  The PFS is a medical device. 
If BCG is sourced locally by the study site, the site should ensure that sufficient quantities of 
BCG are available to support the participant for the study treatment duration, prior to 
randomization. It is recommended that a participant receive the same strain of BCG for the 
duration of study treatment.  Please contact the study team prior to changing the strain of 
BCG that a participant is receiving.  In the event that there is a shortage of the BCG strain 
that a site typically uses (TICE, RIVM, TOKYO172, IMURON-VAC, D2PB302), the 
Investigator may be allowed to use a different BCG strain during re-induction or 
maintenance only, provided that it is permissible for use in these circumstances under the 
auspices of the relevant local authority.  This option should only be used when necessary and 
must be discussed with and approved by the Sponsor prior to implementation.  
6.1. Study Intervention(s) Administered
ARM Name –
Cohort A
A     
B     
C     
Intervention 
Name
PF-06801591 + BCG 
(induction and 
maintenance)
PF-06801591 + BCG 
(induction only)
     
BCG only 
(induction and 
maintenance)
    
Type 
Biological product
Biological product
Biological product
Dosage Form
          PF-06801591: 
Solution for injection     
          PF-06801591: 
Solution for injection      
BCG: intravesical 
instillation
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ARM Name –
Cohort A
A     
B     
C     
BCG: intravesical 
instillation
BCG: intravesical 
instillation
Dose Strength
PF-06801591: 
150 mg/mL, 2 mL 
(300 mg total) 
prefilled syringe 
BCG: full dose as per 
the label (TICE, 
RIVM, TOKYO172, 
IMURON-VAC 
(BCG-1), BCG China 
Strain (D2PB302))         
PF-06801591: 
150 mg/mL, 2 mL 
(300 mg total) prefilled 
syringe 
BCG: full dose as per 
the label (TICE, 
RIVM, TOKYO172, 
IMURON-VAC (BCG-
1), BCG China Strain 
(D2PB302))             
BCG: full dose as 
per the label (TICE, 
RIVM, TOKYO172,
IMURON-VAC 
(BCG-1), BCG 
China Strain 
(D2PB302))
Dosage
PF-06801591: 300 mg 
Q4W                    
BCG:  Induction 
period: 1 dose for 6 
consecutive weeks*        
Maintenance:  D1, D8, 
D15 during Cycles 4, 
7, 13, 19, 25
PF-06801591: 300 mg 
Q4W                     
BCG:  Induction 
period: 1 dose for 6 
consecutive weeks*
BCG: Induction 
period: 1 dose, for 
6 consecutive 
weeks*
Maintenance:  D1, 
D8, D15 during 
Cycles 4, 7, 13, 19, 
25 
Route of 
Administration
PF-06801591: SC 
injection                    
BCG: intravesical 
instillation 
PF-06801591: SC 
injection                   
BCG: intravesical 
instillation
BCG: intravesical 
instillation    
     
IMP and 
NIMP
PF-06801591= IMP
BCG = NIMP 
    
PF-06801591= IMP
BCG = NIMP
BCG = NIMP
Sourcing
PF-06801591: 
Provided centrally by 
the Sponsor 
(manufactured by 
Pfizer)
BCG: Sourced 
centrally/locally by the 
Sponsor or sourced 
locally by the site.**
PF-06801591: 
Provided centrally by 
the Sponsor 
(manufactured by 
Pfizer)
BCG: Sourced 
centrally/locally by the 
Sponsor or sourced 
locally by the site.**
BCG: Sourced 
centrally/locally by 
the Sponsor or 
sourced locally by 
the site.** 
Packaging and 
Labeling
PF 06801591: PFS for 
300 mg dose. Each 
PFS will be labeled as 
required per country 
requirement.
BCG: Commercial 
package and label  
PF 06801591: PFS for 
300 mg dose. Each PFS 
will be labeled as 
required per country 
requirement.
BCG: Commercial 
package and label  
BCG: Commercial 
package and label 
available in local 
market
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ARM Name –
Cohort A
A     
B     
C     
* Following induction period, participants with CIS at randomization who have persistent disease and participants with 
recurrence of high-grade Ta disease may receive re-induction with up to 6 additional weekly doses of BCG.
**If BCG is sourced locally, the investigational sites should ensure that sufficient quantities of BCG are available to 
support the participant for the study treatment duration, prior to randomization.          
    
Group Name 
Cohort B1
Cohort B2
Intervention Name
PF-06801591
PF-06801591
Type 
Biological product
Biological product
Dosage Form
Solution for injection              Solution for injection                   
Dose Strength
150 mg/mL, 2 mL (300 mg 
total) prefilled syringe 
Two 150 mg/mL, 2 mL  prefilled 
syringes (300 mg dose per 
syringe), 600 mg total dose)
Dosage
300 mg Q4W              
    
600 mg Q6W                   
Route of 
Administration
SC injection                   
SC injection                  
IMP and NIMP
PF-06801591= IMP
PF-06801591= IMP
Sourcing
Provided centrally by the 
Sponsor (manufactured by 
Pfizer)
Provided centrally by the Sponsor 
(manufactured by Pfizer)
Packaging and 
Labeling
PFS for 300 mg dose. Each 
PFS will be labeled as 
required per country 
requirement.
PFS for 300 mg dose. Each PFS 
will be labeled as required per 
country requirement.
6.1.1. Medical Devices
1. The medical device used to deliver PF-06801591 is a PFS.
2. Instructions for medical device use are provided in the Investigational Product (IP) 
Manual.
3. All medical device deficiencies (including malfunction, use error, and inadequate 
labeling) shall be documented and reported by the investigator throughout the clinical 
investigation (see Section 8.3.9) and appropriately managed by the sponsor.
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6.1.2. Administration of the Study Intervention
BCG: Qualified and trained investigator site personnel will administer a full dose of BCG 
per labeling guidelines.  In Cohort A, BCG administration will take place as follows:

Induction period: C1D1, C1D8, C1D15, C1D22, C2D1, and C2D8.

Re-induction period, up to 6 consecutive weeks (following induction period, for 
participants with CIS at randomization who have persistent disease and participants 
with recurrence of high-grade Ta disease): Suggested schedule is C4D1, C4D8, 
C4D15, C4D22, C5D1, and C5D8.  Maintenance will then begin on C7D1.  If 
TURBT is performed, schedule for BCG re-induction should be modified according 
to the product label.  

Maintenance period (Arm A and Arm C): Doses on D1, D8, D15 during Cycles C4, 
C7, C13, C19 and C25. For participants that have a re-induction period, the 
maintenance period will begin at C7D1. 
PF-06801591: Qualified and trained investigator site personnel will administer PF-06801591 
at a fixed dose by one SC injection to the abdomen of participants in Cohorts A, and B1.  
One PFS must be administered SC Q4W (last dose at Cycle 25) for a dose of 300 mg PF-
06801591.  
In Cohort B2, qualified and trained investigator site personnel will administer PF-06801591 
as a fixed dose by two SC injections to the abdomen.  Two PFS must be administered SC 
Q6W (last dose at Cycle 17) for a dose of 600 mg PF-06801591.  For the 600 mg SC dose, 
PF-06801591 should be administered to 2 different quadrants of the abdomen.
See Section 8.2.5 for local site injection tolerability assessment. 
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.
On cycles when PF-06801591 and BCG are both administered for Arms A and B of Cohort 
A, BCG will be administered first.  It is strongly preferred that participants randomized to 
Arm A or Arm B receive the first administration of PF-06801591 and BCG at the C1D1 visit 
as long as this can be done while maintaining participant safety. Participants enrolled with 
CIS who have persistent disease and participants with recurrence of high-grade Ta disease 
following first induction are eligible for a re-induction period of up to 6 additional weekly 
treatments.  
In Cohort A, participants randomized with CIS who do not respond within 6 months of 
initiating study intervention and participants with recurrence of high-grade Ta disease at or 
after 6 months of initiating study intervention will enter the post-treatment follow-up period 
for safety visits.
In Cohort B1, participants with persistence of CIS at the 12 week disease assessment may 
continue on PF-06801591 for an additional 3 cycles (until the 24 week disease assessment). 
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This may only occur after the investigator and participant discuss the option of cystectomy, 
and the participant re-consents to 3 additional cycles of PF-06801591 instead of cystectomy.  
Participants with persistence of CIS at the 24 week disease assessment will enter the post-
treatment follow-up period for safety visits. Participants with recurrence of high-grade Ta, T1 
or CIS disease at or after the 12 week disease assessment will enter the post-treatment 
follow-up period for safety visits. Continuation of treatment for 1 additional cycle while 
waiting for confirmation of recurrence of high-grade Ta, T1 or CIS disease by the BICR will 
be allowed at the discretion of the investigator. If the 12 week disease assessment is “Not 
Evaluable” per the BICR, the assessment with a non-evaluable result should be repeated as 
soon as possible.
In Cohort B2, participants with recurrence of high-grade Ta, T1 or CIS disease at or after the 
12 week disease assessment will enter the post-treatment follow-up period for safety visits.
Study staff should refer to the IP Manual for specific instructions on the handling and 
administration of both study interventions.
For participants in Cohorts A, B1, and B2, a cycle is defined as the time from Day 1 dose to 
the next Day 1 dose.  Participants will receive a single dose of PF-06801591 on Day 1 of 
each cycle.  In Cohort A, a cycle will be 28 days (±3 days prior to Cycle 4, ±7 days for Cycle 
4 through EOT), in Cohort B1, a cycle will be 28 days (±3 days prior to Cycle 2, ±7 days for 
Cycle 2 through EOT), and in Cohort B2, a cycle will be 42 days (±3 days prior to Cycle 2, 
±7 days for Cycle 2 through EOT) for SC administration.  Each participant may receive 
PF-06801591 until the earliest of the following events: completion of study treatment (Cycle 
25 for Cohorts A and B1 and Cycle 17 for Cohort B2) recurrence of high-grade disease or 
progression of disease, unacceptable toxicity, withdrawal of consent, participant no longer 
willing to participate in trial, or study termination.
6.2. Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study treatment received and any discrepancies 
are reported and resolved before use of the study treatment.
2. Only participants enrolled in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment. All study treatment 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labeled storage conditions with access limited 
to the investigator and authorized site staff.
3. The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study treatment accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records).
4. Further guidance and information for the final disposition of unused study treatments 
are provided in the Study Reference Manual.
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6.3. Measures to Minimize Bias: Randomization and Blinding
Open-label using 
central 
randomization via 
interactive response 
technology (IRT) 
(IVRS/IWRS) 
Applies to Cohorts 
A, B1, and B2
This is an open-label study; however, the specific intervention to be 
taken by a participant will be assigned using an IVRS/IWRS. 
Potential bias will be reduced by the central randomization.
Before the study is initiated, the telephone number and call-in 
directions for the IVRS and/or the log in information & directions 
for the IWRS will be provided to each site. 
The site will contact the IVRS/IWRS prior to the start of study 
treatment administration for each participant. Randomization 
(Cohort A) or registration (Cohorts B1 and B2) will occur via IRT 
within approximately 28 days of start of screening.  Randomized or 
registered participants will be dosed within 3 days after 
randomization or registration. 
The site will record the randomized intervention assignment on the 
applicable case report form, if required. Once a randomization 
number has been assigned it must not be re-assigned.
As this is an open label study, the sponsor may conduct unblinded reviews of the data during 
the course of the study for the purpose of data cleaning at the patient level.  
6.4. Study Intervention Compliance
Compliance with the protocol required regimen will be assessed by drug accountability 
form/record. Deviation(s) from the prescribed dosage regimen should be recorded in the 
electronic case report form (eCRF).
6.5. Concomitant Therapy
Concomitant treatment considered necessary for the participant’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 participants from screening 
until the end of safety follow-up period will be recorded on the eCRF including the name of 
the procedure or medication, route and duration of treatment, and reason (eg, AE).
6.5.1. Other Anti-tumor/Anti-cancer or Experimental Drugs
Additional anticancer treatment including chemotherapy, hormonal therapy, radiotherapy, 
and experimental anticancer medications are not permitted while participants are receiving 
study treatment.  Additionally, the concurrent use of herbal supplements for an anti-cancer 
treatment is not permitted. Prior intravesical chemotherapy for NMIBC is allowed.
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6.5.2. 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. 
6.5.3. Hematopoietic Growth Factors
Granulocyte-colony stimulating factors may be used to treat treatment emergent neutropenia 
as indicated by the current ASCO guidelines.44
Erythropoietin may be used at the investigator’s discretion for the supportive treatment of 
anemia. Erythropoietin is not approved in some countries for anemia caused by cancer 
treatment. For those countries where the indication and dosage of G-CSF (granulocyte 
colony-stimulating factor) compounds may differ from ASCO guidelines, refer to local 
product label or follow usual clinical practice in those countries.
6.5.4. 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, assuming there is no 
known or expected drug-drug interaction.  
6.5.5. 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.  Narcotic analgesic may hide colonic perforation in 
case of colitis and should be used with caution.  Anti-tumor necrosis factor (TNF) drugs are 
contraindicated in case of perforation, sepsis, or liver insufficiency.
6.5.6. 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 (Section 10.13).
6.5.7. 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.  TURBT is allowed during the study conduct in case of positive 
cystoscopy (presence of malignant or suspicious lesions) and it will be performed as 
indicated by local guidance. BCG administration should be modified according to the 
product label after TURBT. See also 10.9 for disease assessment guidance.
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6.5.8. Radiation Therapy
Radiation therapy is not allowed. 
6.5.9. Vaccines
Live attenuated vaccines within 4 weeks prior to the first dose of PF-06801591 and through 
30 days following the last dose of PF-06801591 are not allowed. Examples of live attenuated 
vaccines include, but are not limited to, the following: measles, mumps, rubella, chickenpox, 
yellow fever, rabies, and oral typhoid vaccine. Seasonal influenza vaccines for injection are 
inactivated virus vaccines and are allowed; however intranasal influenza vaccines (eg, 
FluMist®) are live attenuated vaccines, and are not allowed.  
Drug Interaction with BCG
Immunosuppressants, bone-marrow suppressants and radiation all have the potential to 
interfere with the development of immune response and should not be used concurrently with 
BCG.  Anti-tuberculosis drugs (e.g. isoniazid) should not be used to prevent or treat local 
irritations associated with BCG. Intravesical instillations of BCG should be postponed during 
treatment with antibiotics.
6.6. Dose Modification
Every effort should be made to administer the study treatment on the planned dose and 
schedule. In the event of significant toxicity, dosing may be skipped (PF-06801591 or BCG) 
or delayed (BCG). In the event of multiple toxicities, treatment modifications should be 
based on the worst toxicity observed. Participants are to be instructed to notify investigators 
at the first occurrence of any adverse symptom. Treatment modifications may occur 
independently for each study treatment in the combination based on the observed toxicity and 
the general guidance, as follows:

PF-06801591: No dose reductions are permitted, but the next dosing of PF-06801591 
may be skipped for the cycle based on persisting toxicity

BCG: Dosing can be skipped or delayed according to the product label.
All dose modifications must be clearly documented in the participant’s medical chart and in 
the eCRF. 
Appropriate follow-up assessments should be done until adequate recovery occurs as 
assessed by the investigator. 
In addition to the recommended dose modifications, investigators are encouraged to employ 
best supportive care according to local institutional clinical practices. 
In the event of a treatment interruption for reasons other than treatment-related toxicity 
(eg, elective surgery) for >7 consecutive days, treatment resumption will be decided in 
consultation with the sponsor.
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6.6.1. Dose Modifications for PF-06801591
Table 1.
PF-06801591 Recommended Treatment Modifications for Drug-Related 
Toxicity (Excluding Immune-Related AEs)
Hematologic toxicities
Grade 1 and Grade 2

Continue as per schedule.

Anemia Grade ≥3
(hemoglobin <8 g/dL)

Hold PF-06801591 and monitor weekly until resolution to Grade ≤1 or 
baseline. 

Resume PF-06801591 at the next scheduled dose after recovery to 
Grade ≤1 or baseline. 

Permanently discontinue PF-06801591 if anemia does not resolve to 
Grade ≤1 or baseline within 12 weeks or if the same Grade 3 toxicity 
recurs.

Neutropenia Grade ≥3
(ANC <1000/µL)

Hold PF-06801591 and monitor weekly until resolution to Grade ≤1 or 
baseline. 

Resume PF-06801591 at the next scheduled dose after recovery to 
Grade ≤1 or baseline. 

Permanently discontinue PF-06801591 if neutropenia does not resolve 
to Grade ≤1 or baseline within 12 weeks or if the same Grade 3 
toxicity recurs.

Thrombocytopenia
Grade ≥3 (platelets 
<50,000/µL)

Hold PF-06801591 and monitor weekly until resolution to Grade ≤1 or 
baseline. 

Resume PF-06801591 at the next scheduled dose after recovery to 
Grade ≤1 or baseline. 

Permanently discontinue PF-06801591 if thrombocytopenia does not 
resolve to Grade ≤1 or baseline within 12 weeks or if the same Grade 3 
toxicity recurs.
Non-hematologic toxicities
Grade 1 and Grade 2

Continue as per schedule.
Grade 3

Hold PF-06801591.

Resume PF-06801591 at the next scheduled dose after recovery to 
Grade ≤1 or baseline. 

Permanently discontinue if toxicity does not resolve to Grade ≤1 or 
baseline within 12 weeks or if the same Grade 3 toxicity recurs.

Exceptions are: laboratory values that do not have any clinical 
correlate.

For suspected immune-related toxicity follow guidance in 
Section 6.6.1.2.
Grade 4

Permanently discontinue PF-06801591.

Exceptions are: laboratory values that do not have any clinical 
correlate.

For suspected immune-related toxicity follow guidance in 
Section 6.6.1.2.
6.6.1.1. 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 
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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 participants should be closely observed while receiving the study intervention 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 Section 10.12. 
6.6.1.2. 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 Section 10.13.
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 thyroid stimulating hormone (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.
Clinical management of these events are provided in Section 10.13.
6.6.2. Precautions for Administration of BCG
BCG is an infectious agent, and study personnel who use this product should be aware of 
certain toxicities and precautions when planning administration.  Prior to administration of 
BCG, study personnel should ensure absence of febrile illness, urinary tract infection that 
represents a contraindication to BCG treatment, and gross hematuria.  Seven to 14 days 
should elapse before BCG is administered following biopsy, TURBT, or traumatic 
catheterization.  Algorithms for clinical management of BCG related toxicity based on the 
product label for TICE BCG, can be found in Section 10.14. When managing BCG 
associated toxicity for other strains of BCG, please refer to the appropriate product label for 
the BCG strain given to a participant.  
6.7. Intervention after the End of the Study
There are no interventions planned after the end of this study. 
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7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
     
7.1. Discontinuation of Study Intervention
For participants in Cohort A, it may be necessary for a participant to permanently discontinue 
one of the two study interventions.  In that case, please note that the participant will still 
continue with the other study intervention.  If it is necessary for the participant to 
permanently discontinue both PF-06801591 and BCG, the participant will remain in the 
study and move into the post-treatment follow-up period to allow for an adequate evaluation 
of the study objectives based on the prespecified estimands. 
Note that permanent discontinuation of study treatment does not represent withdrawal from 
the study.
Participants may withdraw from study 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 participant to comply with the protocol-required schedule of study 
visits or procedures at a given study site. 
Reasons for withdrawal of study treatment in Cohorts A, B1, and B2 may include:

Completion of study treatment (25 cycles for Cohort A, Arms A, B and C, and Cohort 
B1, and 17 cycles for Cohort B2)

Participants with CIS at baseline who do not achieve a CR within 6 months of initiating 
study intervention will be withdrawn from study treatment

Recurrence of high-grade disease (Section 10.9) or progression of disease 

Global deterioration of health status requiring discontinuation of study treatment

Unacceptable toxicity

Pregnancy

Significant protocol violation

Lost to follow-up

Participant refused further treatment

Study terminated by sponsor

Death
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Discontinuation of study treatment for abnormal liver function should be considered by the 
investigator when a participant meets one of the conditions outlined or if the investigator 
believes that it is in best interest of the participant.  See Section 10.6 for details.
If a clinically significant finding is identified (including, but not limited to changes from 
baseline in QT interval corrected using Fridericia’s formula [QTcF] after enrollment), the 
investigator or qualified designee will determine if the participant can continue in the study 
and if any change in participant management is needed. This review of the electrocardiogram 
(ECG) printed at the time of collection must be documented. Any new clinically relevant 
finding should be reported as an AE.  Refer to Section 8.2.4 for detailed information on 
criteria for holding or discontinuing study treatment in the case of change in QT interval.
See the SoA for data to be collected at the time of intervention discontinuation and follow-up 
and for any further evaluations that need to be completed.
7.2. Participant Discontinuation/Withdrawal from the Study
A participant may withdraw from the study at any time at his/her own request.  Reasons for 
discontinuation from the study include the following:

Refused further follow-up

Lost to follow-up

Death

Study terminated by sponsor
If a participant withdraws from the study, he/she may request destruction of any remaining 
samples taken and not tested, and the investigator must document any such requests in the 
site study records and notify the sponsor accordingly. 
If the participant withdraws from the study and also withdraws consent (see Section 7.2.1) 
for disclosure of future information, no further 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.
Lack of completion of all or any of the withdrawal/early termination procedures will not be 
viewed as protocol deviations so long as the participant’s safety was preserved.
7.2.1. Withdrawal of Consent 
Participants who request to discontinue receipt of study intervention will remain in the study 
and must continue to be followed for protocol specified follow-up procedures.  The only 
exception to this is when a participant specifically withdraws consent for any further contact 
with him or her or persons previously authorized by the participant to provide this 
information.  Participants should notify the investigator in writing of the decision to 
withdraw consent from future follow-up, whenever possible.  The withdrawal of consent 
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should be explained in detail in the medical records by the investigator, as to whether the 
withdrawal is only from further receipt of study intervention or also from study procedures 
and/or posttreatment study follow-up and entered on the appropriate eCRF page.  In the event 
that vital status (whether the participant is alive or dead) is being measured, publicly 
available information should be used to determine vital status only as appropriately directed 
in accordance with local law.
7.3. Lost to Follow-up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study.

Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record.

Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
All attempts to contact the participant and information received during contact attempts must 
be documented in the participant’s medical record.  In any circumstance, every effort should 
be made to document participant outcome, if possible.  The investigator should enquire about 
the reason for withdrawal, request the participant to return for a final visit, if applicable, and 
follow up with the participant regarding any unresolved AEs.
If it is determined that the participant has died, the site will use permissible local methods to 
obtain the date and cause of death.  If, after all attempts, the participant remains lost to 
follow-up, then the last-known-alive date as determined by the investigator should be 
reported and documented in the participant’s medical records.
8. STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed.  

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study treatment.
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
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.  For patients in screening for Cohort B1, the BICR must 
review screening biopsy, cytology, and imaging prior to registration to confirm diagnosis 
of CIS alone or with concomitant recurrent Ta/T1 disease and absence of muscle-invasive 
bladder cancer and extravesical disease.

Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICD may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.
Medical history of the participants will be collected per the SoA as follows:

Tumor history:  Includes history of NMIBC including details of primary diagnosis and 
treatment history. 

For Cohorts B1 and B2, detailed information about prior BCG usage (number of 
doses administered, date of dosing, dose levels, and strain used), disease persistence 
or recurrence after BCG treatment (including grade and stage) and the date of disease 
persistence or recurrence. 

