Clinical trial NCT04586244
Conditions: Urothelial Carcinoma
Keywords: Muscle-invasive cisplatin-ineligible urothelial carcinoma of the bladder radical cystectomy. epacadostat retifanlimab TIM-3 LAG-3
Sponsor: Incyte Corporation
Start date: 2022-01-14; Completion date: 2024-01-29
Enrollment: 30 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a multicenter, open-label, randomized, Phase 2 umbrella study of various neoadjuvant treatment combinations in participants who have muscle-invasive urothelial carcinoma of the bladder and are cisplatin-ineligible or refusing cisplatin therapy and awaiting radical cystectomy.

Detailed description:
Participants will be stratified based on Programmed cell Death-Ligand 1 (PD-L1) Combined Positive Score ( CPS) \< 10 and PD-L1 CPS ≥ 10.

Arms: arm 1: epacadostat will be administered in combination with retifanlimab. arm 2: retifanlimab will be administered as monotherapy. arm 3: epacadostat will be administered as monotherapy. arm 4: retifanlimab will be administered in combination with INCAGN02385. arm 5: retifanlimab will be administered in combination with INCAGN02385 and INCAGN02390.
Interventions: intervention 1: retifanlimab intervention 2: epacadostat intervention 3: INCAGN02385 intervention 4: INCAGN02390
Intervention descriptions: intervention 1: retifanlimab will be administered via IV over 30 minutes (+ 15 min) on Day 1 of each 28-day cycle, up to 3 cycles, intervention 2: epacadostat will be administered daily twice daily orally up to and including day of surgery. intervention 3: INCAGN02385 will be administered via IV over 30 minutes (-5/+10 min) every 2 weeks. intervention 4: INCAGN02390 will be administered via IV over 30 minutes (-5/+10 min) every 2 weeks.

Protocol documents:
Prot_000.pdf: 
Official Title: 
An Open-Label, Randomized, Phase 2, Umbrella Study of Various 
Neoadjuvant Therapies for Participants With Muscle-Invasive 
Urothelial Carcinoma of the Bladder Who Are Cisplatin-Ineligible or 
Refuse Cisplatin Therapy and Undergoing Radical Cystectomy 
(Optimus) 
NCT Number: 
NCT04586244 
Document Date:     Clinical Study Protocol (Amendment 4): 01 MAR 2022 


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Clinical Study Protocol 
TITLE PAGE 
INCB 24360-901 
An Open-Label, Randomized, Phase 2, Umbrella Study of Various 
Neoadjuvant Therapies for Participants With Muscle-Invasive Urothelial 
Carcinoma of the Bladder Who Are Cisplatin-Ineligible or Refuse 
Cisplatin Therapy and Undergoing Radical Cystectomy (Optimus) 
Product: 
Epacadostat (INCB024360), retifanlimab (INCMGA00012), 
INCAGN02385, INCAGN02390 
IND Number: 
146,743 
EudraCT Number: 
2020-002244-23 
Phase of Study: 
2 
Sponsor: 
Incyte Corporation 
1801 Augustine Cut-Off 
Wilmington, DE 19803 
Original Protocol: 
12 MAY 2020 
Protocol Amendment 1: 
04 SEP 2020 
Protocol Amendment 2: 
02 FEB 2021 
Protocol Amendment 3: 
10 MAY 2021 
Protocol Amendment 2-IT 
14 JUL 2021 
Protocol Amendment 4: 
01 MAR 2022 
This study will be performed in accordance with ethical principles that have their origin in the Declaration of 
Helsinki and conducted in adherence to the study Protocol, applicable Good Clinical Practices, and applicable laws 
and country-specific regulations in which the study is being conducted. 
The information in this document is confidential.  No part of this information may be duplicated, referenced, or 
transmitted in any form or by any means (electronic, mechanical, photocopy, recording, or otherwise) without prior 
written consent. 


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 INVESTIGATOR'S AGREEMENT 
I have read the INCB 24360-901 Protocol Amendment 4 (dated 01 MAR 2022) and agree to 
conduct the study as outlined.  I agree to maintain the confidentiality of all information received 
or developed in connection with this Protocol. 
 
 
 
 
 
(Printed Name of Investigator) 
 
 
 
 
 
 
 
 
(Signature of Investigator) 
 
(Date) 


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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
INVESTIGATOR'S AGREEMENT ................................................................................................2 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF ABBREVIATIONS ..........................................................................................................9 
1. 
PROTOCOL SUMMARY ..........................................................................................13 
2. 
INTRODUCTION ......................................................................................................38 
2.1. 
Study Rationale ...........................................................................................................38 
2.1.1. 
Scientific Rationale for Study Design ........................................................................38 
2.1.2. 
Treatment Group Rationale ........................................................................................40 
2.1.3. 
Retifanlimab ...............................................................................................................41 
2.1.3.1. 
Rationale for Retifanlimab Dose ................................................................................41 
2.1.4. 
Epacadostat .................................................................................................................42 
2.1.4.1. 
Rationale for Epacadostat Dose ..................................................................................42 
2.1.5. 
Combination of Epacadostat Plus Retifanlimab .........................................................42 
2.1.6. 
INCAGN02385 ...........................................................................................................43 
2.1.6.1. 
Rationale for INCAGN02385 Dose............................................................................43 
2.1.7. 
INCAGN02390 ...........................................................................................................43 
2.1.7.1. 
Rationale for INCAGN02390 Dose............................................................................43 
2.1.8. 
Combination of Retifanlimab Plus INCAGN02385 ...................................................44 
2.1.9. 
Combination of Retifanlimab Plus INCAGN02385 Plus INCAGN02390 ................44 
2.1.10. 
Combination of Retifanlimab Plus INCAGN02385 and Combination of 
Retifanlimab Plus INCAGN02385 Plus INCAGN02390...........................................44 
2.2. 
Benefit/Risk Assessment ............................................................................................45 
2.2.1. 
Monotherapy Risks .....................................................................................................45 
2.2.1.1. 
Retifanlimab ...............................................................................................................45 
2.2.1.2. 
Epacadostat .................................................................................................................45 
2.2.2. 
Combination Therapy Risks .......................................................................................45 
2.2.2.1. 
Epacadostat and Retifanlimab ....................................................................................45 
2.2.2.2. 
Retifanlimab, INCAGN02385, and INCAGN02390 ..................................................46 
2.2.3. 
Risks of Delayed Cystectomy .....................................................................................46 
2.2.3.1. 
Treatment-Emergent Adverse Events of Special Interest ...........................................47 
2.2.4. 
Benefits .......................................................................................................................51 


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2.2.5. 
Benefit/Risk Assessment During the COVID-19 Pandemic ......................................51 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................52 
4. 
STUDY DESIGN .......................................................................................................53 
4.1. 
Overall Design ............................................................................................................53 
4.2. 
Overall Study Duration ...............................................................................................54 
4.3. 
Study Termination ......................................................................................................54 
5. 
STUDY POPULATION .............................................................................................55 
5.1. 
Inclusion Criteria ........................................................................................................55 
5.2. 
Exclusion Criteria .......................................................................................................56 
5.3. 
Lifestyle Considerations .............................................................................................60 
5.3.1. 
Meals and Dietary Restrictions ...................................................................................60 
5.4. 
Screen Failures ............................................................................................................60 
5.5. 
Replacement of Participants .......................................................................................61 
5.6. 
Data Safety Monitoring Board ....................................................................................61 
6. 
STUDY TREATMENT ..............................................................................................61 
6.1. 
Study Treatments Administered .................................................................................61 
6.2. 
Preparation, Handling, and Accountability ................................................................64 
6.3. 
Measures to Minimize Bias:  Randomization and Blinding .......................................65 
6.4. 
Study Treatment Compliance .....................................................................................65 
6.5. 
Dose Modifications .....................................................................................................65 
6.5.1. 
Criteria and Procedures for Dose Interruptions and Adjustments of Study 
Drugs ...........................................................................................................................65 
6.5.1.1. 
Retifanlimab, INAGN02385, and INCAGN02390 ....................................................65 
6.5.1.2. 
Epacadostat .................................................................................................................66 
6.5.1.3. 
All Study Treatments ..................................................................................................66 
6.5.2. 
Management of Suspected Infusion Reactions ...........................................................66 
6.5.3. 
Procedures for Participants Exhibiting Immune-Related Adverse Events .................67 
6.5.4. 
Procedures for Participants Exhibiting Drug-Related, Non–Immune-Related 
Adverse Events ...........................................................................................................74 
6.5.5. 
Procedures for Participants in the Epacadostat Groups Exhibiting Serotonin 
Syndrome ....................................................................................................................74 
6.5.6. 
Criteria for Permanent Discontinuation of Study Drug ..............................................76 
6.6. 
Concomitant Medications and Procedures .................................................................76 


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6.6.1. 
Permitted Medications and Procedures ......................................................................77 
6.6.2. 
Restricted Medications and Procedures ......................................................................77 
6.6.3. 
Prohibited Medications and Procedures .....................................................................77 
7. 
DISCONTINUATION OF STUDY TREATMENT AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................79 
7.1. 
Discontinuation of Study Treatment ...........................................................................79 
7.1.1. 
Reasons for Discontinuation .......................................................................................79 
7.1.2. 
Discontinuation Procedures ........................................................................................79 
7.2. 
Participant Withdrawal From the Study .....................................................................80 
7.3. 
Lost to Follow-Up.......................................................................................................80 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................81 
8.1. 
Administrative and General Procedures .....................................................................81 
8.1.1. 
Informed Consent Process ..........................................................................................81 
8.1.2. 
Screening Procedures ..................................................................................................82 
8.1.3. 
Interactive Response Technology Procedure ..............................................................82 
8.1.4. 
Distribution of Reminder Cards ..................................................................................82 
8.1.5. 
Demography and Medical History ..............................................................................83 
8.1.5.1. 
Demographics and General Medical History .............................................................83 
8.1.5.2. 
Disease Characteristics and Treatment History ..........................................................83 
8.2. 
Efficacy Assessments .................................................................................................83 
8.2.1. 
Pathological Complete Response, Major Pathological Response, and 
 ......................................................................83 
8.2.2. 
Health Economics .......................................................................................................83 
8.3. 
Safety Assessments .....................................................................................................83 
8.3.1. 
Adverse Events ...........................................................................................................84 
8.3.2. 
Physical Examinations ................................................................................................84 
8.3.3. 
Vital Signs ..................................................................................................................85 
8.3.4. 
Electrocardiograms .....................................................................................................85 
8.3.5. 
Laboratory Assessments .............................................................................................85 
8.3.5.1. 
Pregnancy Testing ......................................................................................................88 
8.3.6. 
Eastern Cooperative Oncology Group Performance Status ........................................88 
8.3.7. 
Postsurgical Criteria for Adverse Events ....................................................................88 
8.4. 
 Immunogenicity Assessments ..................................................89 


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8.4.1. 
Blood Sample Collection for Monoclonal Antibodies ...............................................90 
8.4.1.1. 
Immunogenicity (Antidrug Antibody) Assessments ..................................................91 
 
91 
8.4.3. 
Bioanalytical Methodology and Sample Analysis ......................................................91 
8.5. 
Pharmacodynamic and Translational Assessments ....................................................91 
8.5.1. 
Timing of Assessments ...............................................................................................91 
8.5.2. 
Tissue Biopsy Collection Requirements .....................................................................92 
 
93 
 
93 
 
93 
 
93 
8.6. 
Unscheduled Visits .....................................................................................................94 
8.7. 
End of Treatment and/or Early Termination ..............................................................94 
8.8. 
Follow-Up ...................................................................................................................94 
8.8.1. 
Safety Follow-Up ........................................................................................................94 
9. 
ADVERSE EVENTS:  DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ......................95 
9.1. 
Definition of Adverse Event .......................................................................................95 
9.2. 
Definition of Serious Adverse Event ..........................................................................96 
9.3. 
Recording and Follow-Up of Adverse Events and/or Serious Adverse Events .........97 
9.4. 
Reporting of Serious Adverse Events .........................................................................99 
9.5. 
Adverse Events of Special Interest ...........................................................................100 
9.6. 
Emergency Unblinding of Treatment Assignment ...................................................101 
9.7. 
Pregnancy .................................................................................................................101 
9.8. 
Warnings and Precautions ........................................................................................102 
9.9. 
Product Complaints ..................................................................................................102 
10. 
STATISTICS ............................................................................................................103 
10.1. 
Sample Size Determination ......................................................................................103 
10.2. 
Populations for Analysis ...........................................................................................103 
10.3. 
Level of Significance ................................................................................................104 
10.4. 
Statistical Analyses ...................................................................................................104 
10.4.1. 
Primary Analysis ......................................................................................................104 
10.4.2. 
Secondary Analysis ..................................................................................................105 


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 ................................................................................................105 
 
 ........................................................................................106 
10.5. 
Interim Analysis ........................................................................................................106 
11. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ................................................................................................107 
11.1. 
Investigator Responsibilities .....................................................................................107 
11.1.1. 
Identification of the Coordinating Principal Investigator .........................................108 
11.2. 
Data Management .....................................................................................................108 
11.3. 
Data Privacy and Confidentiality of Study Records .................................................109 
11.4. 
Financial Disclosure .................................................................................................110 
11.5. 
Publication Policy .....................................................................................................110 
11.6. 
Study and Site Closure..............................................................................................111 
12. 
REFERENCES .........................................................................................................112 
APPENDIX A. INFORMATION REGARDING EFFECTIVENESS OF 
CONTRACEPTIVE METHODS .............................................................................117 
APPENDIX B. THE AMERICAN JOINT COMMITTEE ON CANCER STAGING 
SYSTEM 8TH EDITION, 2017 ...............................................................................118 
APPENDIX C. CRITERIA DEFINING CISPLATIN INELIGIBILITY .................................119 
APPENDIX D. CLAVIEN-DINDO GRADING SYSTEM FOR THE 
CLASSIFICATION OF SURGICAL COMPLICATIONS .....................................120 
APPENDIX E. STUDIES AND PARTICIPANT GROUPS INCLUDED IN SAFETY 
ANALYSIS...............................................................................................................121 
APPENDIX F. CYP1A2, CYP2C8, AND CYP2C19 SUBSTRATES OR OATP1B1 
AND OATP1B3 TRANSPORTERS ........................................................................124 
APPENDIX G. COVID-19 PANDEMIC MITIGATION STRATEGIES AND 
INSTRUCTION ........................................................................................................125 
APPENDIX H. PROTOCOL AMENDMENT SUMMARY OF CHANGES .........................127 
 
LIST OF TABLES 
Table 1: 
Primary and Secondary Objectives and Endpoints .....................................................13 
Table 2: 
Key Study Design Elements .......................................................................................14 
Table 3: 
Schedule of Activities for Participants Receiving Epacadostat Plus 
Retifanlimab (Treatment Group A) ............................................................................16 
Table 4: 
Schedule of Activities for Participants Receiving Retifanlimab Monotherapy 
(Treatment Group B) ..................................................................................................20 


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Table 5: 
Schedule of Activities for Participants Receiving Epacadostat Monotherapy 
(Treatment Group C) ..................................................................................................24 
Table 6: 
Schedule of Activities for Participants Receiving Retifanlimab Plus 
INCAGN02385 (Treatment Group D) ........................................................................28 
Table 7: 
Schedule of Activities for Participants Receiving Retifanlimab Plus 
INCAGN02385 Plus INCAGN02390 (Treatment Group E)......................................33 
Table 8: 
Summary of TEAOSI for Select Studies With Retifanlimab and Epacadostat 
That Occurred Within the First 12 Weeks of Treatment ............................................48 
Table 9: 
Grade 2 or Higher Immune-Related TEAEs for Studies With Retifanlimab 
and Epacadostat (Multiple Tumor Types) ..................................................................49 
Table 10: Grade 2 or Higher Immune-Related TEAEs for Studies With 
INCAGN02385, INCAGN02390, and Retifanlimab..................................................50 
Table 11: Objectives and Endpoints ...........................................................................................52 
Table 12: Exclusionary Laboratory Values ................................................................................57 
Table 13: Study Treatment and Treatment Group Information ..................................................62 
Table 14: Guidelines for Management of Suspected Infusion Reactions ...................................67 
Table 15: Dose Modification and Toxicity Management Guidelines for 
Immune-Related Adverse Events ...............................................................................69 
Table 16: Management Guidelines for Drug-Related, Non–Immune-Related Adverse 
Events .........................................................................................................................74 
Table 17: Signs and Symptoms of Serotonin Syndrome ............................................................75 
Table 18: Required Laboratory Analytes ....................................................................................87 
Table 19: Eastern Cooperative Oncology Group Performance Status ........................................88 
Table 20: Timing of 
 Antidrug Antibody Serum Sample 
Collection ....................................................................................................................90 
 
 
 ...........................91 
Table 22: Sample Size Determination ......................................................................................103 
Table 23: Populations for Analysis ...........................................................................................104 
 
LIST OF FIGURES 
Figure 1: 
Study Design Schema .................................................................................................15 
 


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LIST OF ABBREVIATIONS 
Abbreviations and 
Special Terms 
Definition 
AE 
adverse event 
AESI 
adverse event of special interest 
AJCC 
American Joint Committee on Cancer 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
anti-HBc 
anti–hepatitis B core antibody 
anti-HBs 
anti–hepatitis B surface antibody 
aPTT 
activated partial thromboplastin time 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
AUC0-∞ 
area under the single-dose plasma or serum concentration-time curve 
extrapolated to infinity  
AUC0-t 
area under the plasma or serum concentration-time curve from time = 0 to the 
last measurable concentration at time = t  
BCG 
Bacillus Calmette-Guérin 
BID 
twice daily 
BSA 
body surface area 
 
 
CI 
confidence interval 
Cmax 
maximum observed plasma or serum concentration  
Cmin 
minimum observed plasma or serum concentration over the dose interval  
CO2 
carbon dioxide 
COVID-19 
coronavirus disease 2019 
CPS 
combined positive score 
CR 
complete response  
CSR 
clinical study report 
CT 
computed tomography  
CTCAE 
Common Terminology Criteria for Adverse Events 
CTFG 
Clinical Trials Facilitation and Coordination Group 
CTLA-4 
cytotoxic T-lymphocyte-associated protein 4  
CYP 
cytochrome P450  
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
DSMB 
Data Safety Monitoring Board  


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Abbreviations and 
Special Terms 
Definition 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form  
EDC 
electronic data capture  
EDTA 
ethylenediaminetetraacetic acid 
ELISA 
enzyme-linked immunosorbent assay 
EORTC 
European Organisation for Research and Treatment of Cancer 
EOI 
end of infusion 
EOT 
end of treatment 
ESMO 
European Society for Medical Oncology 
Fc 
fragment crystallizable 
FDA 
Food and Drug Administration 
FGFR 
fibroblast growth factor receptor 
GCP 
Good Clinical Practice 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HIV 
human immunodeficiency virus 
IB 
Investigator's Brochure 
IC50 
concentration that results in 50% inhibition  
IC90 
concentration that results in 90% inhibition  
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
ICF 
informed consent form  
IDO1 
indoleamine 2,3-dioxygenase 
IEC 
independent ethics committee 
IFN-γ  
interferon gamma 
Ig  
immunoglobulin  
IHC  
immunohistochemistry  
IL  
interleukin  
INR 
international normalized ratio 
irAE 
immune-related adverse event 
IRB 
institutional review board 
IRT 
interactive response technology 
IV 
intravenous 


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Abbreviations and 
Special Terms 
Definition 
LAG-3 
lymphocyte activation gene 3 
LFT 
liver function test 
MAOI  
monoamine oxidase inhibitor  
MedDRA 
Medical Dictionary for Regulatory Activities 
miUBC 
muscle-invasive urothelial bladder cancer 
MRC 
Medical Research Council 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
N/A 
not applicable 
NCI 
National Cancer Institute 
NE 
no estimate 
NSAID 
nonsteroidal anti-inflammatory drug 
NSCLC 
non–small cell lung cancer 
NYHA 
New York Heart Association 
ORR  
overall response rate  
OS 
overall survival 
pCR 
pathological complete response 
PD 
progressive disease  
PD-1 
programmed cell death protein 1 
PD-L1 
programmed cell death-ligand 1 
PD-L2 
programmed cell death-ligand 2 
PFS  
progression-free survival  
PK 
pharmacokinetic 
PO 
oral 
PP 
per Protocol 
PR 
partial response 
PS 
performance status 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
Q2W 
every 2 weeks 
Q3W 
every 3 weeks 
Q4W 
every 4 weeks 
 
 
QD 
once daily 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
ribonucleic acid 


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Abbreviations and 
Special Terms 
Definition 
RP2D 
recommended Phase 2 dose 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SD 
stable disease 
SJS 
Stevens-Johnson syndrome 
SNRI 
selective serotonin/norepinephrine reuptake inhibitors  
SoA 
schedule of activities 
SOP 
standard operating procedure  
SSRI 
selective serotonin reuptake inhibitors  
T3/FT3 
triiodothyronine  
T4  
thyroxine  
TEN 
toxic epidermal necrolysis 
TIM-3 
T cell immunoglobulin and mucin domain-containing protein 3 
TEAE 
treatment-emergent adverse event 
TEAOSI 
treatment-emergent adverse event of special interest 
TIL 
tumor-infiltrating lymphocyte 
TSH 
thyroid-stimulating hormone 
TURBT 
transurethral resection of bladder tumor 
ULN 
upper limit of normal 
WBC 
white blood cell 
 


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1. 
PROTOCOL SUMMARY 
This is an umbrella study to investigate the biological rationale and outcomes for selected 
monotherapy and combination therapies in order to inform of potential neoadjuvant treatment 
combinations to be further tested in miUBC in cisplatin-ineligible participants or participants 
who refuse cisplatin-based therapy and are awaiting radical cystectomy. 
Protocol Title: 
An Open-Label, Randomized, Phase 2, Umbrella Study of Various Neoadjuvant Therapies for 
Participants With Muscle-Invasive Urothelial Carcinoma of the Bladder Who Are 
Cisplatin-Ineligible or Refuse Cisplatin Therapy and Undergoing Radical Cystectomy (Optimus) 
Protocol Number:  INCB 24360-901 
Objectives and Endpoints: 
Table 1 presents the primary and major/key secondary endpoints and objectives. 
Table 1: 
Primary and Secondary Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
To determine biologic response in participants 
with muscle-invasive cisplatin-ineligible or those 
refusing cisplatin therapy, urothelial carcinoma of 
the bladder. 
For each treatment group, the primary endpoint is 
the change from baseline in CD8+ lymphocytes 
within resected tumor.  
Secondary 
To evaluate the safety and tolerability of each of 
the treatment groups. 
• 
Safety and tolerability assessed by monitoring 
the frequency and severity of AEs, including 
delay in cystectomy due to AEs. 
To evaluate the preliminary efficacy of each of 
the treatment groups. 
• 
pCR rate, defined as percentage of 
participants with ypT0N0 in each treatment 
group. 
• 
Major pathological response, defined as 
residual ypT0/1/a/isN0M0. 
Overall Design: 
Table 2 presents the key study design elements.  Further study details are presented after the 
table. 


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Table 2: 
Key Study Design Elements 
Study Phase 
Phase 2 
Clinical Indication 
Patients with muscle-invasive urothelial carcinoma of the bladder who are undergoing 
radical cystectomy and are either cisplatin-ineligible or refuse cisplatin therapy. 
Population 
Male and female participants at least 18 years of age who have miUBC and are 
undergoing radical cystectomy and refuse cisplatin therapy or are not eligible for 
cisplatin-based neoadjuvant chemotherapy, based on Galsky criteria. 
Number of 
Participants 
This is a platform design, and new treatment arms may be added or others removed.  
Currently, approximately 81 evaluable participants will be assigned to 1 of 5 treatment 
groups (18 participants in Treatment Groups A, B, D, and E, respectively, and 
9 participants in Treatment Group C). 
Study Design 
This is a multicenter, open-label, randomized, Phase 2, multitreatment group, 
window-of-opportunity, umbrella study for participants with miUBC undergoing 
radical cystectomy who refuse or are not eligible for cisplatin-based neoadjuvant 
chemotherapy.  Participants will be assigned based on tumor tissue PD-L1 CPS ≥ 10 or 
PD-L1 CPS < 10 to 1 of the following treatment groups: 
Treatment Group A (epacadostat plus retifanlimab) 
Treatment Group B (retifanlimab monotherapy) 
Treatment Group C (epacadostat monotherapy) 
Treatment Group D (retifanlimab plus INCAGN02385) 
Treatment Group E (retifanlimab plus INCAGN02385 plus INCAGN02390) 
Total treatment duration is a maximum of 10 weeks to reflect a window of opportunity 
before radical cystectomy. 
The study is a platform study design, which allows for addition of future treatment 
groups. 
Each treatment group will undergo an initial fresh biopsy (while undergoing TURBT) 
followed by neoadjuvant treatment, depending on the treatment group assigned, the 
treatment will be at least 4 weeks, followed by surgery (radical cystectomy).  The 
treatment duration will be a maximum of 10 weeks.  
In all treatment groups, tissue from the surgical specimen(s) will be collected and will 
be compared with the initial biopsy samples to determine biologic response to the 
assigned treatment.  All participants will then be followed for safety for 90 days after 
cystectomy or after the last dose of study treatment if cystectomy is not performed. 
Estimated Duration of 
Study Participation 
Up to 28 days for screening, continuous treatment for 4 to 10 weeks as long as 
participants have not met any criteria for study withdrawal, followed by surgery, 
30-day safety follow-up after the last dose, and 90 days follow-up after cystectomy.  In 
the event that the participant does not undergo a cystectomy, the follow-up visit will be 
90 days after the last dose of study treatment.  The estimated duration of study 
participation is approximately 6 months. 
DSMB 
A DSMB will be used. 
Coordinating 
Principal Investigator 
 MD 
 
Treatment Groups and Duration: 
Figure 1 presents the study design schema, and Table 3 through Table 7 present the SoA. 


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Figure 1: 
Study Design Schema 
 
1Treatment duration is based on date of radical cystectomy.  Participants should receive a minimum of 4 weeks and maximum of 10 weeks of treatment.  
The current sample size represents an estimated number of participants per treatment group in order to attain the necessary evaluable 
paired biopsies.  Additional participants will be enrolled in treatment groups to ensure the number of evaluable paired biopsies are 
obtained.  This is a platform design, and additional treatment arms may be added or removed in the future.   
Adherence to the study design requirements, including those specified in the SoA, is essential and required for study conduct. 


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Table 3: 
Schedule of Activities for Participants Receiving Epacadostat Plus Retifanlimab (Treatment Group A) 
Visit Day (Range) 
Screening 
Treatment (Cycle Is Q4W) 
Precystectomy 
(2 wk Before 
Cystectomy) 
Cystectomy 
(± 2 wk) 
Safety Follow-Up 
Notes 
Days –28 
to –1 
Cycle 1 
Cycle 2 
Cycle 3 
30 Days After 
Cystectomy (or 
After Last Dose 
If Cystectomy 
Not Performed) 
90 Days After 
Cystectomy (or 
After Last Dose 
If Cystectomy 
Not Performed) 
 
Day 1 
Day 1  
(± 3 d) 
Day 1 
(± 3 d) 
Informed consent 
X 
 
 
 
 
 
 
 
Section 8.1.1. 
Inclusion/exclusion 
criteria 
X 
X 
 
 
 
 
 
 
Section 5. 
General and disease 
medical history 
X 
 
 
 
 
 
 
 
Section 8.1.5. 
Prior/concomitant 
medications 
X 
X 
X 
X 
X 
 
X 
X 
Section 6.6. 
Cystectomy 
 
 
 
 
 
X 
 
 
 
Safety assessments 
AE assessments 
X 
X 
X 
X 
X 
X 
X 
X 
Body systems with 
symptoms should be 
physically examined.  AEs 
should be collected until 
90 days after cystectomy or 
the last dose of either study 
drug if cystectomy not 
performed; this may occur 
via telephone. 
Section 8.3.1. 
Physical 
examination/height/ 
body weight 
X* 
X 
X 
X 
X 
 
X 
X 
*Comprehensive physical 
examination (including 
hearing and peripheral 
neuropathy assessments) 
and height at screening 
only. 
Section 8.3.2. 
Vital signs 
X 
X 
X 
X 
X 
 
X 
X 
Section 8.3.3. 
12-lead ECG 
X 
X 
X 
X 
X 
 
X 
 
Section 8.3.4. 
ECOG PS 
X 
X 
X 
X 
X 
 
X 
 
Section 8.3.6. 
Postsurgical safety 
assessments 
 
 
 
 
 
 
X 
 
Section 8.3.7 and 
Appendix D for details. 