For Cohorts B1 and B2, reasons for subject ineligibility or refusal of radical 
cystectomy.

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. 
8.1. Efficacy Assessments
8.1.1. Clinical Assessments
Cytology and cystoscopy results will be read locally by qualified and experienced study 
personnel.  Data obtained from cystoscopy, cytology, biopsy and imaging (computed 
tomography [CT] / magnetic resonance imaging [MRI]) will be evaluated locally during the 
course of the study according to the disease assessment decision algorithm in Section 10.9
and will be used for primary analyses in Cohort A and Cohort B2.
Independent reviewers will provide retrospective central assessment of imaging and tumor 
tissue samples taken during the study for Cohort A. This includes the tumor tissue sample(s) 
taken from the TURBT  supporting the primary diagnosis for the study during the screening 
period, biopsies or TURBT samples collected at the time of recurrence of high-grade disease, 
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disease progression, persistence of CIS (applicable only to participants with CIS at 
randomization), or complete response (applicable only to participants with CIS at 
randomization), and done after a positive cystoscopy or cytology.  
For Cohort B1, independent reviewers will provide central assessment of tumor tissue 
samples (from the TURBT or biopsies supporting the primary diagnosis for the study), 
cytology, and imaging during screening for the purposes of eligibility evaluation prior to 
registration.  During treatment, independent reviewers will provide retrospective central 
assessment of biopsies or TURBT samples collected, as well as cytology, cystoscopy, and 
imaging results and the BICR assessments will be sent to the sites on a regular basis. 
See the Study Manual for process details on sending the tissue sample for blinded 
independent central review (BICR).
8.1.1.1. Cystoscopy 
Cystoscopy should be performed and assessed using the same method and equipment by the 
same study staff (whenever possible), for the duration of the study, in order to reduce 
subjectivity across multiple assessments. White light, blue light or narrow-band imaging are 
allowed in this study and blue light is preferred. Number, size and location of the tumors 
should be documented.
Disease status will be assessed through cystoscopy conducted at screening, every 12 weeks 
for 2 years following randomization, and every 24 weeks during the rest of follow-up, and as 
clinically indicated.  Timing of disease assessment is to be fixed according to the calendar 
(±7 days) starting with randomization for Cohort A and initiation of study intervention for 
Cohorts B1 and B2, and should not be adjusted for study intervention dose modifications.  
Please refer to the Schedule of Activities for disease assessment time points for each Cohort.
Cystoscopy with biopsy is required at the time of recurrence of high-grade disease, disease 
progression, persistence of CIS (applicable only to participants with CIS at randomization), 
or complete response (applicable only to participants with CIS at randomization) as described 
in Section 10.9.  
In Cohort A, biopsy for confirmation of complete response for participants with CIS should 
be performed at the 24 week disease assessment, unless collection at the 12 week disease 
assessment is routinely performed at the given institution.  Please consider that if the bladder 
biopsy collection at the Week 12 disease assessment fails to confirm CR, the biopsy 
collection must be repeated at the Week 24 disease assessment.  If it is not possible to 
perform the bladder biopsy collection by the Week 24 disease assessment, biopsies should be 
collected as soon as possible at the next scheduled disease assessment. 
Timing of disease assessment is to be fixed according to the calendar (±7 days), starting with 
randomization for Cohort A, and initiation of study intervention for Cohorts B1 and B2, and 
should not be adjusted for study treatment dose modifications.  
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For cystoscopy without biopsy, either flexible or rigid cystoscopy may be conducted as per 
the Investigator’s clinical judgement or institutional guidance/preference.  Further 
specifications for the procedure are provided in the Study Manual.
For cystoscopy with biopsy, a full thickness tissue specimen is required to be obtained and 
Sponsor recommends a rigid cystoscopy.  
Cystoscopy results from Cohorts A and B1 provided by the investigator will also be included 
in the BICR assessment.
Independent pathology reviewers will provide central assessment prior to registration for 
Cohort B1, and retrospective central assessment of all biopsies for Cohorts A and B1.  Refer 
to the manual for process details on sending the slides for the BICR assessment.
8.1.1.2. Cytology
Urine cytology should be performed using the same methods and equipment for the duration 
of the study, with results being assessed and adjudicated by the same study staff.  This is to 
reduce subjectivity across multiple assessments.
Disease status will be assessed through urine cytology conducted at screening, every 12 
weeks during the first 2 years from randomization, every 24 weeks during the rest of follow-
up, and as clinically indicated.  Timing of disease assessment should be fixed according to 
the calendar (±7 days), starting with randomization for Cohort A, and initiation of study 
intervention for Cohorts B1 and B2, and should not be adjusted for study treatment dose 
modifications.  Please refer to the Schedule of Activities for disease assessment time points 
for each Cohort.
Cytology results provided by the investigator will also be included in the BICR assessment 
for Cohort A.  For Cohort B1, urine cytology specimens will be included in the BICR 
assessment.
Cytology results are defined as the following:
1.  Positive - if indicative or suggestive of malignant cells: 

High-grade urothelial carcinoma

Suspicious for high-grade urothelial carcinoma 
2.  Negative if NOT indicative or suggestive of malignant cells: 

Negative for high-grade urothelial carcinoma cells 

Presence of low-grade urothelial carcinoma cells 

Atypical urothelial cell not abnormal enough to be considered as cancerous 
3.  Indeterminate: unsatisfactory sample.
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8.1.1.3. Imaging
CT or MRI or urogram of the abdomen and pelvis/urinary tract are the recommended 
imaging modalities.  Other areas may be scanned as clinically indicated.  Imaging should be 
performed with contrast agents unless contraindicated for medical reasons.  The same 
imaging technique used at screening will be employed in the tumor assessments conducted 
on study.  
For Cohort B1, disease status will be assessed through imaging at screening, every 24 weeks 
for 2 years after initiation of study intervention. Imaging will be performed until persistence 
of CIS, recurrence of high-grade disease or disease progression, consent withdrawal, lost to 
follow-up, EOT, or death.  Additional imaging may be performed as clinically indicated. For 
Cohort A and Cohort B2, imaging is done as clinically indicated.
Guidance for integration of imaging in the disease assessment are provided in the disease 
assessment decision algorithm in Section 10.9.
Independent reviewers will provide central assessment prior to registration for Cohort B1, 
and retrospective central assessment of all imaging for Cohorts A and B1.  Refer to the 
manual for process details on sending the scans for the BICR assessment.
8.1.2. Patient Reported Outcomes (PROs)
All PRO questionnaires will be administered electronically and will be completed during the 
visit prior to any other clinical assessments and study procedures, with the exception of the 
PTAB which will be completed immediately after the study intervention.  If laboratory 
assessments are done on a date prior to the main visit date, PROs may be completed as the 
first assessment at the main visit.  PROs will be administered in following order: EORTC 
QLQ-C30, EORTC NMIBC24, EQ5D5L, PGIS, PGIC, TSQ, and PTAB.
As of 12 September 2022, PROs will not be required for Cohort B1 and B2 participants. 
8.1.2.1. EORTC QLQ-C30
The EORTC QLQ-C30 is a well-known, validated and self-administered PRO.45,46  The 
EORTC QLQ-C30 is a 30-question survey, which can be grouped into 5 functional domain 
subscales, including a physical functioning subscale, a role functioning subscale, an 
emotional functioning subscale, a cognitive functioning subscale and a social functioning 
subscale.  Higher scores on the functional domains are indicative of higher levels of 
functioning.  Oncology related symptoms assessed by the EORTC QLQ-C30 include fatigue 
(3 items), pain (2 items), nausea and vomiting (2 items), and dyspnea, insomnia, appetite 
loss, constipation, diarrhea, and financial impact (1 item each).  Higher scores are reflective 
of a greater presence of symptoms.  
8.1.2.2. EORTC QLQ-NMIBC24
The EORTC QLQ NMIBC24 is a PRO developed and tested by the EORTC group 
specifically for patients with non-muscle invasive bladder cancer.47 The NMIBC24 has 24 
items which can be grouped into 6 subscales: urinary symptoms (7 items), malaise (2 items), 
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future worries (4 items), bloating/flatulence (2 items), sexual functioning (2 items), and male 
sexual issues (2 items). The NMIBC24 also assesses intravesical treatment, female sexual 
issues, sexual intimacy, risk of contaminating a partner, and sexual enjoyment (1 item each). 
Higher scores indicate greater impairment, with the exception of the sexual function and 
sexual enjoyment items, where higher scores indicate better function.
8.1.2.3. EuroQol 5 Dimensions, 5-Level (EQ-5D-5L) and Visual Analog Scale (VAS) 
The EQ-5D-5L is a 6-item patient-completed questionnaire designed to assess health status in 
terms of a single index value or utility score.48 There are 2 components, a Health State Profile 
which has individuals rate their level of problems (none, slight, moderate, severe, 
extreme/unable) in 5 areas (mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression), and a VAS in which participants rate their overall health status from 0 
(worst imaginable) to 100 (best imaginable). Published weights are available that allow for 
the creation of a single summary score. Overall scores range from 0 to 1, with lower scores 
representing a higher level of dysfunction. 
8.1.2.4. Patient Global Impression of Severity (PGIS)
The PGIS is a single-item PRO designed to facilitate an anchor-based methodology for 
establishing meaningful within person change (MWPC) of other PRO-based endpoints such 
as the EORTC QLQ-C30 and QLQ-NMIBC24. There are 4 response options, ranging from 
“none” to “severe”. The instrument is available in Section 10.16.1.
8.1.2.5. Patient Global Impression of Change (PGIC)
The PGIC is a single-item PRO designed to assess the participants overall impression of the 
degree of change they have experienced since the start of study treatment.  There are 5 
response options, ranging from “much worse” to “much better”. The instrument is available 
in Section 10.16.2.
8.1.2.6. Patient Treatment Administration Burden (PTAB)
The PTAB questionnaire is a 2-item PRO designed to assess, from the participant 
perspective, any pain associated with the treatment administration and the burden of the 
amount of time required to complete the treatment administration procedures (1 item each). 
The PTAB is available in Section 10.16.3.
8.1.2.7. Treatment Satisfaction Questionnaire (TSQ)
The TSQ is a 3-item PRO designed to assess participant satisfaction with the study 
treatments. The TSQ assesses overall satisfaction with the study treatment, number of 
treatment administrations, and the form of treatment administration (injection into stomach 
and catheter into bladder) (1 item each). The instrument is available in Section 10.16.4.    
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8.2. Safety Assessments
Planned time points for all safety assessments are provided in the SoA. Unscheduled clinical 
laboratory measurements may be obtained at any time during the study to assess any 
perceived safety issues.
8.2.1. Physical Examinations
Physical examinations should be performed according to clinical practice, but will not be 
recorded in the eCRF. Rather, any abnormalities should be recorded in the eCRF as AEs.
8.2.2. Vital Signs

Vital signs will be measured as indicated in the SoA. Any abnormalities will be recorded 
in the eCRF as AEs. 

BP and pulse rate will be assessed in a supine position with a completely automated 
device. Manual techniques will be used only if an automated device is not available.

BP and pulse rate should be preceded by at least 5 minutes of rest for the participant in a 
quiet setting without distractions (eg, television, cell phones).
8.2.3. ECOG Performance Status
Refer to Section 10.10 for ECOG Performance Status Criteria. ECOG will be performed per 
SoA.
8.2.4. Electrocardiograms  
Electrocardiogram (12-Lead)

A single 12-lead ECG tracing (with a 10 second rhythm strip) will be obtained at the 
time points described in the SoA.  

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 participant 
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.  

ECGs will be collected prior to dosing of study intervention as indicated in the SoA.  
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.

For the purposes of eligibility assessment and general safety monitoring, sites must enter 
the QTcF value provided by their ECG machine or calculated manually.  

If the QTcF is prolonged (≥60 msec from the pre-dose baseline or is >500 msec), then the 
ECGs should be reevaluated 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 
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manual reading verifies a QTcF of ≥60 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 ≥60 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 60 msec from the pre-dose baseline or is ≤500 msec, and in 
the judgment of the investigator(s) and sponsor is determined to be due to cause(s) other 
than the study intervention, treatment may be continued with regular ECG monitoring.  If 
in that timeframe the QTcF intervals rise above ≥60 msec from the pre-dose baseline or is 
>500 msec the study intervention will be held until the QTcF interval decreases to 
≤60 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 ≥60 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 participant should undergo continuous ECG monitoring.  A 
cardiologist should be consulted if QTc intervals do not return to less than 500 msec (or 
to <60 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 ≤60 msec from the pre-dose baseline or ≤500 msec, 
depending on the type of change originally observed, participants may restart the study 
intervention.  If the QTcF interval has still not decreased to ≤60 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 participant has a QTcF interval >515 msec or becomes 
symptomatic, the participant 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 the study 
intervention, thorough consideration should be given to potential precipitating factors (eg, 
change in participant clinical condition, effect of concurrent medication, electrolyte 
disturbance) and possible evaluation by specialist.

If participant 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.
8.2.5. Local Site Injection Tolerability Assessment (PF-06801591 only)
Any injection site reactions will be recorded as adverse events.
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8.2.6. Survival Follow-up
To collect OS data for Cohort A participants only, once participants enter the survival 
follow-up period, they will be contacted by telephone every 12 weeks (±7 days) until consent 
withdrawal, lost to follow-up, death, or end of the study (5 years after last participant 
randomized to Cohort A).  If the participant 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.  For Cohort A participants only, any subsequent anti-
cancer therapy (including cystectomy), if administered, will be documented and recorded for 
participants who discontinue the study intervention and continue in post-treatment safety 
follow-up until recurrence of high-grade disease or progression of disease.  The sponsor may 
request that sites complete additional survival follow-up to facilitate planned analyses as 
needed.   
8.2.7. Clinical Safety Laboratory Assessments

See Section 10.2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency. Specimen for laboratory assessments may also be drawn when 
clinically indicated.

Repeat samples do not have to be drawn on C1D1 if the samples were drawn in the prior 
7 days. Laboratory tests may be performed up to 3 days prior to the scheduled clinic visit 
including the C1D1 visit, so that results will be available for review before study 
treatment administration. 

Assessments and physician’s evaluation of the following labs, at a minimum, must be 
performed prior to dosing at visits per Section 1.3, Schedule of Activities:

Pregnancy test (as applicable)

Hematology (per Section 6.6.1)

Liver function: AST, ALT, and bilirubin (per Section 10.13)

Renal function: Creatinine (per Section 10.13)

Any other per protocol lab test(s) that correlate to clinical signs or symptoms 

Results from pregnancy tests, if taken, must be available for review prior to dosing.

Laboratory assessments will be collected per SoA.

Laboratory assessments must be performed, and results reviewed by the treating 
physician as soon as they are available. 

The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents. Clinically significant 
abnormal laboratory findings are those which are not associated with the underlying 
disease, unless judged by the investigator to be more severe than expected for the 
participant’s condition.
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
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within AE/SAE reporting criteria after the last dose of study 
treatment should be repeated until the values return to normal or baseline or are no longer 
considered clinically significant by the investigator or medical monitor.
o
If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified, and the sponsor 
notified.
o
All protocol-required laboratory assessments, as defined in Section 10.2, must be 
conducted in accordance with the SoA.
o
If laboratory values from non-protocol specified laboratory assessments 
performed at the institution’s local laboratory require a change in participant 
management or are considered clinically significant by the investigator (eg, SAE 
or AE or dose modification), then the results must be recorded in the eCRF.
8.2.8. Pregnancy Testing 
Pregnancy tests may be urine or serum tests but must have a sensitivity of at least 
25mIU/mL.
Pregnancy tests will be performed in WOCBP at the times listed in the SoA. Following a 
negative pregnancy test result at screening, appropriate contraception must be commenced 
and a second negative pregnancy test result will be required at the baseline visit prior to the 
participant’s receiving the study intervention. Pregnancy tests will also be done whenever 1 
menstrual cycle is missed during the active treatment period (or when potential pregnancy is 
otherwise suspected) and at the end of the study.  Pregnancy tests may also be repeated if 
requested by IRBs/ ECs or if required by local regulations.  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 result is positive.
8.3. Adverse Events and Serious Adverse Events
The definitions of an AE and an SAE can be found in Section 10.3.
The definitions of device-related safety events (ADEs and SADEs) can be found in 
Section 10.7.  Device deficiencies are covered in Section 8.3.9.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or 
the participant’s legally authorized representative).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue 
and obtain adequate information both to determine the outcome and to assess whether it 
meets the criteria for classification as an SAE, or that caused the participant to discontinue 
the study intervention (see Section 7.1).
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Each participant will be questioned about the occurrence of AEs in a nonleading manner.
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up 
information in an expedited fashion. 
8.3.1. Time Period and Frequency for Collecting AE and SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each participant begins from the time the participant provides informed consent, 
which is obtained before the participant’s participation in the study (ie, before undergoing 
any study-related procedure and/or receiving study intervention), through and including a 
minimum of 90 calendar days after the last administration of the study intervention.  
For participants who are screen failures, the active collection period ends when screen failure 
status is determined.
Follow-up by the investigator continues throughout and after the active collection period and 
until the AE or SAE or its sequelae resolve or stabilize at a level acceptable to the 
investigator and Pfizer concurs with that assessment.
For participants who are screen failures, the active collection period ends when screen failure 
status is determined.
If the participant withdraws from the study and also withdraws consent for the collection of 
future information, the active collection period ends when consent is withdrawn.
If a participant definitively discontinues or temporarily discontinues study intervention 
because of an AE or SAE, the AE or SAE must be recorded on the eCRF and the SAE 
reported using the CT SAE Report Form.
Investigators are not obligated to actively seek AEs or SAEs after the participant has 
concluded study participation. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has completed the study, and he/she considers the event 
to be reasonably related to the study intervention, the investigator must promptly report the 
SAE to Pfizer using the CT SAE Report Form.
8.3.1.1. Reporting SAEs to Pfizer Safety 
All SAEs occurring in a participant during the active collection period as described in 
Section 8.3.1 are reported to Pfizer Safety on the CT SAE Report Form immediately upon 
awareness and under no circumstance should this exceed 24 hours, as indicated in 
Section 10.3. The investigator will submit any updated SAE data to the sponsor within 
24 hours of it being available.
If a participant begins a new anticancer therapy, SAEs occurring during the above-indicated 
active collection period must still be reported to Pfizer Safety irrespective of any intervening 
treatment.  Note that a switch to a commercially available version of the study intervention is 
considered as a new anticancer therapy for the purposes of SAE reporting.
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8.3.1.2. Recording Nonserious AEs and SAEs on the eCRF
All nonserious AEs and SAEs occurring in a participant during the active collection period, 
which begins after obtaining informed consent as described in Section 8.3.1, will be recorded 
on the AE section of the eCRF.
The investigator is to record on the eCRF all directly observed and all spontaneously reported 
AEs and SAEs reported by the participant.
If a participant begins a new anticancer therapy, the recording period for nonserious AEs 
ends at the time the new treatment is started; however, SAEs must continue to be recorded on 
the eCRF during the above-indicated active collection period. Note that a switch to a 
commercially available version of the study intervention is considered as a new anticancer 
therapy for the purposes of SAE reporting.
8.3.2. Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AE and SAE and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3.
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
8.3.3. Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. For each event, the investigator must pursue and 
obtain adequate information until resolution, stabilization, the event is otherwise explained, 
or the participant is lost to follow-up (as defined in Section 7.3).
In general, follow-up information will include a description of the event in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality.  Any information relevant to the event, such as concomitant medications 
and illnesses, must be provided.  In the case of a participant death, a summary of available 
autopsy findings must be submitted as soon as possible to Pfizer Safety. 
Further information on follow-up procedures is given in Section 10.3.
8.3.4. Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and the safety 
of a study intervention under clinical investigation are met.

The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study treatment under clinical investigation. 
The sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRBs/EC), and investigators.
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
Investigator safety reports must be prepared for SUSARs according to local 
regulatory requirements and sponsor policy and forwarded to investigators as necessary.

An investigator who receives  SUSARs or other specific safety information (eg, 
summary or listing of SAEs) from the sponsor will review and then file it along with the  
SRSD(s) for the study and will notify the IRB/EC, if appropriate according to local 
requirements.
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational Exposure
Exposure to the intervention under study during pregnancy or breastfeeding and occupational 
exposure are reportable to Pfizer Safety within 24 hours of investigator awareness.
8.3.5.1. Exposure During Pregnancy
An EDP occurs if: 

A female participant is found to be pregnant while receiving or after discontinuing 
study intervention.

A male participant who is receiving or has discontinued study intervention exposes a 
female partner prior to or around the time of conception.

A female is found to be pregnant while being exposed or having been exposed to 
study intervention due to environmental exposure.  Below are examples of 
environmental exposure during pregnancy:  

A female family member or healthcare provider reports that she is pregnant after 
having been exposed to the study intervention by any routes of exposure (eg, 
injection, ingestion, inhalation, or skin contact).

A male family member or healthcare provider who has been exposed to the study 
intervention by any routes of exposure (eg, injection, ingestion, inhalation, or skin 
contact) then exposes his female partner prior to or around the time of conception.
The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred.  The initial information submitted 
should include the anticipated date of delivery (see below for information related to 
termination of pregnancy). 

If EDP occurs in a participant or a participant’s partner, the investigator must report 
this information to Pfizer Safety on the CT SAE Report Form and an EDP 
Supplemental Form, regardless of whether an SAE has occurred.  Details of the 
pregnancy will be collected after the start of study intervention and until at least 180 
days after the last dose.

If EDP occurs in the setting of environmental exposure, the investigator must report 
information to Pfizer Safety using the CT SAE Report Form and EDP Supplemental 
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Form.  Since the exposure information does not pertain to the participant enrolled in 
the study, the information is not recorded on an eCRF; however, a copy of the 
completed CT SAE Report Form is maintained in the investigator site file.
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 Safety 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 termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
preprocedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
Abnormal pregnancy outcomes are considered SAEs.  If the outcome of the pregnancy meets 
the criteria for an SAE (ie, ectopic pregnancy, spontaneous abortion, intrauterine fetal 
demise, neonatal death, or congenital anomaly in a live-born baby, a terminated fetus, an 
intrauterine fetal demise, or a neonatal death), the investigator should follow the procedures 
for reporting SAEs.  Additional information about pregnancy outcomes that are reported to 
Pfizer Safety as SAEs follows: 

Spontaneous abortion including 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 study intervention. 
Additional information regarding the EDP may be requested by the sponsor.  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 participant with the Pregnant Partner Release of Information 
Form to deliver to his partner.  The investigator must document in the source documents that 
the participant was given the Pregnant Partner Release of Information Form to provide to his 
partner.
8.3.5.2. Exposure During Breastfeeding
An exposure during breastfeeding occurs if: 

A female participant is found to be breastfeeding while receiving or after 
discontinuing study intervention.