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Table 3: 
Schedule of Activities for Participants Receiving Epacadostat Plus Retifanlimab (Treatment Group A) 
(Continued) 
Visit Day (Range) 
Screening 
Treatment (Cycle Is Q4W) 
Precystectomy 
(2 wk Before 
Cystectomy) 
Cystectomy 
(± 2 wk) 
Safety Follow-Up 
Notes 
Days –28 
to –1 
Cycle 1 
Cycle 2 
Cycle 3 
30 Days After 
Cystectomy (or 
After Last Dose 
If Cystectomy 
Not Performed) 
90 Days After 
Cystectomy (or 
After Last Dose 
If Cystectomy 
Not Performed) 
 
Day 1 
Day 1  
(± 3 d) 
Day 1 
(± 3 d) 
Efficacy assessments 
Radiologic tumor 
assessments 
X 
 
 
 
X 
 
 
X 
CT/MRI of the abdomen 
and pelvis and CT scan of 
the thorax (RECIST v1.1). 
Pathological tumor 
assessments 
X 
 
 
 
 
X 
 
 
Pathological tumor 
assessments include 
pathological complete 
response, major 
pathological response, 
 
   
Section 8.2.1. 
Tumor tissue 
sampling 
X 
 
 
 
 
X 
 
 
Section 8.5.2. 
Laboratory assessments 
Blood chemistry 
X 
X* 
X 
X 
X 
 
X 
 
Locally tested. 
*Not necessary if screening 
assessment performed 
within 7 days of C1D1. 
Section 8.3.5. 
Hematology 
X 
X* 
X 
X 
X 
 
X 
 
Locally tested. 
*Not necessary if screening 
assessment performed 
within 7 days of C1D1. 
Section 8.3.5. 
Thyroid function 
X 
 
X 
X 
X 
 
X 
 
Locally tested. 
Lipid panel 
X 
 
X 
 
 
 
 
 
Locally tested. 
Coagulation 
parameters 
X 
 
X 
X 
X 
 
X 
 
Locally tested. 
Urinalysis 
X 
 
X 
X 
X 
 
X 
 
Locally tested. 


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Table 3: 
Schedule of Activities for Participants Receiving Epacadostat Plus Retifanlimab (Treatment Group A) 
(Continued) 
Visit Day (Range) 
Screening 
Treatment (Cycle Is Q4W) 
Precystectomy 
(2 wk Before 
Cystectomy) 
Cystectomy 
(± 2 wk) 
Safety Follow-Up 
Notes 
Days –28 
to –1 
Cycle 1 
Cycle 2 
Cycle 3 
30 Days After 
Cystectomy (or 
After Last Dose 
If Cystectomy 
Not Performed) 
90 Days After 
Cystectomy (or 
After Last Dose 
If Cystectomy 
Not Performed) 
 
Day 1 
Day 1  
(± 3 d) 
Day 1 
(± 3 d) 
Laboratory assessments (continued) 
Pregnancy testing 
(women of 
childbearing 
potential) 
X 
X 
X 
X 
X 
 
X 
 
Locally tested.  Serum at 
screening and 
precystectomy, and urine or 
serum before cystectomy, 
before the first dose on D1 
of each cycle, and at 30-day 
safety follow-up.  
Pregnancy testing will be 
conducted as medically 
indicated or per country or 
institutional requirements. 
Section 8.3.5.1. 
Hepatitis screening 
(HBV and HCV) 
X 
 
 
 
 
 
 
 
Results obtained within the 
last 3 months before C1D1 
are acceptable. 
HIV screening and 
management testing  
HIV viral load 
CD4+ cell count 
X 
 
 
 
X 
 
X 
 
Locally tested. 
Section 8.3.5. 
Other assessments 
Serum sample for 
ADA 
 
X 
X 
 
 
 
X 
 
Preinfusion and safety 
follow-up 30 days after last 
dose. 
Section 8.4.1 and Table 20. 


Incyte Corporation 
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Table 3: 
Schedule of Activities for Participants Receiving Epacadostat Plus Retifanlimab (Treatment Group A) 
(Continued) 
Visit Day (Range) 
Screening 
Treatment (Cycle Is Q4W) 
Precystectomy 
(2 wk Before 
Cystectomy) 
Cystectomy 
(± 2 wk) 
Safety Follow-Up 
Notes 
Days –28 
to –1 
Cycle 1 
Cycle 2 
Cycle 3 
30 Days After 
Cystectomy (or 
After Last Dose 
If Cystectomy 
Not Performed) 
90 Days After 
Cystectomy (or 
After Last Dose 
If Cystectomy 
Not Performed) 
 
Day 1 
Day 1  
(± 3 d) 
Day 1 
(± 3 d) 
Other assessments (continued) 
Dispensing and administration of study drug 
Dispense 
epacadostat 
 
X 
X 
X 
 
 
 
 
Epacadostat will be 
administered daily until 
cystectomy. 
Section 6 and Pharmacy 
Manual. 
Administer 
retifanlimab 
 
X 
X 
X 
 
 
 
 
Section 6 and Pharmacy 
Manual. 
Distribute reminder 
cards 
 
X 
X 
X 
 
 
 
 
Section 8.1.4. 


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Table 4: 
Schedule of Activities for Participants Receiving Retifanlimab Monotherapy (Treatment Group B) 
Visit Day (Range) 
Screening 
Treatment (Cycle Is Q4W) 
Precystectomy 
(2 wk Before 
Cystectomy) 
Cystectomy 
(± 2 wk) 
Safety Follow-Up 
Notes 
Days –28 
to –1 
Cycle 1 
Cycle 2 
Cycle 3 
30 Days After 
Cystectomy (or 
After Last Dose 
If Cystectomy 
Not Performed) 
90 Day After 
Cystectomy (or 
Post Last Dose 
If Cystectomy 
Not Performed) 
Day 1 
Day 1  
(± 3 d) 
Day 1 
(± 3 d) 
Informed consent 
X 
 
 
 
 
 
 
 
Section 8.1.1. 
Inclusion/exclusion 
criteria 
X 
X 
 
 
 
 
 
 
Section 5. 
General and disease 
medical history 
X 
 
 
 
 
 
 
 
Section 8.1.5. 
Prior/concomitant 
medications 
X 
X 
X 
X 
X 
 
X 
X 
Section 6.6. 
Cystectomy 
 
 
 
 
 
X 
 
 
 
Safety assessments 
AE assessments 
X 
X 
X 
X 
X 
X 
X 
X 
Body systems with 
symptoms should be 
physically examined.  AEs 
should be collected until 
90 days after cystectomy or 
the last dose of either study 
drug if cystectomy not 
performed; this may occur 
via telephone. 
Section 8.3.1. 
Physical 
examination/height/
body weight 
X* 
X 
X 
X 
X 
 
X 
X 
*Comprehensive physical 
examination (including 
hearing and peripheral 
neuropathy assessments) 
and height at screening 
only. 
Section 8.3.2. 
Vital signs 
X 
X 
X 
X 
X 
 
X 
X 
Section 8.3.3. 
12-lead ECG 
X 
X 
X 
X 
X 
 
X 
 
Section 8.3.4. 
ECOG PS 
X 
X 
X 
X 
X 
 
X 
 
Section 8.3.6. 
Postsurgical safety 
assessments 
 
 
 
 
 
 
X 
 
Section 8.3.7 and 
Appendix D for details. 


Incyte Corporation 
Page 21 of 146 
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Table 4: 
Schedule of Activities for Participants Receiving Retifanlimab Monotherapy (Treatment Group B) (Continued) 
Visit Day (Range) 
Screening 
Treatment (Cycle Is Q4W) 
Precystectomy 
(2 wk Before 
Cystectomy) 
Cystectomy 
(± 2 wk) 
Safety Follow-Up 
Notes 
Days –28 
to –1 
Cycle 1 
Cycle 2 
Cycle 3 
30 Days After 
Cystectomy (or 
After Last Dose 
If Cystectomy 
Not Performed) 
90 Day After 
Cystectomy (or 
Post Last Dose 
If Cystectomy 
Not Performed) 
Day 1 
Day 1  
(± 3 d) 
Day 1 
(± 3 d) 
Efficacy assessments 
Radiologic tumor 
assessments 
X 
 
 
 
X 
 
 
X 
CT/MRI of the abdomen 
and pelvis and CT scan of 
the thorax (RECIST v1.1). 
Pathological tumor 
assessments 
X 
 
 
 
 
X 
 
 
Pathological tumor 
assessments include 
pathological complete 
response, major 
pathological response, 
 
   
Section 8.2.1. 
Tumor tissue 
sampling 
X 
 
 
 
 
X 
 
 
Section 8.5.2. 
Laboratory assessments 
Blood chemistry 
X 
X* 
X 
X 
X 
 
X 
 
Locally tested. 
*Not necessary if screening 
assessment performed 
within 7 days of C1D1. 
Section 8.3.5. 
Hematology 
X 
X* 
X 
X 
X 
 
X 
 
Locally tested. 
*Not necessary if screening 
assessment performed 
within 7 days of C1D1. 
Section 8.3.5. 
Thyroid function 
X 
 
X 
X 
X 
 
X 
 
Locally tested. 
Lipid panel 
X 
 
X 
 
 
 
 
 
Locally tested. 
Coagulation 
parameters 
X 
 
X 
X 
X 
 
X 
 
Locally tested. 
Urinalysis 
X 
 
X 
X 
X 
 
X 
 
Locally tested. 


Incyte Corporation 
Page 22 of 146 
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Table 4: 
Schedule of Activities for Participants Receiving Retifanlimab Monotherapy (Treatment Group B) (Continued) 
Visit Day (Range) 
Screening 
Treatment (Cycle Is Q4W) 
Precystectomy 
(2 wk Before 
Cystectomy) 
Cystectomy 
(± 2 wk) 
Safety Follow-Up 
Notes 
Days –28 
to –1 
Cycle 1 
Cycle 2 
Cycle 3 
30 Days After 
Cystectomy (or 
After Last Dose 
If Cystectomy 
Not Performed) 
90 Day After 
Cystectomy (or 
Post Last Dose 
If Cystectomy 
Not Performed) 
Day 1 
Day 1  
(± 3 d) 
Day 1 
(± 3 d) 
Laboratory assessments (continued) 
Pregnancy testing 
(women of 
childbearing 
potential) 
X 
X 
X 
X 
X 
 
X 
 
Locally tested.  Serum at 
screening and 
precystectomy, and urine or 
serum before cystectomy, 
before the first dose on D1 
of each cycle, and at 30-day 
safety follow-up.  
Pregnancy testing will be 
conducted as medically 
indicated or per country or 
institutional requirements. 
Section 8.3.5.1. 
Hepatitis screening 
(HBV and HCV) 
X 
 
 
 
 
 
 
 
Results obtained within the 
last 3 months before C1D1 
are acceptable. 
HIV screening and 
management  
HIV viral load 
CD4+ cell count 
X 
 
 
 
X 
 
X 
 
Locally tested. 
Section 8.3.5. 
Other assessments 
Serum sample for 
ADA 
 
X 
X 
 
 
 
X 
 
Preinfusion and safety 
follow-up 30 days after last 
dose. 
Section 8.4.1 and Table 20. 


Incyte Corporation 
Page 23 of 146 
Protocol INCB 24360-901 Am 4  
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Table 4: 
Schedule of Activities for Participants Receiving Retifanlimab Monotherapy (Treatment Group B) (Continued) 
Visit Day (Range) 
Screening 
Treatment (Cycle Is Q4W) 
Precystectomy 
(2 wk Before 
Cystectomy) 
Cystectomy 
(± 2 wk) 
Safety Follow-Up 
Notes 
Days –28 
to –1 
Cycle 1 
Cycle 2 
Cycle 3 
30 Days After 
Cystectomy (or 
After Last Dose 
If Cystectomy 
Not Performed) 
90 Day After 
Cystectomy (or 
Post Last Dose 
If Cystectomy 
Not Performed) 
Day 1 
Day 1  
(± 3 d) 
Day 1 
(± 3 d) 
Dispensing and administration of study drug 
Administer 
retifanlimab* 
 
X 
X 
X 
 
 
 
 
Section 6 and Pharmacy 
Manual. 
*Maximum total treatment 
duration is 10 weeks. 
Distribute reminder 
cards 
 
X 
X 
X 
 
 
 
 
Section 8.1.4. 


Incyte Corporation 
Page 24 of 146 
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Table 5: 
Schedule of Activities for Participants Receiving Epacadostat Monotherapy (Treatment Group C) 
Visit Day (Range) 
Screening 
Treatment (Cycle Is Q4W) 
Precystectomy 
(2 wk Before 
Cystectomy) 
Cystectomy 
(± 2 wk) 
Safety Follow-Up 
Notes 
Days –28 
to –1 
Cycle 1 
Cycle 2 
Cycle 3 
30 Days After 
Cystectomy (or 
After Last Dose 
If Cystectomy 
Not Performed) 
90 Days After 
Cystectomy (or 
After Last Dose 
If Cystectomy 
Not Performed) 
 
Day 1 
Day 1 
(± 3 d) 
Day 1 
(± 3 d) 
Informed consent 
X 
 
 
 
 
 
 
 
Section 8.1.1. 
Inclusion/exclusion 
criteria 
X 
X 
 
 
 
 
 
 
Section 5. 
General and disease 
medical history 
X 
 
 
 
 
 
 
 
Section 8.1.5. 
Prior/concomitant 
medications 
X 
X 
X 
X 
X 
 
X 
X 
Section 6.6. 
Cystectomy 
 
 
 
 
 
X 
 
 
 
Safety assessments 
AE assessments 
X 
X 
X 
X 
X 
X 
X 
X 
Body systems with symptoms 
should be physically 
examined.  AEs should be 
collected until 90 days after 
cystectomy or the last dose of 
either study drug if 
cystectomy not performed; 
this may occur via telephone. 
Section 8.3.1. 
Physical 
examination/height/ 
body weight 
X* 
X 
X 
X 
X 
 
X 
X 
*Comprehensive physical 
examination (including 
hearing and peripheral 
neuropathy assessments) and 
height at screening only. 
Section 8.3.2. 
Vital signs 
X 
X 
X 
X 
X 
 
X 
X 
Section 8.3.3. 
12-lead ECG 
X 
X 
X 
X 
X 
 
X 
 
Section 8.3.4. 
ECOG PS 
X 
X 
X 
X 
X 
 
X 
 
Section 8.3.6. 
Postsurgical safety 
assessments 
 
 
 
 
 
 
X 
 
Section 8.3.7 and Appendix D 
for details. 


Incyte Corporation 
Page 25 of 146 
Protocol INCB 24360-901 Am 4  
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Table 5: 
Schedule of Activities for Participants Receiving Epacadostat Monotherapy (Treatment Group C) (Continued) 
Visit Day (Range) 
Screening 
Treatment (Cycle Is Q4W) 
Precystectomy 
(2 wk Before 
Cystectomy) 
Cystectomy 
(± 2 wk) 
Safety Follow-Up 
Notes 
Days –28 
to –1 
Cycle 1 
Cycle 2 
Cycle 3 
30 Days After 
Cystectomy (or 
After Last Dose 
If Cystectomy 
Not Performed) 
90 Days After 
Cystectomy (or 
After Last Dose 
If Cystectomy 
Not Performed) 
 
Day 1 
Day 1 
(± 3 d) 
Day 1 
(± 3 d) 
Efficacy assessments 
Radiologic tumor 
assessments 
X 
 
 
 
X 
 
 
X 
CT/MRI of the abdomen and 
pelvis and CT scan of the 
thorax (RECIST v1.1).  
Pathological tumor 
assessments 
X 
 
 
 
 
X 
 
 
Pathological tumor 
assessments include 
pathological complete 
response, major pathological 
response, 
 
   
Section 8.2.1. 
Tumor tissue 
sampling 
X 
 
 
 
 
X 
 
 
Section 8.5.2. 
Laboratory assessments 
Blood chemistry 
X 
X* 
X 
X 
X 
 
X 
 
Locally tested. 
*Not necessary if screening 
assessment performed within 
7 days of C1D1. 
Section 8.3.5. 
Hematology 
X 
X* 
X 
X 
X 
 
X 
 
Locally tested. 
*Not necessary if screening 
assessment performed within 
7 days of C1D1. 
Section 8.3.5. 
Thyroid function 
X 
 
X 
X 
X 
 
X 
 
Locally tested. 
Lipid panel 
X 
 
X 
 
 
 
 
 
Locally tested. 
Coagulation 
parameters 
X 
 
X 
X 
X 
 
X 
 
Locally tested. 
Urinalysis 
X 
 
X 
X 
X 
 
X 
 
Locally tested. 


Incyte Corporation 
Page 26 of 146 
Protocol INCB 24360-901 Am 4  
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Table 5: 
Schedule of Activities for Participants Receiving Epacadostat Monotherapy (Treatment Group C) (Continued) 
Visit Day (Range) 
Screening 
Treatment (Cycle Is Q4W) 
Precystectomy 
(2 wk Before 
Cystectomy) 
Cystectomy 
(± 2 wk) 
Safety Follow-Up 
Notes 
Days –28 
to –1 
Cycle 1 
Cycle 2 
Cycle 3 
30 Days After 
Cystectomy (or 
After Last Dose 
If Cystectomy 
Not Performed) 
90 Days After 
Cystectomy (or 
After Last Dose 
If Cystectomy 
Not Performed) 
 
Day 1 
Day 1 
(± 3 d) 
Day 1 
(± 3 d) 
Laboratory assessments (continued) 
Pregnancy testing 
(women of 
childbearing 
potential) 
X 
X 
X 
X 
X 
 
X 
 
Locally tested.  Serum at 
screening and precystectomy, 
and urine or serum before 
cystectomy, before the first 
dose on D1 of each cycle, and 
at 30-day safety follow-up.  
Pregnancy testing will be 
conducted as medically 
indicated or per country or 
institutional requirements. 
Section 8.3.5.1. 
Hepatitis screening 
(HBV and HCV) 
X 
 
 
 
 
 
 
 
Results obtained within the 
last 3 months before C1D1 are 
acceptable. 
HIV screening and 
management testing  
HIV viral load 
CD4+ cell count 
X 
 
 
 
X 
 
X 
 
Locally tested. 
Section 8.3.5. 
Other assessments 


Incyte Corporation 
Page 27 of 146 
Protocol INCB 24360-901 Am 4  
Version 5  
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CONFIDENTIAL 
Table 5: 
Schedule of Activities for Participants Receiving Epacadostat Monotherapy (Treatment Group C) (Continued) 
Visit Day (Range) 
Screening 
Treatment (Cycle Is Q4W) 
Precystectomy 
(2 wk Before 
Cystectomy) 
Cystectomy 
(± 2 wk) 
Safety Follow-Up 
Notes 
Days –28 
to –1 
Cycle 1 
Cycle 2 
Cycle 3 
30 Days After 
Cystectomy (or 
After Last Dose 
If Cystectomy 
Not Performed) 
90 Days After 
Cystectomy (or 
After Last Dose 
If Cystectomy 
Not Performed) 
 
Day 1 
Day 1 
(± 3 d) 
Day 1 
(± 3 d) 
Dispensing and administration of study drug 
Dispense epacadostat 
 
X 
X 
X* 
 
 
 
 
Section 6 and Pharmacy 
Manual. 
Epacadostat will be 
administered daily until 
cystectomy. 
*Cycle 3 is a maximum of 
2 weeks of therapy.  
Maximum total treatment 
duration is 10 weeks.  
Distribute reminder 
cards 
 
X 
X 
X 
 
 
 
 
Section 8.1.4. 


Incyte Corporation 
Page 28 of 146 
Protocol INCB 24360-901 Am 4  
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Table 6: 
Schedule of Activities for Participants Receiving Retifanlimab Plus INCAGN02385 (Treatment Group D) 
Visit Day (Range) 
Screening 
Treatment (Cycle Is Q4W) 
Precystectomy 
(2 wk before 
cystectomy) 
Cystectomy 
(± 2 wk) 
Safety Follow-Up 
Notes 
Days 
–28 to –1 
Cycle 1 
Cycle 2 
Cycle 3 
30 Days After 
Cystectomy (or 
After Last Dose 
If Cystectomy 
Not Performed) 
90 Days After 
Cystectomy (or 
After Last Dose 
If Cystectomy 
Not Performed) 
Day 1 
Day 15  
(± 2 d) 
Day 1  
(± 3 d) 
Day 15 
(± 2 d) 
Day 1  
(± 3 d) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Section 8.1.1. 
Inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
Section 5. 
General and disease 
medical history 
X 
 
 
 
 
 
 
 
 
 
Section 8.1.5. 
Prior/concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Section 6.6. 
Cystectomy 
 
 
 
 
 
 
 
X 
 
 
 
Safety assessments 
AE assessments 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Body systems with 
symptoms should be 
physically examined.  AEs 
should be collected until 
90 days after cystectomy 
or the last dose of either 
study drug if cystectomy 
not performed; this may 
occur via telephone. 
Section 8.3.1. 
Physical 
examination/height/
body weight 
X* 
X 
X 
X 
X 
X 
X 
 
X 
X 
*Comprehensive physical 
examination (including 
hearing and peripheral 
neuropathy assessments) 
and height at screening 
only. 
Section 8.3.2. 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Section 8.3.3. 
12-lead ECG 
X 
X 
 
X 
 
X 
X 
 
X 
 
Section 8.3.4. 
ECOG PS 
X 
X 
 
X 
 
X 
X 
 
X 
 
Section 8.3.6. 
Postsurgical safety 
assessments 
 
 
 
 
 
 
 
 
X 
 
Section 8.3.7 and 
Appendix D. 


Incyte Corporation 
Page 29 of 146 
Protocol INCB 24360-901 Am 4  
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CONFIDENTIAL 
Table 6: 
Schedule of Activities for Participants Receiving Retifanlimab Plus INCAGN02385 (Treatment Group D) 
(Continued) 
Visit Day (Range) 
Screening 
Treatment (Cycle Is Q4W) 
Precystectomy 
(2 wk before 
cystectomy) 
Cystectomy 
(± 2 wk) 
Safety Follow-Up 
Notes 
Days 
–28 to –1 
Cycle 1 
Cycle 2 
Cycle 3 
30 Days After 
Cystectomy (or 
After Last Dose 
If Cystectomy 
Not Performed) 
90 Days After 
Cystectomy (or 
After Last Dose 
If Cystectomy 
Not Performed) 
Day 1 
Day 15  
(± 2 d) 
Day 1  
(± 3 d) 
Day 15 
(± 2 d) 
Day 1  
(± 3 d) 
Efficacy assessments 
Radiologic tumor 
assessments  
X 
 
 
 
 
 
X 
 
 
X 
CT/MRI of the abdomen 
and pelvis and CT scan of 
the thorax (RECIST v1.1).  
Pathological tumor 
assessments 
X 
 
 
 
 
 
 
X 
 
 
Pathological tumor 
assessments include 
pathological complete 
response, major 
pathological response, 
 
   
Section 8.2.1. 
Tumor tissue 
sampling  
X 
 
 
 
 
 
 
X 
 
 
Section 8.5.2. 
Laboratory assessments 
Blood chemistry 
X 
X* 
X 
X 
X 
X 
X 
 
X 
 
Locally tested. 
*Not necessary if 
screening assessment 
performed within 7 days 
of C1D1. 
Section 8.3.5. 


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Table 6: 
Schedule of Activities for Participants Receiving Retifanlimab Plus INCAGN02385 (Treatment Group D) 
(Continued) 
Visit Day (Range) 
Screening 
Treatment (Cycle Is Q4W) 
Precystectomy 
(2 wk before 
cystectomy) 
Cystectomy 
(± 2 wk) 
Safety Follow-Up 
Notes 
Days 
–28 to –1 
Cycle 1 
Cycle 2 
Cycle 3 
30 Days After 
Cystectomy (or 
After Last Dose 
If Cystectomy 
Not Performed) 
90 Days After 
Cystectomy (or 
After Last Dose 
If Cystectomy 
Not Performed) 
Day 1 
Day 15  
(± 2 d) 
Day 1  
(± 3 d) 
Day 15 
(± 2 d) 
Day 1  
(± 3 d) 
Laboratory assessments (continued) 
Troponin I or T 
measurements  
X 
X* 
X 
X 
 
X 
X 
 
 
 
To be performed predose 
on C1D1 (*only if not 
done at screening) and 
C1D15.  Predose is 
defined as within 
3 calendar days prior to 
dosing.  All laboratory 
values should be checked 
prior to dosing.  Day 15 
laboratory values should 
be checked as soon as 
possible.  In case of high 
troponin levels, see 
management guidelines in 
Table 15 and Table 18. 
Hematology 
X 
X* 
X 
X 
X 
X 
X 
 
X 
 
Locally tested. 
*Not necessary if 
screening assessment 
performed within 7 days 
of C1D1. 
Section 8.3.5. 
Thyroid function 
X 
 
 
X 
 
X 
X 
 
X 
 
Locally tested. 
Lipid panel 
X 
 
 
X 
 
 
 
 
 
 
Locally tested. 


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Table 6: 
Schedule of Activities for Participants Receiving Retifanlimab Plus INCAGN02385 (Treatment Group D) 
(Continued) 
Visit Day (Range) 
Screening 
Treatment (Cycle Is Q4W) 
Precystectomy 
(2 wk before 
cystectomy) 
Cystectomy 
(± 2 wk) 
Safety Follow-Up 
Notes 
Days 
–28 to –1 
Cycle 1 
Cycle 2 
Cycle 3 
30 Days After 
Cystectomy (or 
After Last Dose 
If Cystectomy 
Not Performed) 
90 Days After 
Cystectomy (or 
After Last Dose 
If Cystectomy 
Not Performed) 
Day 1 
Day 15  
(± 2 d) 
Day 1  
(± 3 d) 
Day 15 
(± 2 d) 
Day 1  
(± 3 d) 
Laboratory assessments (continued) 
Coagulation 
parameters 
X 
 
 
X 
 
X 
X 
 
X 
 
Locally tested. 
Urinalysis 
X 
 
 
X 
 
X 
X 
 
X 
 
Locally tested. 
Pregnancy testing 
(women of 
childbearing 
potential) 
X 
X 
 
X 
 
X 
X 
 
X 
 
Locally tested.  Serum at 
screening and 
precystectomy, and urine 
or serum before 
cystectomy, before the 
first dose on D1 of each 
cycle, and at 30-day 
safety follow-up.  
Pregnancy testing will be 
conducted as medically 
indicated or per country 
or institutional 
requirements. 
Section 8.3.5.1. 
Hepatitis screening 
(HBV and HCV) 
X 
 
 
 
 
 
 
 
 
 
Results obtained within 
the last 3 months before 
C1D1 are acceptable. 
HIV screening and 
management  
HIV viral load 
CD4+ cell count 
X 
 
 
 
 
 
 
X 
 
X 
 
Locally tested. 
Section 8.3.5. 
Other assessments 


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Table 6: 
Schedule of Activities for Participants Receiving Retifanlimab Plus INCAGN02385 (Treatment Group D) 
(Continued) 
Visit Day (Range) 
Screening 
Treatment (Cycle Is Q4W) 
Precystectomy 
(2 wk before 
cystectomy) 
Cystectomy 
(± 2 wk) 
Safety Follow-Up 
Notes 
Days 
–28 to –1 
Cycle 1 
Cycle 2 
Cycle 3 
30 Days After 
Cystectomy (or 
After Last Dose 
If Cystectomy 
Not Performed) 
90 Days After 
Cystectomy (or 
After Last Dose 
If Cystectomy 
Not Performed) 
Day 1 
Day 15  
(± 2 d) 
Day 1  
(± 3 d) 
Day 15 
(± 2 d) 
Day 1  
(± 3 d) 
Other assessments (continued) 
Serum sample for 
ADA 
 
X 
 
X 
 
 
 
 
X 
 
Preinfusion and safety 
follow-up 30 days after 
last dose. 
Section 8.4.1 and 
Table 20. 
Dispensing and administration of study drug 
Administer 
retifanlimab 
 
X 
 
X 
 
X 
 
 
 
 
Retifanlimab administered 
on D1 of each cycle. 
Section 6.1. 
Administer 
INCAGN02385 
 
 
X 
X 
X 
X 
X 
 
 
 
 
INCAGN02385 is 
administered Q2W. 
Section 6.1. 
Distribute reminder 
cards 
 
X 
X 
X 
X 
X 
 
 
 
 
Section 8.1.4. 
 


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Table 7: 
Schedule of Activities for Participants Receiving Retifanlimab Plus INCAGN02385 Plus INCAGN02390 
(Treatment Group E) 
Visit Day (Range) 
Screening 
Treatment (Cycle Is Q4W) 
Precystectomy 
(2 wk Before 
Cystectomy) 
Cystectomy 
(± 2 wk) 
Safety Follow-Up 
Notes 
Days 
–28 to –1 
Cycle 1 
Cycle 2+ 
Cycle 3 
30 Days After 
Cystectomy (or 
After Last Dose 
If Cystectomy 
Not Performed) 
90 Days After 
Cystectomy (or 
After Last Dose 
If Cystectomy 
Not Performed) 
Day 1 
Day 15  
(± 2 d) 
Day 1  
(± 3 d) 
Day 15 
(± 2 d) 
Day 1  
(± 3 d) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Section 8.1.1. 
Inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
Section 5. 
General and 
disease medical 
history 
X 
 
 
 
 
 
 
 
 
 
Section 8.1.5. 
Prior/concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Section 6.6. 
Cystectomy 
 
 
 
 
 
 
 
X 
 
 
 
Safety assessments 
AE assessments 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Body systems with 
symptoms should be 
physically examined.  
AEs should be collected 
until 90 days after 
cystectomy or the last 
dose of either study drug 
if cystectomy not 
performed; this may 
occur via telephone. 
Section 8.3.1.  
Physical 
examination/height
/body weight 
X* 
X 
X 
X 
X 
X 
X 
 
X 
X 
Comprehensive physical 
examination (including 
hearing and peripheral 
neuropathy assessments) 
and height at screening 
only.  
Section 8.3.2. 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Section 8.3.3.  
12-lead ECG 
X 
X 
 
X 
 
X 
X 
 
X 
 
Section 8.3.4.  


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Table 7: 
Schedule of Activities for Participants Receiving Retifanlimab Plus INCAGN02385 Plus INCAGN02390 
(Treatment Group E) (Continued) 
Visit Day (Range) 
Screening 
Treatment (Cycle Is Q4W) 
Precystectomy 
(2 wk Before 
Cystectomy) 
Cystectomy 
(± 2 wk) 
Safety Follow-Up 
Notes 
Days 
–28 to –1 
Cycle 1 
Cycle 2+ 
Cycle 3 
30 Days After 
Cystectomy (or 
After Last Dose 
If Cystectomy 
Not Performed) 
90 Days After 
Cystectomy (or 
After Last Dose 
If Cystectomy 
Not Performed) 
Day 1 
Day 15  
(± 2 d) 
Day 1  
(± 3 d) 
Day 15 
(± 2 d) 
Day 1  
(± 3 d) 
Safety assessments (continued) 
ECOG PS 
X 
X 
 
X 
 
X 
X 
 
X 
 
Section 8.3.6.  
Postsurgical safety 
assessments 
 
 
 
 
 
 
 
 
X 
 
Section 8.3.7 and 
Appendix D. 
Efficacy assessments 
Radiologic tumor 
assessments  
X 
 
 
 
 
 
X 
 
 
X 
CT/MRI of the abdomen 
and pelvis and CT scan 
of the thorax (RECIST 
v1.1).  
Pathological tumor 
assessments 
X 
 
 
 
 
 
 
X 
 
 
Pathological tumor 
assessments include 
pathological complete 
response, major 
pathological response, 
 
   
Section 8.2.1. 
Tumor tissue 
sampling 
X 
 
 
 
 
 
 
X 
 
 
Section 8.5.2. 
Laboratory assessments 
Blood chemistry 
X 
X* 
X 
X 
X 
X 
X 
 
X 
 
Locally tested. 
*Not necessary if 
screening assessment 
performed within 7 days 
of C1D1. 
Section 8.3.5. 


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Table 7: 
Schedule of Activities for Participants Receiving Retifanlimab Plus INCAGN02385 Plus INCAGN02390 
(Treatment Group E) (Continued) 
Visit Day (Range) 
Screening 
Treatment (Cycle Is Q4W) 
Precystectomy 
(2 wk Before 
Cystectomy) 
Cystectomy 
(± 2 wk) 
Safety Follow-Up 
Notes 
Days 
–28 to –1 
Cycle 1 
Cycle 2+ 
Cycle 3 
30 Days After 
Cystectomy (or 
After Last Dose 
If Cystectomy 
Not Performed) 
90 Days After 
Cystectomy (or 
After Last Dose 
If Cystectomy 
Not Performed) 
Day 1 
Day 15  
(± 2 d) 
Day 1  
(± 3 d) 
Day 15 
(± 2 d) 
Day 1  
(± 3 d) 
Laboratory assessments (continued) 
Troponin I or T 
measurements  
X 
X* 
X 
X 
 
X 
X 
 
 
 
To be performed predose 
on C1D1 (*only if not 
done at screening) and 
C1D15.  Predose is 
defined as within 
3 calendar days prior to 
dosing.  All laboratory 
values should be checked 
prior to dosing.  Day 15 
laboratory values should 
be checked as soon as 
possible.  In case of high 
troponin levels, see 
management guidelines 
in Table 15 and Table 18. 
Hematology 
X 
X* 
X 
X 
X 
X 
X 
 
X 
 
Locally tested. 
*Not necessary if 
screening assessment 
performed within 7 days 
of C1D1. 
Section 8.3.5. 
Thyroid function 
X 
 
 
X 
 
X 
X 
 
X 
 
Locally tested. 
Lipid panel 
X 
 
 
X 
 
 
 
 
 
 
Locally tested. 
Coagulation 
parameters 
X 
 
 
X 
 
X 
X 
 
X 
 
Locally tested. 
Urinalysis 
X 
 
 
X 
 
X 
X 
 
X 
 
Locally tested. 


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Table 7: 
Schedule of Activities for Participants Receiving Retifanlimab Plus INCAGN02385 Plus INCAGN02390 
(Treatment Group E) (Continued) 
Visit Day (Range) 
Screening 
Treatment (Cycle Is Q4W) 
Precystectomy 
(2 wk Before 
Cystectomy) 
Cystectomy 
(± 2 wk) 
Safety Follow-Up 
Notes 
Days 
–28 to –1 
Cycle 1 
Cycle 2+ 
Cycle 3 
30 Days After 
Cystectomy (or 
After Last Dose 
If Cystectomy 
Not Performed) 
90 Days After 
Cystectomy (or 
After Last Dose 
If Cystectomy 
Not Performed) 
Day 1 
Day 15  
(± 2 d) 
Day 1  
(± 3 d) 
Day 15 
(± 2 d) 
Day 1  
(± 3 d) 
Laboratory assessments (continued) 
Pregnancy testing 
(women of 
childbearing 
potential) 
X 
X 
 
X 
 
X 
X 
 
X 
 
Locally tested.  Serum at 
screening and 
precystectomy, and urine 
or serum before 
cystectomy, before the 
first dose on D1 of each 
cycle, and at 30-day 
safety follow-up.  
Pregnancy testing will be 
conducted as medically 
indicated or per country 
or institutional 
requirements. 
Section 8.3.5.1. 
Hepatitis screening 
(HBV and HCV) 
X 
 
 
 
 
 
 
 
 
 
Results obtained within 
the last 3 months before 
C1D1 are acceptable. 
HIV screening and 
management  
HIV viral load 
CD4+ cell count 
X 
 
 
 
 
 
X 
 
X 
 
Locally tested. 
Section 8.3.5. 
Other assessments 


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Table 7: 
Schedule of Activities for Participants Receiving Retifanlimab Plus INCAGN02385 Plus INCAGN02390 
(Treatment Group E) (Continued) 
Visit Day (Range) 
Screening 
Treatment (Cycle Is Q4W) 
Precystectomy 
(2 wk Before 
Cystectomy) 
Cystectomy 
(± 2 wk) 
Safety Follow-Up 
Notes 
Days 
–28 to –1 
Cycle 1 
Cycle 2+ 
Cycle 3 
30 Days After 
Cystectomy (or 
After Last Dose 
If Cystectomy 
Not Performed) 
90 Days After 
Cystectomy (or 
After Last Dose 
If Cystectomy 
Not Performed) 
Day 1 
Day 15  
(± 2 d) 
Day 1  
(± 3 d) 
Day 15 
(± 2 d) 
Day 1  
(± 3 d) 
Other assessments (continued) 
Serum sample for 
ADA 
 
X 
 
X 
 
 
 
 
X 
 
Preinfusion and safety 
follow-up 30 days after 
last dose. 
Section 8.4.1 and 
Table 20. 
Dispensing and administration of study drug 
Administer 
retifanlimab 
 
X 
 
X 
 
X 
 
 
 
 
Retifanlimab 
administered on D1 of 
each cycle.  
Section 6.1. 
Administer 
INCAGN02385 
 
 
X 
X 
X 
X 
X 
 
 
 
 
INCAGN02385 is 
administered Q2W. 
Section 6.1. 
Administer 
INCAGN02390 
 
X 
X 
X 
X 
X 
 
 
 
 
INCAGN02390 is 
administered Q2W 
Section 6.1. 
Distribute reminder 
cards 
 
X 
X 
X 
X 
X 
 
 
 
 
Section 8.1.4. 


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2. 
INTRODUCTION 
2.1. 
Study Rationale 
This is an umbrella study to investigate the biological rationale and outcomes for selected 
monotherapy and combination therapies in order to inform of potential neoadjuvant treatment 
combinations to be further tested in miUBC in cisplatin-ineligible participants or those refusing 
cisplatin therapy and are awaiting radical cystectomy. 
2.1.1. 
Scientific Rationale for Study Design 
Bladder cancer was the 11th most common cancer based on 2018 estimates, accounting for 
approximately 549,000 new cases and 200,000 deaths globally (Global Cancer Observatory 
2019).  In the US, bladder cancer is the fourth most common cancer, with over 70,000 new cases 
each year (CDC 2019).  Urothelial carcinoma is the predominant histologic type of bladder 
cancer in the US and Western Europe, where it accounts for approximately 90% of bladder 
cancers.  Approximately 25% of patients will have muscle-invasive disease and either present 
with or later develop metastases (von der Maase et al 2005).   
Early stage localized disease can be treated initially by TURBT.  Unfortunately, up to 50% of 
patients will have a recurrence of the cancer within 12 months.  Due of this high recurrence rate, 
adjuvant therapy is usually recommended (Cao et al 2015).  Neoadjuvant chemotherapy yields 
Level 1 evidence in the National Comprehensive Cancer Network guidelines (NCCN 2020).  
However, modest improvements are seen with neoadjuvant therapy over radical cystectomy.  
In the MRC/EORTC trial of 976 patients, only 6% absolute increase in OS at 5 years was 
observed over radical cystectomy.  Therefore, there is a need for improved outcomes with use of 
neoadjuvant therapy (International Collaboration of Trialists 1999).  This study will be 
conducted in participants with miUBC who are routinely candidates for radical cystectomy 
alone.  These patients are good candidates for biologic studies, because patients undergo a short 
course of neoadjuvant treatment that precedes surgery without prolonging the routine waiting 
time (usually in the range of 8-10 weeks; Poletajew et al 2014). 
In a SEER-Medicare analysis performed by Gore et al (2009), time from diagnosis to radical 
cystectomy ranged from 4 to 52 weeks in 441 patients with Stage 2 bladder cancer who 
underwent radical cystectomy between 1992 and 2001.  Eighty-nine percent of these patients 
underwent definitive surgical extirpation within 24 weeks of diagnosis, of whom 73% underwent 
cystectomy within 12 weeks. 
Patients who achieve a pCR (pT0) have a better long-term outcome.  In recent meta-analyses, the 
absolute risk reduction in OS is approximately 30%; therefore, pathological downstaging is a 
potential surrogate marker for efficacy and increased survival in neoadjuvant therapies for 
miUBC (Rosenblatt et al 2012). 
In a 50-patient cohort study, the anti–PD-1 antibody pembrolizumab as single-agent therapy, 
given as neoadjuvant therapy in patients with T2-3b bladder cancer, demonstrated a 42% pT0 
rate.  Those with PD-L1 CPS > 10 achieved a 54% pT0 rate, whereas those with PD-L1 
CPS < 10 achieved a 13.3% pT0 rate (Necchi et al 2018). 


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A growing body of data supports that the key to generating immune responses in tumor, 
triggered by administration of immunotherapy, is the expansion and tumor invasion of 
T lymphocytes and the focus of many clinical studies aimed at delivering effective 
immunotherapy for cancer patients has been on the expansion of the T lymphocyte population.  
Vaccine studies have demonstrated the ability to boost tumor specific T cells in the peripheral 
blood, but the key to obtaining tumor regression appears to be TILs (Liakou et al 2007). 
A high prevalence of TILs has been shown to be associated with a favorable response to 
chemotherapy in bladder cancer, even in the setting of more invasive disease (Liakou et al 2007).  
The presence of intratumoral CD8 T cells has shown to predict better disease-free survival and 
OS in bladder cancer patients with muscle invasive disease (Sharma et al 2007).  Liu et al (2018) 
also reported that higher TILs were associated with disease-free survival, with the association 
stronger in muscle invasive as compared with non–muscle invasive disease.  Huang et al (2018) 
demonstrated a significant increase in median OS in patients with metastatic bladder cancer 
having intense TILs infiltration.  Subgroup analysis showed that TILs were prognostic for both 
urothelial carcinoma of bladder and upper tract urothelial carcinoma.  Sharma et al (2007) found 
that CD8 tumor-infiltrating lymphocytes are predictive of survival in muscle-invasive urothelial 
carcinoma.  
The tumor-infiltrating lymphocyte population consists of multiple T-cell populations, including 
CD4+ helper cells, CD8+ cytotoxic T cells, and FoxP3+ Tregs.  This study will use a multiplex 
CD8/FoxP3/granzyme B IHC assay to monitor the overall influx and activation state of these 
populations into the tumor. Subsequent immunohistochemical and transcriptional analyses will 
further characterize the infiltrating T-cell subpopulations. 
Differential response to immunotherapy in urothelial bladder cancer can be based on various 
factors such as the following: 
• T-cell inflamed versus non–T-cell inflamed groups  
• Tumor subtype (luminal vs basal) – where luminal 1,2 are less responsive to 
immunotherapy versus basal subtypes 
This umbrella design study that will test the biological rationale for use of targeted and 
immunotherapy agents for neoadjuvant treatment of cisplatin-ineligible miUBC and potential for 
subsequent efficacy benefit, as shown with other anti–PD-1 inhibitors and at doses shown to add 
minimal/acceptable risk from AEs (ie, positive benefit/risk).  The translational endpoints will 
inform which therapies are viable candidates for further investigation in miUBC.   
The purpose of this study is to examine various treatments (either monotherapy or combination 
therapy) given in the neoadjuvant setting before radical cystectomy.  Study treatment groups 
include the following: 
• Group A:  Epacadostat in combination with retifanlimab 
• Group B:  Retifanlimab monotherapy  
• Group C:  Epacadostat monotherapy 
• Group D:  Retifanlimab plus INCAGN02385 
• Group E:  Retifanlimab plus INCAGN02385 plus INCAGN02390 


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2.1.2. 
Treatment Group Rationale 
Treatment Group A (epacadostat in combination with retifanlimab):  A dose-finding study 
combining epacadostat with retifanlimab is being conducted (INCMGA 0012-102) and 
determined the preliminary RP2D as 600 mg BID.  
 
 
 
Treatment Group B (retifanlimab monotherapy):  Pembrolizumab was approved for the treatment 
of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for 
cisplatin-containing chemotherapy based on efficacy results observed in KEYNOTE-052 
(Balar et al 2017).  An ORR of 29% was observed in all participants.  However, PD-L1 CPS 
≥ 10 had higher ORR versus those with PD-L1 CPS < 10 (47% vs 21%).  Based on these results, 
pembrolizumab was approved in front-line cisplatin-ineligible locally advanced/metastatic 
urothelial cancer of the bladder in patients with PD-L1 CPS ≥ 10.  The rationale for including 
this arm in the study is to investigate the biological immunological changes when a checkpoint 
inhibitor is administered to participants.  In POD1UM-203, retifanlimab was investigated in 
advanced solid tumors, including cisplatin-ineligible locally advanced/metastatic urothelial 
cancer with PD-L1 CPS > 10%.  A total of 29 participants demonstrated an ORR of 38% and a 
disease control rate of 55%.  The median duration of response was not reached when the results 
of the study were reported (Maio et al 2021). 
Treatment Group C (epacadostat):  Epacadostat monotherapy is well-tolerated at doses ranging 
up to 700 mg BID in participants with refractory solid tumors (Beatty et al 2017).  The rationale 
for including a monotherapy group is to investigate tumor immunologic biological changes and 
plasma and tumor kynurenine level changes when it is administered as a monotherapy agent at a 
dose that optimally inhibits production of the immunosuppressive metabolite, kynurenine, by the 
alternate tryptophan pathway mediated by the enzyme IDO1. 
Treatment Group D (retifanlimab plus INCAGN02385):  Recovery of function has been 
accomplished in an in vivo viral model of T-cell exhaustion by simultaneous blockade of PD-1 
and LAG-3 (Blackburn et al 2009).  Further, in murine models, it has been demonstrated that 
PD-1 and LAG-3 act synergistically to promote tumor immune escape, and simultaneous 
blockade of LAG-3 and PD-1 results in synergistic inhibition of tumor growth (Woo et al 2012).  
Combined blockade of these 2 inhibitory receptors markedly improved CD8+ T-cell responses 
(INCAGN02385 IB, Jin et al 2010). 
Treatment Group E (retifanlimab plus INCAGN02385 plus INCAGN02390):  Early clinical 
evidence of the efficacy of these combinations in patients whose disease failed to respond to 
anti–PD-(L)1 therapy has been evolving.  Blockade of the PD-(L)1 axis in combination with 
blockade of either LAG-3 or TIM-3 has resulted in only modest responses in patients whose 
disease failed to respond to anti–PD-1 therapy alone (Ascierto et al 2017, Davar et al 2018).  
Potentially, multiple checkpoint inhibitors are potentially required in order to restore antitumor 
T-cell effector function in situ.  Evidence for this approach was presented by Kauffman et al 
(2018).  Evidence for synergy of anti–PD-1 and anti–TIM-3 was shown in an in vivo murine 
model of chronic infection resulting in T-cell exhaustion characterized by coexpression of TIM-3 
and PD-1.  The triple combination of antibodies directed against PD-1, TIM-3, and LAG-3 
demonstrated enhanced tumor growth inhibition relative to inhibition of either PD-1 plus LAG-3 
or PD-1 plus TIM-3 in a murine model.  In addition, the combination of all 3 antibodies resulted 


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in greater restoration of function to TILs isolated from patients with ovarian cancer.  This 
suggests a requirement for inhibition of all 3 checkpoints in concert is more relevant for 
returning immune function and tumor growth.   
As this is an umbrella study (FDA 2018, CTFG 2019), additional agents may be included in this 
study (as monotherapy or as combinations) via Protocol amendment based on emerging PK, 
pharmacodynamic, and/or safety data once the RP2D for the combination has been established 
by the sponsor. 
2.1.3. 
Retifanlimab 
Retifanlimab is a humanized, hinge-stabilized, IgG4κ monoclonal antibody that recognizes 
human PD-1.  Retifanlimab contains a human IgG4 Fc domain to limit effector function while 
retaining neonatal Fc receptor binding to extend circulating half-life.  Retifanlimab is designed to 
target PD-1–expressing cells, including T cells, and to sustain/restore their effector function by 
blocking checkpoint inhibitory interactions between PD-1 and its 2 ligands, PD-L1 and PD-L2. 
In vitro studies with retifanlimab have demonstrated high affinity binding to both recombinant 
human and cynomolgus monkey PD-1 as well as to PD-1 that is naturally expressed on the cell 
surface, including on T cells.  Consistent with its intended mechanism of action and functional 
properties, retifanlimab has been shown to inhibit the binding of PD-L1 and PD-L2 to PD-1, to 
disrupt the PD-1/PD-L1 inhibitory axis, and to enhance IFN-γ secretion in staphylococcal 
enterotoxin B–stimulated human peripheral blood mononuclear cells with activity comparable to 
pembrolizumab and nivolumab replicas (generated by MacroGenics, Inc based on the published 
sequences of these antibodies).  Retifanlimab does not induce antibody-dependent cellular 
cytotoxicity or complement-dependent cytotoxicity, mitogenic activity, hemolysis, or cytokine 
release. 
Retifanlimab is currently being investigated in locally advanced or metastatic bladder cancer in 
participants who are not eligible for cisplatin therapy and whose tumors express PD-L1 with a 
CPS ≥ 10 (INCMGA 0012-203 [POD1UM-203]). 
2.1.3.1. 
Rationale for Retifanlimab Dose 
Retifanlimab will be administered at 500 mg Q4W.  The selection of this dose is based on 
modeling of clinical PK data from the first-in-human monotherapy study, INCMGA 0012-101, 
in which 37 participants were treated with doses of 1 mg/kg Q2W, 3 mg/kg Q2W, 3 mg/kg 
Q4W, 10 mg/kg Q2W, and 10 mg/kg Q4W.   
Pharmacokinetic data were obtained from 15 participants who received retifanlimab 500 mg 
Q4W in Study INCMGA 0012-101.  The observed AUC0-∞ for 500 mg Q4W is close to the 
steady-state AUC0-t based on the population PK analysis of weight-based doses, as is the 
estimated clearance.  The 500 mg Q4W dose has approximately 58% probability to obtain a 
steady-state trough plasma concentration ≥ 21 µg/mL, which is associated with maximum target 
engagement and greatest probability of efficacy.  Based on these observations, 500 mg Q4W has 
been chosen as the dose regimen.  In addition, retifanlimab 375 mg Q3W was investigated and 
selected as a RP2D and is utilized in clinical trials.  For further details, refer to the 
retifanlimab IB.  


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2.1.4. 
Epacadostat 
IDO1 is an enzyme in an alternative tryptophan metabolism pathway that reduces tryptophan 
levels and generates metabolites (eg, kynurenine and others) that contribute to tumor-derived 
immune suppression.  IDO1-mediated oxidation of tryptophan results in a strong inhibitory 
effect on the development of T-cell responses by blocking T-cell activation and inducing T-cell 
apoptosis (Mellor et al 2003).  IDO1 activity also promotes the differentiation of naive T cells to 
cells with a regulatory phenotype (ie, Tregs; Fallarino et al 2006).  In preclinical models, IDO1 
inhibition has been shown to synergize with blockade of anti–PD-1/PD-L1 in delaying tumor 
growth and increasing survival (Spranger et al 2014).  This effect was shown to be 
T-cell–dependent, lead to enhanced T-cell proliferation and IL-2 production within the tumor, 
and produce a marked increase in the effector-to-regulatory T-cell ratios in the tumors, 
suggesting that the results are the consequence of disabling immunosuppressive mechanisms that 
exist within the tumor microenvironment.  Based on this rationale, combinations of epacadostat 
with a PD-1 or PD-L1 inhibitor are being extensively studied across multiple tumor types 
(epacadostat IB, Fallarino et al 2006, Mellor et al 2003, Spranger et al 2014). 
2.1.4.1. 
Rationale for Epacadostat Dose 
Epacadostat monotherapy is well-tolerated at doses of up to 700 mg BID in participants with 
refractory solid tumors (Beatty et al 2017).  Pharmacodynamic inhibition of plasma IDO1 was 
observed at doses of 100 mg BID or greater, although clinical responses were not observed.  
Specifically, a monotherapy dose of epacadostat 100 mg BID achieved an exposure that 
exceeded the IC50 at steady state, which resulted in optimum efficacy in nonclinical models.  
However, intratumoral pharmacodynamics (eg, changes in the kynurenine/tryptophan ratio) were 
not assessed.  Given the results of the Phase 3 randomized study (ECHO-301/KEYNOTE-252), 
higher doses of epacadostat were investigated in Study POD1UM-102 (see Section 2.1.5 and 
refer to the epacadostat IB) to maintain a steady-state concentration that exceeds the IC90 at all 
times in tumor tissue and in the setting of PD-(L)1 combination therapy, which has been shown 
to induce IDO1.   
2.1.5. 
Combination of Epacadostat Plus Retifanlimab 
The combination of retifanlimab and epacadostat has been assessed in a dose-finding study 
(INCMGA 0012-102, NCT03589651).  As of 13 DEC 2021, 100 participants had been treated 
with the combination of retifanlimab 500 mg Q4W and epacadostat at doses of 100, 400, 600, 
and 900 mg BID.  Epacadostat 900 mg BID exceeded the MTD based on the development of 
Grade 3 rash in 2 of 3 participants, with the third participant developing rash after the 
Protocol-defined DLT window.   
Paired biopsies were collected to measure tumor T-cell infiltration by IHC and intratumoral 
kynurenine by quantitative mass spectrometry imaging.  Increases in total T cells, CD8 T cells, 
and Treg infiltration were observed in the on-treatment biopsies in the majority of the 10 samples 
tested.  Results of the quantitative mass spectrometry imaging analysis showed that intratumoral 
kynurenine levels decreased in 4 of 5 paired samples analyzed.  In addition, epacadostat 600 mg 
BID resulted in durable normalization of plasma kynurenine levels (epacadostat IB, Smith 
et al 2020).   