A female is found to be breastfeeding while being exposed or having been exposed to 
study intervention (ie, environmental exposure).  An example of environmental 
exposure during breastfeeding is a female family member or healthcare provider who 
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reports that she is breastfeeding after having been exposed to the study intervention 
by inhalation or skin contact.  
The investigator must report exposure during breastfeeding to Pfizer Safety within 24 hours 
of the investigator’s awareness, irrespective of whether an SAE has occurred.  The 
information must be reported using the CT SAE Report Form.  When exposure during 
breastfeeding occurs in the setting of environmental exposure, the exposure information does 
not pertain to the participant enrolled in the study, so the information is not recorded on an 
eCRF.  However, a copy of the completed CT SAE Report Form is maintained in the 
investigator site file.
An exposure during breastfeeding report is not created when a Pfizer drug specifically 
approved for use in breastfeeding women (eg, vitamins) is administered in accord with 
authorized use.  However, if the infant experiences an SAE associated with such a drug, the 
SAE is reported together with the exposure during breastfeeding.
8.3.5.3. Occupational Exposure 
An occupational exposure occurs when a person receives unplanned direct contact with the 
study intervention, which may or may not lead to the occurrence of an AE.  Such persons 
may include health care providers, family members, and other roles that are involved in the 
trial participant’s care.
The investigator must report occupational exposure to Pfizer Safety within 24 hours of the 
investigator’s awareness, regardless of whether there is an associated SAE. The information 
must be reported using the CT SAE Report Form.  Since the information does not pertain to a 
participant enrolled in the study, the information is not recorded on an eCRF; however, a 
copy of the completed CT SAE Report Form is maintained in the investigator site file.
8.3.6. Cardiovascular and Death Events 
Not applicable.
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs
Not applicable.
8.3.8. Adverse Events of Special Interest
Any AE that is suspected to be a potential irAE is considered an AE of special interest 
(AESI). Specific guidance for the management of irAEs is provided in Section 10.13. All 
AESIs must be reported as an AE or SAE following the procedures described in 
Sections 8.3.1 through 8.3.4.  An AESI is to be recorded as an AE or SAE on the eCRF.  In 
addition, an AESI that is also an SAE must be reported using the CT SAE Report Form.
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8.3.8.1. Lack of Efficacy
Lack of efficacy (see Section 10.3.1) is reportable to Pfizer Safety only if associated with an 
SAE.
8.3.9. Medical Device Deficiencies
Medical devices being provided for use in this study as the study intervention are supplied as 
a PFS for SC injection. In order to fulfill regulatory reporting obligations worldwide, the 
investigator is responsible for the detection and documentation of events meeting the 
definitions of device deficiency that occur during the study with such devices.
The definition of a medical device deficiency can be found in Section 10.7.
NOTE: Deficiencies fulfilling the definition of an AE/SAE will also follow the processes 
outlined in Section 8.3.1 through 8.3.4 and Section 10.3 of the protocol. 
8.3.9.1. Time Period for Detecting Medical Device Deficiencies

Medical device deficiencies that result in an incident will be detected, documented, 
and reported during all periods of the study in which the medical device is used. Importantly, 
reportable device deficiencies are not limited to problems with the device itself but also 
include incorrect or improper use of the device and even intentional misuse, etc.

If the investigator learns of any device deficiency at any time after a participant has 
been discharged from the study, and such incident is considered reasonably related to a 
medical device provided for the study, the investigator will promptly notify the sponsor.
The method of documenting medical device deficiencies is provided in Section 10.7 and the 
IP Manual. 
8.3.9.2. Follow-Up of Medical Device Deficiencies
AEs and/or SAEs that are associated with the medical device deficiency will follow the 
same processes as other AEs or SAEs, as outlined in Section 8.3.1. (Time Period and 
Frequency for Collecting AE and SAE Information) and Section 8.3.4 Regulatory Reporting 
Requirements for SAEs and Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-Up, and Reporting.
8.3.9.3. Prompt Reporting of Device Deficiencies to Sponsor
Device deficiencies will be reported to the sponsor, within one day after the investigator 
determines that the event meets the protocol definition of a medical device deficiency. 
Information will be provided to the sponsor as described in the IP Manual. 
Any device deficiency that is associated with an SAE must be reported to Pfizer Safety 
within 24 hours upon the investigator’s awareness as outlined in Section 8.3.1.1 and 8.3.1.2.
The sponsor will be the contact for the receipt of device deficiency information.
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8.3.9.4. Regulatory Reporting Requirements for Device Deficiencies

The investigator will promptly report all device deficiencies occurring with any 
medical device provided for use in the study in order for the sponsor to fulfill the legal 
responsibility to notify appropriate regulatory authorities and other entities about certain 
safety information relating to medical devices being used in clinical studies.

The investigator, or responsible person according to local requirements (eg, the head 
of the medical institution), will comply with the applicable local regulatory requirements 
relating to the reporting of device deficiencies to the IRB/EC.

Note: There are additional reporting obligations for medical device deficiencies that 
are potentially related to SAEs (ie, an SADE) that must fulfill the legal responsibility to 
notify appropriate regulatory authorities and other entities about certain safety information 
relating to medical devices being used in clinical studies. 

Any device deficiency that is associated with an SAE must be reported to the sponsor 
within 24 hours after the investigator determines that the event meets the definition of 
a device deficiency.

The sponsor shall review all device deficiencies and determine and document in 
writing whether they could have led to an SAE. These shall be reported to the 
regulatory authorities and IRBs/ECs as required by national regulations.
8.3.10. Medication Errors
Medication errors may result from the administration or consumption of the study 
intervention by the wrong participant, or at the wrong time, or at the wrong dosage strength, 
or from inadvertent exposure.  
Exposures to the intervention under study may occur in clinical trial settings, such as 
medication errors.
Safety Event
Recorded on the eCRF
Reported on the CT SAE Report 
Form to Pfizer Safety Within 24 
Hours of Awareness
Medication errors 
All (regardless of whether 
associated with an AE)
Only if associated with an SAE
Medication errors include:

Medication errors involving participant exposure to the study intervention

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participant

Incorrect study treatment taken by participant

Overdose
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Such medication errors occurring to a study participant are to be captured on the medication 
error page of the eCRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified within 24 hours.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the eCRF and, 
if applicable, any associated AE(s), serious and nonserious, are recorded on an AE page of 
the eCRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
8.4. Treatment of Overdose
Injection of any dose of PF-06801591 greater than one complete PFS for Cohorts A and B1 
and greater than two complete PFS for Cohort B2 at any scheduled administration visit will 
be considered an overdose.
Pfizer does not recommend specific treatment for an overdose.
In the event of an overdose, the investigator/treating physician should:
1. Contact the medical monitor within 24 hours.
2. Closely monitor the participant for any AEs/SAEs and laboratory abnormalities for at 
least 6 months after the overdose of PF-06801591.
3. Document the quantity of the excess dose as well as the duration of the overdose in 
the eCRF.
4. Overdose is reportable to Safety only when associated with an SAE.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the medical monitor based on the clinical evaluation of the participant.
8.5. Pharmacokinetics
Blood samples to provide serum for the analysis of PF-06801591 pre-dose/Ctrough
concentrations will be collected as outlined in the SoA for Arms A and B only in Cohort A.  
As of 12 September 2022, no PK samples will be collected from participants in Cohorts B1 
and B2.  The PK sampling schedule may be modified based on emerging PK data.
All efforts will be made to obtain pre-dose PK samples within 2 hours prior to PF-06801591 
dosing.  However, samples obtained outside that time window will not be captured as a 
protocol deviation, as long as they are collected on the day of, and prior to, PF-06801591 
administration, and the exact time (24-hour clock time) of the sample collection is noted on 
the source document and data collection tool (eg, eCRF).  If a scheduled blood sample 
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collection cannot be completed for any reason, the missed sample time may be rescheduled 
with agreement of the clinical investigator, participant, 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 
as well as other internal exploratory purposes unless prohibited by local regulations or ethics 
committee decision.  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 laboratory manual.

The PK samples must be processed and shipped as indicated in the instructions provided 
to the investigator site to maintain sample integrity. Any deviations from the PK sample 
handling procedure (eg, sample collection and processing steps, interim storage or 
shipping conditions), including any actions taken, must be documented and reported to 
the sponsor.  On a case-by-case basis, the sponsor may make a determination as to 
whether sample integrity has been compromised.
8.6. Pharmacodynamics
The biospecimens for pharmacodynamic (PD) assessments will be collected per the SoA and 
are also listed in Section 8.8. 
Pre-dose blood samples will be collected to enable measurements which may include but are 
not limited to: immune repertoire, proteomic profiles, circulating free deoxyribonucleic acid 
(cfDNA) or epigenetics at the timepoints specified in the SoA.
As part of understanding the PD of the study intervention, samples may be used for 
evaluation of the bioanalytical method, as well as for other internal exploratory purposes 
unless prohibited by local regulations or ethics committee decision.  These data will not be 
included in the clinical study report (CSR).
Some samples may be analyzed using a validated analytical method in compliance with 
applicable SOPs while others will be analyzed using a non-characterized assay (non-
validated).  
The PD samples must be processed and shipped as indicated in the instructions provided to 
the investigator site to maintain sample integrity.  Any deviations from the PD sample 
handling procedure (eg, sample collection and processing steps, interim storage or shipping 
conditions), including any actions taken, must be documented and reported to the sponsor.  
On a case-by-case basis, the sponsor may make a determination as to whether sample 
integrity has been compromised. 
As of 12 September 2022, no PD samples will be collected from participants enrolled in 
Cohorts B1 and B2.
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8.7. Genetics
8.7.1. Specified Genetics
No specific samples will be collected for genetic analyses.
8.7.2. Banked Biospecimens for Genetics
Approximately 4 mL blood sample optimized for DNA isolation (Prep D1) will be collected 
as local regulations and IRBs/IECs allow.
Banked Biospecimens may be used for research related to drug response and NMIBC. Genes 
and other analytes (eg, proteins, RNA non-drug metabolites) may be studied using the 
banked samples. 
Unless prohibited by local regulations (eg, China and other countries as applicable) or 
IRB/EC decision, participants will be asked to indicate on the consent form whether they will 
allow their Banked Biospecimens to also be used to design and conduct research in order to 
gain a further understanding of other diseases and to advance science, including development 
of other medicines for patients.  This component of the sample banking is optional for 
participants; they may still participate in the study even if they do not agree to the additional 
research on their Banked Biospecimens.  The optional additional research does not require 
the collection of any further samples.
See Section 10.5 for Information regarding genetic research. Details on processes for 
collection and shipment and destruction of these samples can be found in the laboratory 
manual.
8.8. Biomarkers
Unless prohibited by local regulations or IRB/EC decision, the following samples for 
biomarker research are required and will be collected from all participants in this study as 
specified in the SoA:

Pre-treatment tumor tissue samples to enable assessment of PD-L1 status and cluster of 
differentiation 8 (CD8) + TIL, whole exome sequencing and gene expression analyses

4 mL whole blood samples at baseline and on treatment to enable immune repertoire 
analyses, epigenetic profiling and filtering of somatic mutation data

Two 10 mL blood samples at baseline and on treatment to be processed to plasma to 
enable assessment of cfDNA

Approximately one 10 mL blood sample at baseline and on treatment to be processed to 
serum to facilitate proteomic profiling  
The objectives of biomarker analyses applied to pre-treatment (TURBT), on-treatment and 
end-of-treatment tumor biospecimen are to evaluate candidate predictive biomarkers that 
may be proven useful in identifying participants who may preferentially benefit from the 
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study treatments and to evaluate mechanisms of action and/or resistance for each of the 
combinations being assessed. 
As of 12 September 2022, no biomarker samples will be collected from participants enrolled 
in Cohorts B1 and B2.
8.8.1. Tumor Tissue Assessments 
Tumor biospecimens representing tissue samples from tumor resection or biopsy will be used 
to analyze candidate DNA, RNA, or protein markers, or relevant signature of markers for 
their ability to identify those participants who are most likely to benefit from treatment with 
the study drugs.
Participants must provide formalin-fixed paraffin-embedded (FFPE) tissue from the TURBT 
supporting the primary diagnosis for the study and taken within 12 weeks prior to 
randomization. An FFPE tumor tissue block is requested for all subjects, however, if an 
FFPE tissue block cannot be provided to due to local, regional or institutional policies, 15 
unstained slides (10 minimum) containing recently cut, 5µm sections on positively charged 
slides will be acceptable.  This sample will also be used to reconfirm the diagnosis.
Independent pathology reviewers will provide central assessment of biopsies supporting the 
primary diagnosis for the study prior to registration in Cohort B1, and retrospective central 
assessment of all biopsies for participants in Cohorts A and B1.  Refer to the laboratory 
manual for process details on sending the slides for the BICR assessment.
Samples collected during biopsy procedures performed throughout the study (as clinically 
indicated) should adhere to the same requirements/procedures as the archival samples.
8.8.2. Other Biomarker Assessments
8.8.2.1. Cluster of Differentiation 8 Immunohistochemistry (CD8 IHC)
Immunohistochemistry for CD8 will be performed to quantify the number/proportion of 
CD8+ T lymphocytes infiltrating each participant’s tumor sample. 
8.8.2.2. Circulating Free DNA (cfDNA)
cfDNA in double spun plasma samples previously noted in Section 8.6 may be used to 
quantify/examine cfDNA in pre and post-treatment blood samples.
8.8.3. Immunogenicity Assessments: Analysis of Anti-PF-06801591 Antibodies (ADA) 
and Neutralizing Anti-PF-06801591 Antibodies (NAb)
Blood samples to provide serum for detection of ADA and NAb against PF-06801591 will be 
collected into appropriately labeled tubes at times specified in the SoA for Arms A and B 
only in Cohort A.  As of 12 September 2022, no immunogenicity samples will be collected 
for ADA and NAb analyses from participants enrolled in Cohorts B1 and B2.  Additional 
instructions for sample collection, processing, storage, and shipping will be provided in the 
lab manual. On PF-06801591 dosing days when immunogenicity is assessed, the blood 
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samples for ADA analysis should be taken prior to PF-06801591 administration, preferably 
at the same time as the companion blood sample for the determination of PF-06801591 
concentration, which will be collected in conjunction with the ADA/NAb sample collection 
to facilitate immunogenicity assessment. The actual date and time (24-hour clock time) of 
each sample will be recorded.
The ADA/NAb 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 for ADA.  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. Genetic analyses will not be performed on these blood 
samples. Participant confidentiality will be maintained. Samples collected for this purpose 
will be retained in accordance with local regulations and, if not used within this timeframe, 
will be destroyed.
8.8.4. Specified Gene Expression (RNA) Research
An FFPE tissue sample for RNA isolation will be collected as noted previously in 
Section 8.8.1.  The samples will be analyzed by RNA seq. transcriptome profiling to identify 
signatures associated with response, resistance and adverse events in response to treatment.
Although it is anticipated that most samples will be consumed by planned analyses during the 
course of the study, any unused samples may be stored at a facility selected by the sponsor 
indefinitely or for a maximum of 10 years (or according to local regulations) following the 
last participant’s last visit for the study. 
8.8.5. Specified Protein Research 
Approximately 5 mL serum sample for protein analyses will be collected.  The sample(s) 
may be analyzed for proteomic signatures associated with response or resistance to therapy in
pre-treatment and on-treatment samples.
Details on processes for collection and shipment of these sample(s) can be found in the 
laboratory manual.
Although it is anticipated that most samples will be consumed by planned analyses during the 
course of the study, any unused samples may be stored at a facility selected by the sponsor 
indefinitely or for a maximum of 10 years (or according to local regulations) following the 
last participant’s last visit for the study.
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8.9. Health Economics
Medical resource utilization data, associated with medical encounters, will be collected in the 
eCRF by the investigator and study-site personnel for all participants throughout the study. 
Protocol-mandated procedures, tests, and encounters are excluded.
9. STATISTICAL CONSIDERATIONS
9.1. Estimands and Statistical Hypotheses
9.1.1. Estimands
Estimands are defined below for the primary and key secondary endpoints.
Table 2 defines the possible clinical outcomes for the EFS evaluation. The clinical definitions 
of recurrence of high-grade disease, progressive disease, persistence of CIS, recurrence of 
low-grade disease and CR are included in Section 10.9. For Cohort A, in participants with 
CIS at randomization “persistence of CIS” is defined as persistence of CIS after induction or, 
if re-induction is administered, after re-induction. Persistence of CIS after induction with CR 
after re-induction is not considered persistence of CIS. For Cohort B1 persistence of CIS is 
defined as persistence of CIS at the 12 week or 24 week disease assessment. Persistence of 
CIS at the 12 week disease assessment followed by CR at the 24 week disease assessment is 
not considered persistence of CIS.   The censoring and event date options to be considered 
for the EFS analyses are presented in Table 3.
9.1.1.1. Cohort A
Primary Estimand (EFS for Arm A vs Arm C) and Key Secondary Estimand (EFS for Arm B 
vs Arm C): treatment effect, estimated based on data from all randomized participants, of 
each experimental arm (Arm A and Arm B) on EFS compared to Arm C from randomization 
to the earliest of recurrence of high-grade disease, progression of disease, persistence of CIS, 
or death, regardless of tolerability, duration of study treatment or initiation of subsequent 
anti-cancer therapy. The date of the event (event as defined in Table 2) is the date of disease 
assessment documenting recurrence of high-grade disease, progression of disease,
persistence of CIS (applicable only to participants with CIS at randomization), or death, 
whichever occurs earlier. The date of persistence of CIS is the earliest date when persistence 
of CIS is observed, if CR is not observed after re-induction.

Variable: EFS defined as the time from randomization until recurrence of high-grade 
disease, progression of disease, persistence of CIS, or death due to any cause, whichever 
occurs first.

Censoring: See Table 3

Population-level summary measure: hazard ratio for EFS including all randomized 
participants. 
Supportive Estimand 1 (EFS): treatment effect, estimated based on data from all randomized 
participants, of each experimental arm (Arm A and Arm B) on EFS compared to Arm C from 
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randomization to the earliest of recurrence of high-grade disease, progression of disease, 
persistence of CIS, or death, regardless of tolerability, duration of study treatment or 
initiation of subsequent anti-cancer therapy. The date of the event (event as defined in 
Table 2) is the date of disease assessment documenting recurrence of high-grade disease, 
progression of disease, date of randomization for participants with persistent CIS (applicable 
only to participants with CIS at randomization), or death, whichever occurs earlier.

Variable: EFS defined as the time from randomization until recurrence of high-grade
disease, progression of disease, persistence of CIS, or death due to any cause, whichever 
occurs first.

Censoring: see Table 3

Population-level summary measure: hazard ratio for EFS including all randomized 
participants. 
Supportive Estimand 2 (EFS): treatment effect of each experimental arm (Arm A and Arm B) 
on EFS compared to Arm C from randomization to the earliest of recurrence of high-grade 
disease, progression of disease, persistence of CIS, or death, regardless of tolerability, 
duration of study treatment, or initiation of subsequent anti-cancer therapy; data from 
randomized participants who do not meet per-protocol criteria as defined below are excluded. 
The date of the event (event as defined in Table 2) is the date of disease assessment 
documenting recurrence of high-grade disease, progression of disease, persistence of CIS 
(applicable only to participants with CIS at randomization), or death, whichever occurs 
earlier. The date of persistence of CIS is the earliest date when persistence of CIS is 
observed, if CR is not observed after re-induction.

Variable: EFS defined as the time from randomization until recurrence of high-grade 
disease, progression of disease, persistence of CIS, or death due to any cause, whichever 
occurs first.

Censoring: see Table 3

Population-level summary measure: hazard ratio for EFS excluding randomized 
participants who did not receive at least one dose of study drug, did not meet inclusion 
criteria 2 or 3, or met exclusion criteria 1 or 2.
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Table 2.
Possible Clinical Outcomes for Participants with or without CIS at 
Randomization and EFS Evaluation
Population
Disease Assessment
EFS Event 
Y/N
Participants with CIS at 
randomization
Progressive disease [a] before achieving a CR for 
participants with CIS only at randomization
Y
Progressive disease after achieving a CR
Y
Recurrence of high-grade disease before achieving a CR 
for participants with CIS and concurrent papillary 
disease at randomization.
Y
Recurrence of high-grade disease after achieving a CR
Y
Persistence of CIS (non-CR) [b]
Y
Recurrence of low-grade disease 
N
Participants without CIS at 
randomization
Progressive disease
Y
Recurrence of high-grade disease
Y
Recurrence of low-grade disease 
N
[a] Including appearance of new high-grade Ta or T1 disease for participants with CIS only at randomization.
[b] Persistence of CIS after induction, with CR after re-induction is not considered an event.
Table 3.
Outcome and Event Dates for EFS 
Scenario
Date of event/censoring
Outcome
No adequate baseline assessment
Date of randomization [a]
Censored [a]
Event
- After at most one missing or inadequate 
post-baseline disease assessment, OR
- ≤ 24 weeks after the date of 
randomization
Date of event
Event
Event
- After 2 or more missing or inadequate 
post-baseline disease assessments
Date of last adequate disease assessment 
[b] documenting no event
Censored
No event
Date of last adequate disease assessment 
[b] documenting no event
Censored
[a] However, if the participant dies ≤24 weeks after the date of randomization the death is an event with date on death 
date
[b] An adequate post-baseline disease assessment is defined as an assessment with progression of disease (all 
participants), recurrence of high-grade disease (all participants), recurrence of low-grade disease (all participants), CR 
(participants with CIS at randomization), persistence of CIS disease (participants with CIS at randomization), or no 
evidence of disease (participants with papillary disease and no CIS at randomization).
Key Secondary Estimand (OS): treatment effect, estimated based on data from all 
randomized participants, of each experimental arm (Arm A and Arm B) on OS compared to 
Arm C regardless of tolerability, duration of study treatment, initiation of subsequent anti-
cancer therapy or participant’s request to discontinue study procedures. 

Variable: OS.
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
Censoring: data for participants not known to have died are censored at the time of last 
contact. 