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Based on these observations, 600 mg BID was chosen as the RP2D for epacadostat in 
combination with retifanlimab and is the dose regimen being used in this study.  It is also the 
monotherapy dose that is being investigated in this study.  Refer to the epacadostat IB for further 
information. 
In Study INCMGA 0012-102, the frequency of proliferating T cells in the circulation and the 
concentration of CXCL9 and CXCL10 was monitored.  Participants presented an early increase 
on treatment in the frequency of proliferating and activated T cells.  These changes were 
consistent with the changes observed in the monotherapy study.  Refer to the epacadostat IB for 
further information. 
2.1.6. 
INCAGN02385 
INCAGN02385 is an Fc-modified IgG1κ monoclonal antibody that binds to human LAG-3 with 
an estimated affinity of 1.7 nM and was chosen for clinical development based on its selectivity 
for human LAG-3, with no cross-reactivity to related Ig superfamily proteins.  INCAGN02385 
functions as a potent LAG-3 antagonist antibody via its ability to inhibit LAG-3 binding to major 
histocompatibility complex class II, leading to enhanced T-cell receptor signaling.  Additional 
information regarding preclinical and in vitro experience with INCAGN02385 can be found in 
the INCAGN02385 IB. 
2.1.6.1. 
Rationale for INCAGN02385 Dose 
As of 21 MAR 2021, a total of 22 unique participants had been enrolled and received at least 
1 dose of INCAGN02385 at doses of 25, 75, 250, 350, and 750 mg Q2W IV in an open-label, 
nonrandomized, dose-escalation, and cohort-expansion study (NCT03538028).  All doses were 
well-tolerated; no DLTs were observed, and there were no treatment-related deaths.  
INCAGN02385 PK was independent of dose after the first dose and showed moderate to high 
interindividual variability.  At a dose of 350 mg Q2W (N = 3), the steady-state AUC was 
30,200 µg/mL∙h.  The dose of 350 mg Q2W was chosen for INCAGN02385 based on the results 
that the receptor on the surface of the cells was fully occupied at trough concentration and that 
the pharmacodynamic marker supported this dose to be pharmacologically active as measured by 
an increase in peripheral T-cell activation observed at doses > 250 mg. Refer to the 
INCAGN02385 IB for further information.  
2.1.7. 
INCAGN02390 
INCAGN02390 is a recombinant, aglycosylated, fully human IgG1κ monoclonal antibody that 
binds to the extracellular domain of the TIM-3 receptor.  Antagonist TIM-3 antibodies have 
demonstrated enhanced antitumor activity in several mouse tumor models when combined with 
blockade of the PD-1/PD-L1 pathway (Ngiow et al 2011, Sakuishi et al 2010).  Additional 
information regarding preclinical and in vitro experience with INCAGN02390 can be found in 
the INCAGN02390 IB. 
2.1.7.1. 
Rationale for INCAGN02390 Dose 
As of 28 JUN 2021, a total of 40 unique participants had been enrolled and received at least 
1 dose of INCAGN02390 at doses of 10, 30, 100, 200, 400, 800, and 1600 mg IV Q2W in the 
open-label, nonrandomized, dose-escalation, and cohort expansion study (NCT03652077) 


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evaluating INCAGN02390 monotherapy.  All doses were well-tolerated, no DLTs were 
observed, and there were no treatment-related deaths.  INCAGN02390 showed supraproportional 
PK after first dose from 30 mg to 800 mg Q2W and low interindividual variability on PK 
exposures.  At a dose of 400 mg Q2W, the mean steady-state AUC determined in 4 participants 
was 43,400 µg/mL∙h.  The dose of 400 mg was chosen for INCAGN02390 based on the results 
that the TIM-3 receptor was fully occupied on the surface of circulating monocytes.  Refer to the 
INCAGN02390 IB for further information.   
2.1.8. 
Combination of Retifanlimab Plus INCAGN02385  
It has been demonstrated in murine models that PD-1 and LAG-3 act synergistically to promote 
tumor immune escape, and simultaneous blockade of LAG-3 and PD-1 results in synergistic 
inhibition of tumor growth (Woo et al 2012).  Evidence for synergy of anti–PD-1 and 
anti–TIM-3 was shown in an in vivo murine model of chronic infection resulting in T-cell 
exhaustion characterized by coexpression of TIM-3 and PD-1.  Combined blockade of these 
2 inhibitory receptors markedly improved CD8+ T-cell responses (Jin et al 2010, 
INCAGN02385 IB, INCAGN02390 IB).   
RELATIVITY-047, a Phase 3 study in patients with previously untreated unresectable or 
metastatic melanoma, demonstrated an improvement in PFS when nivolumab was combined 
with relatlimab (10.1 vs 4.63 months; Lipson et al 2021).  Additional clinical activity was 
demonstrated with the combination of pembrolizumab and eftilagimod in patients with PD-L1 
unselected metastatic second-line treatment for head and neck squamous cell carcinoma (ORR: 
31.4%; Peguero et al 2019).  As such, this study investigates the combination of retifanlimab and 
INCAGN02385 in cisplatin-ineligible urothelial carcinoma.  
2.1.9. 
Combination of Retifanlimab Plus INCAGN02385 Plus INCAGN02390 
Early clinical evidence of the efficacy of retifanlimab plus INCAGN02385 plus INCAGN02390 
in patients with disease that has failed to respond to anti–PD-(L)1 therapy has been evolving.  
Blockade of the PD-(L)1 axis in combination with blockade of either LAG-3 or TIM-3 has 
resulted in only modest responses in patients with disease that has failed to respond to anti–PD-1 
therapy alone (Ascierto et al 2017, Davar et al 2018).  Potentially, multiple checkpoint inhibitors 
may be required in order to restore antitumor T-cell effector function in situ (Kaufmann 
et al 2018).  In this study, the triple combination of antibodies directed against PD-1, TIM-3, and 
LAG-3 demonstrated enhanced tumor growth inhibition relative to inhibition of either PD-1 plus 
LAG-3 or PD-1 plus TIM-3 in a murine model.  In addition, the combination of all 3 antibodies 
resulted in greater restoration of function to TILs isolated from patients with ovarian cancer.  
This suggests a requirement for inhibition of all 3 checkpoints in concert is more relevant for 
returning immune function and tumor growth inhibition 
2.1.10. 
Combination of Retifanlimab Plus INCAGN02385 and Combination of 
Retifanlimab Plus INCAGN02385 Plus INCAGN02390  
INCAGN 2385-201 in an ongoing Phase 1/2 study evaluating the safety and preliminary efficacy 
of combinations of the Phase 1 doses of INCAGN02385 and INCAGN02390 together with 
retifanlimab 500 mg Q4W.  As of 28 JUN 2021, a total of 21 unique participants had been 
enrolled and received at least 1 dose of INCAGN02385 at a dose of 350 mg Q2W IV in 
combination with INCAGN02390 400 mg Q2W (N= 10) or INCAGN02390 400 mg Q2W plus 


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retifanlimab 500 mg Q4W (N = 11) in this open-label, nonrandomized, safety evaluation and 
cohort expansion study.  During Phase 1 of INCAGN 2385-201, no DLTs were observed; 
19 participants had at least 1 TEAE.  Based on the results from the monotherapy trials as well as 
the INCAGN 2385-201 study, the dose for Treatment Group D will be retifanlimab 500 mg 
Q4W IV in combination with INCAGN02385 350 mg Q2W IV.  For Treatment Group E, the 
dose will be retifanlimab 500 mg Q4W IV in combination with INCAGN02385 350 mg Q2W IV 
and INCAGN02390 400 mg Q2W IV.   
2.2. 
Benefit/Risk Assessment  
2.2.1. 
Monotherapy Risks 
2.2.1.1. 
Retifanlimab 
PD-1 inhibitors have proven efficacy against a wide variety of cancer types, including 
neoadjuvant treatment of muscle invasive bladder cancer (Necchi et al 2018).  The available 
preclinical and clinical data strongly suggest that the pharmacology and clinical activity of 
retifanlimab are similar to experience with other drugs of this class (Chen et al 2019, 
Condamine et al 2019, Lakhani et al 2017, Mehnert et al 2018).  Thus, it is logical to study 
retifanlimab in this disease as monotherapy and in combinations in which PD-1 inhibitors are the 
backbone therapy.  
As of the data cutoff date of 23 SEP 2021, 660 unique participants have been exposed to 
retifanlimab as monotherapy.  Results from the dose-escalation and dose-expansion portion of 
the retifanlimab monotherapy study (POD1UM-101) demonstrated acceptable tolerability.  In the 
dose-escalation portion, no DLTs have been observed at any dose level up to 10 mg/kg Q2W.  
An MTD was not reached.  Refer to the retifanlimab IB for further information. 
2.2.1.2. 
Epacadostat 
A total of 216 participants have been treated with epacadostat monotherapy, including healthy 
participants (INCB 24360-102, INCB 24360-103, INCB 24360-104, INCB 24360-105, 
INCB 24360-106, and INCB 24360-107) and participants with advanced malignancies 
(INCB 24360-101 and INCB 24360-210).  In the Phase 1 clinical study in participants with 
refractory solid tumors (INCB 24360-101), doses up to 700 mg BID were given without an MTD 
determined.   
2.2.2. 
Combination Therapy Risks 
2.2.2.1. 
Epacadostat and Retifanlimab 
Retifanlimab and epacadostat are immunomodulatory agents; therefore, irAEs may be associated 
with their coadministration.  Experience with other immuno-oncology agents that target 
endogenous immunosuppressive mechanisms has demonstrated that irAEs can affect any organ 
or tissue but most frequently occur in the skin (rash), gastrointestinal system (diarrhea/colitis), 
liver (hepatitis), lungs (pneumonitis), endocrine system (endocrinopathies due to inflammation of 
the pituitary, thyroid and adrenal glands), and kidneys (nephritis).  Management of irAEs should 
follow the general approach that has been used for other immuno-oncology agents.  See 
Section 6.5.3 for the irAE dose modification and monitoring guidance. 


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There is a rare chance that epacadostat, when administered alone or in combination with other 
serotonergic agents, could cause an increase in serotonin levels in the brain that might trigger 
serotonin syndrome (Boyer and Shannon 2005).  This syndrome has been most closely 
associated with use of MAOIs, meperidine, linezolid, or methylene blue.  Selective serotonin 
reuptake inhibitors, SNRIs, and MAOIs are permitted in the study.  Serotonin syndrome usually 
manifests with autonomic changes, mental status changes, and neurological findings.  Procedures 
for participants in the epacadostat groups exhibiting serotonin syndrome are presented in 
Section 6.5.5. 
Treatment-emergent AEs reported in > 10% of participants included fatigue, nausea, decreased 
appetite, abdominal pain, pruritus, maculopapular rash, anemia, rash, dyspnea, constipation, 
pyrexia, and diarrhea.  Serious TEAEs occurred in 39 participants (39%).  The most frequently 
reported serious TEAEs were dyspnea (6%), maculopapular rash (5%), and pleural effusion 
(3%).  Treatment-emergent AEs led to discontinuation of epacadostat for 16 participants 
(16.0%).  The most frequently reported TEAE leading to discontinuation of epacadostat was 
maculopapular rash (7.0%).  The MTD of epacadostat in combination with retifanlimab 500 mg 
was determined to be 600 mg BID.  Epacadostat 900 mg BID exceeded the MTD based on the 
occurrence of Grade 3 maculopapular rash in 2 of 3 participants during the DLT evaluation 
period.  Overall, the following DLTs were reported: 
• 400 mg BID:  1 DLT of Grade 3 maculopapular rash 
• 600 mg BID:  1 DLT of Grade 3 maculopapular rash, 1 DLT of Grade 3 acneiform 
dermatitis, and 1 DLT of Grade 3 abdominal pain 
• 900 mg BID:  2 DLTs of Grade 3 maculopapular rash 
Five participants (5.0%) had fatal TEAEs:  acute respiratory distress syndrome and COVID-19 
pneumonia (1 participant) and ascites, cardiovascular disorder, respiratory failure, and 
thrombocytopenia (1 participant each).  None of the fatal TEAEs were considered related to 
epacadostat.  For further information, refer to the epacadostat IB. 
2.2.2.2. 
Retifanlimab, INCAGN02385, and INCAGN02390 
For the combination of INCAGN02385 and INCAGN02390, 5 participants had serious TEAEs 
(asthenia, pancreatitis, dyspnea and hypoxia and rectal hemorrhage, vulval hemorrhage, pyrexia, 
vasculitis, COVID-19, and sepsis).  Of these TEAEs, only 1 (vasculitis) was considered related 
to both study drugs by the investigator.  One participant had a fatal TEAE (sepsis), which was 
considered not related to INCAGN02385 or INCAGN02390 by the investigator.   
For the combination of retifanlimab, INCAGN02385, and INCAGN02390, 2 participants 
experienced TEAEs (1 participant had acute respiratory failure, and another had pericardial 
effusion and myocarditis).  The pericardial effusion (Grade 2) and myocarditis (Grades 2 and 3) 
were considered related to INCAGN02385, INCAGN02390, and retifanlimab by the investigator 
and resolved following interruption of study drugs.  This participant discontinued from the study 
due to progressive disease. 
2.2.3. 
Risks of Delayed Cystectomy 
Overall survival has been associated with the pathological tumor stage of radical cystectomy.  
The 5-year OS estimates range from 81% to 93% for patients with pT0 disease but decrease to 


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46% to 48% in patients with PT3 disease (Hautmann et al 2012).  The impact of the time to 
definitive treatment with radical cystectomy after completion of neoadjuvant therapy is not 
well-studied, with various results mainly from single-institution experiences.  In an analysis by 
Park et al (2016), the timing of radical cystectomy had no impact on OS, whereas Alva 
et al (2012) demonstrated that delays of up to 5 months between the end of neoadjuvant 
chemotherapy and radical cystectomy served as potential thresholds that conferred worse 
outcomes after radical cystectomy.  Gore et al (2009) established from a Surveillance, 
Epidemiology, and End Results Medicare Program analysis that there is an increase in mortality 
when radical cystectomy is delayed for more than 12 weeks from time to diagnosis to radical 
cystectomy in patients who had not received neoadjuvant therapy.  A recent analysis by Chu 
et al (2019) with more than 1500 participants demonstrated that compared with timely surgery, 
delays in radical cystectomy longer than 11 weeks after the completion of neoadjuvant 
chemotherapy significantly compromised patient survival.  It should be noted that delays in 
radical cystectomy were not necessarily due to AEs from neoadjuvant chemotherapy.  In fact, in 
the study by Chu et al (2019), 13% of participants who did not have neoadjuvant chemotherapy 
versus 22% of those who received neoadjuvant therapy experienced delays in radical cystectomy 
> 12 weeks, defined as more than 12 weeks for patients proceeding directly to radical cystectomy 
if no neoadjuvant therapy was provided or 11 weeks after the completion of treatment for those 
treated with neoadjuvant therapy. 
2.2.3.1. 
Treatment-Emergent Adverse Events of Special Interest  
Based on the review of outcomes in patients who had delays in radical cystectomy > 12 weeks, it 
is imperative that there are minimal treatment delays > 11 weeks after completion of neoadjuvant 
therapy to radical cystectomy in this study.  To better understand the rates of AEs in the first 
12 weeks of treatment with the agents (3 cycles of treatment) to be administered in this study as 
well as the time to resolution for these AEs, an analysis was conducted on drug-related 
TEAOSI.  The TEAOSI were chosen based on the likelihood that they may delay surgery.  Since 
this study uses investigational agents, the rate of resolution of these TEAOSI within 12 weeks 
from start of treatment was also calculated.  This conservative timeframe was chosen as opposed 
to 11 weeks after neoadjuvant therapy to simulate the potential risk for patients not receiving any 
neoadjuvant therapy.   
An analysis was conducted after 12 weeks from start of treatment on select studies that include 
retifanlimab or epacadostat to further characterize their safety profiles, as detailed in the SAP 
(see Appendix E).  Table 8 and Table 9 provide summaries from the data on file in the SAP.  The 
TEAOSI were selected based on the likelihood they may cause potential delay in surgery.  As 
such, TEAOSI was defined as any of the following:   
• Select Grade 3 or higher AEs 
− Cardiac disorders; ear and labyrinth disorders; endocrine disorders; 
gastrointestinal disorders; hepatobiliary disorders; infections/infestations; 
injury/bleeds; hemorrhages; metabolism and nutrition disorders; musculoskeletal 
and connective tissue disorders; benign/malignant neoplasms; nervous system 
disorders; psychiatric disorders; renal/urinary disorders; reproductive system and 
breast disorders; respiratory, thoracic, and mediastinal disorders; skin and 
subcutaneous tissue disorders; and vascular disorders  


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• Adverse events leading to hospitalization 
• Fatal AEs 
• Grade 2 or higher irAEs 
2.2.3.1.1. Retifanlimab and Epacadostat 
The studies that were selected had completed data at the time of analysis.  They included 
participants who had recurrent disease of various metastatic solid tumors.  Studies included 
monotherapy treatments with retifanlimab and epacadostat.  For combination regimens, the 
dose-finding study with epacadostat in combination with retifanlimab in solid tumors as well as 
epacadostat in combination with pembrolizumab were included (see Appendix E).  Of note, 
2 trials of epacadostat in combination with pembrolizumab in recurrent urothelial cancer were 
included, but these had halted accrual early due to the lack of benefit observed in the completed 
ECHO-301 trial in recurrent melanoma (Long et al 2019). 
Table 8: 
Summary of TEAOSI for Select Studies With Retifanlimab and Epacadostat 
That Occurred Within the First 12 Weeks of Treatment 
 
Retifanlimab 
(N = 647) 
Epacadostat 
(N = 159) 
Number (%) of participants with select Grade 3 or higher 
AEs related to study drug 
8 (1.2) 
4 (2.5) 
Probability (95% CI) of unresolved Grade 3 or higher 
AEs related to study drug at week 12 (all participants) 
0.01 (0.00, 0.01) 
0.02 (0.01, 0.05) 
Median (95% CI) time (in weeks) from start of treatment 
to resolution of Grade 3 or higher AEs related to study 
drug (among participants with Grade 3 or higher AEs, 
n = 8 for retifanlimab, n = 4 for epacadostat) 
9.0 (4.0, NE) 
14.1 (9.9, NE) 
Number of participants with at least 1 AE related to study 
drug leading to hospitalization (%)  
20 (3.1) 
4 (2.5) 
Probability (95% CI) of unresolved AEs related to study 
drug that led to hospitalization (all participants) 
0.01 (0.00, 0.02) 
0.02 (0.01, 0.05) 
Median (95% CI) time (in weeks) to resolution of AEs 
related to study drug that led to hospitalization (among 
participants with AEs leading to hospitalization) 
7.7 (4.4, 10.3) 
13.7 (9.9, 42.4) 
Number (%) of fatal AEs related to study drug 
2 (0.3)a 
0 (0) 
Number (%) of Grade 2 or higher irAEs  
41 (6.3) 
17 (10.7) 
Probability (95% CI) of unresolved Grade 2 or higher 
irAEs (all participants) 
0.03 (0.02, 0.05) 
0.08 (0.05, 0.13) 
Median (95% CI) time (in weeks) to resolution of Grade 2 
or higher irAEs (among participants with Grade 2 or 
higher irAEs) 
12.3 (9.0, 18.7) 
NE (9.9, NE) 
NE = not estimable. 
Note:  Kaplan-Meier estimates based on time from start of treatment. 
a For retifanlimab, fatal outcomes were due to progression of disease. 


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The overall rates of Grade 3/4 SAEs related to study drug are favorable when compared with 
cisplatin-based chemotherapy, in particular, in the Phase 3 SWOG 1817 trial in neoadjuvant 
miUBC, in which at least one-third of participants had severe hematologic or gastrointestinal 
effects (Grossman et al 2003).  The rates of such SAEs were not observed in Incyte-sponsored 
trials.  In addition, the participant population for our trials is those with recurrent metastatic solid 
tumors who have undergone multiple lines of treatment and are more likely to experience higher 
rates of hospitalization or fatal outcomes predominantly due to progression of disease.   
Among participants with Grade 2 or higher irAEs, the median time to resolution of these AEs is 
> 12 weeks.  However, not all of these irAEs would result in delay in surgery.  In particular, 
Grade 2 immune-related TEAEs that were not resolved in 12 weeks did not typically delay 
surgery.  Taking this into account, only 10 of 647 participants (1.5%) treated with retifanlimab 
and 9 of 159 participants (5.7%) treated with epacadostat experienced a Grade 3 to 5 
immune-related TEAE that was unresolved in 12 weeks and potentially delayed surgery.  
It should be noted that the epacadostat-containing regimen was in combination with other 
immune checkpoint inhibitors (pembrolizumab and nivolumab).  However, 8 of these 
9 participants (88.9%) received epacadostat in combination with pembrolizumab and only 
1 participant received epacadostat monotherapy.  
Table 9: 
Grade 2 or Higher Immune-Related TEAEs for Studies With Retifanlimab 
and Epacadostat (Multiple Tumor Types) 
 
Resolved at 
Week 12 From 
Start of 
Treatment 
N (%) 
Unresolveda at 
Week 12 From 
Start of 
Treatment 
N (%) 
Death at 
Week 12 
N (%) 
Total 
N (%) 
Retifanlimab (N = 647) 
Participants with any Grade 2 or 
higher immune-related TEAEs 
18 (43.9) 
21 (51.2) 
2 (4.9) 
41 (6.3) 
Participants with Grade 2 
immune-related TEAEs 
7 (33.3) 
14  66.7) 
0 (0.0) 
21 (3.2) 
Participants with Grade 3/4 
immune-related TEAEs 
14 (63.6) 
8 (36.4) 
0 (0.0) 
22 (3.4) 
Participants with Grade 5 (fatal) 
immune-related TEAEs 
0 (0.0) 
0 (0.0) 
2 (100.0) 
2 (0.3) 
Epacadostat (N = 159) 
Participants with any Grade 2 or 
higher immune-related TEAEs 
4 (23.5) 
13 (76.5) 
0 (0.0) 
17 (10.7) 
Participants with Grade 2 
immune-related TEAEs 
2 (20.0) 
8 (80.0) 
0 (0.0) 
10 (6.3) 
Participants with Grade 3/4 
immune-related TEAEs 
3 (25.0) 
9 (75.0) 
0 (0.0) 
12 (7.5) 
Participants with Grade 5 (fatal) 
immune-related TEAEs 
0 (0.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
Note:  Participants who had Grade 2 as well as Grade 3 or higher immune-related TEAEs are reported. 
a Includes participants with immune-related TEAEs that started before Week 12 and resolved/recovered after Week 12. 


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The rates of treatment-related grade 3/4 SAEs as well as SAEs that require hospitalization were 
considerably low (1.2% and 2.5% for retifanlimab and epacadostat, respectively), and a 
population-level median time to resolution is not estimable.  The estimated probabilities (95% 
CI) of unresolved treatment-related grade 3/4 SAEs and SAEs that required hospitalizations in a 
treated population were 0.01 (0.00, 0.01) and 0.01 (0.00, 0.02) for retifanlimab and 0.02 (0.01, 
0.05) and 0.02 (0.01, 0.05) for epacadostat, respectively. 
Also, in the PURE-01 study investigating pembrolizumab as neoadjuvant treatment in miUBC, 
there were a few irAEs that subsequently did not delay planned surgery (Necchi et al 2018).   
2.2.3.1.2. INCAGN02385 and INCAGN02390 Monotherapy and in Combination With 
Retifanlimab 
Three dose-finding studies were conducted investigating the safety and tolerability of 
INCAGN02385 monotherapy (INCAGN 2385-101, NCT 03538028; N = 22), INCAGN02390 
monotherapy (INCAGN 2390-101, NCT03652077; N = 40), and doublet therapy with 
INCAGN02385/INCAGN02390 (N = 10) and triplet therapy with retifanlimab/INCAGN02385 
and INCAGN02390 (N = 11; –INCAGN 2385-201, NCT04370704).  In total, 83 participants 
were enrolled between the 3 studies (see Appendix E).  In the INCAGN02385 monotherapy 
study, 8 participants had serious TEAEs, none of which were considered related to 
INCAGN02385 by the investigator.  In the INCAGN02390 monotherapy study, the only 
drug-related TEAOSI observed within the first 12 weeks of treatment was Grade 2 or higher 
irAE in 2 participants (1 case of diarrhea that resolved in 9 days and 1 case of lymphopenia).  
Also, no participants experienced a Grade 3 or higher TEAOSI in the INCAGN02385 
monotherapy study.  One participant in the INCAGN02385 plus INCAGN02390 plus 
retifanlimab arm experienced a Grade 3 pericardial effusion and myocarditis that were related to 
treatment per the investigator and resolved following interruption of study drugs.  This 
participant discontinued from the study due to progressive disease (see Table 10). 
Table 10: 
Grade 2 or Higher Immune-Related TEAEs for Studies With 
INCAGN02385, INCAGN02390, and Retifanlimab 
 
INCAGN02385 
Monotherapy 
(N = 22) 
INCAGN02390 
Monotherapy 
(N = 40) 
INCAGN02385 Plus  
INCAGN02390 
(N = 10) 
INAGN02385 Plus 
INCAGN02390 Plus 
Retifanlimab 
(N = 11) 
Participants with any 
Grade 2 or higher 
immune-related TEAEs 
0 
2 
0 
1 
Participants with 
Grade 2 
immune-related TEAEs 
0 
2 
0 
0 
Participants with 
Grade 3/4 
immune-related TEAEs 
0 
0 
0 
1 
Participants with 
Grade 5 (fatal) 
immune-related TEAEs 
0 
0 
0 
0 


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In conclusion, the lower rates of Grade 3/4 SAEs of interest compared to those with 
cisplatin-based treatments, the reasonable time to resolution of both overall SAEs and those 
leading to hospitalization, as well as the lower overall Grade 3/4 immune-related TEAEs that 
were not resolved in 12 weeks from start of treatment, which is typically the timeframe observed 
for patients not on neoadjuvant chemotherapy as opposed to the more generous timeframe of 
11 weeks after the last dose of neoadjuvant therapy, all provide a favorable safety profile for 
these agents that would warrant further investigation of their utility in the neoadjuvant setting for 
miUBC. 
2.2.4. 
Benefits 
Greater immunomodulatory effects in the tumor microenvironment could potentially enhance the 
clinical benefit in participants with miUBC.  By  providing broader inhibition of the 
immunosuppressive environment driven by myeloid-deprived suppressor cells, Tregs, and other 
immune cells and factors, it is hypothesized that this additional benefit may not come at the cost 
of additional toxicity or that additional immune toxicities (by incidence or severity) will be 
manageable by drug interruption and temporary use of immunosuppressive therapies 
(eg, corticosteroids). 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of each compound may be found in the respective Investigator's Brochures 
(epacadostat IB, INCAGN02385 IB, INCAGN02390 IB, and retifanlimab IB). 
2.2.5. 
Benefit/Risk Assessment During the COVID-19 Pandemic 
Participants to be enrolled into this study have advanced or metastatic malignancies and may be 
at higher risk for complications if they contract COVID-19.  In this Phase 2 study population, 
standard of care therapy options for the malignancies are limited and no effective therapies or 
standards of care exist.  An ESMO multidisciplinary panel highlighted the importance of clinical 
cancer research to find better therapeutic options for participants even during the pandemic, 
including potential investigational therapies similar to immunotherapy with a known survival 
benefit (Curigliano et al 2020).  Preliminary data released based on real-world data indicate that 
the use of immunotherapy either alone or in combination with chemotherapy does not appear to 
increase the risk of hospitalization upon COVID-19 infection (Horn et al 2020) or cause an 
increased risk of mortality (Lee et al 2020).   
During the COVID-19 pandemic, additional risks to participants exist either related to going to a 
healthcare facility or as a result of study-related activities.  Potential participants with known or 
suspected active COVID-19 infection are ineligible as per Exclusion Criterion 14.  It is at the 
principal investigator's discretion to balance the risk/benefit while considering the participant's 
safety, existing comorbidities, and current malignancy.   
Participants who are diagnosed with COVID-19 during the study will be monitored with safety 
procedures as described in Section 8.3 and with additional safety assessments as per standard of 
care.  Additional information regarding the flexibility of assessments and strategy for participant 
management during the dynamic pandemic as applicable is described in Appendix G. 