Population-level summary measure: hazard ratio for OS, including all randomized 
participants.
9.1.1.2. Cohorts B1 and B2
Due to the decision to close enrollment in Cohorts B1 and B2, the Cohort B1 and B2 
estimands are no longer required.
9.2. Sample Size Determination
9.2.1. Cohort A
Approximately 999 participants (including a minimum of 250 participants with CIS) will be 
randomized in a 1:1:1 ratio to 1 of the 3 treatment arms (A, B, or C) with approximately 333 
participants randomized to each treatment arm. Participants were stratified by the presence of 
CIS (yes vs no) and geography (US vs Western Europe and Canada vs ROW).
The primary objective is to demonstrate that PF-06801591 given in combination with BCG 
(maintenance and induction) is superior to BCG alone (induction and maintenance) in 
prolonging EFS in participants with high-risk NMIBC. 
The key secondary objectives are: 
1)
To demonstrate that PF-06801591 given in combination with BCG (induction only) 
is superior to BCG alone (induction and maintenance) in prolonging EFS in 
participants with high-risk NMIBC.
2) To demonstrate that PF-06801591 + BCG (induction and maintenance) is superior to 
BCG (induction and maintenance) in prolonging OS in participants with high-risk 
NMIBC, and 
3) To demonstrate that PF-06801591 + BCG (induction) is superior to BCG (induction 
and maintenance) in prolonging OS in participants with high-risk NMIBC.
The primary objective will be tested at a significance level of 0.025 (1-sided) associated with 
hypothesis H01 described below:  
H01: HREFS(AvsC) ≥1 vs. H11: HREFS(AvsC) <1
where HREFS(AvsC) is the hazard ratio for EFS for Arm A vs Arm C.
In addition, the following statistical hypotheses will be tested to address the key secondary 
objectives:
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            H02: HREFS(BvsC) ≥1 vs. H12: HREFS(BvsC) <1
            H03: HROS(AvsC) ≥1 vs. H13: HROS(AvsC) <1
H04: HROS(BvsC) ≥1 vs. H14: HROS(BvsC) <1
where HREFS(BvsC) is the hazard ratio for EFS for Arm B vs Arm C, HROS(AvsC) is the hazard 
ratio for OS for Arm A vs Arm C, and HROS(BvsC) is the hazard ratio for OS for Arm B vs 
Arm C.
A graphical approach with group sequential testing outlined in Bretz et al. (2009) 31 will be 
used to strongly control the family-wise type I error rate at a 1-sided 0.025 level as shown in 
Figure 5 The initial 1-sided alpha allocated to H01 is 0.025. If H01 is statistically significant, 
H02 and H03 will be formally tested at initial 1-sided alpha of 0.023 and 0.002, respectively. If 
H02 is statistically significant, alpha recycling will be applied to evaluate H03 at 1-sided 0.025 
level. If H03 is statistically significant, all the alpha will be recycled to formally test H04.  
Based on protocol amendment 5, the IA2 will be removed, and the FA for EFS based on a 
calendar-based data cut-off date will be conducted. Randomization to Cohort A was 
completed on 16 November 2021 and the EFS FA data cut-off date will be set to allow for 
approximately 3 years of follow-up after last randomized participant.  The treatment period 
was completed on 16 November 2023.  Based on the blinded observed EFS events accrual 
rate and assuming equal event rate across three arms, approximately 261 EFS events are 
expected to have occurred across all three arms by (approximately 174 events for each two-
arm comparison) by the EFS FA data cut-off date.
For the primary endpoint, if the true HR is 0.69, 174 EFS events in Arm A and Arm C 
combined will provide 68.7% power to detect a difference using a 1-sided log-rank test at a 
significance level of 0.025. 
One interim and one final efficacy analyses are planned for OS endpoints.  A 2-look group 
sequential design with Haybittle-Peto α spending function will be used to determine the 
efficacy boundary.  The IA for OS will be performed at the time of the final analysis for EFS.  
The FA for OS will be performed at the end of the study, which is approximately 5 years 
after the last participant has been randomized in Cohort A.
Cohort A will be considered positive if the primary objective is met.
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Figure 5.
Testing Strategy
9.2.2. Cohorts B1 and B2
Approximately 110 participants with BCG-unresponsive CIS will be enrolled in Cohort B1; 
this takes into account 10% of participants not meeting eligibility criteria. This sample size 
will allow for a 95% CI width for the CR rate to not exceed 0.21. The CR rate will be 
estimated in BCG-unresponsive CIS participants treated with PF-06801591.
Table 4 provides exact 95% CIs for CR rate based on different possible observed responses 
in the BCG unresponsive CIS Cohort (Cohort B1).
Table 4.
Sample Size and Exact 95% CIs for CR Rate – BCG Unresponsive CIS 
Cohort B1
Number of 
participants 
Number of 
observed CRs
Observed CR 
rate
95% CI for True CR Rate
100
20
20%
(12.67%, 29.18%)
25
25%
(16.88%, 34.66%)
30
30%
(21.24%, 39.98%)
35
35%
(25.73%, 45.18%)
40
40%
(30.33%, 50.28%)
45
45%
(35.03%, 55.27%)
H02: Arm B vs C: EFS
α2=0.023
H01: Arm A vs C: EFS 
α1=0.025
H03: Arm A vs C: OS
α3=0.002 if H01 is rejected but H02is not
α3=0.025 if H01 and H02 are rejected
H04: Arm B vs C: OS
α4= α3
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Table 4.
Sample Size and Exact 95% CIs for CR Rate – BCG Unresponsive CIS 
Cohort B1
Number of 
participants 
Number of 
observed CRs
Observed CR 
rate
95% CI for True CR Rate
50
50%
(39.83%, 60.17%)
55
55%
(44.73%, 64.97%)
60
60%
(49.72%, 69.67%)
In addition, approximately 50 participants with BCG-unresponsive recurrent high-grade 
Ta/T1 disease will be enrolled in Cohort B2 to further assess safety and efficacy of PF-
06801591. The sample size is based on logistic feasibility and not driven by statistical 
considerations.
As of 31 August 2022, enrollment in Cohorts B1 and B2 was closed by the sponsor for 
business strategy reasons so the planned sample sizes will not be reached in these Cohorts.  
9.3. Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled 
All participants who sign the ICD
Full Analysis Set (Cohort A) -
Randomly Assigned to Study 
treatment
All participants who are randomized. Participants will be classified 
according to the study treatment assigned at randomization.
Full Analysis Set (Cohort B1)
All participants who receive at least 1 dose of study drug and are BCG 
unresponsive with CIS. 
Full Analysis Set (Cohort B2)
All participants who receive at least 1 dose of study drug and are BCG 
unresponsive with papillary disease only. 
Per Protocol
Participants randomized excluding those who did not receive at least 1 
dose of study drug, did not meet inclusion criteria 2 or 3, or met exclusion 
criteria 1 or 2.
Safety
All participants who receive at least 1 dose of study drug. For Cohort A, 
participants will be classified according to the study treatment assigned at 
randomization unless the incorrect treatment(s) was/were received 
throughout the dosing period in which case participants will be classified 
according to the first study treatment received. 
Biomarker
The biomarker populations are a subset of the safety population and will 
include participants with at least 1 of the PD or biomarkers evaluated at 
pre and/or post dose.
Immunogenicity
Immunogenicity population is a subset of the safety population and will 
include participants who have at least 1 ADA/NAb sample collected for 
PF-06801591.
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Population
Description
PK
The PK concentration analysis population is a subset of the safety 
population and will include participants who have at least 1 post-1st dose 
concentration measurement above the lower limit of quantitation (LLQ) 
for PF-06801591. 
The PK parameter population is the same as the PK concentration analysis 
population.
9.4. Statistical Analyses
The SAP will be developed and finalized before database lock and will describe the 
participant populations to be included in the analyses, and procedures for accounting for 
missing, unused, and spurious data. This section is a summary of the planned statistical 
analyses of the primary and secondary endpoints.
9.4.1. Efficacy Analyses
9.4.1.1. Cohort A
Endpoint
Statistical Analysis Methods
Primary endpoint of 
EFS for Arm A vs 
Arm C and key 
secondary endpoint 
of EFS for Arm B vs 
Arm C: defined as 
time from 
randomization to the 
time of recurrence of 
high-grade disease, 
progression of 
disease in high risk 
NMIBC, or death 
due to any cause as 
assessed by the 
investigator.
For the primary analysis of EFS, all data from randomized participants will be 
included. The treatment effect will be estimated using a Cox’s Proportional Hazard 
model stratified by randomization strata to calculate the hazard ratio along with 95% 
CI for EFS between each experimental arm and Arm C *.
For the supportive analysis 2 of EFS, data from randomized participants who did not 
meet the per-protocol population criteria will be excluded.  The treatment effect will 
be estimated using a Cox’s Proportional Hazard model stratified by randomization 
strata to calculate the hazard ratio along with 95% CI for EFS between each 
experimental arm and Arm C *. 
For the primary analysis of EFS and supportive analysis 2 of EFS, the date of the 
event (event as defined in Table 2) is the date of disease assessment documenting 
recurrence of high-grade disease, progression of disease, persistence of CIS 
(applicable only to participants with CIS at randomization) or death, whichever 
occurs earlier.  For the supportive analysis 1 of EFS, the date of the event (event as 
defined in Table 2) is the date of disease assessment documenting recurrence of high-
grade disease, progression of disease, date of randomization for participants with 
persistence of CIS (applicable only to participants with CIS at randomization), or 
death, whichever occurs earlier.  EFS data will be censored as outlined in Table 3.
A stratified log-rank test (one-sided) stratified by randomization stratification factors 
will be used at the significance level associated with the testing strategy outlined in 
Section 9.2.
Kaplan-Meier estimates (product-limit estimates) will be presented by treatment arm 
together with a summary of associated statistics including the median EFS time with 
2-sided 95% CIs.  EFS rates at different time points will be estimated with 
corresponding 2-sided 95% CIs.  The CIs for the median will be calculated according 
to Brookmeyer and Crowley (1982) and the CIs for the survival function estimates at 
the time points will be derived using the log-log transformation according to 
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Kalbfleisch and Prentice (2002) (with back transformation to a CI on the 
untransformed scale).50,51  The estimate of the standard error will be computed using 
Greenwood’s formula.
An additional analysis for EFS, using the same methodology as the primary estimand 
and key secondary estimand, will be performed based on BICR results.
Key Secondary:  OS
The treatment effect for OS will be estimated using a Cox’s Proportional Hazard 
model stratified by randomization strata to calculate the hazard ratio for OS between 
each experimental arm and Arm C, including all randomized participants. Data for 
participants not known to have died are censored at the time of last contact. 
A stratified log-rank test (one-sided) stratified by randomization stratification factors 
will be used at the interim and/or final analyses at the significance level associated 
with the testing strategy outlined in Section 9.2.
OS will be analyzed using Kaplan-Meier methods. In order to account for the group 
sequential design in Cohort A, the repeated CI (RCI) method (Jennison and Turnbull, 
2000),49 will be used to construct the 2-sided RCIs for the hazard ratio at the interim 
and the final analyses of OS.
In addition, the unadjusted 95% CIs for the hazard ratio will also be reported at the 
interim and the final analyses for OS.
Kaplan-Meier estimates (product-limit estimates) will be presented by treatment arm
together with a summary of associated statistics including the median OS time with 
2-sided 95% CIs. OS rates at different time points will be estimated with 
corresponding 2-sided 95% CIs. The CIs for the median will be calculated according 
to Brookmeyer and Crowley (1982) and the CIs for the survival function estimates at 
the time points will be derived using the log-log transformation according to 
Kalbfleisch and Prentice (2002) (with back transformation to a CI on the 
untransformed scale).50,51   The estimate of the standard error will be computed using 
Greenwood’s formula.
Secondary: DSS, 
defined as the time 
from randomization 
to death resulting 
from bladder cancer, 
as assessed by the 
investigator.
The treatment effect will be estimated using a Cox’s Proportional Hazard model 
stratified by randomization strata to calculate the hazard ratio for DSS between each 
experimental arm and Arm C.
Kaplan-Meier estimates (product-limit estimates) will be presented by treatment arm 
together with a summary of associated statistics including the median DSS time with 
2-sided 95% CIs.  DSS rates at various time points will be estimated with 
corresponding 2-sided 95% CIs.  The CIs for the median will be calculated according 
to Brookmeyer and Crowley (1982) and the CIs for the survival function estimates at 
the time points will be derived using the log-log transformation according to 
Kalbfleisch and Prentice (2002) (with back transformation to a CI on the 
untransformed scale). 50,51  The estimate of the standard error will be computed using 
Greenwood’s formula. 
Secondary: CR as 
assessed by 
investigator, defined 
as histologic 
Complete response rate for participants with CIS at randomization will be calculated 
along with the 2-sided 95% CI using the Clopper-Pearson method for each treatment 
arm. Participants with inadequate data for disease assessment (eg, no follow-up 
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disappearance of 
malignancy on 
bladder biopsy with 
negative cytology 
and cystoscopy or 
negative cytology 
and positive 
cystoscopy with 
biopsy-proven low-
grade Ta lesion or 
non-malignant tissue 
for participants with  
CIS at 
randomization
assessments) will be considered as non-responders in the assessment of complete 
response. 
The difference in CR rates between each experimental arm (Arm A and Arm B) and 
the control arm (Arm C) will be tested with a 2-sided p-value using a stratified 
analysis stratified by the randomization stratum of geographic region.
An additional analysis for CR rate, using the same methodology as above, will be 
performed based on BICR results.  
Secondary: Duration 
of CR as assessed by 
investigator,
defined as the time 
from the first 
documentation of 
complete response to 
the date of an EFS 
event for 
participants with CR 
and with CIS at 
randomization.  
Duration of CR will be summarized by treatment arm using Kaplan-Meier methods
and displayed graphically, where appropriate.  The median duration of CR and 95% 
CI for the median will be provided for each treatment arm, as well as duration of CR 
rates at different time points. The CIs for the median will be calculated according to 
Brookmeyer and Crowley (1982) and the CIs for the survival function estimates at 
the time points will be derived using the log-log transformation according to 
Kalbfleisch and Prentice (2002) with back transformation to a CI on the 
untransformed scale. 50,51 The estimate of the standard error will be computed using 
Greenwood’s formula.
Duration of CR will be censored as defined for the primary analysis of EFS except 
for censoring due to no baseline assessment which is not applicable for participants 
with CR.
An additional analysis of duration of CR, using the same methodology as above, will 
be performed based on BICR results.  
Secondary:
Time to recurrence 
of low-grade disease 
as assessed by 
investigator, defined 
as the time from 
randomization to the 
date of first 
documentation of 
recurrence of low-
grade disease or 
death due to any 
cause.  
The treatment effect will be estimated using a Cox’s Proportional Hazard model 
stratified by randomization strata to calculate the hazard ratio for time to recurrence 
of low-grade disease between each experimental arm and Arm C.
Time to recurrence of low-grade disease will be analyzed using Kaplan-Meier 
methods. Kaplan-Meier estimates (product-limit estimates) will be presented by 
treatment arm together with a summary of associated statistics including the median 
time to recurrence of low-grade disease with 2-sided 95% CIs.  Time to recurrence of 
low-grade disease rates at various time points will be estimated with corresponding 
2-sided 95% CIs.  The CIs for the median will be calculated according to 
Brookmeyer and Crowley (1982) and the CIs for the survival function estimates at 
the time points will be derived using the log-log transformation according to 
Kalbfleisch and Prentice (2002) (with back transformation to a CI on the 
untransformed scale). 50,51  The estimate of the standard error will be computed using 
Greenwood’s formula.
Time to recurrence of low-grade disease will be censored as defined in Table 3 for 
the primary analysis of EFS but with event being recurrence of low-grade disease or 
death due to any cause.
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Secondary: Time to 
cystectomy, defined 
as time from 
randomization to 
cystectomy.
The treatment effect will be estimated using a Cox’s Proportional Hazard model 
stratified by randomization strata to calculate the hazard ratio for time to cystectomy 
between each experimental arm and Arm C.
Time to cystectomy will be analyzed using Kaplan-Meier methods. Kaplan-Meier 
estimates (product-limit estimates) and corresponding 2-sided 95% CIs will be 
presented. Participants without cystectomy will be censored at date last known not to 
have a cystectomy.
* If there are large deviations from the proportional hazards assumption, the clinical meaning of the hazard ratio becomes 
difficult, if not impossible, to interpret. In such situations the Restricted Mean Survival Time (RMST) methodology 
[Royston and Parmar, 2011; Uno, Wei, et al., 2014; Zhang, 2013]  can be more meaningfully used than the Cox 
proportional hazards model to derive an estimate of relative treatment effect.
9.4.1.2. Cohorts B1 and B2
Due to the decision to close enrollment in Cohorts B1 and B2, the Cohort B1 and B2 study 
objectives are no longer required.
9.4.2. Safety Analyses
All safety analyses will be performed on the Safety Population.
Endpoint
Statistical Analysis Methods
Secondary
Simple summary statistics (descriptive) will be presented for participants with SAEs, 
AEs of special interest, laboratory test abnormalities and other secondary safety 
endpoints during the on-treatment period (defined as the time from the first dose of study 
treatment through minimum (30 days + last dose of study treatment, start day of new 
anti-cancer drug therapy – 1 day) unless otherwise described in the Statistical Analysis 
plan (SAP).
9.4.3. Other Analyses 
Descriptive statistics will be used to summarize all participant characteristics, treatment 
administration/compliance, safety parameters, and biomarkers. Data will also be displayed 
graphically, where appropriate. PK, pharmacodynamic (PD), immunogenicity, PRO, and 
biomarker exploratory analyses will be described in the statistical analysis plan finalized 
before database lock. 
9.4.3.1. Patient Reported Outcomes
The EORTC QLQ-C30 & NMIBC24, and EQ-5D-5L will be scored according to their 
respective user guides. 
For the EORTC QLQ-C30 & NMIBC24 and EQ-5D-5L, missing items will be handled per 
the respective scoring manuals of each questionnaire. For the PGIS, PGIC, PTAB, and TSQ, 
there will be no adjustments for missing data.
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Summary statistics [mean (and SD), median, range and 95% CI] of absolute scores will be 
reported for all of the subscales of the EORTC QLQ-C30 & NMIBC24, PTAB, and the EQ-
5D-5L. The mean change of absolute scores from baseline (and 95% CI) will also be 
assessed. Longitudinal mixed effect-model analyses will be used to assess change from 
baseline in the EORTC QLQ-C30 & NMIBC24 domains and EQ-5D-5L between the 3 
treatment arms in Cohort A. Additional exploratory analyses may be performed, such as 
analyses of time to deterioration or improvement, if warranted.
9.4.3.2. Pharmacokinetics
The pre-dose (Ctrough) 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) for each arm of Cohort A and pooled across both 
arms of Cohort A.  The summary will be presented by cycle and study day.
9.4.3.3. Immunogenicity 
ADA/ NAb data for PF-06801591 will be summarized for each arm of Cohort A and pooled  
across Cohort A. 
9.4.3.4. 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.
9.4.3.5. Biomarkers
In Cohort A, biomarker data will be assessed separately for tumor tissue and peripheral 
blood. Summary statistics for levels of PD-L1 expression, and number and percentage of 
participants with tumors categorized with baseline PD-L1 expression level (high vs low) will 
be presented by arm for Cohort A and overall. For exploratory biomarkers, summary 
statistics for pre-treatment biomarkers will be presented and summary statistics for on-
treatment biomarkers will additionally include the ratio to baseline for continuous 
biomarkers, and a contingency table for non-continuous biomarkers, as appropriate.
9.5. Interim Analyses (Cohort A only)
Prior to protocol amendment 5, an interim futility analysis of EFS was conducted after 620 
participants were randomized to Cohort A, with a total of 25 EFS events for all 3 arms 
combined.  The goal of this futility analysis was to assess if enrollment in an experimental 
arm should be stopped for futility.  
Any safety evaluation performed at the time of the IA for EFS was based on the safety 
analysis set.
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Access to the IA results for the futility analysis of EFS was limited to the EDMC 
(Section 9.5.1) and independent reporting team.
The Statistical Analysis Plan will describe the planned interim analyses in greater detail.
9.5.1. External Data Monitoring Committee (EDMC)
This study will use an external data monitoring committee (EDMC) to review cumulative 
safety data during the study conduct, as well as review the IA results for the futility analysis 
of EFS. In order to confirm that the safety profile of PF-06801591 plus BCG regimen 
remains aligned with that expected from each agent separately, a review of safety data will be 
performed by the EDMC approximately 6 weeks after 20 participants in each of the 3 arms 
have been randomized and received at least 1 dose of study treatments. The EDMC will 
convene to monitor safety in the study (Cohort A only) approximately every 6 months 
thereafter until the final analysis of EFS is conducted. The EDMC charter describes the role 
of the EDMC and data reviews in more detail.  
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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1. Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with the following:
o
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines
o
Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines
o
Applicable laws and regulations, including applicable privacy laws.

The protocol, protocol amendments, ICD, SRSD(s), and other relevant documents 
(eg, advertisements) must be reviewed and approved by the sponsor and submitted to 
an IRB/IEC by the investigator and reviewed and approved by the IRB/IEC before 
the study is initiated.

Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study participants.

Protocols and any substantial amendments to the protocol will require health 
authority approval prior to initiation except for changes necessary to eliminate an 
immediate hazard to study participants.

The investigator will be responsible for the following:
o
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC
o
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures
o
Providing oversight of the conduct of the study at the site and adherence to 
requirements of Code of Federal Regulations, Title 21 (21CFR), ICH GCP 
guidelines, the IRB/IEC, European regulation 536/2014 for clinical studies (if 
applicable), European Medical Device Regulation 2017/745 for clinical device 
research, and all other applicable local regulations
10.1.1.1. 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 regulatory authority in any area of the world, or if the investigator is aware 
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of any new information that might influence the evaluation of the benefits and risks of 
the study intervention, 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 participants against any 
immediate hazard, and of any serious breaches of this protocol or of ICH GCP that 
the investigator becomes aware of.
10.1.2. Financial Disclosure
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
10.1.3. Informed Consent Process

The investigator or his/her representative will explain the nature of the study, 
including the risks and benefits, to the participant or his/her legally authorized 
representative and answer all questions regarding the study. The participant or their 
legally authorized representative should be given sufficient time and opportunity to 
ask questions and to decide whether or not to participate in the trial.

Participants must be informed that their participation is voluntary. Participants or 
their legally authorized representative will be required to sign a statement of informed 
consent that meets the requirements of 21 CFR 50, local regulations, ICH GCP 
guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center.

The investigator must ensure that each study participant or his or her legally 
authorized representative is fully informed about the nature and objectives of the 
study, the sharing of data related to the study and possible risks associated with 
participation, including the risks associated with the processing of the participant’s 
personal data. The participant must be informed that his/her personal study-related 
data will be used by the sponsor in accordance with local data protection law. The 
level of disclosure must also be explained to the participant.

The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities.

The investigator further must ensure that each study participant or his or her legally 
authorized representative is fully informed about his or her right to access and correct 
his or her personal data and to withdraw consent for the processing of his or her 
personal data.
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
The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICD.

Participants must be re-consented to the most current version of the IRB/EC-
approved ICD(s) during their participation in the study as required per local 
regulations.

A copy of the ICD(s) must be provided to the participant or the participant’s legally 
authorized representative.
Participants who are rescreened are required to sign a new ICD. 
The ICD will contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research. The investigator or authorized designee will 
explain to each participant the objectives of the exploratory research. Participants will be told 
that they are free to refuse to participate and may withdraw their consent at any time and for 
any reason during the storage period. A separate signature will be required to document a 
participant’s agreement to allow any remaining specimens to be used for exploratory 
research. Participants who decline to participate in this optional research will not provide this 
separate signature.
10.1.4. Data Protection

All parties will comply with all applicable laws, including laws regarding the 
implementation of organizational and technical measures to ensure protection of 
participant data.

Participants’ personal data will be stored at the study site in encrypted electronic form 
and will be password protected to ensure that only authorized study staff have access.  
The study site will implement appropriate technical and organizational measures to 
ensure that the personal data can be recovered in the event of disaster.  In the event of 
a potential personal data breach, the study site shall be responsible for determining 
whether a personal data breach has in fact occurred and, if so, providing breach 
notifications as required by law.

To protect the rights and freedoms of natural persons with regard to the processing of 
personal data, participants will be assigned a single, participant-specific numerical 
code. Any participant records or datasets that are transferred to the sponsor will 
contain the numerical code; participant names will not be transferred. All other 
identifiable data transferred to the sponsor will be identified by this single, 
participant-specific code. The study site will maintain a confidential list of 
participants who participated in the study, linking each participant’s numerical code 
to his or her actual identity. In case of data transfer, the sponsor will protect the 
confidentiality of participants’ personal data consistent with the Clinical Study 
Agreement and applicable privacy laws.
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
Information technology systems used to collect, process, and store study-related data 
are secured by technical and organizational security measures designed to protect 
such data against accidental or unlawful loss, alteration, or unauthorized disclosure or 
access. 