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3. 
OBJECTIVES AND ENDPOINTS 
Table 11 presents the objectives and endpoints. 
Table 11: 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
To determine biologic response in participants 
with muscle-invasive cisplatin-ineligible or those 
refusing cisplatin therapy, urothelial carcinoma of 
the bladder. 
For each treatment group, the primary endpoint is 
the change from baseline in CD8+ lymphocytes 
within resected tumor. 
Secondary 
To evaluate the safety and tolerability of each of 
the treatment groups. 
• Safety and tolerability assessed by monitoring 
the frequency and severity of AEs, including 
delay in cystectomy due to AEs. 
To evaluate the preliminary efficacy of each of 
the treatment groups. 
• pCR rate, defined as percentage of participants 
with ypT0N0 in each treatment group. 
• Major pathological response, defined as 
residual ypT0/1/a/isN0M0. 


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Table 11: 
Objectives and Endpoints (Continued) 
Objectives 
Endpoints 
4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is an open-label, randomized, Phase 2 umbrella study of various neoadjuvant therapies for 
miUBC (ie, Galsky et al 2011) undergoing radical cystectomy. 
This study will test the biological rationale for use of targeted and immuno-oncology agents for 
neoadjuvant treatment of cisplatin-ineligible or participants refusing cisplatin therapy miUBC 
and potential for subsequent efficacy benefit, as shown with other anti–PD-1 inhibitors and at 
doses shown to add minimal/acceptable risk from side effects (ie, positive benefit/risk).  The 
translational endpoints will inform which therapies are viable candidates for further 
investigation in miUBC.  This study is an umbrella design where future treatment arms may be 
added or removed at the discretion of the sponsor.   
Participants will be randomized into 1 of the following treatment groups: 
• Treatment Group A:  epacadostat in combination with retifanlimab 
• Treatment Group B:  retifanlimab monotherapy  
• Treatment Group C:  epacadostat (IDO1 inhibitor) monotherapy 
• Treatment Group D: retifanlimab plus INCAGN02385 
• Treatment Group E: retifanlimab plus INCAGN02385 plus INCAGN02390 
Tumor tissue will be tested centrally to determine PD-L1 CPS score. 
Participants will be randomized into treatment groups according to the schema in Figure 1.  
Participants with PD-L1 CPS < 10 or PD-L1 CPS ≥ 10 will be randomized at a 2:2:1:2:2 ratio 
into Groups A, B, C, D and E, respectively.  Participants who passed screening for PD-L1 
CPS < 10 will not be randomized into a group once that group has reached the allowed number 


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of participants with PD-L1 CPS < 10.  Similarly, participants with PD-L1 CPS ≥ 10 will be 
randomized into a group once that group has reached the allowed number of participants with 
PD-L1 CPS ≥ 10.  This will ensure that the desired proportion of participants who have PD-L1 
CPS < 10 and PD-L1 CPS ≥ 10 within each group will be enrolled. 
For Treatment Group C, the subgroup of participants with PD-L1 CPS < 10 or PD-L1 CPS 
≥ 10 that reaches 5 participants will hold enrolling participants to that particular subgroup 
and will continue to enroll until 4 participants in the other subgroup are enrolled. 
After signing the ICF, screening assessments may be completed over a period of up to 28 days.  
Treatment cycles are 28 days unless otherwise noted.  Each participant enrolled in the study will 
receive a minimum of 1 treatment cycle if, in the judgment of the investigator, the participant has 
not met any criteria for study withdrawal.  The treatment duration will be approximately 4 to 
10 weeks.  The radical cystectomy is typically scheduled 8 to 10 weeks with an average of 
8 weeks from the TURBT (ie, approximately Day 56; Poletajew et al 2014). 
Precystectomy assessments will be performed within 2 weeks before surgery.  Participants are 
followed for safety as well as radiographic imaging for 90 days after cystectomy or the last dose 
of study treatment in the event cystectomy is not performed. 
4.2. 
Overall Study Duration 
The study begins when the first participant signs the ICF.  The end of the study is defined as the 
date of the last scheduled procedure shown in the SoA of the last participant in the study 
globally. 
A participant is considered to have completed the study if he/she has completed all parts of the 
study including the last scheduled procedure shown in the SoA. 
The estimated duration of study participation is approximately 6 months from start of study 
treatment. 
4.3. 
Study Termination 
The investigator retains the right to terminate study participation at any time, according to the 
terms specified in the study contract.  The investigator is to notify the IRB/IEC in writing of the 
study's completion or early termination, send a copy of the notification to the sponsor or 
sponsor's designee, and retain 1 copy for the site study regulatory file. 
The sponsor may terminate the study electively, if required by regulatory decision or upon 
advice of the DSMB.  If the study is terminated prematurely, the sponsor will notify the 
investigators, the IRBs and IECs, and regulatory bodies of the decision and reason for 
termination of the study.  The DSMB will recommend termination of the study if warranted, as 
described in Section 5.6. 


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5. 
STUDY POPULATION 
Deviations from eligibility criteria are not allowed because they can potentially jeopardize the 
scientific integrity of the study, regulatory acceptability, and/or participant safety.  Therefore, 
adherence to the criteria as specified in the Protocol is essential.  Prospective approval of 
Protocol deviations to recruitment and enrollment criteria, also known as Protocol waivers or 
exemptions, are not permitted. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
1. Ability to comprehend and willingness to sign a written ICF for the study. 
2. Men or women aged 18 years or older.  
3. Histologically confirmed transitional cell urothelial carcinoma.  Participants with mixed 
histologies are required to have a dominant (ie, 50% at least) transitional cell pattern.  
4. Clinical stage T2-T3b, N0, M0 muscle invasive urothelial carcinoma by CT (or MRI) 
(Stage II-IIIA per AJCC 2018). 
a. Concomitant upper tract tumors should be excluded.  However, previous history of 
surgery for upper tract tumors may be allowed, provided that it was a noninvasive pT 
(ie, pT < 2N0M0 stage). 
5. Refuse cisplatin therapy (does not apply in France) or are ineligible for cisplatin therapy 
per modified Galsky criteria with exclusion of ECOG PS 2 participants (see 
Appendix C). 
a. Participants with CTCAE v4 ≥ Grade 2 audiometric hearing loss (Galsky Criteria).  
b. Participants with CTCAE v4 ≥ Grade 2 peripheral neuropathy (Galsky Criteria).  
c. Creatinine clearance of < 60 mL/min but ≥ 30 mL/min (measured by the 
Cockcroft-Gault formula or 24-hour urine). 
d. New York Heart Association Class III heart failure. 
6. Eligible for radical cystectomy by the following:  
a. Fit and planned for radical cystectomy according to local guidelines. 
b. Able to receive a minimum of 4 weeks of neoadjuvant treatment on study before date 
of scheduled radical cystectomy. 
c. Willing and able to delay surgery by a maximum of 12 weeks, if necessary. 
7. Removed during Protocol Amendment 4. 
8. ECOG PS 0 or 1.  
9. Pretreatment tumor biopsy must be a tumor block or 20 unstained slides from biopsy of 
primary tumor containing at least 20% tumor. 


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10. Willingness to avoid pregnancy or fathering children based on the criteria below. 
a. Male participants with childbearing potential must agree to take appropriate 
precautions to avoid fathering children (with at least 99% certainty) from screening 
through 100 days in the US and 190 days in Europe after the last dose of study drug 
and must refrain from donating sperm during this period.  Permitted methods that are 
at least 99% effective in preventing pregnancy (see Appendix A) should be 
communicated to the participants and their understanding confirmed. 
b. Women participants with childbearing potential must have a negative serum and/or 
pregnancy test at screening and before the first dose of study drug on Day 1 and must 
agree to take appropriate precautions to avoid pregnancy (with at least 99% certainty) 
and from donating oocytes from screening through 100 days in the US and 190 days 
in Europe after the last dose of study drug.  Permitted methods that are at least 99% 
effective in preventing pregnancy (see Appendix A) should be communicated to the 
participants and their understanding confirmed. 
c. Women participants without childbearing potential (ie, surgically sterile with a 
hysterectomy and/or bilateral oophorectomy OR ≥ 12 months of amenorrhea). 
d. Women participants without childbearing potential should refrain from donating 
oocytes from screening through 190 days after the last dose of study drug. 
5.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
1. Participation in any other study in which receipt of an investigational study drug or 
device occurred within 28 days or 5 half-lives (whichever is longer) before first dose.  
For investigational agents with long half-lives (eg, 5 days), enrollment before the 
fifth half-life requires medical monitor approval.  
2. Previously received systemic therapy for bladder cancer or received prior treatment with 
checkpoint inhibitor agents (such as anti–PD-1, anti–PD-L1, anti–PD-L2, or 
anti–CTLA-4).  
3. Evidence of measurable nodal or metastatic disease.  
4. Concurrent anticancer therapy (eg, chemotherapy, radiation therapy, surgery, 
immunotherapy, biologic therapy, hormonal therapy, investigational therapy, intravesical 
therapy or tumor embolization). 
5. Has had major surgery within 4 weeks before enrollment (C1D1).  
6. Has had known additional malignancy other than miUBC that is progressing or requires 
active treatment, or history of other malignancy within 2 years of study entry with the 
exception of cured basal cell or squamous cell carcinoma of the skin, superficial bladder 
cancer, prostate intraepithelial neoplasm, carcinoma in situ of the cervix, or other 
noninvasive or indolent malignancy, or cancers from which the participant has been 
disease-free for > 1 year, after treatment with curative intent.  


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7. Has active autoimmune disease requiring systemic immunosuppression with 
corticosteroids (> 10 mg daily doses of prednisone or equivalent) or immunosuppressive 
drugs within 2 years of Day 1 of study treatment. 
8. Participants with laboratory values at screening defined in Table 12. 
Table 12: 
Exclusionary Laboratory Values 
Laboratory Parameter 
Exclusion Criterion 
Hematology 
a Platelets 
< 100 × 109/L 
b Hemoglobin 
< 8 g/dL 
c ANC 
< 1.5 × 109/L 
Hepatic 
d ALT 
≥ 2 × ULN  
e AST 
≥ 2 × ULN  
f 
Total bilirubin 
≥ 1.5 × ULN unless conjugated bilirubin ≤ ULN (conjugated bilirubin 
only needs to be tested if total bilirubin exceeds ULN).  If there is no 
institutional ULN, then direct bilirubin must be < 40% of total 
bilirubin.  
Renal 
g CrCl 
< 30 mL/min calculated by Cockcroft-Gault equation (glomerular 
filtration rate can also be used in place of CrCl) 
Coagulation 
h INR or PT 
> 1.5 × ULN unless on therapeutic anticoagulants 
i 
aPTT 
> 1.5 × ULN 
Cardiac 
j 
Treatment Groups D and 
E only:  troponin I or 
troponin T  
> 2 × institutional ULN  
Participants with troponin I or troponin T levels between > 1 and 
2 × ULN will be permitted if repeat levels within 24 hours are 
≤ 1 × ULN.a  
a If repeat troponin I or troponin T levels are > 1 to 2 × ULN within 24 hours, the participant may undergo a cardiac 
evaluation and be considered for treatment, following a discussion with the sponsor's medical monitor or designee.  
When repeat levels within 24 hours are not available, a repeat test should be conducted as soon as possible.  If 
troponin I or troponin T repeat levels beyond 24 hours are >1 to < 2 × ULN, the participant may undergo a cardiac 
evaluation and be considered for treatment, following a discussion with the sponsor's medical monitor or designee. 


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9. Active autoimmune disease requiring systemic immunosuppression in excess of 
physiologic maintenance doses of corticosteroids (> 10 mg/day of prednisone or 
equivalent). 
Notes: 
• Physiologic corticosteroid replacement therapy at doses > 10 mg daily doses of 
prednisone or equivalent for adrenal or pituitary insufficiency and in the absence of 
active autoimmune disease is permitted.  
• Participants with a condition that require intermittent use bronchodilators, inhaled 
steroids, or local steroid injections may be admitted (eg, asthma or chronic 
obstructive pulmonary disease exacerbation). 
• Participants using topical, ocular, intra-articular, intranasal steroids (with minimal 
systemic absorption) may be admitted. 
• Brief course of corticosteroids for prophylaxis (eg, contrast dye allergy) or study 
treatment-related standard premedication are permitted.  
10. Has known active hepatitis B or C (defined as follows) or HIV, HBV, HCV, or hepatitis 
D virus coinfection: 
a. Active hepatitis B infection is defined by positive HBsAg and positive total anti-HBc 
results.  The following exceptions are allowed: 
• Participants with results positive for HBsAg and total anti-HBc and negative for 
IgM anti-HBc with a sustained viral response that is HBV DNA level 
< 1000 IU/mL for at least 12 months after the end of antiviral therapy with no 
pre-existing cirrhosis are eligible for this study.  The following conditions should 
be followed: 
− Initiate a prophylactic antiviral therapy and remain on it for the study duration 
and for 6 months after the last dose of study treatment. 
− Assess the potential risk of drug-drug interaction with the prescribed antiviral 
therapy and assigned study drug. 
− Monitor every 2 cycles by performing HBV viral load and HBsAg serology 
test.  The need for additional serology tests (eg, total anti-HBc, IgM anti-HBc, 
anti-HBs) is per the investigator's discretion. 
− Consider increasing monitoring of LFTs (ie, at least every other week) for the 
first 3 months of antiviral therapy to allow proactive management of potential 
hepatitis flare risk on antiviral therapy. 
• Participants with results positive for HBsAg and total anti-HBc and negative for 
IgM anti-HBc who are receiving antiviral therapy at study entry but show 
undetectable HBV DNA (<10 IU/mL under the limit of detection per laboratory) 
are eligible for the study.  The following conditions should be followed: 
− Monitor every 2 cycles by performing HBV viral load and HBsAg serology 
test.  The need for additional serology tests (eg, total anti-HBc, IgM anti-HBc, 
anti-HBs) is per the investigator's discretion.   


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− Consider increasing monitoring of LFTs (ie at least every other week) for the 
first 3 months of antiviral therapy to allow proactive management of potential 
hepatitis flare risk on antiviral therapy. 
− Assess the potential of drug-drug interaction with the prescribed antiviral 
therapy and assigned study drug. 
b. Active hepatitis C is defined by a positive hepatitis C antibody result and quantitative 
HCV RNA results greater than lower limits of detection of the assay. 
Note:  Participants who have had definitive treatment for HCV are permitted if HCV 
RNA is undetectable.   
11. Participants who are known to be HIV-positive, unless all of the following criteria are 
met: 
a. CD4+ count ≥ 300/μL. 
b. Undetectable viral load. 
c. Receiving antiretroviral therapy that is not a potential risk for a drug-drug interaction 
with the assigned study drugs.   
12. Has known carcinomatous meningitis.  
13. Active infection requiring systemic antibiotics ≤ 14 days from first dose of study drug.  
Note:  A short course of antibiotics as part of the regimen for TURBT is permitted. 
14. Participants with known or suspected active COVID-19 infection. 
15. Use of probiotics within 28 days from first dose of study drug.   
16. Current use of prohibited medication as noted in Section 6.6.3. 
17. Has not recovered to ≤ Grade 1 from toxic effects of previous therapy and/or 
complications from previous surgical intervention before starting study therapy.  
Note:  Participants with stable chronic AEs (≤ Grade 2) not expected to resolve 
(eg, alopecia) are exceptions and may enroll. 
Note:  Participants with a history of peripheral neuropathy ≥ Grade 2 will be excluded. 
18. History or presence of an abnormal ECG that, in the investigator's opinion, is clinically 
meaningful.  A screening QTcF interval > 450 milliseconds is excluded. 
19. History of a gastrointestinal condition (eg, inflammatory bowel disease, Crohn disease, 
ulcerative colitis) that may affect oral drug absorption.  
20. Has received a live vaccine within 30 days of planned start of study therapy. 
Note:  Examples of live vaccine include, but are not limited to, the following:  measles, 
mumps, rubella, chicken pox/zoster, yellow fever, rabies, BCG, and typhoid vaccine.  
Seasonal influenza vaccines for injection are generally killed virus vaccines and are 
allowed; however, intranasal influenza vaccines are live-attenuated vaccines and are not 
allowed.  


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21. Participants with impaired cardiac function or clinically significant cardiac disease: 
a. New York Heart Association Class III or IV cardiac disease, including preexisting 
clinically significant ventricular arrhythmia, congestive heart failure, or 
cardiomyopathy 
b. Unstable angina pectoris. 
c. Acute myocardial infarction ≤ 6 months before study participation. 
d. Other clinically significant heart disease (eg, ≥ Grade 3 hypertension). 
22. Inability or unlikeliness to comply with the dose schedule and study evaluations, in the 
opinion of the investigator. 
23. Prior allogenic tissue/solid organ transplant. 
24. For all participants:  
a. Evidence of interstitial lung disease or active, noninfectious pneumonitis.  
b. Has known hypersensitivity to any of the study drugs, excipients, including mannitol 
or another monoclonal antibody which cannot be controlled with standard measures 
(eg, antihistamines and corticosteroids).  
c. Any ≥ Grade 2 immune-related toxicity while receiving prior immunotherapy.  
25. For all participants: 
a. History of serotonin syndrome after receiving 1 or more serotonergic drugs. 
b. Concomitant use of medications that are known to be substrates of CYP1A2, 
CYP2C8, or CYP2C19 with narrow therapeutic window are prohibited (see 
Section 6.6.3). 
c. Patients who are receiving or required to receive medications that are known to be 
UGT1A9 inhibitors (see Section 6.6.3). 
26. For participants enrolled in France, the following are excluded:  vulnerable populations 
according to article L.1121-6 of the French Public Health Code and adults under legal 
protection or who are unable to express their consent per article L.1121-8 of the French 
Public Health Code. 
5.3. 
Lifestyle Considerations 
No restrictions are required. 
5.3.1. 
Meals and Dietary Restrictions 
Participants should maintain a normal diet unless modifications are required to manage an AE 
such as hyperphosphatemia, diarrhea, nausea, or vomiting.  
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently assigned to study treatment. 
Test with results that fail eligibility requirements may be repeated during screening if the 
investigator believes the result to be in error.  For screening assessments that are repeated, the 
most recent available result before treatment assignment will be used to determine eligibility.  


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Additionally, a participant who fails screening may repeat the screening process if the 
investigator believes that there has been a change in eligibility status.  Participants who rescreen 
must be assigned a new participant number. 
5.5. 
Replacement of Participants 
Participants in Treatment Groups A, B, D, and E (those with 18 participants per group) who are 
not able to provide evaluable paired biopsies will be replaced to ensure that there are 
8 participants with paired biopsies for each of 2 CPS subgroups (CPS < 10 and CPS ≥ 10) for a 
total of 16 paired biopsies.  Participants in Treatment Group C (epacadostat monotherapy group 
[9 participants]) who are not able to provide evaluable paired biopsies will be replaced to ensure 
there are 8 paired biopsies.  Additionally, participants who have not received at least 4 weeks of 
neoadjuvant study treatment will be replaced. 
5.6. 
Data Safety Monitoring Board 
This study will use an independent DSMB to monitor safety for all treatment groups as needed 
throughout the duration of the study as specified in the DSMB charter.  In addition, the DSMB 
will assess safety data for all participants receiving epacadostat plus retifanlimab combination 
therapy and epacadostat monotherapy (Treatment Groups A and C, respectively) on a regular 
basis and will make a recommendation related to epacadostat dose adjustments as deemed 
necessary (see Section 6.5.1.2). 
Specific details regarding composition, responsibilities, and governance, including the roles and 
responsibilities of the various members and the sponsor and protocol team, and requirements for 
and proper documentation of DSMB reports, minutes, and recommendations will be described in 
the DSMB charter. 
6. 
STUDY TREATMENT 
6.1. 
Study Treatments Administered 
Study treatment information for infused study drugs and oral study drug are presented 
respectively.  At visits where oral study drug is administered in the clinic in combination with 
retifanlimab, the oral study drug should be administered just before the start of the retifanlimab 
infusion.  The order of administration of study drugs should be retifanlimab followed by 
INCAGN02385 followed by INCAGN02390.  For details regarding infusion of study drugs, 
please refer to the Pharmacy Manual. 
Table 13 presents the study treatment information.  Retifanlimab, epacadostat, INCAGN02385, 
and INCAGN02390 will be provided by the sponsor.


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Table 13: 
Study Treatment and Treatment Group Information 
 
Study Treatment 1 
Study Treatment 2 
Study Treatment 3 
Study Treatment 4 
Study 
treatment 
name: 
Retifanlimab  
(INCMGA00012) 
Epacadostat 
(INBC024360) 
INCAGN02385 
INCAGN02390 
Mechanism of 
action: 
Inhibitor of PD-1 
IDO1 inhibitor 
LAG-3 inhibitor 
TIM-3 inhibitor 
Dosage 
formulation: 
25 mg/mL liquid formulation 
300 mg and 100 mg tablets 
50 mg/mL 
Solution for infusion 
50 mg/ mL 
Solution for infusion 
Unit dose 
strength(s) 
/dosage 
level(s): 
Dose level:  500 mg Q4W 
Dose level:  600 mg BID or 
400 mg BID 
Dose level:  350 mg Q2W 
Dose level:  400 mg Q2W 
Administration 
instructions: 
Administered IV over 
30 minutes (+ 15 min) on Day 1 
of each 28-day cycle 
For the 600 mg BID dose, 
two 300 mg tablets BID. 
For the 400 mg BID dose 
reduction,  
one 300 mg and one 100 mg 
tablet. 
Both dose levels should be 
administered without regard to 
food.  Drug should be 
administered daily up to and 
including day of surgery. 
IV (30-minute infusion with 
filter followed by flush) Q2W 
IV (30-minute infusion with 
filter followed by flush) Q2W 
Treatment 
Group A: 
500 mg IV over 30 minutes 
(+ 15 min) on Day 1 of each 
28-day cycle 
600 mg BID or 400 mg BID 
N/A 
N/A 
Treatment 
Group B: 
500 mg IV over 30 minutes 
(+ 15 min) on Day 1 of each 
28-day cycle 
N/A 
N/A 
N/A 
Treatment 
Group C: 
N/A 
600 mg BID or 400 mg BID 
N/A 
N/A 


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Table 13: 
Study Treatment and Treatment Group Information (Continued) 
 
Study Treatment 1 
Study Treatment 2 
Study Treatment 3 
Study Treatment 4 
Treatment 
Group D: 
500 mg IV over 30 minutes 
(+ 15 min) on Day 1 of each 
28-day cycle followed by 
10 minute flush 
N/A 
350 mg IV over 30 minutes 
(−5/+10 min) Q2W followed by 
10 minute flush 
N/A 
Treatment 
Group E: 
500 mg IV over 30 minutes 
(+ 15 min) on Day 1 of each 
28-day cycle followed by 
10 minute flush 
N/A 
350 mg IV over 30 minutes 
(−5/+10 min) Q2W followed by 
10 minute flush 
400 mg IV over 30 minutes 
(−5/+10 min) Q2W followed by 
10 minute flush 
Route of 
administration: 
IV 
PO 
IV 
IV 
Packaging and 
labeling: 
Study drug will be provided in 
vials. 
Each vial will be labeled as 
required per country 
requirement. 
Study drug will be provided in 
bottles. 
Each bottle will be labeled as 
required per country 
requirement. 
Study drug will be provided in 
vials. 
Each vial will be labeled as 
required per country 
requirement. 
Study drug will be provided in 
vials. 
Each vial will be labeled as 
required per country 
requirement. 
Storage: 
Stored upright under 
refrigeration at 2°C to 8°C 
(36°F-46°F) and protected from 
light 
Stored at room temperature at 
15°C-30°C (59°F-86°F) 
Stored upright under 
refrigeration at 2°C to 8°C 
(36°F-46°F) and protected from 
light 
Stored upright under 
refrigeration at 2°C to 8°C 
(36°F-46°F) and protected from 
light 
Status of 
treatment in 
participating 
countries: 
Investigational 
Investigational 
Investigational 
Investigational 


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6.2. 
Preparation, Handling, and Accountability 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatments received and any discrepancies are reported and 
resolved before use of the study treatment. 
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. 
The investigator (or designee) is responsible for study treatment accountability, reconciliation, 
and record maintenance (ie, receipt, reconciliation, and final disposition records).  Inventory and 
accountability records must be maintained and readily available for inspection by the study 
monitor and are open to inspection at any time by any applicable regulatory authorities.  The 
investigator or designee must maintain records that document: 
• Delivery of study drug(s) to the study site. 
• Inventory of study drug(s) at the site. 
• Participant use of the study drug(s) including tablet and/or vial counts as applicable 
from each supply dispensed. 
• For participants receiving retifanlimab, INCAGN02385, and INCAGN02390:  
Lot numbers and/or vial numbers (as applicable) of study drug used to prepare the 
infusion solution. 
• Return of study drug(s) to the investigator or designee by participants receiving 
epacadostat. 
The investigational product must be used only in accordance with the Protocol.  The investigator 
will also maintain records adequately documenting that the participants were provided the 
specified study drug.  These records should include dates, quantities, and any available batch or 
serial numbers or unique code numbers assigned to the investigational product and study 
participants. 
Completed accountability records will be archived by the site.  The investigator or designee will 
be expected to collect and retain all used, unused, and partially used containers of study drug 
until verified by the study monitor (unless otherwise agreed to by the sponsor).  At the 
conclusion of the study, the investigator or designee will oversee shipment of any remaining 
study drug back to the sponsor or its designee for destruction according to institutional SOPs.  
If local procedures mandate on-site destruction of the investigational supply, the site should 
(where local procedures allow) maintain the investigational supply until the study monitor 
inspects the accountability records in order to evaluate compliance and accuracy of 
accountability by the investigative site.  At sites where the study drug is destroyed before 
monitor inspection, the monitors rely on documentation of destruction per the site SOP. 
Further guidance and information for the final disposition of unused study treatments are 
provided in the Pharmacy Manual. 


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6.3. 
Measures to Minimize Bias:  Randomization and Blinding 
This is an open-label, stratified randomized study with a translational primary endpoint of 
change in CD8+.  Post PD-L1 testing, participants will be randomized to Treatment Group A, B, 
C, D, or E based on PD-L1 CPS value (see Figure 1) at a 2:2:1:2:2 ratio, respectively, if 
participants are eligible for Treatments D and E based on exclusionary criteria.  If participants 
are not eligible for Treatments D and E based on exclusionary criteria, participants will be 
randomized to Treatment Group A, B, or C based on PD-L1 CPS value (see Figure 1) at a 2:2:1 
ratio. This will ensure that the planned number of participants will be enrolled into each 
treatment group with PD-L1 CPS balanced within each treatment group.  Additional details on 
randomization will be included in the IRT specifications document.   
6.4. 
Study Treatment Compliance 
The site personnel must emphasize compliance with all study-related treatments to the 
participant.  Appropriate steps should be taken to optimize compliance during the study.  
Participants in the epacadostat treatment groups will be instructed to bring all unused study drugs 
with them to the study visits in order for site personnel to conduct tablet counts to assess study 
drug accountability.  The drug accountability documentation will be used by the sponsor to 
calculate treatment compliance. 
For participants in the retifanlimab, INCAGN02385, and INCAGN02390 treatment groups, 
compliance will be calculated by the sponsor based on study drug accountability and infusion 
records documented by the site staff and monitored by the sponsor/designee. 
6.5. 
Dose Modifications 
6.5.1. 
Criteria and Procedures for Dose Interruptions and Adjustments of Study Drugs 
6.5.1.1. 
Retifanlimab, INAGN02385, and INCAGN02390 
Dose modification of retifanlimab, INCAGN02385, or INCGN02390 is not permitted.  If a dose 
interruption is necessary for management of drug-related TEAEs, study drugs will be reinitiated 
at the starting doses.   
Individual decisions regarding dose modifications of study treatment should be made using 
clinical judgment in consultation with the medical monitor (whenever possible), taking into 
account relatedness of the AE to the study treatment and the participant's underlying condition.  
Adverse events that have a clear alternative explanation, or transient (≤ 72 hours) abnormal 
laboratory values without associated clinically significant signs or symptoms, may be exempt 
from dose-interruption rules. 
Decisions regarding these dose interruptions and restarts of retifanlimab, INCAGN02385, or 
INCAGN02390 will be made according to Table 14 for suspected infusion reactions, Table 15 
for irAEs, and Table 16 for non-irAEs.   
Safety concerns should be discussed with the sponsor immediately upon occurrence or 
awareness. 