The sponsor maintains SOPs on how to respond in the event of unauthorized access, 
use, or disclosure of sponsor information or systems.
10.1.5. Committees Structure
This study will use an EDMC and a Steering Committee.
The EDMC will be responsible for ongoing monitoring of the safety of participants in the 
study according to the charter. The recommendations made by the EDMC to alter the 
conduct of the study will be forwarded to Pfizer for final decision. Pfizer will forward such 
decisions, which may include summaries of aggregate analyses of endpoint events and of 
safety data that are not endpoints, to regulatory authorities, as appropriate.
The Steering Committee will include leading experts in the field of oncology. The committee 
is a general resource for the latest developments in the use of immunotherapies for patients 
with bladder cancer and will provide advice on several aspects of the protocol including, but 
not limited to, medical questions, responses to regulatory feedback, and protocol amendment 
design, as needed.
10.1.6. Dissemination of Clinical Study Data
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the EudraCT/CTIS, and/or 
www.pfizer.com, and other public registries in accordance with applicable local 
laws/regulations. In addition, Pfizer reports study results outside of the requirements of local 
laws/regulations pursuant to its standard operating procedures (SOPs).
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 
product, regardless of the geographical location in which the study is conducted.   These 
results are submitted for posting in accordance with the format and timelines set forth by US 
law.
EudraCT/CTIS
Pfizer posts European Union (EU) Basic Results on EudraCT/CTIS for all Pfizer-sponsored 
interventional studies that are in scope of EU requirements. 
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www.pfizer.com
Pfizer posts CSR synopses and plain-language study results summaries on www.pfizer.com 
for Pfizer-sponsored interventional studies at the same time the corresponding study results 
are posted to www.clinicaltrials.gov. CSR synopses will have personally identifiable 
information anonymized.
Documents within marketing applications
Pfizer complies with applicable local laws/regulations to publish clinical documents included 
in marketing applications. Clinical documents include summary documents and CSRs 
including the protocol and protocol amendments, sample CRFs, and SAPs. Clinical 
documents will have personally identifiable information anonymized.
Data Sharing
Pfizer provides researchers secure access to participant-level data or full CSRs for the 
purposes of “bona-fide scientific research” that contribute to the scientific understanding of 
the disease, target, or compound class.  Pfizer will make data from these trials available 
18 months after study completion.  Participant-level data will be anonymized in accordance 
with applicable privacy laws and regulations.  CSRs will have personally identifiable 
information redacted.
Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses.  Research teams must include a biostatistician.  Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes.
10.1.7. Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the sponsor or designee electronically (eg, laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the eCRF.

Guidance on completion of CRFs will be provided in the CRF Completion 
Requirements document.

The investigator must ensure that the eCRFs are securely stored at the study site in 
encrypted electronic form and are password protected to prevent access by 
unauthorized third parties.

The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
This verification may also occur after study completion. It is important that the 
investigator(s) and their relevant personnel are available during the monitoring visits 
and possible audits or inspections and that sufficient time is devoted to the process.
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
Monitoring details describing strategy , including definition of study-critical data 
items and processes (eg, risk-based initiatives in operations and quality such as risk 
management and mitigation strategies and analytical risk-based monitoring), 
methods, responsibilities, and requirements, including handling of noncompliance 
issues and monitoring techniques (central, virtual, or on-site monitoring), are 
provided in the data management plan maintained and utilized by the sponsor or 
designee. 

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data.

Records and documents, including signed ICDs, pertaining to the conduct of this 
study must be retained by the investigator for 15 years after study completion unless 
local regulations or institutional policies require a longer retention period. No records 
may be destroyed during the retention period without the written approval of the 
sponsor. No records may be transferred to another location or party without written 
notification to the sponsor. The investigator must ensure that the records continue to 
be stored securely for so long as they are maintained.

When participant data are to be deleted, the investigator will ensure that all copies of 
such data are promptly and irrevocably deleted from all systems.

The investigator(s) will notify sponsor or its agents immediately of any regulatory 
inspection notification in relation to the study.  Furthermore, the investigator will 
cooperate with sponsor or its agents to prepare the investigator site for the inspection 
and will allow sponsor or its agent, whenever feasible, to be present during the 
inspection.  The investigator site and investigator will promptly resolve any 
discrepancies that are identified between the study data and the participant’s medical 
records.  The investigator will promptly provide copies of the inspection findings to 
sponsor or its agent.  Before response submission to the regulatory authorities, the 
investigator will provide sponsor or its agents with an opportunity to review and 
comment on responses to any such findings.
10.1.8. Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available.

Definition of what constitutes source data can be found in the study monitoring plan.
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10.1.9. Use of Medical Records
There may be instances when copies of medical records for certain cases are requested by 
Pfizer Safety, where ethically and scientifically justified and permitted by local regulations, 
to ensure participant safety.
Due to the potential for a participant to be re-identified from their medical records, the 
following actions must be taken when medical records are sent to the sponsor or sponsor 
designee:
•
The investigator or site staff must redact personal information from the medical 
record. The personal information includes, but is not limited to, the following: participant 
names or initials, participant dates (eg, birth date, date of hospital admission/discharge, date 
of death), participant identification numbers (eg, Social Security number, health insurance 
number, medical record number, hospital/institution identifier), participant location 
information (eg, street address, city, country, postal code, IP address), participant contact 
information (eg, telephone/fax number, email address).
•
Each medical record must be transmitted to the sponsor or sponsor designee using 
systems with technical and organizational security measures to ensure the protection of 
personal data (eg, Florence is the preferred system if available). 
•
There may be unplanned situations where the sponsor may request medical records 
(eg, sharing medical records so that the sponsor can provide study-related advice to the 
investigator). The medical records should be submitted according to the procedure described 
above.
10.1.10. Study and Site Closure
The study start date is the date of the first participant’s first visit.
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time upon notification to the contract 
research organization (CRO) if requested to do so by the responsible IRB/IEC or if such 
termination is required to protect the health of Study Participants.
Reasons for the early closure of a study site by the sponsor may include but are not limited 
to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor’s procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator
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
Discontinuation of further study treatment development
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the ECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of 
the reason for termination or suspension, as specified by the applicable regulatory 
requirements.  The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up.
If the sponsor decides to terminate the study for a reason unrelated to the safety of PF-
06801591 or BCG, participants may continue to receive that study intervention(s) per the 
investigator’s judgment and protocol-specified safety assessments will continue to be 
performed for these participants until the end of the study as defined in Section 4.4. 
Nonsafety related study procedures and assessments may be stopped upon written 
notification from the sponsor will be detailed upon notification of decision to terminate the 
study.
Study termination is also provided for in the clinical study agreement.  If there is any conflict 
between the contract and this protocol the contract will control as to termination rights.
10.1.11. Publication Policy

The results of this study may be published or presented at scientific meetings by the 
Investigator after publication of the overall study results or one year after end of the 
study (or study termination), whichever comes first. 

The investigator agrees to refer to the primary publication in any subsequent 
publications such as secondary manuscripts, and to submit all manuscripts or 
abstracts to the sponsor 30 days before submission. This allows the sponsor to protect 
proprietary information and to provide comments and the Investigator will, on 
request, remove any previously undisclosed confidential information before 
disclosure, except for any study- or Pfizer intervention-related information necessary 
to the appropriate scientific presentation or understanding of the study results.

For all publications relating to the study, the Investigator will comply with recognized 
ethical standards concerning publications and authorship, including those established 
by the International Committee of Medical Journal Editors.

The sponsor will comply with the requirements for publication of the overall study 
results covering all Investigator sites. In accordance with standard editorial and 
ethical practice, the sponsor will support publication of multicenter studies only in 
their entirety and not as individual site data. In this case, a coordinating investigator 
will be designated by mutual agreement.

Authorship of publications for the overall study results will be determined by mutual 
agreement and in line with International Committee of Medical Journal Editors 
authorship requirements.
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
If publication is addressed in the clinical study agreement, the publication policy set 
out in this section will not apply.
10.1.12. Sponsor’s Qualified Medical Personnel
The sponsor will designate a medically qualified individual (MQI, also known as the medical 
monitor) to advise the investigator on study-related medical questions. The contact 
information for the study medical monitor is documented in the Study Team Contact List 
located in the Investigator Site File. 
Participants are provided with a Pfizer study information card at the time of informed consent 
which includes contact information for their investigator in case of study-related medical 
questions. The study information card contains, at a minimum, (a) study number, (b) 
participant’s study identification number, and (c) principal investigator contact information.
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10.2. Appendix 2: Clinical Laboratory Tests
Hematology and blood chemistry will be drawn at the time points described in the SoA.  

The tests detailed in Table 5 will be performed by the local laboratory.

Protocol-specific requirements for inclusion or exclusion of participants are detailed 
in Section 5 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.

Pregnancy Testing 

Refer to Section 5.1 Inclusion Criteria for screening pregnancy criteria.

Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at monthly intervals (eg, Day 1 of each cycle) during intervention as 
per SoA. Following a negative pregnancy test result at screening, appropriate 
contraception must be commenced, and a second negative pregnancy test result 
will then be required at the baseline visit on C1D1 before the participant may 
receive the study treatment. Pregnancy tests will also be done whenever 1 
menstrual cycle is missed during the active treatment period (or when potential 
pregnancy is otherwise suspected) and at the end of 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 from participation 
if the serum pregnancy result is positive.

Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at the end of relevant systemic exposure plus an additional 30 days.

At Day 90 and Day 180 after EOT, pregnancy status should be discussed (may 
be done by telephone, unless the participant is visiting the site for other 
reasons) and pregnancy test can be conducted as necessary.

Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the 
absence of pregnancy at any time during the subject’s participation in the 
study.
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Table 5.
Protocol Specified Laboratory Tests
Hematology
Chemistry
Coagulation
Serology
Urinalysisa
Pregnancy 
Test or 
Postmenopaus
al Status
Hematocrit
ALT
INR
HBsAg, 
Urine dipstick for 
urine protein: If 
positive, collect a 
spot urine to 
calculate UPCR 
or collect 24-hr 
and microscopic 
(Reflex Testing).
For female 
participants of 
childbearing 
potential, serum 
or urine test 
(sensitivity 
≥25 mIU/mL);
For female 
postmenopausal 
participants 
under the age of 
60 and not using 
hormonal 
contraception or 
HRT a serum 
FSH test is 
required at 
screening only, 
to confirm 
postmenopausal 
status.
Hemoglobin
AST
PTT or aPTTc
HCV Abd
LDH
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 Bilirubinb
BUN or Urea
Creatinine
Uric Acid
Glucose 
(non-fasted)
Albumin
Phosphorous or 
Phosphate
Lipase
Amylase
Thyroid function 
test + reflex free 
T4 and free T3
ACTH
Cohorts B1 and 
B2 only: 
CK (If total CK ≥ 
3 x ULN, then 
measure 
isoenzymes CK-
MB and CK-
MM)
ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; CK = creatine kinase; 
CK-MB = creatine kinase-muscle type, myocardial band; CK-MM = creatine kinase-skeletal muscle; FSH = follicle 
stimulating hormone; HBsAg = hepatitis B antigen; HCV = hepatitis C virus; INR = international normalized ratio; LDH 
= lactate dehydrogenase; PTT = partial thromboplastin time; aPTT = activated partial thromboplastin time; T3 = 
triiodothyronine; T4 = thyroxine; UPCR = urine protein to creatinine ratio
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. 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) or INR, alkaline 
phosphatase, total bile acids, and acetaminophen drug and/or protein adduct levels.
c. Use either PTT or aPPT consistently at all time points for each participant throughout the course of the study.
d. In the case of apparent ongoing HBV or HCV infection, reflex serum viral load testing will be performed.
Investigators must document their review of each laboratory safety report.
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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting
10.3.1. Definition of AE
AE Definition

An AE is any untoward medical occurrence in a participant or clinical study 
participant, temporally associated with the use of study treatment, whether or not 
considered related to the study treatment.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of study treatment.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements),
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator. Any abnormal laboratory test 
results that meet any of the conditions below must be recorded as an AE:

Is associated with accompanying symptoms.

Requires additional diagnostic testing or medical/surgical intervention.

Leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional concomitant 
drug treatment, or other therapy.

Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdoses should be reported regardless of sequelae.

The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as an AE or SAE if they fulfill the definition of an AE or SAE and meet the 
requirements as per Section 8.3.8.1. Also, “lack of efficacy” or “failure of expected 
pharmacological action” does not constitute an AE or SAE.
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Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.

Worsening of signs and symptoms of the malignancy under study should be 
recorded as AEs in the appropriate section of the eCRF.  Disease progression 
assessed by measurement of malignant lesions on radiographs or other methods 
should not be reported as AEs. 
10.3.2. Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, death 
due to progression of disease).
An SAE is defined as any untoward medical occurrence that, at any dose:
a. Results in death
b.  Is life-threatening
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, that 
hypothetically might have caused death, if it were more severe.
c.  Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.
Hospitalization for elective treatment of a preexisting condition that did not worsen from 
baseline is not considered an AE.
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d.  Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption.
e.  Is a congenital anomaly/birth defect
f.  Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but 
may jeopardize the participant or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These events 
should usually be considered serious.
Examples of such events include invasive or malignant cancers, 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.

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 active collection 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 active collection period, then the event 
leading to death must be recorded as an AE on the eCRF, and as an SAE with 
CTCAE Grade 5 (see the Assessment of Intensity section).

Suspected transmission via a Pfizer product of an infectious agent, pathogenic or 
non-pathogenic, is considered serious.  The event may be suspected from clinical 
symptoms or laboratory findings indicating an infection in a participant exposed to 
a Pfizer product.  The terms “suspected transmission” and “transmission” are 
considered synonymous.  These cases are considered unexpected and handled as 
serious expedited cases by pharmacovigilance personnel.  Such cases are also 
considered for reporting as product defects, if appropriate.
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10.3.3. Recording and Follow-Up of AE and/or SAE
AE and SAE Recording/Reporting
The table below summarizes the requirements for recording adverse events on the eCRF 
and for reporting serious adverse events on the CT SAE Report Form to Pfizer Safety.  
These requirements are delineated for 3 types of events: (1) SAEs; (2) nonserious adverse 
events (AEs); and (3) exposure to the intervention under study during pregnancy or 
breastfeeding, and occupational exposure.  
It should be noted that the CT SAE Report Form for reporting of SAE information is not 
the same as the AE page of the eCRF. When the same data are collected, the forms must 
be completed in a consistent manner.  AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the eCRF and the CT SAE 
Report Form for reporting of SAE information
Safety Event
Recorded on the eCRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
SAE
All
All
Nonserious AE
All
None
Exposure to the 
intervention under study 
during pregnancy or 
breastfeeding, and 
occupational exposure
All AEs/SAEs associated 
with exposure during 
pregnancy or breastfeeding
Occupational exposure is 
not recorded.
All (And EDP 
supplemental form for 
EDP)  
Note:  Include all SAEs 
associated with exposure 
during pregnancy or 
breastfeeding. Include all 
AEs/SAEs associated with 
occupational exposure.

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event.

The investigator will then record all relevant AE/SAE information in the eCRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to Pfizer Safety in lieu of completion of the CT SAE Report 
Form/AE/SAE eCRF page.

There may be instances when copies of medical records for certain cases are 
requested by Pfizer Safety. In this case, all participant identifiers, with the 
exception of the participant number, will be redacted on the copies of the medical 
records before submission to Pfizer Safety.
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
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 
GRADE
Clinical Description of Severity
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
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.

The investigator will also consult the IB and/or Product Information, for marketed 
products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred, and the investigator has 
minimal information to include in the initial report to the sponsor. However, it is very 
important that the investigator always make an assessment of causality for every 
event before the initial transmission of the SAE data to Pfizer Safety.

The investigator may change his/her opinion of causality in light of follow-up 
information and send a SAE follow-up report with the updated causality 
assessment.
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
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.

If the investigator does not know whether or not the study intervention caused the 
event, then the event will be handled as “related to study intervention” for reporting 
purposes, as defined by the sponsor. 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 eCRF, and report such an 
assessment in the dedicated section of the CT SAE Report Form and in accordance 
with the SAE reporting requirements.
Follow-Up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
sponsor to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care providers.

If a participant dies during participation in the study or during a recognized 
follow-up period, the investigator will provide Pfizer Safety with a copy of any 
post-mortem findings including histopathology.

New or updated information will be recorded in the originally completed eCRF.

The investigator will submit any updated SAE data to the Sponsor within 24 hours 
of receipt of the information.
10.3.4. Reporting of SAEs
SAE Reporting to Pfizer Safety via CT SAE Report Form

Facsimile transmission of the CT SAE Report Form is the preferred method to 
transmit this information to Pfizer Safety.

In rare circumstances when the facsimile is not working, notification by telephone 
is acceptable with a copy of the CT SAE Report Form sent by overnight mail or 
courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF Report Form pages within the designated 
reporting time frames.
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10.4. Appendix 4: Contraceptive Guidance
10.4.1. Male Participant Reproductive Inclusion Criteria
Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 6 months after the last dose of study intervention, 
which corresponds to the time needed to eliminate reproductive and BCG transmission 
risks of the study intervention(s).  

Refrain from donating sperm
PLUS either:
Be abstinent from heterosexual or homosexual intercourse as their preferred and usual 
lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent 
OR
Must agree to use contraception/barrier as detailed below

Agree to use a male condom and should also be advised of the benefit for 
a female partner to use a highly effective method of contraception as a 
condom may break or leak when having sexual intercourse with a woman 
of childbearing potential who is not currently pregnant.
10.4.2. Female Participant Reproductive Inclusion Criteria
A female participant is eligible to participate if she is not pregnant or breastfeeding, 
including participants who intend to interrupt breastfeeding, and at least one of the 
following conditions applies:
Is not a woman of childbearing potential (WOCBP) 
OR
Is a WOCBP and using a contraceptive method that is highly effective (with a 
failure rate of <1% per year) preferably with low user dependency, as 
described in the table below during the intervention period and for at least 6  
months after the last dose of study intervention which corresponds to the time 
needed to eliminate any reproductive safety risk of the study intervention; and 
agrees not to donate eggs (ova, oocytes) for the purpose of reproduction 
during this period. As for participants using a highly effective methods that is 
user dependent, this contraception method must be used together with a 
second effective method of contraception, as described below. The 
investigator should evaluate the effectiveness of the contraceptive method in 
relationship to the first dose of study intervention.
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
The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy.
10.4.3. Woman of Childbearing Potential
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study treatment, additional evaluation should be considered.
Women in the following categories are not considered WOCBP
1. Premenopausal female with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than 
the above, (eg, mullerian agenesis, androgen insensitivity), investigator discretion 
should be applied to determining study entry.
Note: Documentation for any of the above conditions can come from the site 
personnel’s review of the participant’s medical records, medical examination, or 
medical history interview. The method of documentation should be recorded in the 
participant’s medical record for the study.
2. Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. In addition, a

high FSH level in the postmenopausal range must be used to confirm a 
postmenopausal state in women under 60 years of age and not using hormonal 
contraception or HRT. 

Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-estrogen hormonal highly effective contraception methods if they 
wish to continue their HRT during the study. Otherwise, they must discontinue 
HRT to allow confirmation of postmenopausal status before study enrollment.
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10.4.4. Contraception Methods     
Contraceptive use by men or women should be consistent with local availability/regulations 
regarding the use of contraceptive methods for those participating in clinical trials. 
CONTRACEPTIVES ALLOWED DURING THE STUDY INCLUDE:
Highly Effective Methods That Have Low User Dependency 

Implantable progestogen-only hormone contraception associated with inhibition of ovulation

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

Bilateral tubal occlusion

Vasectomized partner
o
Vasectomized partner is a highly effective contraceptive method provided that the partner is the 
sole sexual partner of the woman of childbearing potential and the absence of sperm has been 
confirmed. If not, an additional highly effective method of contraception should be used. 
Spermatogenesis cycle is approximately 90 days.
Highly Effective Methods That Are User Dependent

Combined (estrogen and progesterone containing) hormonal contraception associated with inhibition of 
ovulation
o
oral
o
intravaginal
o
transdermal

Progestogen-only hormone contraception associated with inhibition of ovulation 
o
oral
o
injectable

Sexual Abstinence
o
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study intervention. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant.

One of the following effective barrier methods must be used in addition to the highly effective methods 
listed above that are user dependent:
o
Male or female condom with or without spermicide
o
Cervical cap, diaphragm, or sponge with spermicide
o
A combination of male condom with either cervical cap, diaphragm, or sponge with spermicide
(double-barrier methods)
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10.5. Appendix 5: Genetics
Use/Analysis of DNA

Genetic variation may impact a participant’s response to study intervention, 
susceptibility to, and severity and progression of disease. Therefore, where local 
regulations and IRB/IEC allow, a blood sample will be collected for DNA analysis.

Genetic research may consist of the analysis of one or more candidate genes or the 
analysis of genetic markers throughout the genome or analysis of the entire genome 
(as appropriate).

The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to study intervention or study interventions of this class, 
treatments for the disease(s) under study or the disease(s) themselves.

The results of genetic analyses may be reported in the CSR or in a separate study 
summary or may be used for internal decision-making without being included in a 
study report.

The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality.

The samples will be retained as indicated:

Samples for specified genetic analysis (see Section 8.7) will be stored for up to 
15 years or other period as per local requirements or will not be stored beyond the 
completion of this study (eg, Clinical Study Report finalization).

Samples for banking (see Section 8.7.2) will be stored indefinitely or other period 
as per local requirements.  

Participants may withdraw their consent for the storage and/or use of their Banked 
Biospecimens at any time by making a request to the investigator; in this case, any 
remaining material will be destroyed.  Data already generated from the samples will 
be retained to protect the integrity of existing analyses.   