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6.5.1.2. 
Epacadostat  
Epacadostat may be reduced to 400 mg BID per guidance in Table 15  for irAEs.  If dose 
interruption is necessary for management of treatment-related TEAEs, retifanlimab will be 
reinitiated at 500 mg Q4W and epacadostat at 600 mg or 400 mg BID.  Only 1 dose reduction of 
epacadostat is permitted.  If the same AE that required epacadostat dose reduction reoccurs at the 
same severity or greater, regardless of the causality to epacadostat, epacadostat should be 
discontinued.  If a participant who is being treated with epacadostat 400 mg BID has a different 
AE that is considered unrelated to epacadostat by the investigator, the participant may resume 
study treatment at 400 mg BID when the AE resolves.  Once a participant is started on the 
400 mg BID dose of epacadostat, dose escalation to the 600 mg BID dose is not permitted.  
Additionally, information regarding management of participants receiving the epacadostat 
combination who experience serotonin syndrome is presented in Section 6.5.5.  
6.5.1.3. 
All Study Treatments 
Decisions on any treatment dose reduction, interruption, or restart can also be jointly made, when 
needed, by the investigator and medical monitor on a case-by-case basis. 
Safety concerns should be discussed with the sponsor immediately upon occurrence or awareness 
to determine if the participant should continue or discontinue study treatment. 
To reduce the risk of delays in radical cystectomy due to TEAEs, if treatment is withheld for 
more than 2 weeks in any treatment arm, then the participant will discontinue study treatment. 
Study treatment should only be resumed if it allows for a minimum of an additional 2 weeks of 
therapy before radical cystectomy. 
6.5.2. 
Management of Suspected Infusion Reactions 
Infusion or hypersensitivity reactions may be observed with administration of any foreign 
protein.  Premedication with acetaminophen/paracetamol and a histamine blocker should be 
considered for participants who have had previous systemic reactions to protein product 
infusions or when recommended by institutional policy. 
Guidelines for management of suspected infusion reactions are provided in Table 14. 


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Table 14: 
Guidelines for Management of Suspected Infusion Reactions 
Grade 
Descriptiona 
Treatment 
Subsequent Infusions 
1 
Mild reaction; interruption 
or slowed rate of infusion 
indicated; intervention not 
indicated. 
Monitor vital signs closely until 
medically stable. 
Premedication with antipyretics 
(eg, acetaminophen/paracetamol) 
and a histamine blocker 
(eg, diphenhydramine) should be 
considered for participants who have 
had previous systemic reactions to 
protein product infusions or when 
recommended by institutional policy. 
2 
Requires infusion 
interruption but responds 
promptly to symptomatic 
treatment 
(eg, antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated for 
≤ 24 hours. 
First occurrence:  Stop infusion 
and initiate appropriate medical 
measures (eg, IV fluids, 
antihistamines, NSAIDs, 
antipyretics, narcotics, per 
institutional preferences). 
Monitor vital signs until 
medically stable. 
If symptoms resolve within 
1 hour, infusion may be resumed 
at 50% of the original infusion 
rate. 
Subsequent occurrences (after 
recommended prophylaxis):  
Permanently discontinue study 
treatment. 
Premedicate at least 30 minutes 
before infusion with antihistamines 
(eg, diphenhydramine 50 mg PO) 
and antipyretics 
(eg, acetaminophen/paracetamol 
500-1000 mg PO). 
Additional supportive measures may 
be acceptable (per institutional 
preference) but should be discussed 
with medical monitor. 
Next infusion should start at 50% of 
the original infusion rate.  If no 
reaction, rate of infusion can be 
increased by 25% every 15 minutes 
until a rate of 100% has been 
reached.  Subsequent infusions can 
begin at 100%. 
3 or 4 
Grade 3:  Prolonged (ie, 
not rapidly responsive to 
symptomatic medication 
and/or brief interruption of 
infusion); recurrence of 
symptoms following initial 
improvement; 
hospitalization indicated for 
other clinical sequelae (eg, 
renal impairment, 
pulmonary infiltrates). 
Grade 4:  Life-threatening; 
pressor or ventilatory 
support indicated. 
Stop infusion and initiate 
appropriate medical therapy 
(eg, IV fluids, antihistamines, 
NSAIDs, antipyretics, narcotics, 
oxygen, pressors, epinephrine, 
corticosteroids, per institutional 
preferences). 
Monitor vital signs frequently 
until medically stable.  
Hospitalization may be 
indicated. 
Permanently discontinue study 
treatment. 
If rapidly responsive to symptomatic 
medication and/or to brief 
interruption of infusion, study drug 
does not need to be permanently 
discontinued, per NCI CTCAE v5. 
a Per NCI CTCAE v5.0, appropriate resuscitation equipment should be available at the bedside and a physician readily available 
during the period of study treatment administration. 
6.5.3. 
Procedures for Participants Exhibiting Immune-Related Adverse Events 
Adverse events of a potential immunologic etiology or irAEs may be defined as an AE of 
unknown etiology associated with drug exposure and consistent with an immune phenomenon.  
Immune-related AEs may be predicted based on the nature of the compounds, their mechanism 
of action, and reported experience with immunotherapies that have a similar mechanism of 
action.  Special attention should be paid to AEs that may be suggestive of potential irAEs.  
An irAE can occur shortly after the first dose or several months after the last dose of treatment. 


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If an irAE is suspected, efforts should be made to rule out neoplastic, infectious, metabolic, 
toxic, or other etiologic causes before labeling an AE as an irAE. 
Recommendations for the management of specific immune-mediated AEs known to be 
associated with other PD-1 inhibitors are detailed in Table 15 and Section 6.5.6.  Algorithms for 
the evaluation of selected immune toxicities that have previously been attributed to PD-1 
inhibitors and management guidelines for irAEs not detailed elsewhere in the Protocol should 
follow the ASCO or ESMO Clinical Practice Guidelines (Brahmer et al 2018, Haanen 
et al 2018). 
If an irAE warrants study treatment interruption, all study drugs should be withheld. 
Dose modification and toxicity management guidelines for irAEs are provided in Table 15. 


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Table 15: 
Dose Modification and Toxicity Management Guidelines for Immune-Related Adverse Events 
irAE 
Toxicity Grade or Conditions 
(CTCAE v5.0) 
Action Taken With Study Treatment 
AE Management With Corticosteroid and/or Other 
Supportive Care Therapiesa 
Pneumonitis 
Grade 1 
No action 
None. 
Grade 2 
Withhold until ≤ Grade 1 
• Evaluate participants with suspected pneumonitis with 
radiographic imaging and administer systemic corticosteroids 
per local practice followed by taper. 
• Add prophylactic antibiotics for opportunistic infections. 
Grades 3 or 4 or recurrent Grade 2 
Permanently discontinue 
Diarrhea/colitis 
Grade 1 
No action 
None. 
Grades 2 or 3 
Withhold until ≤ Grade 1 
• Consider prompt initiation of standard antidiarrheal agents and 
other necessary supportive care as needed (eg, oral and/or 
IV fluids). 
• Administer systemic corticosteroids per local practice 
followed by taper. 
• Consider prophylactic antibiotics per local practice. 
• Consider gastrointestinal consultation and performing 
endoscopy to rule out colitis. 
• Consider stool sample evaluation to rule out 
Clostridium difficile and infectious etiologies. 
Grade 4 or recurrent Grade 3 
Permanently discontinue 
AST/ALT elevation 
and/or increased total 
bilirubin/hepatitis 
Grade 1 
No action 
None 
Grade 2 ALT or AST increase 
or 
Total bilirubin increases to 
> 1.5 × and up to 3 × ULN 
Withhold until ≤ Grade 1 
• Administer systemic corticosteroids per local practice 
followed by taper. 
• Consider monitoring liver enzymes weekly (or more 
frequently) until liver enzyme value returns to baseline or is 
stable. 
• Consider monitoring total bilirubin, direct bilirubin, and 
alkaline phosphatase weekly (or more frequently). 
Grades 3 or 4 ALT or AST 
increase 
or 
In participants with liver 
metastases with baseline Grade 2 
elevation of AST or ALT, hepatitis 
with AST or ALT increases ≥ 50% 
and lasts ≥ 1 week 
or 
Total bilirubin increases to 
> 3 × ULN 
Permanently discontinue 


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Table 15: 
Dose Modification and Toxicity Management Guidelines for Immune-Related Adverse Events (Continued) 
irAE 
Toxicity Grade or Conditions 
(CTCAE v5.0) 
Action Taken With Study Treatment 
AE Management With Corticosteroid and/or Other 
Supportive Care Therapiesa 
Endocrinopathies 
• Hypothyroidism 
• Hyperthyroidism 
• Type 1 diabetes 
mellitus 
• Hyperglycemia 
• Adrenal insufficiency 
• Hypophysitis 
Grades 1 or 2 hypothyroidism, 
hyperthyroidism, or Type 1 
diabetes mellitus 
No action 
None. 
Grades 3 or 4 hypothyroidism 
Withhold until ≤ Grade 1 or is otherwise 
clinically stable 
Initiate thyroid replacement hormones (eg, levothyroxine, 
liothyronine) per standard of care. 
Grades 3 or 4 hyperthyroidism 
Withhold until ≤ Grade 1 or is otherwise 
clinically stable 
Initiate symptomatic management. 
Grades 3 or 4 Type 1 diabetes 
mellitus (or hyperglycemia) 
Withhold until ≤ Grade 1 or is otherwise 
clinically stable 
Initiate treatment with antihyperglycemics or insulin as clinically 
indicated. 
Grade 1 adrenal insufficiency 
No action 
None. 
Grade 2 adrenal insufficiency 
Withhold until ≤ Grade 1 or otherwise 
clinically stable 
Initiate treatment with hormone replacement therapy as clinically 
indicated. 
Grades 3 or 4 adrenal insufficiency Withhold until ≤ Grade 1 after corticosteroid 
taper to ≤ 10 mg/day prednisone or equivalent 
or is otherwise clinically stable 
Administer prednisone or equivalent at initial dose of 
1-2 mg/kg/day followed by a taper and initiate treatment with 
hormone replacement therapy as clinically indicated. 
Grade 1 hypophysitis 
No action 
None. 
Grade 2 (asymptomatic) 
hypophysitis 
• Withhold until ≤ Grade 1 
• May restart study drug after controlled by 
hormone replacement therapy 
Initiate treatment with hormone replacement therapy. 
Grade 2 (symptomatic; 
eg, headaches, visual disturbances) 
hypophysitis 
• Withhold until ≤ Grade 1 
• May restart study drug after controlled by 
hormone replacement therapy, if indicated, 
and corticosteroid taper is complete 
• Administer corticosteroids at initial dose of 1-2 mg/kg/day 
prednisone or equivalent followed by a taper and initiate 
treatment with hormone replacement therapy as clinically 
indicated. 
• Consult with endocrinologist as needed. 
Grades 3 or 4 (symptomatic) 
Permanently discontinue 
Nephritis and renal 
dysfunction 
Grade 1 
No action 
None. 
Grades 2 or 3 increased blood 
creatinine 
Withhold until ≤ Grade 1 
Administer corticosteroids per local practice followed by taper. 
Grade 4 increased blood creatinine 
Permanently discontinue 


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Table 15: 
Dose Modification and Toxicity Management Guidelines for Immune-Related Adverse Events (Continued) 
irAE 
Toxicity Grade or Conditions 
(CTCAE v5.0) 
Action Taken With Study Treatment 
AE Management With Corticosteroid and/or Other 
Supportive Care Therapiesa 
Skin 
(eg, SJS, TEN) 
Grade 1 
No action 
None. 
Grade 2 
No action 
Manage with topical corticosteroids with or without drug 
interruption. 
Grade 3b, persistent Grade 2 
(≥ 2 weeks), or suspected SJSc 
Withhold until ≤ Grade 1 after corticosteroid 
taper to ≤ 10 mg/day prednisone or equivalent 
• Administer corticosteroids per local practice followed by 
taper.  Additionally, oral histamine blockers such as 
diphenhydramine or famotidine (per institutional preference) 
may be utilized as needed. 
• Refer to dermatology consult if no resolution with these 
measures. 
• Refer to dermatology consult if SJS or TEN is suspected. 
Grade 4 or confirmed Grade 4 SJSc 
or TENd 
Permanently discontinue 
• Administer prednisone or equivalent at initial dose of 
1-2 mg/kg/day followed by a taper. 
• Refer to dermatology consult. 
Myocarditis 
Grade 2 
Permanent discontinuation of study drug  
 
• Treatment with systemic corticosteroids should be initiated 
(initial dose of 1-2 mg/kg/day of prednisone or equivalent).  
Taper as appropriate. 
• Refer to cardiology consult. 
• Manage cardiac symptoms according to standard of care and 
with guidance from cardiology.  Consider cardiac MRI and 
myocardial biopsy for diagnosis. 
Grades 3 or 4 
Permanently discontinue 


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Table 15: 
Dose Modification and Toxicity Management Guidelines for Immune-Related Adverse Events (Continued) 
irAE 
Toxicity Grade or Conditions 
(CTCAE v5.0) 
Action Taken With Study Treatment 
AE Management With Corticosteroid and/or Other 
Supportive Care Therapiesa 
Troponin I or troponin T 
increase 
All troponin elevations (including 
asymptomatic elevations) 
Withhold INCMGA00012, INCAGN02385, 
INCAGN02390, and epacadostat until 
resolved to baseline 
• All troponin elevations (including asymptomatic elevations) 
will require a dose delay in order for the participant to undergo 
a cardiac evaluation via prompt cardiology consult and 
diagnostic workup including, at minimum, ECG and 
echocardiogram (plus cardiac MRI and further relevant 
biological markers [brain natriuretic peptide, creatine kinase] 
per the cardiologist's recommendation) and a confirmatory test 
repeated within 24 hours. 
− If troponin elevation is not confirmed within 24 hours in an 
asymptomatic participant, the dose delay may not be needed 
provided that the cardiac evaluation is completed and a 
cardiologist has made the recommendation to proceed with 
treatment. 
− Otherwise, if troponin elevation is confirmed, continue 
serial monitoring until recovery.  Consider corticosteroids 
per treating physician.  Dosing may resume when troponin 
level resolves to baseline provided that the cardiac 
evaluation is completed and a cardiologist has made the 
recommendation to proceed with treatment. 
Important nervous 
system events 
(eg, Guillain-Barré 
syndrome, autoimmune 
encephalitis, 
myasthenia gravis, 
autonomic neuropathy, 
transverse myelitis) 
Grade 2 
Withhold until ≤ Grade 1 
• Refer to neurology consult. 
• Initiate treatment with systemic corticosteroids (initial dose of 
1-2 mg/kg/day of prednisone or equivalent).  Taper as 
appropriate. 
• For Grade 2 transverse myelitis, consider permanent 
discontinuation. 
• Manage symptoms according to standard of care and with 
guidance from neurology. 
Grades 3 or 4 
Permanently discontinue 


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Table 15: 
Dose Modification and Toxicity Management Guidelines for Immune-Related Adverse Events (Continued) 
irAE 
Toxicity Grade or Conditions 
(CTCAE v5.0) 
Action Taken With Study Treatment 
AE Management With Corticosteroid and/or Other 
Supportive Care Therapiesa 
All other irAEs 
Grades 2 or 3 based on severity and 
type of reaction 
Withhold until ≤ Grade 1 
• Based on severity of AE, administer corticosteroids. 
• Ensure adequate evaluation to confirm etiology or exclude 
other causes. 
Recurrent Grade 3 or persistent 
Grades 2 or Grade 3 
Permanently discontinue 
Grade 4e (excluding 
endocrinopathies) 
Permanently discontinue 
a As general instructions, the following should be followed: if treatment-related toxicity does not resolve to Grade 0-1 within 12 weeks after the last dose of study drug, or if the 
corticosteroid dose cannot be reduced to ≤ 10 mg prednisone or equivalent per day within 12 weeks, study drug should be permanently discontinued.  Severe and life-threatening 
irAEs should be treated with IV corticosteroids followed by oral corticosteroids.  Other immunosuppressive treatment should begin if irAEs are not controlled by corticosteroids. 
b Participants with Grade 3 rash in the absence of desquamation, with no mucosal involvement, not requiring systemic corticosteroids, and resolving or improving to ≤ Grade 1 
within 14 days do not have to interrupt study treatment.  Permanent discontinuation of study treatment may be necessary if there is recurrence of Grade 3 rash after resuming 
study treatment. 
c Grade 3 SJS is defined as skin sloughing covering < 10% BSA with associated signs (eg, erythema, purpura, epidermal detachment, mucous membrane detachment).  Grade 4 
SJS is defined as skin sloughing covering 10-30% BSA with associated signs (eg, erythema, purpura, epidermal detachment, mucous membrane detachment). 
d Toxic epidermal necrolysis is Grade 4 by definition and is defined as skin sloughing covering ≥ 30% BSA with associated symptoms (eg, erythema, purpura, epidermal 
detachment). 
e If Grade 4 lipase/amylase elevation is asymptomatic and abdominal imaging suggests no pathology, then study drug administration may continue with medical monitor approval. 


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6.5.4. 
Procedures for Participants Exhibiting Drug-Related, Non–Immune-Related 
Adverse Events 
The guidance presented in Table 16 should be followed as best practice for decisions regarding 
management of non-irAEs for participants receiving retifanlimab as monotherapy or in 
combination with epacadostat. 
Table 16: 
Management Guidelines for Drug-Related, Non–Immune-Related Adverse 
Events 
Drug-Related, Non-Immune–Related 
Grade 
Action Taken With Study 
Treatment 
Any drug-related, non–immune-related AE 
1 
No action 
2 
No action 
3 
Withhold until ≤ Grade 1a 
4 
Permanently discontinuea 
a For Treatment Group A, if retifanlimab dosing is held, dosing for epacadostat must also be held.  Participants are 
allowed, however, to receive retifanlimab monotherapy if epacadostat is discontinued due to drug-related, 
non-irAEs.  For Treatment Groups D and E, in all cases where retifanlimab dosing is held, dosing for the other 
combination drug must also be held.  Participants are allowed, however, to receive retifanlimab monotherapy if 
INCAGN02385 and/or INCAGN02390 is discontinued.   
6.5.5. 
Procedures for Participants in the Epacadostat Groups Exhibiting Serotonin 
Syndrome 
There is a rare chance that epacadostat, when administered alone or in combination with other 
serotonergic agents, could cause an increase in serotonin levels in the brain that might trigger 
serotonin syndrome (Boyer and Shannon 2005).  This syndrome has been most closely 
associated with use of MAOIs, meperidine, linezolid, or methylene blue.  Preclinical data 
suggest that serotonin syndrome is unlikely after treatment with either epacadostat alone or in 
combination with MAOIs such as linezolid (Zhang et al 2019).  For more information, refer to 
the epacadostat IB. 
Selective serotonin reuptake inhibitors, SNRIs, and MAOIs are permitted in the study.  Serotonin 
syndrome usually manifests with autonomic changes, mental status changes, and neurological 
findings.  These mild, moderate, and severe signs and symptoms of serotonin syndrome 
(summarized in Table 17) should be evaluated in the context of possible comorbid conditions as 
well.  A neurology consult is recommended to diagnose or confirm serotonin syndrome or to rule 
out other etiologies. 
The following procedures will be implemented if participants exhibit the signs/symptoms of 
serotonin syndrome, including tremor; hyperreflexia; spontaneous, ocular, or inducible clonus; 
together with agitation, fever, diaphoresis, or muscle rigidity: 
• Immediately interrupt all study treatment administration. 
• Immediately interrupt any MAOI, SSRI, or SNRI administration. 


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• Provide appropriate medical management of the participant until all signs/symptoms 
are resolved (eg, IV fluids and/or sympathomimetic amines for hypotension, 
benzodiazepines for agitation, administration of 5-hydroxytryptamine antagonists 
such as cyproheptadine). 
• If etiologies other than serotonin syndrome are excluded, study treatment 
administration may be resumed unless other AE management guidelines apply for the 
specific event. 
• If participant chooses to remain in the study, restart treatment with epacadostat after 
the MAOI, SSRI, or SNRI has been discontinued, no sooner than 5 half-lives have 
elapsed for the specific MAOI, SSRI, or SNRI in question, and after resolution of 
signs/symptoms of serotonin syndrome.  The MAOI, SSRI, or SNRI administration 
MAY NOT be restarted. 
• If participant chooses to withdraw from the study or must restart treatment with the 
MAOI, SSRI, or SNRI, the participant should be scheduled for a follow-up visit.  
Treatment with the MAOI, SSRI, or SNRI may be initiated 2 weeks after resolution 
of signs and symptoms of serotonin syndrome. 
• If a participant had experienced moderate or severe unconfounded serotonin 
syndrome in the opinion of the investigator, without concomitant MAOI, SSRI, or 
SNRI usage or serotonergic concomitant medications, study treatment should be 
permanently discontinued. 
Table 17: 
Signs and Symptoms of Serotonin Syndrome 
Seriousness 
Autonomic Signs 
Neurologic Signs 
Mental Status 
Other 
Mild 
• Afebrile or 
low-grade fever  
• Tachycardia 
• Mydriasis 
• Diaphoresis or 
shivering 
• Intermittent tremor 
• Akathisia  
• Myoclonus  
• Mild hyperreflexia  
• Restlessness 
• Anxiety 
Not applicable 
Moderate 
• Increased 
tachycardia  
• Fever (up to 41°C) 
• Diarrhea with 
hyperactive bowel 
sounds  
• Diaphoresis with 
normal skin color  
• Hyperreflexia 
• Inducible clonus 
• Ocular clonus (slow 
continuous lateral eye 
movements)  
• Myoclonus 
• Easily startled 
• Increased 
confusion 
• Agitation and 
hypervigilance 
• Rhabdomyolysis  
• Metabolic acidosis 
• Renal failure  
• Disseminated 
intravascular 
coagulopathy 
(secondary to 
hyperthermia)  
Severe 
Temperature often 
more than 41°C 
(Secondary to 
increased tone)  
• Increased muscle tone 
(lower limb > upper) 
• Spontaneous clonus 
• Substantial myoclonus 
or hyperreflexia  
• Delirium 
• Coma 
As above  
Source:  Boyer and Shannon 2005. 


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6.5.6. 
Criteria for Permanent Discontinuation of Study Drug 
The occurrence of unacceptable toxicity not caused by the underlying disease will require that 
the study treatment be permanently discontinued.  Unacceptable toxicity is defined as follows: 
• Occurrence of an AE that is related to study treatment that, in the judgment of the 
investigator or the sponsor's medical monitor, compromises the participant's ability to 
continue study-specific procedures or is considered to not be in the participant's best 
interest. 
• Persistent AE requiring a delay of study treatment for more than 2 weeks (14 days) 
unless a greater delay has been approved by the sponsor. 
• Any AE defined in the dose modification guidelines requiring that the study drug be 
discontinued. 
The following criteria will require permanent discontinuation of a treatment group and 
evaluation by the DSMB: 
• A maximum of 4 out of 18 participants in Treatment Groups A, B, D, or E or 2 out of 
9 participants in Treatment Group C who experience Grade 3 to Grade 5 SAEs in 
vital organs (eg, lung, heart, liver, kidney) clearly attributable to treatment-related 
AEs.   
• A maximum of 4 out of 18 participants in Treatment Groups A, B, D, or E or 2 out of 
9 participants in Treatment Group C who require a delay in surgery of > 11 weeks 
from the start of therapy (see Section 2.2.3).  The delay of surgery should be clearly 
attributable to side effects of study treatment rather than other non–treatment-related 
factors (eg, operating room availability). 
• A maximum of 4 out of 18 participants in Treatment Groups A, B, D, or E or 2 out of 
9 participants in Treatment Group C who experience postsurgical complications due 
to study treatment. 
See Section 6 for study drug and study treatment discontinuation/modifications. 
6.6. 
Concomitant Medications and Procedures 
All concomitant medications and treatments (including over-the-counter or prescription 
medicines, vitamins, vaccines, and/or herbal supplements) must be recorded in the eCRF.  Any 
prior medication received up to 30 days before the first dose of study treatment and 90 days after 
radical cystectomy (unless associated with the treatment of an AE, which should be collected 
regardless of timing), or until the participant begins a new anticancer therapy, whichever occurs 
first, will be recorded in the eCRF.  If radical cystectomy is not performed then concomitant 
medications must be recorded up to 30 days from the last dose of study treatment.  Any addition, 
deletion, or change in the dose of these medications will also be recorded.  Concomitant 
medications administered for the management of SAEs as defined in Section 9.2 should be 
recorded regardless of when they were provided.  Concomitant treatments/procedures that are 
required to manage a participant's medical condition during the study will also be recorded in the 
eCRF.  The medical monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. 


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6.6.1. 
Permitted Medications and Procedures 
Recommended supportive measures for specific toxicities are described in Section 6.5.  Growth 
factors, bisphosphonates, anticoagulants, and transfusional support will also be permitted but 
should be discussed with the medical monitor before implementing. 
Antiretroviral therapy should be continued for participants who are known to be HIV-positive.  
Note:  Participants must be receiving antiretroviral therapy that is not a potential risk for a 
drug-drug interaction with the assigned study drugs. 
The use of corticosteroids is permitted in the following situations: 
• Acute treatment for an AE. 
• Physiologic corticosteroid replacement therapy at doses > 10 mg daily of prednisone 
or equivalent for adrenal or pituitary insufficiency and in the absence of active 
autoimmune disease. 
• Participants with asthma who require intermittent use of bronchodilators, inhaled 
steroids, or local steroid injections. 
• Topical, ocular, intra-articular, or intranasal steroids (with minimal systemic 
absorption). 
• Brief course of corticosteroids for prophylaxis (eg, < 3 weeks for contrast dye 
allergy), study treatment–related premedication as per standard, chronic obstructive 
pulmonary disease exacerbation, or for treatment of nonautoimmune conditions (eg, 
delayed-type hypersensitivity reaction caused by a contact allergen). 
• As described in Section 6.5.5, SSRIs, SNRIs, and MAOIs are permitted in the study. 
6.6.2. 
Restricted Medications and Procedures 
Radiation therapy to a symptomatic solitary lesion or to the brain may be considered on an 
exceptional case-by-case basis after consultation with the medical monitor.  The participant must 
have clear measurable disease outside the radiated field. 
For participants in epacadostat-containing treatment groups (Treatment Groups A and C), an 
epacadostat metabolite is a moderate in vitro inhibitor of CYP1A2; thus, it is recommended to 
avoid or limit caffeine consumption (eg, no more than 1 cup of coffee per day).  
6.6.3. 
Prohibited Medications and Procedures 
The following medications and measures are prohibited: 
• Other anticancer therapies, including investigational treatments. 
• Systemic immunosuppression for active autoimmune disease using 
immunosuppressive drugs or corticosteroids (> 10 mg daily of prednisone or 
equivalent) within 2 years of Day 1 of study treatment and throughout the treatment 
period (with the exception of acute treatment for an AE). 
• Chronic use of systemic steroids (> 10 mg daily of prednisone or equivalent).  
Exceptions for steroid use are outlined in Section 6.6.1. 


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• Live vaccines within 28 days before the first administration of study drug, during the 
study and for a duration of 5 half-lives (approximately 90 days) after the last dose of 
study treatment. 
• Chronic doses of products containing acetyl-para-aminophenol (also known as APAP, 
acetaminophen, or paracetamol) in excess of 2 g or 2000 mg total daily dose. 
• Prohibited medications and procedures for epacadostat-containing treatment groups 
(Treatment Groups A and C): 
− Use of any UGT1A9 inhibitors, including acitretin, amitriptyline, androsterone, 
cyclosporine, dasatinib, diclofenac, diflunisal, efavirenz, erlotinib, flutamide, 
gefitinib, gemfibrozil, glycyrrhetinic acid glycyrrhizin, imatinib, imipramine, 
ketoconazole (systemic), mycophenolic acid, niflumic acid, nilotinib, 
phenobarbital, phenylbutazone, phenytoin, probenecid, quinidine, ritonavir, 
sorafenib, sulfinpyrazone, valproic acid, and verapamil. 
− Use of warfarin for participants receiving epacadostat doses greater than 300 mg 
BID.  An alternative to warfarin should be considered.  If an alternate cannot be 
found, the participant may not be enrolled.  If anticoagulation is needed during the 
conduct of the study and nonwarfarin regimens are not feasible, the participant 
must discontinue study therapy. 
− Chronic use of systemic antibiotics (> 14 days) unless medical monitor review 
and approval.   
• Due to the potential concern for epacadostat metabolite inhibition of CYP1A2, 
CYP2C8 and CYP2C19, and OATP1B1 and OATP1B3 transporters with doses of 
epacadostat ≥ 600 mg BID, the medications listed in Appendix F are prohibited for 
concomitant use. 
• Participants should seek alternatives that are not in the class.  If alternatives cannot be 
found, the medical monitor should be contacted to discuss if enrollment is 
appropriate. 


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7. 
DISCONTINUATION OF STUDY TREATMENT AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Study Treatment 
7.1.1. 
Reasons for Discontinuation 
Participants must be discontinued from study treatment for the following reasons: 
• Consent is withdrawn.   
Note:  Consent withdrawn means that the participant has explicitly indicated that they 
do not want to be followed any longer; in this case no further data, except data in 
public domain, may be solicited from or collected on the participant.  Participants 
may choose to discontinue study treatment and remain in the study to be followed for 
progression and survival. 
• If, during the course of the study, a participant is found not to have met eligibility 
criteria, the participant should be withdrawn from study treatment.  
• Further participation would be injurious to the participant's health or well-being, in 
the investigator's medical judgment. 
• Unacceptable toxicity as noted in Section 6.5.   
• Investigator's decision to withdraw the participant from study treatment.  
• The participant becomes pregnant, confirmed by a positive serum pregnancy test. 
• The participant must discontinue if he/she has suspected or confirmed disease 
progression or is not responding to treatment. 
• The treatment group is terminated by the DSMB; see Section 6.5.6. 
• The study is terminated by the sponsor. 
• The study is terminated by the local health authority, IRB, or IEC. 
A participant may be discontinued from study treatment as follows: 
• If a participant is noncompliant with study procedures or study drug/treatment 
administration in the investigator's opinion, the sponsor should be consulted for 
instruction on handling the participant. 
7.1.2. 
Discontinuation Procedures 
In the event that the decision is made to permanently discontinue the study treatment, the 30-day 
post–last dose safety follow-up visit and the 90-day post-cystectomy safety follow-up visits 
should be conducted.  In the event the participant does not undergo a cystectomy, the last 
follow-up visit will be 90 days post last dose of study treatment.  Reasonable efforts should be 
made to have the participant return for the follow-up visits.  These visits are described in Table 3 
through Table 7.  The last date of the last dose of study drug(s)/treatment and the reason for 
discontinuation of study treatment will be recorded in the eCRF. 


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If a participant is discontinued from study treatment: 
• The study monitor or sponsor must be notified. 
• The reason(s) for withdrawal must be documented in the participant's medical record 
and the primary reason for withdrawal must be included in the eCRF. 
• The Safety Follow-up visits should be performed and dates recorded. 
• The status of the participant should be updated to EOT in the IRT. 
• Participants must be followed for safety until the time of the follow-up visit or until 
study drug/treatment–related toxicities resolve, return to baseline, or are deemed 
irreversible, whichever is longest. 
If the participant discontinues study treatment and actively withdraws consent for collection of 
follow-up data (safety follow-up or disease assessment), then no additional data collection 
should occur; however, participants will have the option of withdrawing consent for study 
treatment but continuing in the follow-up period of the study for safety/efficacy assessments. 
7.2. 
Participant Withdrawal From the Study 
A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, compliance, or 
administrative reasons. 
If the participant withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 
See Table 3 through Table 7 for data to be collected at the time of study discontinuation and 
follow-up and for any further evaluations that need to be completed. 
7.3. 
Lost to Follow-Up 
A participant will be considered lost to follow-up if he/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. 


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8. 
STUDY ASSESSMENTS AND PROCEDURES 
8.1. 
Administrative and General Procedures 
8.1.1. 
Informed Consent Process 
• The informed consent process will include 2 separate consent forms for this study; the 
screening consent and treatment consent, which is inclusive of all treatment groups.  
Participants will be required to sign both consents if they are deemed eligible and are 
enrolled into the study. 
• The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions 
regarding the study. 
− Informed consent must be obtained before any study-related procedures are 
conducted, unless otherwise specified by the Protocol. 
− Informed consent must be obtained using the IRB/IEC-approved version in a 
language that is native and understandable to the participant.  A template will be 
provided by the sponsor or its designee.  The sponsor or its designee must review 
and acknowledge the site-specific changes to the ICF template.  The ICF must 
include a statement that the sponsor or its designee and regulatory authorities have 
direct access to participant records. 
− The ICF must contain all required elements and describe the nature, scope, and 
possible consequences of the study in a form understandable to the study 
participant. 
• 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 applicable requirements and regulations for the country(ies) in 
which the study is being conducted as well as the IRB/IEC or study center. 
• The participant must be informed that his/her personal study-related data will be used 
by the sponsor in accordance with local data protection laws.  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 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 ICF. 
• Participants must provide consent to the most current version of the ICF(s) during 
their participation in the study. 
• A copy of the ICF(s) must be provided to the participant. 


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A participant who is rescreened is not required to sign another ICF if the rescreening occurs 
within 28 days from the previous ICF signature date. 
8.1.2. 
Screening Procedures 
For each participant, the diagnostic biopsy or sample from the TURBT procedure shall be 
provided to the sponsor's central testing laboratory for analysis at the time of screening.   
Screening is the interval between signing the ICF and the day the participant is enrolled in the 
study (Cycle 1 Day 1).  Screening may not exceed 28 days.  Assessments that are required to 
demonstrate eligibility may be performed over the course of 1 or more days during the screening 
process. 
Procedures conducted as part of the participant's routine clinical management (eg, blood count, 
imaging study) and obtained before signing of informed consent may be used for screening or 
baseline purposes provided the procedure meets the Protocol-defined criteria and has been 
performed in the timeframe of the study (ie, within 28 days of Cycle 1 Day 1).  Screening 
laboratory assessments must be performed within 28 days of Cycle 1 Day 1.  If chemistry and 
hematology laboratory assessments were performed more than 7 days before Cycle 1 Day 1, then 
the tests must be repeated and eligibility confirmed before study treatment administration on 
Cycle 1 Day 1.  Results of a test performed before the participant signing consent as part of 
routine clinical management are acceptable in lieu of a screening test if performed within the 
specified timeframe.  For participants who are enrolled in the study, information associated with 
eligibility requirements must be entered into the appropriate eCRF pages. 
Tests with results that fail eligibility requirements may be repeated during screening if the 
investigator believes the results to be in error.  For screening assessments that are repeated, the 
most recent available result before treatment assignment will be used to determine eligibility.  
Additionally, a participant who fails screening may repeat the screening process if the 
investigator believes that there has been a change in eligibility status.  Participants who rescreen 
must be assigned a new participant number. 
See Sections 5.4 and 5.5 for information regarding screen failures and replacement of 
participants, respectively. 
8.1.3. 
Interactive Response Technology Procedure 
Each participant will be identified in the study by a participant ID number, which is a 
combination of the site ID and participant number.  Site staff should contact the IRT to obtain the 
participant ID number during screening.  Site staff will also be asked to enter the outcome of the 
participant's PD-L1 CPS testing during screening into the IRT to obtain the treatment 
assignment.  The treatment assignment will be done as described in Section 4.1, and any 
participants who do not meet study inclusion/exclusion criteria will fail screening.  Additionally, 
the IRT will be contacted at each regular study visit to update the study drug supply.  Additional 
details are provided in the IRT Manual. 
8.1.4. 
Distribution of Reminder Cards  
All participants will be provided with reminder cards.  Participants in Treatment Groups A, B, 
and C will be provided with a reminder card at Day 1 of each treatment cycle, while participants 


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in Groups D and E will be provided with a reminder card at Day 1 of each cycle and Day 15 of 
Cycles 1 and 2.  The reminder card will indicate the date/time of the next visit as well as other 
visit-specific procedures and reminders (ie, not take their morning dose of oral study drug before 
the next visit).  
 
 
8.1.5. 
Demography and Medical History 
8.1.5.1. 
Demographics and General Medical History 
Demographic data and general medical history will be collected at screening by the investigator 
or qualified designee and will include year of birth/age, race, ethnicity, medical and surgical 
history, and current illnesses.  Medical history will include relevant medical or surgical treatment 
within the last 10 years that are considered to be clinically significant by the investigator. 
8.1.5.2. 
Disease Characteristics and Treatment History 
A disease-targeted medical and treatment history will be collected at screening.  Details 
regarding the participant's malignancy under study, including date of diagnosis, initial and 
current cancer stage, tumor histology, and relevant disease characteristics, and prior treatments, 
including systemic treatments, radiation, and surgical procedures, will be recorded. 
8.2. 
Efficacy Assessments 
The primary translational endpoint of this study is the change in tumor-infiltrating immune 
CD8+ T effector cells at the time of cystectomy compared to pretreatment.  Subsequent 
immunohistochemical and transcriptional analysis will further characterize the infiltrating T-cell 
subpopulations.  
8.2.1. 
Pathological Complete Response, Major Pathological Response, 
 
 
Efficacy analysis for the pCR rate 
 will include all 
participants who met the eligibility criteria, had at least 1 cycle of study treatment, and 
underwent cystectomy or withdrew for progression of disease.  pCR is defined as pT0 and in situ 
cancer on the basis of histological evaluation of the TURBT and cystectomy samples by local 
institutional analysis.  Major pathological response is defined as residual ypT0/1/a/isN0M0 on 
the basis of histological evaluation of the TURBT and cystectomy samples.  
 
 
 
   
8.2.2. 
Health Economics 
Not applicable.  
8.3. 
Safety Assessments 
See Section 6.5 for guidelines regarding the management of relevant laboratory or other safety 
assessment abnormalities. 


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8.3.1. 
Adverse Events 
Adverse events will be monitored from the time the participant signs the ICF until 90 days after 
cystectomy or the last dose of either study drug if cystectomy not performed.  If cystectomy is 
not performed, then AEs are collected at least 28 days after the last dose of study treatment or 
until the start of new anticancer therapy, whichever occurs first.  Adverse events that begin or 
worsen after informed consent should be recorded on the Adverse Events Form in the eCRF 
regardless of the assumption of a causal relationship with the study treatment(s).  Conditions that 
were already present at the time of informed consent should be recorded on the Medical History 
Form in the eCRF.  Adverse events (including laboratory abnormalities that constitute AEs) 
should be described using a diagnosis whenever possible rather than by individual underlying 
signs and symptoms. 
Adverse events 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 for following-up on AEs that are serious, 
considered related to the study treatment/procedures, or that caused the participant to discontinue 
the study treatment.  Care will be taken not to introduce bias when detecting AEs and/or SAEs.  
Open-ended and nonleading verbal questioning of the participant, such as "How are you 
feeling?" is the preferred method to inquire about AE occurrences.  Adverse events may also be 
detected when they are volunteered by the participant during the screening process or between 
visits or through physical examinations, laboratory tests, or other assessments.  The definition, 
reporting, and recording requirements for AEs are described in Section 9. 
All SAEs will be recorded and reported to the sponsor or designee within 24 hours.  The 
investigator will submit any updated SAE data to the sponsor within 24 hours of it being 
available. 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts.  All SAEs, will be followed until resolution, stabilization, the event 
is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). 
8.3.2. 
Physical Examinations 
Physical examinations must be performed by a medically qualified individual, such as a licensed 
physician, physician's assistant, or an advanced registered nurse practitioner, as local law 
permits.  Abnormalities identified after the first dose of study treatment constitute an AE if they 
are considered clinically meaningful, induce clinical signs or symptoms, require concomitant 
therapy, or require changes in study treatment (with the exception of abnormalities associated 
with disease progression).  Investigators should pay special attention to clinical signs related to 
previous serious illnesses. 
At the screening visit, a comprehensive physical examination should be conducted.  The 
comprehensive physical examination will include height and body weight, and assessment of the 
following organ or body systems:  skin; head, eyes, ears, nose, and throat; thyroid; lungs; 
cardiovascular system; abdomen (liver, spleen); extremities; and lymph nodes; as well as a brief 
neurological examination.  Audiometric hearing and peripheral neuropathy will be assessed as 


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per Galsky criteria (Galsky et al 2011).  Height will be measured at the screening only.  
Weight should be assessed at the study visits as indicated in the SoA. 
During the study, targeted examinations as indicated in the SoA will be conducted unless 
otherwise clinically indicated.  Participants will be assessed by the investigator or medically 
qualified designee per institutional standard of care.  These assessments should be an evaluation 
as indicated by participant symptoms, AEs, or other findings and documented on the AE eCRF.  
8.3.3. 
Vital Signs 
Vital sign measurements (should be taken before blood collection for laboratory tests) include 
blood pressure, pulse, respiratory rate, and body temperature and are to be taken as specified in 
the SoA.  If vital signs cannot be taken before blood collection for laboratory tests, there must be 
a minimum of 30 minutes from the completion of the blood collection procedures to the 
beginning of the vital signs collection.  Blood pressure and pulse will be taken with the 
participant in the recumbent, semi recumbent, or sitting position after 5 minutes of rest.  
Abnormal vital sign results identified after the first dose of study treatment constitute an AE if 
they are considered clinically meaningful, induce clinical signs or symptoms, require 
concomitant therapy, or require changes in study treatment. 
8.3.4. 
Electrocardiograms 
Single 12-lead ECG will be obtained as outlined in the SoA using an ECG machine that 
automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals.  All 
12-lead ECGs will be performed with the participant in a recumbent or semirecumbent position 
after 5 minutes of rest.  Electrocardiograms will be conducted predose.  
The 12-lead ECGs will be interpreted by the investigator at the site to be used for immediate 
participant management.  Additional 12-lead ECGs may be performed as clinically indicated to 
manage participant safety.  The decision to include or exclude a participant or withdraw a 
participant from the study treatment based on an ECG flagged as "Abnormal, Clinically 
Significant" is the responsibility of the investigator, in consultation with the sponsor's medical 
monitor, as appropriate.  Clinically notable abnormalities that are considered clinically 
significant in the judgment of the investigator are to be reported as AEs.   
8.3.5. 
Laboratory Assessments 
See Table 18 for the list of clinical laboratory tests to be performed and the SoAs for the timing 
and frequency.  A certified laboratory local to the investigative site will perform all clinical 
laboratory assessments for safety (ie, blood chemistries, hematology assessments, coagulation 
tests, thyroid function, lipid panel, serology, and urinalysis).  The investigative site will enter the 
laboratory results and laboratory normal ranges into the eCRF.  Additional testing may be 
required by the sponsor based on emerging safety data.  Additional tests may also be performed 
for specific combinations or if clinically indicated. 
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.  All laboratory tests with values considered clinically significantly 
abnormal during participation in the study or within 30 days after the last dose of study treatment 


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should be repeated until the values return to normal or baseline or are no longer considered 
clinically significant by the investigator or medical monitor. 
Screening laboratory assessments must be performed within 7 days of Cycle 1 Day 1 do not need 
to be repeated before study treatment administration on Cycle 1 Day 1.  Laboratory samples 
collected on study Day 1 must be performed before study treatment administration.  After 
Cycle 1, predose laboratory procedures can be conducted up to 72 hours before study treatment 
administration (within the 3-day study window), and results should be reviewed by the 
investigator or qualified designee and found to be acceptable before a new cycle of treatment is 
initiated. 
Laboratory checks of HIV viral load and CD4+ cell count will be performed at screening, before 
cystectomy, and then at the 30-day safety follow-up visit. 


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Table 18: 
Required Laboratory Analytes 
Serum Chemistries 
Hematology 
Urinalysis  
Serology 
Coagulation 
Albumin 
Alkaline phosphatase 
ALT 
AST 
Amylase 
Bicarbonate or CO2a or HCO3 (if 
clinically indicated) 
Blood urea nitrogen or urea 
Calcium 
Chloride 
Creatinine 
Glucose 
Lactate dehydrogenase 
Lipase 
Potassium 
Sodium 
Total bilirubin 
Direct bilirubin (if total bilirubin 
is elevated above ULN) 
Total protein 
Uric acid 
Troponin I or T (All treatment 
groups for screening, Treatment 
Groups D and E only during 
treatment cycles, per local 
standard) 
  
Complete blood count, 
including: 
• Hemoglobin 
• Hematocrit 
• Platelet count 
• Red blood cell count 
• White blood cell count 
 
Differential count, including: 
• Basophils 
• Eosinophils 
• Lymphocytes 
• Monocytes 
• Neutrophils 
 
Absolute values must be 
provided for: 
• WBC differential 
laboratory results 
Color and appearance 
pH and specific gravity 
Bilirubin 
Glucose 
Ketones 
Leukocytes 
Nitrite 
Occult blood 
Protein 
Microscopic examination 
(if blood or protein is 
abnormal) 
HIV screening and management: 
HIV viral load 
CD4+ cell count 
 
Hepatitis B surface antigen 
Hepatitis B surface antigen antibody 
Hepatitis B core antibody 
HBV-DNA 
HCV antibody 
HCV-RNA 
PT 
PTT or aPTT 
INR 
Thyroid Panel 
Pregnancy Testing 
Lipid Panel 
TSH 
T4 
T3/FT3 (based on local 
availability) 
Female participants of childbearing 
potential only require a serum test at 
screening and precystectomy.  A 
urine or serum pregnancy test is 
required before cystectomy, before 
the first dose on Day 1 of every cycle 
before dose administration, and at the 
30-day safety follow-up visit; in 
Europe, a urine or serum pregnancy 
test is also required 190 days after 
the last dose of study treatment. 
Pregnancy tests (serum or urine) 
should be repeated if required by 
local regulations. 
Total cholesterol 
Triglycerides 
Low-density 
lipoprotein 
cholesterol 
High-density 
lipoprotein 
cholesterol 
Note:  Additional tests may be required, as agreed upon by the investigator and sponsor, based on emerging safety data. 
a If considered standard by region. 


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8.3.5.1. 
Pregnancy Testing 
A serum pregnancy test will be required for all women of childbearing potential at screening and 
at the precystectomy visit.  The serum pregnancy test performed at screening must be performed 
within 72 hours before the first dose of study treatment.  Urine or serum pregnancy tests will be 
performed locally as outlined in Table 3 to Table 7, as medically indicated (eg, in case of loss of 
menstrual cycle, when pregnancy is suspected), or per country-specific requirements.  
Additionally, monthly telephone visits should take place to check pregnancy status (via testing, 
including home urine pregnancy tests) during the period when contraception is mandatory, which 
is 190 days after the last dose of study treatment for European sites.  If a urine pregnancy test is 
positive, the results should be confirmed with a serum pregnancy test. 
If the serum pregnancy test is negative after a urine test was positive, the investigator will assess 
the potential benefit/risk to the participant and determine whether it is in the participant's best 
interest to resume study treatment and continue participation in the study. 
If a pregnancy is confirmed by a serum pregnancy test, see Section 9.7 for reporting 
requirements. 
8.3.6. 
Eastern Cooperative Oncology Group Performance Status 
Eastern Cooperative Oncology Group PS will be assessed according to the criteria in Table 19.  
Table 19: 
Eastern Cooperative Oncology Group Performance Status 
Grade 
Performance Status 
0 
Fully active, able to carry on all predisease 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 et al 1982. 
8.3.7. 
Postsurgical Criteria for Adverse Events 
In the PURE-01 study, where pembrolizumab was administered as neoadjuvant therapy before 
radical cystectomy in patients with miUBC, the medical and surgical reported AEs are listed in 
Table 2 of Necchi et al (2018).  Postsurgical complications were consistent with previously 
reported findings.  Clavien Dindo > Grade II complications (see Appendix D) occurred in 
15 participants (30%), and the most frequent complications were sepsis (n = 10; 20%) and 
subocclusion (n = 8; 16%).  However, there were a few delayed immune-related AEs, including 
pyrexia (n = 3; 6%), pruritus (n = 3; 6%), and xerostomia (n = 2; 4%).  All of the latter AEs 
occurred within 2 months postoperatively, and three participants required corticosteroid 
treatment.  
As noted in Mitropoulos et al (2012), a more rigid criteria of measuring postsurgical 
complications may have resulted in perceived higher rates of complications.  The following 


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quality criteria will be followed for postsurgical AEs at 30 days after cystectomy (or after last 
dose if cystectomy is not performed) for accurate and comprehensive reporting: 
• Define the method of accruing data:  retrospective/ prospective; through chart 
review/telephone interview/face to face interview/other. 
• Define who collected the data:  medical doctor/nurse/data manager/other, and 
whether he or she was involved in the treatment. 
• Indicate the duration of follow-up:  30 days. 
• Include outpatient information. 
• Include mortality data and causes of death. 
• Include definitions of complications. 
• Define procedure-specific complications. 
• Report intraoperative and postoperative complications separately. 
• Use a severity grading-system for postoperative complications (avoiding the 
distinction minor/major); the Clavien-Dindo systems is recommended. 
• Postoperative complications should be presented in a table either by grade or by 
complications type (specific grades should always be provided; grouping in not 
accepted). 
• Include risk factors:  American Society of Anesthesiologists score, Charlson score, 
ECOG PS, other. 
• Include readmissions and causes. 
• Include reoperations, types, and causes. 
• Include the percentage of participants lost to follow-up. 
All Grade 3 and Grade 4 AEs reported and any reported postsurgical complication will be added 
for internal analysis of data. 
8.4. 
 Immunogenicity Assessments 
 
 
 
 
 
Participants in Treatment Group A receiving combination therapy should take their scheduled 
oral dose of epacadostat immediately before the start of retifanlimab infusion.  The exact date 
and time of the dose administered at the clinic should be recorded and entered into the EDC.  
 
 


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  Instructions 
for sample preparation and shipping will be provided in the Laboratory Manual. 
Any changes in the timing or addition of timepoints for any planned study assessments must be 
documented and approved by the relevant study team member and then archived in the sponsor 
and site study files but will not constitute a Protocol Amendment.  The IRB/IEC will be 
informed of any safety issues that require alteration of the safety monitoring scheme or 
amendment of the ICF. 
8.4.1. 
Blood Sample Collection for Monoclonal Antibodies 
Blood samples for 
 ADA analysis will be obtained at the visits indicated in the 
appropriate SoA.  Timing of 
 ADA assessments for retifanlimab, INCAGN02385, and 
INCAGN02390 are outlined in Table 20.  
 
  Predose is defined as within 
24 hours before administration of study drug.  
 
 
Table 20: 
Timing of 
 Antidrug Antibody Serum Sample 
Collection  
Study Visit 
Assessment 
Timing of Sample Collection 
Cycle 1 Day 1 for Treatment Groups A and B 
 ADA 
Preinfusion 
 
 
Cycle 2 Day 1 for Treatment Groups A and B 
 ADA 
Preinfusion 
 
 
Safety follow-up (30-day) for Treatment 
Groups A and B 
ADA 
Untimed ADA sample 
Cycle 1 Day 1 for Treatment Groups D and E 
 ADA 
Predose/preinfusion of INCAGN02385 
and/or INCAGN02390 and retifanlimab 
Sample must be collected before 
dose/infusion of other agents 
 
 
 
 
 
 
 
 
 
 
 
Cycle 2 Day 1 for Treatment Groups D and E 
 ADA 
Predose/preinfusion 
30-day safety follow-up for Treatment Groups 
D and E 
ADA 
Untimed sample 


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8.4.1.1. 
Immunogenicity (Antidrug Antibody) Assessments 
Blood samples will be assessed for antibodies binding to retifanlimab, INCAGN02385, and 
INCAGN02390 and the titer of confirmed positive samples will be reported.  Other analyses may 
be performed to verify the stability of antibodies to retifanlimab, INCAGN02385, and 
INCAGN02390 and/or further characterize the immunogenicity of study drug. 
The detection and characterization of antibodies to retifanlimab, INCAGN02385, and 
INCAGN02390 will be performed using a validated assay method by or under the supervision of 
the sponsor or designee.  All samples collected for detection of antibodies to study drugs will 
also be evaluated for concentration to enable interpretation of the antibody data.  Antibodies may 
be further characterized and/or evaluated for their ability to neutralize the activity of the study 
drug. 
 
 
  
 
 
 
 
 
 
 
8.4.3. 
 Bioanalytical Methodology and Sample Analysis 
All the bioanalysis work will be performed by Incyte or its designee.  Serum concentrations of 
retifanlimab monotherapy or in combination with other oral therapies will be measured using a 
quantitative sandwich ELISA method.  Plasma concentrations of epacadostat will be measured 
using validated liquid chromatography–tandem mass spectrometry assays. 
The generation of ADA directed against retifanlimab will be monitored using a bridging ELISA 
method. 
8.5. 
Pharmacodynamic and Translational Assessments 
8.5.1. 
Timing of Assessments 
 
 
 
 
 
. 


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The tumor infiltrating lymphocyte population consists of multiple T cell populations, including 
CD4+ helper cells, CD8+ cytotoxic T cells, and FoxP3+ Tregs.  The primary translational 
endpoint of this study is the change in tumor-infiltrating immune CD8+ T effector cells at the 
time of cystectomy compared to pretreatment.  This study will use a multiplex 
CD8/FoxP3/granzyme B IHC assay to monitor the overall influx and activation state of these 
populations into the tumor.  Subsequent immunohistochemical and transcriptional analyses will 
further characterize the infiltrating T-cell subpopulations. 
 
 
 
 
 
 
 
8.5.2. 
Tissue Biopsy Collection Requirements 
All tumors will have an initial assessment for PD-L1 CPS score for participant stratification.  
The PD-L1 IHC 22C3 pharmDx assay must be used for PD-L1 CPS score testing, which will be 
done centrally.   
 
 
 
 
 
Screening sample and PD-L1 testing will be performed via the sample collected from the 
TURBT procedure.  Tumor tissue must be formalin-fixed, paraffin-embedded and contain a 
minimum of 20% tumor cells.  Tumor block or 20 unstained slides are necessary for the planned 
analysis to be conducted after the initial PD-L1 assessments. 
Mandatory tumor biopsies will be collected as specified below: 
• Screening:  Pretreatment biopsies will be obtained when the participant undergoes 
TURBT. 
− At sites where the participant had TURBT performed elsewhere, pretreatment 
biopsy will be obtained from the TURBT or other diagnostic procedure. 
− At study sites where the TURBT is conducted, a portion of the biopsy will also be 
immediately flash-frozen on dry ice to allow for amino acid metabolite analysis.  
The remaining tissue will be collected and stored as formalin-fixed, 
paraffin-embedded samples.    


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• Cystectomy:  If a flash-frozen biopsy was obtained during the TURBT and the 
participant was randomized to Treatment Groups A, B, or C, then a portion of the 
biopsy at cystectomy will also be immediately flash-frozen on dry ice to allow for 
amino acid metabolite analysis.  This will be done during the grossing period with a 
maximum of 30 minutes of ischemic time.  If a flash-frozen biopsy was not obtained 
during TURBT, one is not needed during cystectomy.  
 