Banked Biospecimens will be labeled with a code.  The key between the code and the 
participant’s personally identifying information (eg, name, address) will be held at the 
study site and will not be provided to the sample bank.  
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10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury, but adapt 
are termed “adaptors.”  In some participants, transaminase elevations are a harbinger of a 
more serious potential outcome.  These participants fail to adapt and therefore are 
"susceptible" to progressive and serious liver injury, commonly referred to as drug-induced 
liver injury (DILI).  Participants who experience a transaminase elevation above 3 times the 
upper limit of normal (× ULN) should be monitored more frequently to determine if they are 
an “adaptor” or are “susceptible.”
In the majority of DILI cases, elevations in aspartate aminotransferase (AST) and/or alanine 
aminotransferase (ALT) precede total bilirubin (TBili) elevations (>2 × ULN) by several 
days or weeks.  The increase in TBili typically occurs while AST/ALT is/are still elevated 
above 3 × ULN (ie, AST/ALT and TBili values will be elevated within the same lab sample).  
In rare instances, by the time TBili elevations are detected, AST/ALT values might have 
decreased.  This occurrence is still regarded as a potential DILI.  Therefore, abnormal 
elevations in either AST OR ALT in addition to TBili that meet the criteria outlined below 
are considered potential DILI (assessed per Hy’s law criteria) cases and should always be 
considered important medical events, even before all other possible causes of liver injury 
have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the 
participant’s individual baseline values and underlying conditions.  Participants who present 
with the following laboratory abnormalities should be evaluated further as potential DILI 
(Hy’s law) cases to definitively determine the etiology of the abnormal laboratory values:

Participants with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili value >2 × ULN 
with no evidence of hemolysis and an alkaline phosphatase value <2 × ULN or not 
available;

For participants with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:
o
Preexisting AST or ALT baseline values above the normal range: AST or ALT values 
>2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is smaller).
o
Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches >3 × ULN 
(whichever is smaller).
Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor. The participant 
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should return to the investigator 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 and TBili for suspected cases of 
Hy’s Law, additional laboratory tests should include albumin, creatine kinase (CK), direct 
and indirect bilirubin, gamma-glutamyl transferase (GGT), prothrombin time (PT) or 
international normalized ratio (INR), total bile acids, and alkaline phosphatase. Consideration 
should also be given to drawing a separate tube of clotted blood and an anticoagulated tube 
of blood for further testing, as needed, for further contemporaneous analyses at the time of 
the recognized initial abnormalities to determine etiology.  A detailed history, including 
relevant information, such as review of ethanol, acetaminophen (either by itself or as a 
coformulated product in prescription or over-the-counter medications), recreational drug, 
supplement (herbal) use and consumption, family history, sexual history, travel history, 
history of contact with a jaundiced person, surgery, blood transfusion, history of liver or 
allergic disease, and potential occupational exposure to chemicals, should be collected.  
Further testing for acute hepatitis A, B, C, D, and E infection and liver imaging (eg, biliary 
tract) and collection of serum sample for acetaminophen drug and/or protein adduct levels 
may be warranted.
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the LFT abnormalities has yet been found.  Such potential DILI (Hy’s law) 
cases are to be reported as SAEs, irrespective of availability of all the results of the 
investigations performed to determine etiology of the LFT abnormalities.  
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.
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10.7. Appendix 7: AEs, ADEs, SAEs, USADEs and Device Deficiencies: Definition and 
Procedures for Recording, Evaluating, Follow-Up, and Reporting in Medical Device 
Studies
Definitions of a Medical Device Deficiency
The definitions and procedures detailed in this Section are in accordance with ISO 14155 and 
the European MDR 2017/745 for clinical device research (if applicable). 
Both the investigator and the sponsor will comply with all local reporting requirements for 
medical devices.
The detection and documentation procedures described in this protocol apply to all sponsor 
medical devices provided for use in the study (see Section 6.1.1) for the list of sponsor 
medical devices).
10.7.1. Definition of AE and ADE
AE and ADE Definition

An AE is defined in Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-Up, and Reporting

An ADE is defined as an adverse event related to the use of an investigational 
medical device.  This definition includes any adverse events resulting from 
insufficient or inadequate instructions for use, deployment, implantation, 
installation, or operation, or any malfunction of the investigational medical device 
as well as any event resulting from use error or from intentional misuse of the 
investigational medical device.
10.7.2. Definition of SAE, SADE, and Unanticipated Serious Adverse Device Effect
An SAE is defined in Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-Up, and Reporting.  
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SAE definition:
An SAE is defined in Appendix 10.3.
SADE Definition

An SADE is defined as an ADE that has resulted in any of the consequences 
characteristic of an SAE.

Any device deficiency that might have led to an SAE if appropriate action had not 
been taken, intervention had not occurred, or circumstances had been less fortunate.
USADE Definition

A USADE (also identified as UADE in US Regulation 21 CFR 813.3) is an SADE
which by its nature, incidence, severity, or outcome has not been identified in the 
current version of the risk analysis management file.
10.7.3. Definition of Device Deficiency
Device Deficiency Definition

A device deficiency is an inadequacy of a medical device with respect to its 
identity, quality, durability, reliability, safety, or performance.  Device deficiencies 
include malfunctions, use errors, and inadequate information supplied by the 
manufacturer.
10.7.4. Recording/Reporting and Follow-Up of Device Deficiencies
Device Deficiency Recording

When a device deficiency occurs, it is the responsibility of the investigator to 
review all documentation (eg, hospital progress notes, laboratory reports, and 
diagnostic reports) related to the event.

The investigator will then record all relevant device deficiency information in the 
participant’s medical records, in accordance with the investigator’s normal clinical 
practice.

If an AE (either serious or nonserious) associated with the device deficiency 
occurs, then the AE must be entered into the AE section of the CRF. 

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to Pfizer Safety.
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
There may be instances when copies of medical records for certain cases are 
requested by Pfizer Safety.  In this case, all participant identifiers, with the 
exception of the participant number, will be redacted on the copies of the medical 
records before submission to Pfizer Safety. Refer to Section 10.1.9 Use of Medical 
Records for actions that must be taken when medical records are sent to the sponsor 
or sponsor designee.

For device deficiencies, it is very important that the investigator describes any 
corrective or remedial actions taken to prevent recurrence of the incident.

A remedial action is any action other than routine maintenance or servicing of a 
medical device where such action is necessary to prevent recurrence of a device 
deficiency.  This includes any amendment to the device design to prevent 
recurrence.

The PI will notify the sponsor study team by contact method (eg, telephone, email) 
within 1 business day of determining that the incident meets the protocol definition 
of a medical device deficiency.

The Pfizer study team will also capture the required information on the Medical 
Device Complaint Form along with any associated AE (either serious or 
nonserious) when applicable and send to the appropriate product quality complaint 
group.

If the PI determines that the medical device deficiency may have injured the 
participant (ie, the medical device deficiency is associated with an AE or SAE), 
then the PI will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis will 
be documented in the participant’s medical record and recorded as the AE or SAE 
rather than the individual signs/symptoms. All relevant details related to the role of 
the device in regard to the SAE must be included in the narrative section of the CT 
SAE Report Form as outlined in protocol Section 8.3.1.1 Reporting SAEs to Pfizer 
Safety and Section 8.3.1.2 Recording Non-serious AEs and SAEs on the CRF.
Assessment of Causality Occurring in Conjunction With a Medical Device Deficiency

If an AE or SAE has occurred in conjunction with a medical device deficiency, the 
investigator must assess the relationship between each occurrence of the AE or 
SAE and the medical device deficiency. The investigator will use clinical judgment 
to determine the relationship.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.
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
Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.

The investigator will also consult the IB in thier assessment.

For each device deficiency, the investigator must document in the medical notes 
that he/she has reviewed the AE/SAE/device deficiency and has provided an 
assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the sponsor. However, it is 
very important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to the sponsor.

The investigator may change their opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-Up of \ Medical Device Deficiency

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
sponsor to elucidate the nature and/or causality of the AE or SAE/device deficiency 
as fully as possible.  This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other healthcare providers.

Follow-up applies to all participants, including those who discontinue study 
intervention.

New or updated information regarding the nature of the device deficiency will be 
recorded in the originally completed Medical Device Complaint form by the Pfizer
study team.

New or updated information regarding any SAE that was potentially associated 
with the medical device deficiency will be submitted to Pfizer Safety on the CT 
SAE Report Form/Medical Device Constituent Supplemental Form within 24 hours 
of receipt of the information according to the requirements provided in Appendix 
10.3.
      
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10.8. Appendix 8: Country-specific Requirements
10.8.1. France Contrat Unique
This country specific appendix captures operational items not included in the mandatory 
contract format for France (i.e. French “Contrat Unique”), which Pfizer includes in standard 
contract language for other countries.  
1. GCP Training
Before enrolling any participants, the investigator and any subinvestigators will complete 
the Pfizer-provided Good Clinical Practice training course (“Pfizer GCP Training”) or 
training deemed equivalent by Pfizer.  Any investigators who later join the study will do 
the same before performing study-related duties.  For studies of applicable duration, the 
investigator and subinvestigators will complete Pfizer GCP Training or equivalent every 
3 years during the term of the study, or more often if there are significant changes to the 
ICH GCP guidelines or course materials. 
2. Study Intervention
No participants or third-party payers will be charged for study intervention.
3. Record Retention
If the investigator becomes unable for any reason to continue to retain study records for 
the required period (e.g., 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 the retention requirements have been met.
4. SUSARs
Pursuant to a sponsor’s safety reporting obligations under 21 CFR 312.32(c)(1), Pfizer 
will report to the investigator all Serious Unexpected Suspected Adverse Reactions 
(“SUSARs”). Investigator will receive and review SUSAR reports and report SUSARs to 
the responsible IRB/IEC according to institution’s guidelines. Institution will retain 
SUSAR reports consistent with Section 10.1.7 of the Protocol.
5. Collection of Ethnic Origin Information
Information regarding ethnic origin will be collected in this study in compliance with the 
French Data Protection Authority (CNIL): Deliberation no. 2016-262 of 21 July 2016 
amending the reference methodology for the processing of the personal data conducted in 
connection with biomedical research (MR-001), § 2.2.3 Nature of the data.
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Individuals participating in this study will consent that this information can be collected in 
the study before they enter the study.
The electronic Case Report Form (eCRF) will be used as the source file for ethnic origin in 
France. This information will not be recorded in the participant’s medical records.
10.8.2. Japan-specific Regulatory Requirements
10.8.2.1. Definitions of Serious Adverse Event, Serious Adverse Event Caused by 
Medical Device, and Unanticipated Serious Adverse Event Caused by Medical Device
Definition of serious adverse event caused by medical device
A serious adverse event caused by medical device is defined as an adverse event caused by a 
medical device which led to an outcome characteristic to serious adverse events, or a device-
related incident whose recurrence might lead to death or serious deterioration in health.
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10.9. Appendix 9: Decision Algorithm for Disease Assessment 
Abbreviations: CIS = carcinoma in situ
The above diagram illustrates how cystoscopy, urine cytology, biopsy and imaging should be 
integrated to assess achievement of CR for participants with CIS at baseline, recurrence of 
high-grade disease, persistence of CIS or progression of disease.  Participants enrolled in 
Cohort A with CIS with persistent disease and participants with recurrence of high-grade Ta 
disease following first induction period are eligible for a re-induction period of up to 6 
additional weekly doses of BCG treatments (see study Schema for Cohort A).  Below, 
definitions are provided for no evidence of disease, CR, recurrence of high-grade disease, 
persistence of CIS, and progression of disease. 
Cytology results are defined as the following:
1. Positive - if indicative or suggestive of malignant cells: 

High-grade urothelial carcinoma

Suspicious for high-grade urothelial carcinoma 
2. Negative if NOT indicative or suggestive of malignant cells: 

Negative for high-grade urothelial carcinoma cells 

Presence of low-grade urothelial carcinoma cells 

Atypical urothelial cell not abnormal enough to be considered as cancerous 
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3. Indeterminate: unsatisfactory sample.
In Cohort B1, when cystoscopy is negative and cytology is positive at a given disease 
assessment timepoint, biopsies must be collected from the bladder dome, trigone, right lateral 
wall, left lateral wall, anterior and posterior wall, and prostatic urethra for male participants.
For participants in Cohort B1, decision to continue treatment following disease assessment 
will be made by the investigator as described in the diagram above with BICR review of 
disease assessment (including tumor tissue samples, cytology, cystoscopy and imaging) 
occurring in an expedited manner. For participants in Cohort B1 continuation of treatment for 
1 additional cycle while waiting for confirmation of recurrence of high-grade Ta, T1 or CIS 
disease by the BICR will be allowed at the discretion of the investigator. If the 12 week 
disease assessment is “Not Evaluable” per the BICR, the assessment with a non-evaluable 
result should be repeated as soon as possible.
In case of discordant results at a given disease assessment timepoint with negative cytology 
as assessed by the investigator and positive cytology as assessed by the BICR, the following 
assessments should be performed as soon as possible:

Cystoscopy with collection of random biopsies from bladder (dome, trigone, right and 
left lateral wall, and anterior and posterior wall) and prostatic urethra in male participants 
OR collection of suspicious lesions, if present;

Cytology;

Imaging
No Evidence of Disease only applies to participants without CIS at baseline (Cohort A and 
Cohort B2) and is defined as disease that was completely resected prior to randomization 
(Cohort A)/initiation of study intervention (Cohort B2) and does not meet the criteria of 
progression of disease, recurrence of high-grade disease, or recurrence of low-grade disease 
while on study. The date of imaging, biopsy, cystoscopy, or cytology (whichever result of the 
available assessments is earliest) that supports no evidence of disease will be used as the date 
of no evidence of disease.
Complete Response, in participants with CIS at baseline, is defined as histologic 
disappearance of malignancy on bladder biopsy with negative cytology and cystoscopy or 
negative cytology and positive cystoscopy with biopsy-proven low-grade Ta lesion or non-
malignant tissue. The date of biopsy, cystoscopy, or cytology (whichever is earliest) will be used 
as the date of Complete Response. See section 8.1.1.1 for guidance regarding timing of these 
biopsies.
Persistence of CIS, in participants with CIS at baseline in Cohort A, is defined as 
persistence of CIS after induction or re-induction (if re-induction is administered). For 
participants in Cohort B1, persistence of CIS is defined as persistence of CIS at the 12 week 
or 24 week disease assessment. This will require a cystoscopy or cytology positive result 
with biopsy positive for CIS. The date of positive biopsy, cystoscopy, or cytology (whichever 
positive result is earliest) will be used as the date of persistence of CIS.
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Recurrence of high-grade disease is defined as re-appearance of high-grade disease (high-
grade Ta, T1 or CIS) after randomization/initiation of study intervention or re-appearance of 
high-grade disease after CR for participants with CIS at baseline or re-appearance of high-
grade disease before CR for participants with CIS and concurrent papillary disease at 
baseline in Cohort A or B1. This will require a cystoscopy or cytology positive result, with 
biopsy positive for T1, high-grade Ta and/or CIS. The date of positive biopsy, cystoscopy, or 
cytology (whichever positive result is earliest) will be used as the date of recurrence of high-
grade disease.  In Cohort B1, if the investigator determines that high-grade disease is present, 
the participant may continue on study for 1 additional cycle, until BICR review confirms 
diagnosis of high-grade disease.  At that time, if high-grade disease recurrence is confirmed 
by the BICR, the participant must discontinue study treatment.
Recurrence of low-grade disease is defined as re-appearance of low-grade disease (low-
grade Ta) after randomization (Cohort A)/initiation of study intervention (Cohort B). This 
will require a cystoscopy or cytology positive result, with biopsy positive for low-grade Ta. 
The date of positive biopsy, cystoscopy or cytology (whichever positive result is earliest) will 
be used as the date of recurrence of low-grade disease.
Progression of disease is defined as any of the following:

Lamina propria invasion (eg, increase from Ta to T1 or CIS to T1)

Muscle invasive disease (stage ≥ T2)

Lymph node positive disease (N+)

Metastatic disease (M1)

Appearance of high-grade Ta or T1 in participants with CIS only at baseline (Cohort 
A and Cohort B1) before achieving a CR.
This will require a cystoscopy or cytology positive result with imaging positive and/or 
biopsy positive for disease progression as described above. The date of positive biopsy, 
imaging for new lesion, positive cystoscopy, or positive cytology (whichever positive 
result is earliest) will be used as the date of progression. 
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10.10. Appendix 10: ECOG PS
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. 1982.52
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10.11. Appendix 11: ECG Findings of Potential Clinical Concern
ECG Findings That May Qualify as Adverse Events (AEs)

Marked sinus bradycardia (rate <40 bpm) lasting minutes.

New PR interval prolongation >280 msec.

New prolongation of QTcF to >480 msec (absolute) or by ≥60 msec from baseline.

New-onset atrial flutter or fibrillation, with controlled ventricular response rate: ie, 
rate <120 beats per minute (bpm).

New-onset type I second-degree (Wenckebach) atrioventricular (AV) block of 
>30 seconds’ duration.

Frequent premature ventricular complexes (PVCs), triplets, or short intervals 
(<30 seconds) of consecutive ventricular complexes.
ECG Findings That May Qualify as Serious Adverse Events (SAEs)

QTcF prolongation >500 msec.

New ST-T changes suggestive of myocardial ischemia.

New-onset left bundle branch block (QRS >120 msec).

New-onset right bundle branch block (QRS >120 msec).

Symptomatic bradycardia.

Asystole:

In awake, symptom-free participants in sinus rhythm, with documented periods 
of asystole ≥3.0 seconds or any escape rate <40 bpm, or with an escape rhythm 
that is below the AV node. 

In awake, symptom-free participants with atrial fibrillation and bradycardia 
with 1 or more pauses of at least 5 seconds or longer. 

Atrial flutter or fibrillation, with rapid ventricular response rate: rapid = rate 
>120 bpm.

Sustained supraventricular tachycardia (rate >120 bpm) (“sustained” = short 
duration with relevant symptoms or lasting >1 minute).

Ventricular rhythms >30 seconds’ duration, including idioventricular rhythm (rate 
<40 bpm), accelerated idioventricular rhythm (40< x <100), and 
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monomorphic/polymorphic ventricular tachycardia >100 bpm (such as torsades de 
pointes).

Type II second-degree (Mobitz II) AV block.

Complete (third-degree) heart block.
ECG Findings That Qualify as Serious Adverse Events

Change in pattern suggestive of new myocardial infarction.

Sustained ventricular tachyarrhythmias (>30 seconds’ duration).

Second- or third-degree AV block requiring pacemaker placement.

Asystolic pauses requiring pacemaker placement.

Atrial flutter or fibrillation with rapid ventricular response requiring cardioversion.

Ventricular fibrillation/flutter.

At the discretion of the investigator, any arrhythmia classified as an adverse 
experience.
The enumerated list of major events of potential clinical concern are recommended as “alerts” or 
notifications from the core ECG laboratory to the investigator and Pfizer study team, and not to be 
considered as all inclusive of what to be reported as AEs/SAEs.
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10.12. Appendix 12: Recommendations for Management of Allergic/Hypersensitivity 
Reactions, Cytokine Release Syndrome or Anaphylaxis
Following the first administration 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 administration and may include 
symptoms such as rash, urticaria, polyarthritis, myalgias, polysynovitis, fever, and, if severe, 
glomerulonephritis. 
All participants should be closely observed while receiving PF-06801591.  Monitoring for 
clinical signs of a systemic reaction should continue thereafter for clinical signs of allergic 
reactions/hypersensitivity.
In the case of a hypersensitivity reaction, the participant will be treated symptomatically, 
with supportive care and further monitoring until the end of the study. 
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 participant.
Detailed guidance on treatment, dose interruptions and potential retreatment is provided in 
Section 6.6.1.
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10.13. Appendix 13: Management of Immune-related Adverse Events (irAEs) 
Gastrointestinal irAEs
Severity of Diarrhea/Colitis
(NCI-CTCAE v5.0)
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 participant 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 hours; 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 5 mg/kg (if no 
contraindication).
-Note: infliximab should not be
used in cases of perforation or 
sepsis.
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Dermatological irAEs
Grade of Rash 
(NCI-CTCAE v5.0)
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 v5.0)
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 v5.0)
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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Renal irAEs
Grade of Creatinine Increased
(NCI-CTCAE v5.0)
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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Cardiac irAEs
Myocarditis
Initial Management
Follow-up
Management
New onset of cardiac signs or 
symptoms and / or new laboratory
cardiac biomarker elevations (e.g.
troponin I, 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
(e.g. azathioprine,
cyclosporine A, 
abatacept).
*Local guidelines, or eg. ESC or AHA guidelines
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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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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
* If a study participant experiences immune-related grade 3 or 4 endocrinopathies (hypothyroidism,
hyperthyroidism, adrenal insufficiency, type I diabetes mellitus) management guidelines should be followed, 
including withholding of study drug, as indicated. Treatment may be resumed once symptoms and/or
laboratory tests improve, and the participant’s condition becomes stable and well controlled with or without 
supportive treatment.
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Other irAEs (not described above)
Grade of other irAEs 
(NCI-CTCAE v5.0)
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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10.14. Appendix 14 Management of BCG Associated Toxicity
Systemic BCG Reaction
The language in this section is based on the TICE USPI and provides an example of 
management of BCG associated toxicity. The product label for the strain of BCG 
administered should be used for reference if other than TICE.
Deaths have been reported as a result of systemic BCG infection and sepsis.  Participants
should be monitored for the presence of symptoms and signs of toxicity after each 
intravesical treatment. Febrile episodes with flu-like symptoms lasting more than 72 hours, 
fever ≥103°F, systemic manifestations increasing in intensity with repeated instillations, or 
persistent abnormalities of liver function tests suggest systemic BCG infection and may 
require antituberculous therapy. Local symptoms (prostatitis, epididymitis, orchitis) lasting 
more than 2 to 3 days may also suggest active infection. 
Acute, localized irritative toxicities of TICE® BCG may be accompanied by systemic 
manifestations, consistent with a “flu-like” syndrome. Systemic adverse effects of 1 to 2 
days’ duration such as malaise, fever, and chills often reflect hypersensitivity reactions. 
However, symptoms such as fever of ≥38.5°C (101.3°F), or acute localized inflammation 
such as epididymitis, prostatitis, or orchitis persisting longer than 2 to 3 days suggest 
active infection, and evaluation for serious infectious complication should be 
considered.
In participants who develop persistent fever or experience an acute febrile illness consistent 
with BCG infection, 2 or more antimycobacterial agents should be administered while 
diagnostic evaluation, including cultures, is conducted. BCG treatment should be 
discontinued.
Negative cultures do not necessarily rule out infection. Physicians using this product should 
be familiar with the literature on prevention, diagnosis, and treatment of BCG-related 
complications and, when appropriate, should consult an infectious disease specialist or other 
physician with experience in the diagnosis and treatment of mycobacterial infections.
TICE BCG is sensitive to the most commonly used antituberculous agents (isoniazid, 
rifampin, and ethambutol). TICE BCG is not sensitive to pyrazinamide.
Intravesical instillations of BCG should be postponed during treatment with antibiotics, since 
antimicrobial therapy may interfere with the effectiveness of TICE BCG (see 
PRECAUTIONS). TICE BCG should not be used in individuals with concurrent infections.
Source: TICE USPI40
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10.15. Appendix 15 Alternative Measures During Public Emergencies
The alternative study measures described in this section are to be followed during public 
emergencies, including the COVID-19 pandemic. This Section applies for the duration of the 
COVID-19 pandemic globally and will become effective for other public emergencies only 
upon written notification from Pfizer. 
Use of these alternative study measures are expected to cease upon the return of business as 
usual circumstances (including the lifting of any quarantines and travel bans/advisories). 
10.15.1. Telehealth Visits
In the event that in-clinic study visits cannot be conducted, every effort should be made to 
follow up on the safety of study participants at scheduled visits per the Schedule of 
Activities or unscheduled visits. Telehealth visits may be used to continue to assess 
participant safety and collect data points. Telehealth includes the exchange of healthcare 
information and services via telecommunication technologies (e.g., audio, video, video-
conferencing software) remotely, allowing the participant and the investigator to 
communicate on aspects of clinical care, including medical advice, reminders, education, and 
safety monitoring. The following assessments must be performed during a telehealth visit:

Review and record any AEs and SAEs since the last contact. Refer to Section 8.3.

Review and record any new concomitant  treatments or changes in concomitant  
treatments since the last contact.

Review and record contraceptive method and results of pregnancy testing if 
applicable for the participant. Confirm that the participant is adhering to the 
contraception method(s) required in the protocol. Refer to Section 10.4 and 
Section 10.15.2.1 of this Section regarding pregnancy tests.

Assess ECOG performance status
The following assessments are strongly recommended to be performed if applicable for the 
visit:
PROs (EORTC-QLQ-C30, EORTC NMIBC24, EQ-5D-5L, PGIS, PGIC) 
Study participants must be reminded to promptly notify site staff about any change in their 
health status.
10.15.2. Alternative Facilities for Safety Assessments
Alternative facilities to the study site may be used as described in this section.
10.15.2.1. Laboratory Testing
If a study participant is unable to visit the site for protocol-specified safety laboratory 
evaluations, testing may be conducted at a local laboratory if permitted by local 
regulations. Note that per protocol, participants may have safety labs completed at a local 
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laboratory even in the absence of a public emergency; however, this section is included to 
highlight the option to use local labs if needed to facilitate collection of safety laboratory 
assessments during a public emergency.  The local laboratory may be a standalone institution 
or within a hospital. The following safety laboratory evaluations may be performed at a local 
laboratory:  

Hematology panel

Chemistry panel (including ACTH & Thyroid Function Tests for applicable visits)

Coagulation panel

Urinalysis

Pregnancy test (if applicable for the participant)
If a local laboratory is used, qualified study site personnel must order, receive, and review 
results. Site staff must collect the local laboratory reference ranges and certifications/
accreditations for filing at the site. Laboratory test results are to be provided to the site staff 
as soon as possible.  The local laboratory reports should be filed in the participant’s source 
documents/medical records. Relevant data from the local laboratory report should 
be recorded on the eCRF. 
If a participant requiring pregnancy testing cannot visit a local laboratory for pregnancy 
testing, a home urine pregnancy testing kit with a sensitivity of at least 25 IU/mL may be 
used by the participant to perform the test at home, if compliant with local regulatory 
requirements. The pregnancy test outcome should be documented in the participant’s source 
documents/medical records and relevant data recorded on the eCRF. Confirm that the 
participant is adhering to the contraception method(s) required in the protocol.
10.15.2.2. Electrocardiograms
If the participant is unable to visit the study site for ECGs, the participant may visit an 
alternative facility to have the ECGs performed. Qualified study site personnel must order, 
receive, and review results. Note that per protocol, participants may have ECGs completed at 
an alternative facility to the site even in the absence of a public emergency; however, this 
section is included to highlight the option to use an alternative facility if needed to allow 
completion of ECGs during a public emergency.
10.15.3. Study Intervention
If the safety of a trial participant is at risk because they cannot complete required evaluations 
or adhere to critical mitigation steps, then discontinuing that participant from study 
intervention must be considered.
This guidance below is intended to support decision making, but it is not meant to supersede 
clinical assessment of any individual study participant case.
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Regarding the continued administration of PF-06801591 and BCG for ongoing 
participants who have active confirmed (positive by regulatory authority-approved test) or 
presumed (test pending/clinical suspicion) SARS-CoV2 infection, the following is 
recommend:

For symptomatic participants with active SARS-CoV2 infection, study drug treatment 
should be delayed for at least 14 days from the start of symptoms. This delay is 
intended to allow the resolution of symptoms of SARS-CoV2 infection.

Prior to restarting treatment, the participant should be afebrile for 72 hours, and SARS-
CoV2-related symptoms should have recovered to ≤ Grade 1 for a minimum of 72 
hours.  It is requested that the site inform the study team when treatment is restarted.

PF-06801591 treatment may be delayed within the allowed treatment window in order 
to meet these criteria; however, PF-06801591 will not be given out of the allowed 
treatment window and may be skipped as needed in order to meet these re-treatment 
criteria.

Continue to consider potential drug-drug interactions for any concomitant medication 
administered for treatment of SARS-CoV2 infection.
10.15.4. Home Health Visits
A home health care service may be utilized to facilitate scheduled visits per the Schedule of 
Activities if feasible and locally permitted. Home health visits include a healthcare provider 
conducting an in-person study visit at the participant’s location, rather than an in-person 
study visit at the site. All assessments must be performed by someone meeting local 
requirements for performing the assessments. The following may be performed during a 
home health visit:

Physical Examination

Weight

Vital Signs

ECG

PROs

Review and record any AEs and SAEs since the last contact. Refer to Section 8.3.

Review and record any new concomitant treatments or changes in concomitant 
treatments since the last contact.

Review and record contraceptive method if applicable for the participant. Confirm 
that the participant is adhering to the contraception method(s) required in the 
protocol. 

Assess ECOG performance status

Laboratory sample collection
o
Hematology panel
o
Chemistry panel (including ACTH & Thyroid Function Tests for applicable 
visits)
o
Coagulation panel
o
Urinalysis
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o
Pregnancy test (if applicable for the participant)
10.15.5. Adverse Events and Serious Adverse Events
If a participant has COVID-19 during the study, this should be reported as an adverse event 
(AE) or serious adverse events (SAE) and appropriate medical intervention provided. 
It is recommended that the investigator discuss temporary or permanent discontinuation of 
study intervention with the study sponsor. 
10.15.6. Efficacy Assessments
If the participant is unable to visit the study site for CT/MRI, the participant may visit an 
alternative facility to have the CT/MRI performed. Qualified study site personnel must order, 
receive, and review results. Note that per protocol, participants may have imaging completed 
at an alternative facility to the site even in the absence of a public emergency; however, this 
section is included to highlight the option to use an alternative facility if needed to allow 
completion of imaging during a public emergency.
10.15.7. Independent Oversight Committees
The EDMC and Steering Committee will be notified in a timely manner of any risk 
mitigation strategies adopted for the study based on a risk/benefit assessment.  The 
committees may also make recommendations for risk mitigation strategies for the study as 
needed.
Timing of planned EDMC and Steering Committee meetings may be adjusted as needed in 
response to a public emergency.  In the event that a planned meeting of the EDMC or 
Steering Committee must be postponed, the study team may consider issuing an update as 
applicable.  Ad hoc EDMC or Steering Committee meetings may be held to discuss any 
issues within the committee remit.  Any proposed changes to the planned meeting schedule 
will be communicated to committee members.  
If any changes to the SAP or to the committee charter for the EDMC or the Steering 
Committee are needed as a result of a public emergency, they will be communicated to the 
committee members.
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10.16. Appendix 16: Patient Reported Outcomes
10.16.1. Patient Global Impression of Severity
Please choose the response below that best describes the severity of your bladder 
cancer over the past 7 days. (select only ONE response):
None
Mild
Moderate
Severe
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10.16.2. Patient Global Impression of Change
Please choose the response below that best describes the overall change in your 
bladder cancer since you started taking the study medication (Select only ONE 
response):
Much better
A little better
No change
A little worse
Much worse
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10.16.3. Patient Treatment Administration Burden Questionnaire 
(Administer Post Procedure)
Please consider the [ARMS RECEIVING PF-06801591 & BCG insert: two-part] treatment 
administration procedure [ARMS RECEIVING PF-06801591 & BCG insert: (catheter to 
your bladder followed by injection into your stomach ); ARMS RECEIVING BCG ONLY: 
(catheter to your bladder); ARM RECEIVING PF-06801591 ONLY: (injection into your 
stomach)] that you just received for your bladder cancer.
1. How would you characterize any pain you may have experienced during the 
administration of treatment?
□0   No pain 
□1   Mild pain 
□2   Moderate Pain
□3   Severe pain 
□4   Extremely severe pain
2. How would you characterize the amount of time needed to complete the [ARMS 
RECEIVING PF-06801591 & BCG INSERT: two-part] treatment administration 
procedure?
□0   Not at all burdensome
□1   Slightly burdensome
□2   Somewhat burdensome
□3   Very burdensome
□4   Extremely burdensome
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10.16.4. Treatment Satisfaction Questionnaire (TSQ)
Please consider the treatment that you received in the past 4 weeks for your bladder cancer 
[ARMS RECEIVING PF-06801591 ONLY INSERT: (injection into your stomach); ARMS 
RECEIVING BCG ONLY INSERT: (catheter to your bladder); ARMS RECEIVING PF-
06801591 & BCG INSERT: (catheter to your bladder followed by injection into your 
stomach)].
1. Over the past 4 weeks, how satisfied were you with the form of treatment administration 
that you received?
□0   Very Dissatisfied
□1   Dissatisfied
□2   Neither satisfied nor dissatisfied
□3   Satisfied
□4   Very Satisfied
2. Over the past 4 weeks, how satisfied were the number of treatment administrations that 
you received?
□0   Very Dissatisfied
□1   Dissatisfied
□2   Neither satisfied nor dissatisfied
□3   Satisfied
□4   Very Satisfied
3. Over the past 4 weeks, how satisfied were you overall with the treatment that you 
received?
□0   Very Dissatisfied
□1   Dissatisfied
□2   Neither satisfied nor dissatisfied
□3   Satisfied
□4   Very Satisfied
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10.17. Appendix 17: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the table of contents (TOC).  The protocol amendment summary of changes 
tables for past amendment(s) can be found below:
Amendment 4: 22 November 2022
Overall Rationale for the Amendment: Sponsor has closed enrollment to Cohorts B1 and 
B2 due to a business strategy decision.
Description of Change
Brief Rationale
Section # and Name
Substantial Modifications
A statement explaining that 
enrollment to Cohorts B1 and 
B2 has been closed and that 
previously enrolled Cohort B1 
and B2 participants may 
continue study treatment was 
added.
Enrollment to Cohorts B1 
and B2 has been closed 
for business strategy 
reasons, but previously
enrolled participants in 
these Cohorts will be 
permitted to continue 
treatment.
1.1 Synopsis 
2.1.2 Study Rationale for the 
BCG-Unresponsive Cohort 
(Cohorts B1 and B2)
4.1.2 Cohorts B1 and B2
9.2.2 Cohorts B1 and B2
A statement that Cohort B1 and 
B2 study objectives are no 
longer required was added.  
Cohort B1 and B2 estimands 
were removed from Sections 
1.1, 3.2, and 9.1.1.2. Efficacy 
endpoint statistical analysis 
methods were deleted from 
Section 9.4.1.2, and Section 
9.4.1.3 Cohort B2, was deleted.
Given the small numbers 
of participants enrolled in 
Cohorts B1 and B2, it 
will no longer be feasible 
to complete the Cohort 
B1 and B2 analyses as 
previously planned.
1.1 Synopsis 
3.2 BCG-Unresponsive 
Cohorts (Cohorts B1 and 
B2)  
9.1.1.2 Cohorts B1 and B2
9.4.1.3 Cohort B2
The following updates were 
made to the Schedule of 
Activities (SoA) – Cohorts B1 
and B2 and to the 
corresponding protocol text: 
clarification that cohort B1 
imaging is only applicable until 
end of treatment which per 
protocol does not exceed 2 
years, the Cycle 14 biopsy 
confirming CR for Cohort B1 
participants was removed, 
Study procedures only 
intended to facilitate 
Cohort B1 and B2 study 
objectives and endpoints 
that are not needed to 
properly monitor 
participants enrolled in 
Cohort B1 and B2 are no 
longer needed and have 
been removed.
1.3 Schedule of Activities 
(SoA) Screening and 
Treatment Period – Cohorts 
B1 and B2
1.3 Schedule of Activities 
End of Treatment Visit and 
Follow-Up Period – Cohorts 
B1 and B2
8.1.1.1. Cystoscopy
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PROs for Cohorts B1 and B2 
were removed, collection of 
immunogenicity, PK, PD, and 
biomarker samples for Cohorts 
B1 and B2 were removed, 
disease follow-up after EOT 
and survival follow-up were 
removed, and abbreviations 
that are no longer applicable 
were removed.
8.1.1.3. Imaging
8.1.2. Patient Reported 
Outcomes (PROs)
8.5. Pharmacokinetics
8.6. Pharmacodynamics
8.8 Biomarkers
8.8.3. Immunogenicity 
Assessments: Analysis of 
Anti-PF-06801591 
Antibodies (ADA) and 
Neutralizing Anti PF-
06801591 Antibodies (NAb)
Clarifications that disease 
assessment and survival 
follow-up after EOT will now 
only be applicable to Cohort A 
were added, language 
regarding disease follow-up 
and survival follow-up for 
Cohorts B1 and B2 was 
deleted, and Figures 2 and 4 
were updated to remove
disease follow-up and survival 
follow-up for Cohorts B1 and 
B2.
Given the small numbers 
of participants enrolled in 
Cohorts B1 and B2, 
efficacy objectives are no 
longer applicable and/or 
feasible and therefore it is 
no longer necessary to 
collect disease follow-up 
and survival follow-up 
after EOT for Cohort B1 
and B2 participants.
1.2 Schema
1.2 Schema Figure 2 
B8011006 Study Schematic 
- Cohorts B1 and B2
4.1.2 Figure 4 Cohorts B1 
and B2
8.1.1. Clinical Assessments
8.2.6. Survival Follow-up
The requirement for random 
bladder biopsies in the event of 
discordant cytology results 
between investigator and BICR 
was removed. 
Study procedures only 
intended to facilitate 
Cohort B1 and B2 study 
objectives and endpoints 
that are not needed to 
properly monitor 
participants in Cohort B1 
and B2 are no longer 
needed and have been 
removed.
8.1.1.2 Cytology
Cohorts B1 and B2 were 
removed from the PK, 
Given the small numbers 
of participants enrolled in 
Cohorts B1 and B2, it 
9.4.3.2. Pharmacokinetics
9.4.3.3. Immunogenicity
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immunogenicity, and 
biomarker analyses.
will no longer be feasible 
to analyze Cohort B1 and 
B2 PK, immunogenicity, 
and biomarker data as 
originally planned. 
9.4.3.5. Biomarkers
Non Substantial Modifications
The EDMC will no longer 
review data from Cohorts B1 
and B2. 
External data monitoring 
is no longer needed for 
Cohorts B1 and B2 that 
have been closed to 
enrollment.
1.1 Synopsis
1.2 Schema, Cohorts B1 and 
B2
2.3. Benefit/Risk 
Assessment
4.1.1. BCG-Naïve Cohort 
(Cohort A)
9.5.1. External Data 
Monitoring Committee 
(EDMC)
A clarification that the sponsor 
may request that sites complete 
additional survival follow-up 
for Cohort A to facilitate 
planned analyses as needed 
was added.
This will enable 
availability of the most 
current survival data to 
support Cohort A 
objectives at the time of 
planned analyses.
1.3 Schedule of Activities 
(SoA) End of Treatment 
Visit and Follow-Up Period 
– Cohort A
8.2.6. Survival Follow-up
It was clarified that 
participants meeting Inclusion 
12c are not required to receive 
BCG maintenance or a second 
induction course of BCG per 
inclusion criterion 13.
This clarification was 
made per the Protocol 
Amendment Changes and 
Clarification letter dated 
12 May 2022 and adds 
clarity to the originally 
intended Inclusion 
criteria.
5.1 Inclusion Criteria
It was clarified that if CK ≥ 3 x 
ULN, the isoenzymes CK-MB 
and CK-MM are to be 
measured.
This clarification was 
made per the Protocol 
Amendment Changes and 
Clarification letter dated 
12 May 2022 and adds 
more specificity to the 
type of isoenzymes to be 
10.2 Appendix 2: Clinical 
Laboratory Tests Table 6 
Protocol Specified 
Laboratory Tests
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measures if CK ≥ 3 x 
ULN.
Protocol amendment 3 
summary of changes moved 
from this Protocol Amendment 
Summary of Changes Table to 
Appendix 17 and replaced in 
this table with the current 
summary of changes for 
protocol amendment 4.
Summary of Changes 
Table updated with 
changes for current 
amendment and changes 
for previous amendment 
moved to Appendix 17.
Protocol Amendment 
Summary of Changes Table
10.17. Appendix 17: 
Protocol Amendment 
History
Typos, punctuation,  and 
grammar were corrected as 
applicable.
Editorial updates
All
Amendment 3: 12 January 2022
Overall Rationale for the Amendment:  Modification of dose level and schedule of PF-
06801591 for participants in Cohort B2 in order to explore possibility of reducing dosing 
frequency burden for participants, their caregivers and the healthcare system.
1.1 Synopsis
1.2 Study Schema
1.3 Schedule of Activities
2.1 Study Rationale
2.1.2 Study Rationale for the 
BCG-Unresponsive Cohort 
(Cohorts B1 and B2)
2.2.1 Clinical Background
2.3 Benefit/Risk Assessment
3.2 Objectives, Estimands 
and Endpoints for Cohorts 
B1 and B2
4.1.2 Overall Design 
Cohorts B1 and B2
Language was added to 
support the dosing 
modification to Cohort B2.  
Updated language provides 
rationale for the updated 
design, and updates to 
objectives, endpoints, and 
study procedures for Cohort 
B2.
Update was included to 
support updated Cohort B2 
dosing regimen.
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4.3.1 Justification for Dose 
of PF-06801591
6.1 Study Intervention 
Administered
7.1 Discontinuation of Study 
Intervention
8.4 Treatment of Overdose
1.3 Schedule of Activities
Frequency of urinalysis was 
updated for Cohorts B1 and 
B2.
Updated to more clinically 
appropriate time points.
5. Study Population
Sentence was added to 
describe Sponsor eligibility 
approval process.
Process update added for 
clarification to sites.
5.1 Inclusion Criteria
Allowance for prior 
treatment with Verity strain 
of BCG was added.
Verity strain is the same 
strain as the Imuron-vac 
strain, but with a different 
brand name. Allowance 
added for clarity.
8.5 Pharmacokinetics
9.4.3.2 Pharmacokinetics
Post-dose PK samples were 
added for participants in 
Cohort B2.
Sampling time point was 
added to support PK 
analysis of Cohort B2 
dosing regimen.
10.2 Clinical Laboratory 
Tests Table 6
Creatine kinase testing was 
added to the chemistry panel 
for Cohorts B1 and B2.
Test added to support 
collection of additional 
safety data for Sasanlimab.
10.9 Decision Algorithm for 
Disease Assessment
Definition of “No Evidence 
of Disease” was added, as 
this previously appeared 
only in the CRF completion 
guidelines but not in the 
protocol.
Clarification to sites.
1.1 Synopsis
3.2 Objectives, Estimands 
and Endpoints for Cohorts 
B1 and B2
Clarification of censoring 
strategy and primary 
estimand text for Cohorts 
B1 and B2.
Editorial update.
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9.1.1.2 Estimands Cohorts 
B1 and B2
9.4.1.2 Efficacy Analyses 
Cohort B1
7.1 Discontinuation of Study 
Intervention
9.1.1.1 Cohort A Table 2
Description of EFS events 
and discontinuation criteria 
for participants with CIS at 
baseline was clarified.
Clarification for sites.
9.4.3.1 Patient Reported 
Outcomes Analyses
9.4.3.2 Pharmacokinetics 
9.4.3.3 Immunogenicity
9.4.3.5 Biomarker Analyses
Editorial updates were made 
to match the Statistical 
Analysis Plan.
Editorial update for 
document consistency.
2.1 Study Rationale for 
Cohort A
Repetitive text was 
removed.
Editorial update.
10.17 Protocol Amendment 
History
Section was updated to 
summarize changes included 
in Amendment 2.
Amendment 2 changes were 
moved to appendix.
10.18 Abbreviations
List of abbreviations was 
updated with missing items.
Editorial update.
All
The word ‘patient’ was 
replaced with ‘participant’ 
where necessary.
Editorial update.
All
Typos and inconsistencies 
were corrected, minor 
clarifications were added, 
sections were harmonized, 
language that is not 
applicable has been 
removed.
Editorial update.
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Amendment 2 (21 September 2021)
Overall Rationale for the Amendment: Addition of two non-randomized Cohorts to enroll 
participants with BCG unresponsive NMIBC (Cohorts B1 and B2) and evaluate single-agent 
PF-06801591 in this population. Data from Cohort B1 and Cohort B2 will be analyzed 
separately from the data of the randomized Cohort A in BCG-naïve high-risk NMIBC. The 
study design of Cohort A is not modified.  
Section # and Name
Description of Change
Brief Rationale
Title and short title
Title was updated. 
Update was to include patient 
population being studied in 
Cohorts B1 and B2.
1 Protocol Summary
2 Introduction
3 Objectives, Estimands and 
Endpoints
4 Study Design
5 Study Population
6 Study Intervention
7 Discontinuation of Study 
Intervention and Participant 
Discontinuation/Withdrawal
8 Study Assessments and 
Procedures
9 Statistical Considerations
10 Supporting 
Documentation
Addition of language 
regarding background, 
rationale, study design, 
objectives and endpoints,  
eligibility, procedures, 
statistical considerations 
and supporting 
documentations for newly 
added Cohorts B1 and B2.  
The original arms of the 
study (Arms A, B and C) 
are now labeled as cohort 
A and language applying 
to cohort A has been 
labeled and differentiated 
from cohorts B1 and 2 
throughout the protocol.
Language supports addition of 
two non-randomized Cohorts 
(B1 and B2) to evaluate 
single-agent PF-06801591 in 
participants with BCG 
unresponsive NMIBC.
1.1 Synopsis
Cohort A CR objective 
was changed from 
“evaluate” to “estimate”.
Updated to appropriate 
terminology.
1.3 SoA for Cohort A
Edited with a reminder that 
all screening procedures 
must be completed within 
28 days of randomization.
Clarification for sites.
1.3 SoA for Cohort A
Added “pulse rate” to be 
performed.
Added to match text in section 
8.2.2.  Also clarified that 
pulse rate will be ‘performed’ 
and not ‘collected’ since this 
data is not collected on the 
CRF.
1.3 SoA for Cohort A
Edited to clarify that 
methods of testing for 
tuberculosis during 
Clarification for sites 
regarding acceptable 
tuberculosis testing methods.
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Section # and Name
Description of Change
Brief Rationale
screening may be per local 
practices.
1.3 SoA for Cohort A and 
Table 6 
(Formerly Table 5)
Updated to remove HCV 
RNA/HBcAB test.  
This test is not necessary for 
screening or on study as it 
cannot test for active 
infection.
1.3 SoA for Cohort A
Edited to clarify need for 
reflex testing for positive 
HBV surface antigen.  
This is already in Table 6.
Reminder to sites that this 
reflex testing must be done, 
per language already in Table 
6.
1.3 SoA for Cohort A
Edited to clarify screening 
cystoscopy to state that it 
is required and not “as 
clinically indicated”.
Clarification for sites to 
prevent errors in screening 
procedures.
1.3 SoA for Cohort A
Edited to remove notes 
regarding immunogenicity 
testing for  cycles 1 and 2.
Editorial change.
1.3 SoA for Cohort A
Edited to clarify timing of 
disease assessments as 
being fixed according to 
the calendar based on 
randomization.
Clarification regarding study 
procedure timing.
1.3 SoA for Cohort A and 
8.2.6 Survival Follow-up
Updated to add a reminder 
that cystectomy must be 
recorded as follow-up 
cancer treatment post 
treatment discontinuation. 
Clarification for sites.
1.3 SoA for Cohort A
Updated to remove 
biomarker sampling at 
End of Treatment.
This sample is not needed at 
EoT to support biomarker 
objectives.
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Section # and Name
Description of Change
Brief Rationale
2.1 Study Rationale
Updated with most recent 
data from the Keynote-057 
study.
Update with current data 
supporting study rationale.
3.1 Objectives and 
Estimands
CR objective was changed 
from “evaluate” to
“estimate”.
Updated to appropriate 
terminology.
5.1 Inclusion Criteria
Edited to clarify inclusion 
#3 and that the TURBT 
within 12 weeks of 
randomization must be 
positive (i.e. show tumor 
tissue that is HG Ta, T1 or 
CIS).  
Eligibility clarification for 
sites.
5.2 Exclusion Criteria
Exclusion #4 was updated 
to clarify that sites should 
contact sponsor to discuss 
prior malignancies before 
patients join the study.
Eligibility clarification for 
sites.
6 Study Intervention
Updated to clarify that 
sites may use BCG strain 
that is not listed in the 
protocol, only in the case 
of serious BCG shortage 
and when permitted by 
local health authorities and 
after review with the 
sponsor.
Clarification on actions to be 
taken when BCG shortage 
affects strains being used in 
the study.
6.1 Study intervention
Updated to clarify the 
dosage form and dosage 
for PF-06801591.
Updated to use correct 
terminology.
6.6 Dose Modifications
Updated to clarify that 
BCG dose can be skipped. 
Dose modification 
clarification for BCG, per 
BCG label.
6.6.2 Precautions for 
Administration of BCG
Updated to clarify 
requirements for BCG 
dosing when a UTI is 
present.
Dose modification 
clarification for BCG, per 
BCG label.
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Section # and Name
Description of Change
Brief Rationale
7.2 Participant 
Discontinuation / 
Withdrawal from Study
Clarification that 
destruction of samples can 
be requested by the 
participant for remaining 
samples only.
Clarification on policy.
8.1.1.1 Cystoscopy
Updated to clarify timing 
of disease assessment 
(every 12 weeks from 
randomization for Cohort 
A).  
Clarification for sites.
8.1.1.1 Cystoscopy
Updated to clarify timing 
around biopsy to confirm 
complete response for 
those participants with 
CIS at randomization.
Clarification for sites on 
timing of biopsy.
8.1.1.1 Cystoscopy
Updated to clarify that 
biopsy samples will be 
reviewed by the BICR.
Clarification to sites regarding 
which samples will be 
reviewed by BICR. 
8.1.1.2 Cytology
Updated to clarify timing 
of disease assessment.
Clarification for sites.
8.2 Safety Assessments
Clarification added 
regarding timing of 
unscheduled safety labs.
Per Pfizer standard protocol 
template update.
8.2.4 Electrocardiograms
Updated to clarify that 
ECG method of QTc 
calculation during 
screening must only be 
QTcF.
Clarification for sites 
regarding QTc calculation 
method.
8.2.8 Pregnancy Testing
Clarification around 
timing of pregnancy 
testing added.
Per Pfizer standard protocol 
template update.
Table 3 Outcome and Event 
Dates for EFS
Updated to clarify EFS 
scenarios in the case of no 
adequate baseline disease 
assessment.
Statistical analysis 
clarifications in case of 
missing or inadequate data.
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Section # and Name
Description of Change
Brief Rationale
9.4.1.1 Efficacy Analyses -
Cohort A
Updated to remove 
“defined above” which 
was referring to time 
points. “Specific time 
points” was changed to 
“the time points” for 
consistency.
Editorial changes.
9.4.1.1 Efficacy Analyses –
Cohort A
Updated to remove text 
“no baseline disease 
assessments” as an 
example of participants 
with inadequate data for 
disease assessment, as it is 
not applicable for patients 
with CIS who are being 
evaluated for CR.
Clarification of language to 
match update in SAP as only 
participants with CIS are 
being assessed for CR.
9.4.3 Other Analyses
Updated to clarify 
language regarding PK, 
PD and immunogenicity 
analysis.
Editorial update.
10.4.1 Male Participant 
Reproductive Inclusion 
Criteria
Text was updated to 
clarify rationale for 
contraception. 
Clarification for sites.
10.4.4 Contraception 
Methods
Allowance for injectable 
birth control was removed.
Per Pfizer standard protocol 
template update.
10.9 Decision Algorithm for 
Disease Assessment
Updated to clarify 
definition of dates for 
response, recurrence and 
persistence of disease.
Clarification for sites on entry 
of overall assessment data.
10.9 Decision Algorithm for 
Disease Assessment
Cytology result definitions 
added.
Clarification for sites.
10.13 Management of irAEs
Updated to include 
clarifying footnote in the 
Endocrine irAE table.
Clarification for sites 
regarding monitoring of 
endocrine irAEs.
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Section # and Name
Description of Change
Brief Rationale
10.13 Management of irAEs
Website links for 
management of cardiac 
irAEs were removed.
Site should follow instructions 
in the table, and consult with 
cardiologist, who may choose 
to use most recent available 
references.
10.15.3 Study Intervention
Updated to include 
clarification on timing of 
PF-06801591 dosing in 
the event that a participant 
is diagnosed with SARS-
CoV2.
Clarification on timing of PF-
06801591 dosing when doses 
are delayed due to SARS-
CoV2 infection.
10.16 Patient Reported 
Outcomes
Updated to remove 
examples of the EORTC-
QLQ-C30, EORTC 
NMIBC24 and EQ-5D-5L. 
These questionnaires are 
copyrighted and must be 
removed for public disclosure 
compliance.
10.17 Protocol Amendment 
History
Section was added to 
summarize changes 
included in previous 
protocol amendments.
Update to the standard Pfizer 
protocol template.
10.18 Abbreviations
List of abbreviations was 
updated with missing or 
unused terms.
Editorial update.
All
Typos and inconsistencies 
were corrected, minor 
clarifications were added, 
language that is not 
applicable has been 
removed, and formatting 
of graphics was updated 
for readability as needed.
Editorial update.
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Amendment 1 (26-June-2020)
Overall Rationale for the Amendment:
•
The following PROs will now be completed during Safety Follow-Up in addition to 
the timepoints specified in the original protocol: EORTC QLQ-C30, EORTC QLQ-
NMIBC24, EQ-5D-5L, PGIS, PGIC.  This is reflected in Section 1.3, Schedule of Activities. 
The addition of these PROs during Safety Follow-Up was requested by the European 
regulatory authority and will allow for collection of the PROs after an EFS event for 
participants that have had an EFS event so that a potential difference due to drug effects can 
be evaluated.
Section # and Name
Description of Change
Brief Rationale
1.1 Synopsis
2 Introduction
Sasanlimab, the generic name 
for PF-06801591 was added to 
the header, title page and 
Introduction 
Title Page
1.1 Synopsis
The protocol acronym CREST 
was added to the protocol title 
page and the short protocol title 
1.1 Synopsis
1.2 Schema
4.1 Overall Design
9.2 Sample size
Western EU was updated to 
Western Europe 
Clarification made to 
account for Brexit
1.3 SoA
Updated to indicate that 
participants must sign consent 
prior to any trial-specific 
procedure.
Clarification for sites
1.3 SoA
Updated to indicate that active 
tuberculosis may be excluded by 
laboratory test or skin test per 
the applicable local guidelines 
or BCG product label.  Chest x-
ray may continue to be used as 
well.
Clarification to sites 
regarding acceptable 
methods of tuberculosis 
testing
1.3 SoA
8.2.7 Clinical safety labs
Updated to indicate that 
laboratory tests may be 
performed up to 3 days prior to 
the scheduled clinic visit, so that 
results will be available for 
review before study treatment 
administration, including C1D1.
Clarification for sites 
regarding timing of lab 
tests
1.3 SoA 
8.2.7 clinical safety lab tests
Updated to clarify the minimum 
labs to be reviewed prior to 
dosing.
Updated to clarify for 
site required labs to be 
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Section # and Name
Description of Change
Brief Rationale
reviewed prior to dosing 
for safety purposes
1.3 SOA
10.2 Clinical lab tests
10.4 
Contraceptive Guidance
For female postmenopausal 
participants under the age of 60 
and not using hormonal 
contraception or HRT, a serum 
FSH test is required at screening 
only, to confirm postmenopausal 
status. FSH is not required for 
participants not meeting these 
criteria.  
Clarification on 
requirement for 
confirming 
postmenopausal status 
for WOCBP
1.3 SoA
BCG will be administered first 
on days when a participant 
receives both BCG and PF-
06801591.
Clarification for sites 
around timing of two 
study interventions
1.3 SoA
8.1.2 Patient Reported 
Outcomes
If labs are done on a date prior 
to the main visit date, PROs may 
be completed as the first 
assessment at the main visit.
Clarification around 
timing of PROs when 
labs are done a day 
earlier
1.3 SoA
8.5 Pharmacokinetics
PK samples should be taken 
within 2 hours prior to dosing 
including at the EOT visit if the 
EOT visit is on the same date as 
the last dose of study drug.
Clarification around 
timing of PK samples in 
relation to study drug 
dosing
1.3 SoA
The footnote symbols in Section 
1.3, Schedule of Activities, for 
BCG administration were 
updated to correctly indicate that 
the suggested BCG re-induction 
schedule is during Cycles 4 and 
5 and that maintenance BCG 
may be given during Cycles 4, 
7, 13, 19, and 25.
Editorial update of 
footnote symbols
1.3 SoA
7.2 Participant 
Discontinuation/Withdrawal 
from study
The window for the EOT visit 
was defined as being within 7 
days after the last dose of PF-
06801591 or BCG (whichever is 
later) or decision to permanently 
discontinue both drugs and 
references to an early 
discontinuation visit were 
removed because participants 
that discontinue early will have 
an EOT visit. References to 
Clarification on timing 
of EOT visit
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Section # and Name
Description of Change
Brief Rationale
early discontinuation were also 
removed in Section 7.2.
1.3 SoA
AEs will be collected during 
Safety Follow-Up, but not 
during Disease Follow-Up 
extending beyond Safety 
Follow-Up with the exception of 
treatment-related SAEs.
Clarification on 
collection of AEs during 
post treatment study 
periods
1.3 SoA
10.2 Clinical Laboratory 
Tests
Pregnancy status will be 
checked at 90 and 180 days after 
EOT for applicable participants.
Clarification on timing 
of pregnancy testing in 
the post treatment study 
period
2.2.1 Clinical background
Safety and efficacy data was 
updated in line with the October 
2019 PF-06801591 IB.
Update of available 
safety and efficacy data 
to align with most recent 
IB.
2.3 Benefit/Risk 
Assessment
Source for additional 
information on BCG was 
clarified to be the local product 
label and the SRSD for BCG 
was clarified to be the TICE 
USPI.
Clarification on source 
of SRSD for BCG
4.1 Overall Design
6.1.2 Administration of 
Study Intervention
Clarification that the 
maintenance period begins at 
C7D1 for participants that 
receive re-induction.
Clarification for sites on 
start of maintenance 
period
4.3.2 BCG
BCG dosing is 1 therapeutic 
dose. This may be 1 or more 
vials depending on the strain and 
the applicable BCG product 
label should be consulted.
Clarification on dose of 
BCG for sites using 
different strains of BCG
5.1 Inclusion criteria
Inclusion criterion 2 was 
updated to include a reference to 
the WHO grading system for 
bladder cancer.  
Grading system used for 
the study was clarified
5.1 Inclusion Criteria
8.1.1 Clinical Assessments
8.8.1 Tumor Tissue 
Assessments
Inclusion criterion 4 was 
updated to clarify that if a 
participant has had multiple 
TURBTs within 12 weeks prior 
to randomization, tumor tissue 
should be provided from the 
TURBT supporting the primary 
diagnosis for the study.
Clarification on which 
tumor tissue to be sent 
for analysis
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Section # and Name
Description of Change
Brief Rationale
5.2 Exclusion criteria
6.5.9 Vaccines
Information about vaccines was 
updated in exclusion criterion 12 
was added to state that live 
attenuated vaccines are not 
allowed as concomitant 
medications and to provide 
examples.
Clarification on 
permitted vaccines while 
on study
5.3 Lifestyle considerations
6.1.1 Medical Devices
8.3 Adverse events and 
SAEs
8.3.6 Cardiovascular and 
Death Events
10.3 Adverse Events
10.4 Contraceptive 
Guidance
Updated due to Pfizer protocol 
template updates.  
Sponsor protocol 
template updates
6.0 Study Intervention
It is recommended that 
participants receive the same 
strain of BCG throughout the 
duration of study treatment.
Reminder to sites 
regarding BCG strain
6.1 Study Intervention
The name of the CHENGDU 
Danish strain was corrected to 
BCG China strain.
Strain terminology 
corrected
6.1 Study Intervention
Updated to indicate that BCG is 
a NIMP in all countries.
Categorization of BCG 
as non -IMP
6.1.2 Administration of 
Study Intervention
It is strongly preferred that 
participants start PF-06801591 
and BCG on the same date if 
possible.
Clarification on timing 
of study drugs
6.1.2 Administration of 
Study Intervention
Clarification that the visit 
window is ±3 days for visits 
prior to Cycle 4 and ±7 days for 
Cycle 4 through EOT.
Visit window 
clarification
6.5.3 Hematopoietic 
Growth Factors
Updated to clarify that 
erythropoietin may not be 
approved for anemia in some 
countries and local guidelines 
should be followed in that case.
Clarification on 
acceptable treatment for 
anemia
6.6.2 Precautions for 
administration of BCG
10.14 Management of irAEs
Updated to clarify that the TICE 
USPI language is provided in 
the protocol as an example for 
BCG-related AE management, 
but the product label for the 
strain of BCG administered 
Source of AE 
management information 
clarified
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Section # and Name
Description of Change
Brief Rationale
should be used for reference if 
other than TICE.
7.1 Discontinuation of 
Study Intervention
Reference to Section 8.2.4 for 
participants with a change in QT 
interval was added.
Cross reference added
8.1.1 Efficacy Assessments
8.1.1.1 Cystoscopy
8.1.1.2 Cytology
8.1.1.3 Imaging
Updated to clarify that biopsies, 
tumor tissue, cytology results, 
and imaging will be submitted 
for BICR assessment.  
Additional details are now given 
on the scope of biopsy and 
tumor tissue to be provided for 
BICR.
Clarification on what 
BICR will review
8.2.7 Clinical Safety Labs
Clarified to state that laboratory 
assessments must be reviewed 
prior to dosing at each visit.
Reminder to sites to 
review labs prior to 
dosing
8.3.10 Medication errors
Medication error examples were 
updated 
Clarification to sites
8.4 Overdose
Definition of overdose and 
instructions for overdose were 
updated 
Clarification and update 
to definitions
8.6 Pharmacodynamics
8.8 Biomarkers
Clarification that PK, PD, and 
biomarker samples will not be 
collected if prohibited by local 
regulations and/or IRBs/ECs.
Clarification on sample 
collection
8.5 Pharmacokinetics
Clarifications about PK samples 
and analysis of PK samples.
Clarifications to site
8.8.3 Immunogenicity
Updated to clarify the timing 
and type of immunogenicity 
assessments.
Clarifications on sample 
test timing
9.2 Sample size 
determination
Hypothesis numbering for the 
secondary objectives were 
corrected.  
Editorial correction
9.3 Population for analysis
Clarification that the PK 
parameter population is the 
same as the PK concentration 
analysis population.
PK population 
clarification
9.4.3.2 Pharmacokinetics
9.4.3.3 Immunogenicity
Updated to remove specific 
details of the ADA and NAb 
analyses, as these will be 
outlined in the SAP.
Editorial update
9.5 Interim Analysis
Table 4
Updated to include  minus signs 
for the efficacy z-value 
boundaries for IA 1 (for both 
Editorial update
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Section # and Name
Description of Change
Brief Rationale
Arm A vs Arm C and Arm B vs 
Arm C) that had been 
inadvertently omitted in the 
original protocol.  
10.1.5 Committees 
Structure
Updated to provide information 
about the Steering Committee.
Clarification
10.2 
Updated to remove the 
requirement for a pre-dose 
C1D1 serum sample for 
cytokine measurement that did 
not appear in the SoA.
Editorial update
10.2 Clinical Laboratory 
Tests
Table 5
Updated to indicate that either 
PTT or aPTT may be reported 
for the coagulation panel.
Testing clarification
10.8 Country specific 
amendments
Updated to include country 
specific requirements in France 
(Contrat Unique) and Japan 
(regulatory language for medical 
device studies).
Regional requirement 
added
10.12 Recommendations for 
management of 
Allergic/Hypersensitivity 
Reactions
Corrected to refer to Section 
6.6.1 of the protocol for 
guidance on treatment, dose 
interruptions, and potential 
retreatment.
Editorial update
10.13 Management of irAEs
The cardiac irAE section of 
Section 10.13 was updated to 
give troponin I, as opposed to 
troponin, as an example of a 
cardiac biomarker that may be 
elevated and to include 
abatacept as an example of an 
immunosuppressant to treat 
cardiac irAEs.
Clinical update and 
clarification
10.15 Alternative Measures 
during Public Emergencies
Added in response to the 
COVID-19 pandemic and any 
potential future public 
emergencies.
Addition post COVID-
19 pandemic
All
Typos and inconsistencies were 
corrected, minor clarifications 
were added, language that is not 
applicable has been removed, 
formatting of graphics was 
Editorial update
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Section # and Name
Description of Change
Brief Rationale
updated for readability as 
needed, and the abbreviation list 
was updated.
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10.18. Appendix 18: Abbreviations
Abbreviation
Term
Ab
antibody
ACTH
adrenocorticotropic hormone 
ADA
anti-drug antibodies
ADE
adverse device effect
ADL
activities of daily living
AE
adverse event
AESI
adverse events of special interest
Ag
antigen
AHA
American Heart Association
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ANOVA
analysis of variance
aPTT
activated partial thromboplastin time
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
AUA
American Urological Association
AUC
Area Under the Curve
AV
atrioventricular
BBS
Biospecimen Banking System
BC
bladder cancer
BCG
Bacille Calmette Guérin 
BICR
blinded independent central review
BNP
B-type natriuretic peptide
BP
blood pressure
bpm
beats per minute
BUN
blood urea nitrogen
CD8
cluster of differentiation-8
cfDNA
circulating free DNA
CFR
Code of Federal Regulations
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CIS
carcinoma in situ
CK
creatine kinase
CK-MB
creatine kinase-muscle type, myocardial band
CK-MM
creatine kinase-skeletal muscle
Cmax
maximum observed concentration
CNIL
French data protection authority
CONSORT
Consolidated Standards of Reporting Trials
COVID-19
coronavirus disease 2019
CR
complete response
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Abbreviation
Term
CREST
Combination of sasanlimab and alternative BCG Regimens to Evaluate 
outcomes with Subcutaneous anti-PD-1 Treatment
CRF
case report form
CRO
contract research organization
CSR
clinical study report
CT
computed tomography / clinical trial
CTCAE
Common Terminology Criteria for Adverse Events
CTLA-4
cytotoxic T lymphocyte-associated antigen 4
Ctrough
concentration at trough
CxDx
cycle x day x
DILI
drug-induced liver injury
DLT
dose-limiting toxicity
DNA
deoxyribonucleic acid
DSS
disease-specific survival
EAU
European Association of Urology
EC
Ethics committee
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDMC
external data monitoring committee
EDP
exposure during pregnancy
EFS
event free survival
EMA
European Medicines Agency
EORTC
European Organisation for Research and Treatment of Cancer
EORTC-GU
EORTC-Genito-Urinary
EORTC-QLQ 
NMIBC24
EORTC-Quality of Life Questionnaire Non-Muscle Invasive Bladder 
Cancer 24 (items)
EOT
end of treatment
ESC
European Society of Cardiology
EQ-5D-5L
EuroQol 5 Dimensions, 5-Level
EU
European Union
EudraCT
European Clinical Trials Database
FA
final analyses
FDA
Food and Drug Administration
FFPE
formalin-fixed paraffin-embedded
FSH
follicle-stimulating hormone
FT4
free thyroxine
GCP
Good Clinical Practice
G-CSF
granulocyte colony-stimulating factor
GGT
gamma-glutamyl transferase
GH
growth hormone
HBcAb
hepatitis B core antibody
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Abbreviation
Term
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HG
High-grade
HIPPA
Health Insurance Portability and Accountability Act
HR
hazard ratio
HRQoL
health-related quality of life
HRT
hormone replacement therapy
IA
interim analysis
IB
Investigator's Brochure
ICD
informed consent document
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IgA
immunoglobulin A
IGF-1
insulin-like growth factor 1
IgG
immunoglobulin G
IHC
immunohistochemistry
IL
interleukin
IMP
investigational medicinal product
IND
Investigational new drug
INF-y
interferon-y
INR
international normalized ratio
IP
investigational product
irAE
immune-related adverse events
IRB
Institutional Review Board
IRT
interactive response technology
ISO
International Organization for Standardization
IUD
Intrauterine Device
IUS
Intrauterine hormone-releasing system
IV
Intravenous
IVRS
interactive voice response system
IWRS
Interactive Web Response System
LDH
lactate dehydrogenase
LFT
liver function test
LH
luteinizing hormone
LLQ
lower limit of quantitation
mAbs
monoclonal antibodies
MQI
Medically qualified individual
MRI
magnetic resonance imaging
MTD
maximum tolerated dose 
MWPC
meaningful within person change
N+
lymph node positive disease
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Abbreviation
Term
N/A
not applicable
NAb
neutralizing antibodies
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse 
Events
NIMP
non-investigational medicinal product
NMIBC
non-muscle invasive bladder cancer
NSCLC
non-small cell lung cancer
ORR
objective response rate
OS
overall survival
PCD
primary completion date
PD
pharmacodynamics; progressive disease
PD-1
programmed death - 1
PD-L
programmed death - ligand
PFS
pre-filled syringe 
PGIC
Patient Global Impression of Change
PGIS
Patient Global Impression of Severity
PK
pharmacokinetics
PR
partial response
PRL
prolactin
PRO
patient reported outcome
PS
performance status
PT
prothrombin time
PTAB
Patient Treatment Administration Burden
PTT
partial thromboplastin time
PVC
premature ventricular complexes
Q3W
every 3 weeks
Q4W
every 4 weeks
Q6W
Every 6 weeks
QLQ-C30
Quality of Life Questionnaire–30 (items)
QT
time from the beginning of the QRS complex to the end of the T wave
QTc
QT interval corrected for heart rate
QTcF
QTc corrected using Fridericia's formula
QW
once weekly
QxW
every X weeks
RCI
repeated confidence interval
RMST
restricted mean survival time
RNA
ribonucleic acid
ROW
rest of world
SADE
serious adverse device effect
SAE
serious adverse event
SAP
Statistical Analysis Plan
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Abbreviation
Term
SARS-CoV2
severe acute respiratory syndrome coronavirus
SC
subcutaneous
SCCHN
squamous cell carcinoma of the head and neck
SD
standard deviation
SE
standard error
SoA
schedule of activities
SOC
standard of care
SOP
standard operating procedure
SRSD
single reference safety document
SUSAR
Suspected Unexpected Serious Adverse Reaction
SWOG
Southwest Oncology Group
T1
stage of cancer in which the cancer cells are only growing in the most 
superficial layer of tissues and have not grown into deeper tissues; in 
bladder cancer, T1 is defined as an invasion into the lamina propria 
without invasion into the muscularis propria
t1/2
terminal phase half-life
T3
triiodothyronine
T4
thyroxine
Ta
stage of bladder cancer defined as a non-invasive papillary carcinoma
TBili
total bilirubin
TCC
transitional cell carcinoma
TEAE
treatment-emergent adverse event
TIL
tumor infiltrating lymphocytes
Tmax
time to first occurrence of Cmax
TNF
tumor necrosis factor
TRAE
Treatment-related adverse event
TSH
thyroid stimulating hormone
TSQ
Treatment Satisfaction Questionnaire
TURBT
transurethral resection of the bladder tumor
UC
urothelial cancer
ULN
upper limit of normal 
UPCR
urine protein:creatinine ratio
US
United States
USA
United States of America
USADE
unexpected serious adverse device effect  
USPI
United States Prescribing Information
UTI
Urinary tract infection
VAS
visual analog scale 
WBC
white blood cells
WHO
World Health Organization
WOCBP
woman/women of childbearing potential
   
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