 
 
   
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 


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8.6. 
Unscheduled Visits 
Unscheduled study visits may occur at any time if medically warranted.  Any assessments 
performed at those visits should be recorded in the eCRF.  
8.7. 
End of Treatment and/or Early Termination 
When the participant permanently discontinues study treatment, whether the participant is 
terminating the study early or the participant has completed the study, the precystectomy visit 
should be conducted.  If the treatment visit is within 2 weeks of the cystectomy visit, then all the 
evaluations for both the treatment visit and the precystectomy visit should be conducted.  The 
participant should be encouraged to return for the follow-up visit. 
8.8. 
Follow-Up 
8.8.1. 
Safety Follow-Up 
The safety follow-up period is the interval between the cystectomy and the scheduled 90-day 
safety follow-up visit.  All participants will have the safety follow-up visits at 30 days after 
radical cystectomy (or last dose if cystectomy procedure is not performed) and 90 days after 
cystectomy.  In the event the participant does not undergo a cystectomy, the follow-up visit will 
be 90 days after last dose of study treatment.  If radical cystectomy is not performed, then AEs 
and SAEs must be reported up until 1) at least 28 days after the last dose of study treatment or 
the start of a new anticancer therapy or 2) until toxicities resolve, return to baseline, or are 
deemed irreversible, whichever is longer.  Reasonable efforts should be made to have the 
participant return for the follow-up visit and report any AEs that may occur during this period.  
If the participant cannot return to the site for the safety follow-up visit (eg, lives far away), the 
participant should be contacted by telephone for assessment of AEs and SAEs.  Sites should be 
instructed to document this contact in the eCRF. 
If a participant is scheduled to begin a new anticancer therapy before the end of the 30- or 90-day 
safety follow-up period, then the safety follow-up visit should be performed before the new 
anticancer therapy is started. 


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9. 
ADVERSE EVENTS:  DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING 
9.1. 
Definition of Adverse Event 
Adverse Event Definition 
• An AE is any untoward medical occurrence associated with the use of a drug in humans, whether or 
not it is considered drug-related. 
• An AE can therefore be any unfavorable or unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of study 
treatment. 
Additional Guidance for Events Meeting the Adverse Event Definition 
• Any safety assessments (eg, ECG, vital signs measurements), including those that worsen from 
baseline, considered clinically significant in the medical and scientific judgment of the investigator 
(ie, not related to progression of underlying disease) are to be reported as an AE. 
• Abnormal laboratory test results are to be reported as an AE if they are considered clinically 
meaningful, induce clinical signs or symptoms, require concomitant therapy, or require changes in 
study drug.  Whenever possible, a diagnosis (eg, anemia, thrombocytopenia) should be recorded in 
the eCRF rather than the abnormal laboratory result (eg, low hemoglobin, platelet count decreased). 
• Exacerbation of a chronic or intermittent pre-existing condition/disease, including either an increase 
in the frequency and/or intensity of the condition, is to be reported as an AE. 
• New conditions detected or diagnosed after the start of study treatment administration even though 
they may have been present before the start of the study are to be reported as AEs. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction are to be reported as 
AEs. 
•  Signs and/or symptoms from dosing errors of a study drug/treatment (eg, overdose) or a concomitant 
medication are to be reported as an AE. 
• "Lack of efficacy," "disease progression," or "failure of expected pharmacological action" will not be 
reported as an AE or SAE.  Such instances will be captured in the efficacy assessments. 
• 
 
  The SAE and AE reporting from the TURBT 
procedure will be recorded as part of medical history.  A secondary consent specific to the treatment 
arm is also signed prior to the patient starting study treatment. 
• Pre-existing diseases or conditions with expected fluctuations in signs or symptoms should be 
reported as an AE only if the investigator judges the fluctuation to have worsened more than 
expected during study participation. 


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9.2. 
Definition of Serious Adverse Event 
If an event is not an AE per the 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). 
A serious adverse event 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 adverse drug experience that 
places the participant, in the opinion of the initial reporter, at immediate risk of death from the adverse 
experience as it occurs.  This does not include an adverse drug experience that, had it occurred in a 
more severe form, might have caused death. 
c.  Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (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 or planned surgery (eg, stent replacement, hip surgery) is not 
considered an SAE. 
Hospitalization for medical interventions in which no unfavorable medical occurrence occurred (ie, 
elective procedures or routine medical visits) are not considered SAEs. 
d. Results in persistent or significant 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), that may interfere with or prevent everyday life functions but do not constitute a 
substantial disruption. 
e.  Is a congenital anomaly/birth defect 
f.  Is an important medical event 
An important medical event is an event that may not result in death, be immediately life-threatening, or 
require hospitalization but may be considered serious when, based on appropriate medical judgment, 
the event may jeopardize the participant and may require medical or surgical intervention to prevent 
one of the outcomes listed in the above definition.  Examples of such events include new invasive or 
malignant cancers, intensive treatment in an emergency department or at home for allergic 
bronchospasm, blood dyscrasias, or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse, or suspected transmission of an infectious agent via a medicinal 
product.  Secondary malignancies should always be considered as SAEs.   


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9.3. 
Recording and Follow-Up of Adverse Events and/or Serious Adverse 
Events 
Adverse Event and Serious Adverse Event Recording 
• An AE/SAE that begins or worsens after informed consent is signed should be recorded on the 
Adverse Event Form in the eCRF.  Conditions that were present at the time informed consent was 
given should be recorded on the Medical History Form in the eCRF. 
• When an AE/SAE 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 (or delegate) 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 in 
lieu of completing the Adverse Event Form in the eCRF. 
• There may be rare instances when copies of medical records for certain cases are requested.  In this 
case, all participant identifiers, with the exception of the participant number, will be redacted by the 
site staff on the copies of the medical records before submission.  These records can be submitted to 
Incyte Pharmacovigilance by email/fax per the contact information listed in the Study Reference 
Manual or as per SAE completing guidelines 
• 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.  When a clear diagnosis cannot be identified, each sign or 
symptom should be reported as a separate AE/SAE. 
To the extent possible, each AE/SAE should be evaluated to determine the following: 
• The severity grade (CTCAE v5.0 Grade 1 to 5).  See below for further instructions on the assessment 
of intensity. 
• Whether there is at least a reasonable possibility that the AE is related to the study treatment 
(including study drug[s] and/or reference therapy):  suspected (yes) or not suspected (no).  See below 
for further instructions on the assessment of causality. 
• The start and end dates, unless unresolved at the final safety follow-up visit. 
• The action taken with regard to study drug and/or reference therapy as a result of the AE/SAE(s). 
• The event outcome (eg, not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequelae, fatal, unknown). 
• The seriousness, as per the SAE definition provided in Section 9.2. 
• The action taken with regard to the event.  Note:  If an AE is treated with a concomitant medication 
or nondrug therapy, this action should be recorded on Adverse Event Form and the treatment should 
be specified on the appropriate eCRF (eg, Prior/Concomitant Medications, Procedures and Non-Drug 
Therapy). 
Assessment of Intensity 
The severity of AEs will be assessed using CTCAE v5.0 Grades 1 through 5.  If an event is not 
classified by CTCAE, the severity of the AE will be graded according to the scale below to estimate the 
grade of severity. 
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 1:  Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; treatment 
not indicated. 


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• Grade 2:  Moderate; minimal, local, or noninvasive treatment indicated; limiting age-appropriate 
activities of daily living. 
• Grade 3:  Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living. 
• Grade 4:  Life-threatening consequences; urgent treatment indicated. 
• Grade 5:  Fatal. 
Assessment of Causality 
• The investigator is obligated to assess the relationship between study treatment and each occurrence 
of each AE/SAE.  If reference therapy is used in combination with an Incyte study drug or multiple 
Incyte study drugs are used, the relationship to each study drug/reference therapy must be assessed 
(ie, for the Incyte product[s] and for the other product[s] that are used in combination with the Incyte 
product).  If appropriate, the relationship to the combination may be assessed as well. 
• A "reasonable possibility" of a relationship conveys that there are medical facts, evidence, and/or 
arguments to suggest a causal relationship, rather than that a relationship cannot be ruled out. 
• The investigator will use clinical judgment to determine the possibility of a relationship. 
• The investigator will also consult the RSI in the IB or Product Information for study drug/treatment, 
or marketed products, respectively, in making his/her assessment. 
• Alternative causes, such as underlying or concurrent disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study treatment administration, will be 
considered and investigated. 
• 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. 
• With regard to assessing causality of SAEs: 
− There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report.  However, the causality assessment is one of the criteria 
used when determining regulatory reporting requirements.  Therefore, it is very important that 
the investigator always make an assessment of causality based on the available information 
for every event before the initial transmission of the SAE. 
− The investigator may change his/her opinion of causality in light of follow-up information and 
submit the updated causality assessment. 
Follow-Up of Adverse Events and Serious Adverse Events 
• 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 
professionals. 
• Once an AE is detected, it should be followed in the AE eCRFs until it has resolved or until it is 
judged to be permanent; assessment should be made at each visit (or more frequently if necessary) of 
any changes in severity, the suspected relationship to the study drug, the interventions required to 
treat the event, and the outcome. 
• When the severity of an AE changes over time for a reporting period (eg, between visits), each 
change in severity will be reported as a separate AE until the event resolves. 


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• If a participant dies during participation in the study or during a recognized follow-up period, the 
investigator will provide the sponsor with a copy of any postmortem findings, including 
histopathology 
• Updated SAE information will be recorded in the originally completed eCRF and reported to Incyte 
Pharmacovigilance (either via email/fax if paper SAE form is used or in the SAE EDC CRF) until 
resolution, stabilization, the event is otherwise explained, or the participant is lost to follow-up. 
• Any updated SAE data (including SAEs being downgraded to nonserious) will be submitted to the 
sponsor (or designee) within 24 hours of receipt of the information. 
9.4. 
Reporting of Serious Adverse Events 
Regardless of suspected causality (eg, relationship to study drug[s] or study procedure[s]), all 
SAEs occurring after the participant has signed the ICF through 90 days after the last dose of 
study treatment or until the participant starts a new anticancer therapy, must be reported to the 
sponsor (or designee) within 24 hours of learning of its occurrence unless otherwise specified by 
the Protocol.  The investigator will submit any updated SAE data to the sponsor (or designee) 
within 24 hours of it being available. 
Investigators are not obligated to actively seek SAE information after the safety follow-up visit 
or 90 days after the last dose of study drug/treatment.  If the investigator learns of any SAE, 
including death, at any time after a participant has been withdrawn from the study, and he/she 
considers the event to be reasonably related to the study treatment or study participation, then the 
investigator must notify the sponsor (or designee) within 24 hours of becoming aware of the 
event. 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts.  All SAEs and AESIs (as defined in Section 9.5) will be followed 
until resolution, stabilization, the event is otherwise explained, or the participant is lost to 
follow-up (as defined in Section 7.3). 
Prompt notification by the investigator to the sponsor regarding an SAE is essential so that legal 
obligations and ethical responsibilities toward the safety of participants and the safety of a study 
treatment under clinical investigation are met. 
If the SAE is not documented in the Reference Safety Information of the respective IB 
(retifanlimab IB, epacadostat IB, INCAGN02385 IB, and INCAGN02390 IB) for the study drug 
(new occurrence) and is thought to be related to the sponsor's study drug, the sponsor or its 
designee may urgently require further information from the investigator for expedited reporting 
to health authorities.  The sponsor or its designee may need to issue an Investigator Notification 
to inform all investigators involved in any study with the same drug that this SAE has been 
reported.  Suspected unexpected serious adverse reactions will be collected and reported to the 
competent authorities and relevant ethics committees in accordance with Directive 2001/20/EC 
or as per national regulatory requirements in participating countries. 
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, IRB/IEC, and investigators. 


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Investigator safety reports must be prepared for suspected unexpected serious adverse reactions 
according to local regulatory requirements and sponsor policy and forwarded to investigators as 
necessary. 
An investigator who receives an investigator safety report describing an SAE or other specific 
safety information (eg, summary or listing of SAEs) from the sponsor will review and then file it 
along with the IB and will notify the IRB/IEC, if appropriate, according to local requirements. 
Serious Adverse Event Reporting 
• Information about all SAEs is collected and recorded on the Adverse Event Form in the eCRF. 
• The investigator must report within 24 hours of learning of its occurrence any SAE via the EDC 
system (primary method) or by completing the Serious Adverse Event Report Form in English (only 
if the EDC system is not available.  The contact information for Incyte Pharmacovigilance by 
email/fax is listed in the Incyte Reference Guide for Completing the Serious Adverse Event Report 
Form). 
• In circumstances where the EDC system is not accessible for reporting SAE information (initial 
and/or follow-up SAE information) to the sponsor within 24 hours, refer to the Incyte Reference 
Guide for Completing the Serious Adverse Event Report Form.  Once the EDC system is functional, 
the SAE report should be retrospectively added to the EDC system and follow-up should be 
completed through the EDC.  The original copy of the Serious Adverse Event Report Form and the 
email or facsimile confirmation sheet must be kept at the study site (refer to the Incyte Reference 
Guide for Completing the Serious Adverse Event Report Form for details and for the email address 
or fax number). 
• Follow-up information is also recorded in the eCRF and transmitted to Incyte Pharmacovigilance via 
the EDC system.  The follow-up report should include information that was not provided previously, 
such as the outcome of the event, treatment provided, action taken with study drug because of the 
SAE (eg, dose reduced, interrupted, or discontinued), or participant disposition (eg, continued or 
withdrew from study participation).  Each recurrence, complication, or progression of the original 
event should be reported as follow-up to that event, regardless of when it occurs. 
• Contacts for SAE reporting can be found in the Study Manual. 
9.5. 
Adverse Events of Special Interest 
No specific AEs are expected to be sent to the sponsor within an expedited manner outside the 
AEs that meet the seriousness category as described in Section 9.2.  Adverse events of special 
interest will include irAEs that will be coded according to MedDRA along with all other AEs, as 
well as postsurgical complications using Clavien-Dindo Grading System (see Appendix D).  
Immune response AEs will be tabulated by preferred term and system organ class and by events 
of Grade 3 or higher. 
As suggested by CIOMS VI, Management of Safety Information from Clinical Trials 
(CIOMS 2005), an AESI is described as follows:  an AESI (serious or nonserious) is one of 
scientific and medical concern specific to the sponsor's product or program, which requires 
ongoing monitoring and rapid communication by the investigator to the sponsor.  Such events 
may require further investigation in order to characterize and understand them.  Depending on 
the nature of the event, rapid communication by the trial sponsor to other parties may also be 
necessary (eg, regulators). 


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CIOMS VI further elaborates that an AESI is a noteworthy event for the particular product or 
class of products that a sponsor wishes to monitor carefully.  It could be serious or nonserious 
(eg, hair loss, loss of taste, impotence) and could include events that might be potential 
precursors or prodromes for more serious medical conditions in susceptible individuals.  Such 
events should be described in Protocols or Protocol Amendments, and instructions should be 
provided for investigators as to how and when they should be reported to the sponsor. 
The description of the AESI should include the following: 
• The definition of the event 
• Whether it is a measurable quantity.  If so, how will the measurement be done? 
• Whether it is a clinical event.  If so, how will it be confirmed? 
AESIs should be captured in the eCRF.  Data management should be alerted to the presence of 
any AESIs so that the correct form can be included.  If special communication needs are required 
(eg, reporting within a specific timeframe), the investigator will need to determine and describe 
the mechanism (paper form or a trigger in the eCRF for a new form to be generated in the system 
to collect additional data) and exact timeframe (number of days) for expedited reporting. 
9.6. 
Emergency Unblinding of Treatment Assignment 
Not applicable. 
9.7. 
Pregnancy 
Pregnancy, in and of itself, is not regarded as an AE unless there is suspicion that study drug may 
have interfered with the effectiveness of a contraceptive medication or method.  When a 
pregnancy has been confirmed in a participant during maternal or paternal exposure to study 
drug, the following procedures should be followed in order to ensure safety: 
• The study drug must be discontinued immediately (female participants only; if the 
female participant is no longer pregnant and meets the treatment continuation criteria 
within 12 weeks of the scheduled start of a cycle, study treatment may be resumed 
after approval has been received from the sponsor medical monitor. 
• The investigator must complete and submit the Incyte Clinical Trial Pregnancy Form 
to the sponsor or its designee within 24 hours of learning of the pregnancy. 
Data on fetal outcome are collected for regulatory reporting and drug safety evaluation.  
Follow-up should be conducted for each pregnancy to determine outcome, including spontaneous 
or voluntary termination, details of the birth, and the presence or absence of any birth defects, 
congenital abnormalities, or maternal and/or newborn complications, by following until the first 
well-baby visit.  Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported 
by the investigator to the sponsor or its designee.  Pregnancy follow-up information should be 
recorded on the same form and should include an assessment of the possible causal relationship 
to the sponsor's study drug to any pregnancy outcome, as well as follow-up to the first well-baby 
visit or the duration specified in local regulations, whichever is later.  Refer to the Incyte 
Reference Guide for Completing the Clinical Trial Pregnancy Form or Study Reference Manual. 


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Any SAE occurring during pregnancy of a study participant must be recorded on the 
Serious Adverse Event Report Form and submitted to the sponsor or its designee. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, or ectopic pregnancy) are considered SAEs (if occurring in the study participant) and 
must be reported as described in Section 9.4.  If an abnormal pregnancy outcome is reported in a 
study participant's partner, the event should be reported to the sponsor on the Clinical Trial 
Pregnancy Form. 
9.8. 
Warnings and Precautions 
Special warnings or precautions for the study treatment, derived from safety information 
collected by the sponsor or its designee, are presented in the IB for each study drug 
(retifanlimab IB, epacadostat IB, INCAGN02385 IB, and INCAGN02390 IB).  Additional safety 
information collected between IB updates will be communicated in the form of Investigator 
Notifications.  Any important new safety information should be discussed with the participant 
during the study as necessary.  If new significant risks are identified, they will be added to the 
ICF. 
9.9. 
Product Complaints 
The sponsor collects product complaints on study drugs and drug delivery systems used in 
clinical studies in order to ensure the safety of study participants, monitor quality, and facilitate 
process and product improvements. 
All product complaints associated with material packaged, labeled, and released by the sponsor 
or its designee will be reported to the sponsor.  All product complaints associated with other 
study material will be reported directly to the respective manufacturer. 
The investigator or his/her designee is responsible for reporting a complete description of the 
product complaint via email or other written communication to the sponsor contact or respective 
manufacturer as noted in the packaging information.  Any AE associated with a product 
complaint should be recorded as described in Section 9.3. 
If the investigator is asked to return the product for investigation, he/she will return a copy of the 
product complaint communication with the product. 


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10. 
STATISTICS 
10.1. 
Sample Size Determination 
Approximately 81 participants will be enrolled in this study.  Per treatment group, the evaluable 
paired biopsies in Table 22 are needed. 
Table 22: 
Sample Size Determination 
Treatment Group 
Number of 
Participants 
Estimated Number 
of Paired Biopsies 
A:  Epacadostat plus retifanlimab 
18 
16 
B:  Retifanlimab monotherapy  
18 
16 
C:  Epacadostat monotherapy  
9 
8 
D:  Retifanlimab plus INCAGN02385 
18 
16 
E:  Retifanlimab plus INCAGN02385 plus INCAGN02390 
18 
16 
Total  
81 
72 
For each group, the power consideration is based on the change from baseline in CD8+ T 
effector cells.  Eight evaluable paired biopsies in Treatment Group C will provide 80% power to 
detect a mean change from baseline in the degree of 1 standard deviation of the change variable 
at 2-sided alpha = 0.10 level.   
For Treatment Groups A and B, the 16 evaluable paired biopsies will provide > 95% power to 
detect the same degree of the mean change for the entire group and 80% power at 2-sided 
alpha = 0.10 level for both PD-L1 subgroups combined (PD-L1 CPS < 10 and PD-L1 CPS ≥ 10). 
10.2. 
Populations for Analysis 
Table 23 presents the populations for analysis. 


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Table 23: 
Populations for Analysis 
Population 
Description 
Translational 
evaluable populationa  
The translational evaluable population includes all participants enrolled in the 
study who have the following: 
• Completed a baseline scan. 
• Received at least 4 weeks of neoadjuvant study treatment. 
− Treatment Groups A and C need to receive epacadostat dosing up to 
and including day of surgery. 
• Provided evaluable paired biopsies (pretreatment core biopsy and surgical 
resection biopsy). 
Safety evaluable 
The safety evaluable population includes all enrolled participants who 
received at least 1 dose of study drug.  All safety analyses will be conducted 
using the safety evaluable population. 
Efficacy evaluable 
The efficacy evaluable population will include participants with efficacy 
endpoint data available. 
• For endpoints that are change from baseline, participants with assessments 
both at baseline and at the time of cystectomy will be included. 
• For endpoints that are evaluated at the time of cystectomy, participants 
with assessments at cystectomy will be included. 
/pharmacodynamic 
evaluable 
 
 
  
The pharmacodynamic evaluable population will include all participants who 
received at least 1 dose of any study treatment and provided at least 1 plasma 
sample (1 pharmacodynamic measurement). 
a The sponsor determines whether the samples are sufficiently evaluable for primary, secondary, 
 
analysis. 
10.3. 
Level of Significance 
The level of significance for the primary end point is 2-sided 10%.  The mean change from 
baseline will be assessed using a paired t-test in each treatment group for the primary endpoint.  
The significance of all secondary 
 analyses will be assessed at 2-sided 10% level.  
All CIs will be reported at 80%.  No multiplicity control will be applied to the assessments.  
10.4. 
Statistical Analyses 
10.4.1. 
Primary Analysis 
For each treatment group, the primary endpoint is change from baseline in immune (CD8+ 
T effector) cells.  The mean paired difference will be calculated as [post treatment] – 
[pretreatment].  The difference will be testing using a paired t-test with n – 1 degrees of freedom, 
where n is the number of evaluable paired samples.  The CI for the mean paired difference will 
be reported based on the t-distribution with n – 1 degrees of freedom.  A summary of reasons for 
excluding participants from the analysis will be provided. 


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10.4.2. 
Secondary Analysis 
Safety and tolerability assessed by monitoring the frequency and severity of AEs, including 
delay in cystectomy due to AEs.   
Safety analyses will be conducted for the safety population.  Adverse events will be coded by the 
MedDRA dictionary, and TEAE (ie, AEs reported for the first time or worsening of a 
pre-existing event after first dose of study drug) will be tabulated by preferred term and system 
organ class for all events, related events, and events of Grade 3 or higher.  Quantitative safety 
variables and their changes from baseline (laboratory, vital signs, etc) will be summarized with 
descriptive statistics.  Clinically notable abnormal values will be flagged and tabulated based on 
predefined criteria. 
The clinical laboratory data will be analyzed using summary statistics; no formal treatment group 
comparisons are planned.  In addition, distributions of key laboratory parameters may be plotted 
over time; these values will also be classified into CTCAE toxicity grades, and tabulated.  
Descriptive statistics and mean change from baseline will be determined for vital signs at each 
assessment time.  Vital sign results will be reviewed for clinically notable abnormalities. 
Descriptive statistics and mean change from baseline will be determined for each ECG parameter 
at each assessment time.  Electrocardiogram results will be reviewed for clinically notable 
abnormalities according to predefined criteria.  Participants exhibiting clinically notable ECG 
abnormalities will be listed. 
Pathological CR rates as well as major pathological response rates at the time of radical 
cystectomy will be assessed as secondary endpoints.  For pCR, the percentage of participants 
with ypT0N0, and for major pathological response, the percentage of participants with 
ypT0/1/a/isN0 in each treatment group, respectively, will be calculated, and its 80% CI will be 
estimated using the Clopper-Pearson method.  Assessments will be performed by the pathologist 
using the biopsies from radical cystectomy. 


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10.5. 
Interim Analysis 
No formal interim analysis for evaluating efficacy or futility is planned in this study.  Periodic 
safety reports will be produced in accordance with the DSMB charter (see Section 5.6). 


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11. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
11.1. 
Investigator Responsibilities 
• The Protocol, Protocol amendments, ICF, IB, and other relevant documents (eg, 
advertisements) must be submitted to an IRB/IEC by the investigator and reviewed 
and approved by the IRB/IEC before the study is initiated. 
• The investigator is responsible for ensuring that the safety reports provided by the 
sponsor are reviewed and processed in accordance with regulatory requirements, the 
policies and procedures established by the IRB/IEC, and institutional requirements. 
• Any amendments to the Protocol will require approval from both Health Authorities 
and IRB/IEC before implementation of changes made to the study design, except for 
changes necessary to eliminate an immediate hazard to study participants. 
• The investigator will be responsible for the following: 
− 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. 
− Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures. 
− Providing oversight of the conduct of the study at the site and adherence to GCP, 
IRB/IEC requirements, institutional requirements, and applicable laws and 
country-specific regulations. 
• Adhering to the Protocol as described in this document and agreeing that changes to 
the Protocol procedures, with the exception of medical emergencies, must be 
discussed and approved, first, by the sponsor or its designee and, second, by the 
IRB/IEC.  Each investigator is responsible for enrolling participants who have met 
the specified eligibility criteria. 
• Retaining records in accordance with all local, national, and regulatory laws but for a 
minimum period of at least 2 years after the last marketing application approval in an 
ICH region and until there are no pending or contemplated marketing applications in 
an ICH region, or if not approved, 2 years after the termination of the test article for 
investigation to ensure the availability of study documentation should it become 
necessary for the sponsor or a regulatory authority to review. 
− The investigator must not destroy any records associated with the study without 
receiving approval from the sponsor.  The investigator must notify the sponsor or 
its designee in the event of accidental loss or destruction of any study records.  If 
the investigator leaves the institution where the study was conducted, the sponsor 
or its designee must be contacted to arrange alternative record storage options. 


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− All eCRF data entered by the site (including audit trail), as well as computer 
hardware and software (for accessing the data), will be maintained or made 
available at the site in compliance with applicable record retention regulations.  
The sponsor will retain the original eCRF data and audit trail. 
11.1.1. 
Identification of the Coordinating Principal Investigator 
A coordinating principal investigator will be appointed by the sponsor medical monitor prior to 
the end of the study.  As part of his or her responsibilities, the coordinating principal investigator 
will review the final CSR.  Agreement with the final CSR will be documented by the dated 
signature of the coordinating principal investigator. 
11.2. 
Data Management 
Data management will be performed in a validated EDC system.  The investigator will be 
provided with access to an EDC system so that an eCRF can be completed for each participant. 
The site will be provided with eCRF completion guidelines for instructions on data entry in the 
eCRF.  The study monitor will reference the Monitoring Plan in order to ensure that each issue 
identified is appropriately documented, reported, and resolved in a timely manner in accordance 
with the plan's requirements.  Other data outside the EDC system required in the study conduct 
of the Protocol such as documents or results transmitted to the sponsor via a central laboratory or 
specialized technical vendors, and as designated by the sponsor, will have their own data flow 
management plans, or study charters, 
, as applicable. 
The sponsor (or designee) will be responsible for: 
• Managing the integrity of the data and the quality of the conduct of the study, such as 
ensuring that study monitors perform ongoing source data verification to confirm that 
data entered into the eCRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently 
approved Protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements. 
• Managing and reconciling the data generated, and/or collected including documents 
and results such as laboratory or imaging data analyzed centrally by a designated 
vendor of the sponsor. 
The investigator will be responsible for: 
• Recording, or ensuring the recording of, all relevant data relating to the study in the 
eCRF. 
• Delivering, or ensuring the delivery of, all other results, documents, data, know-how, 
or formulas relating to the study to the sponsor or designee electronically and/or 
centrally (eg, laboratory data, imaging data, 
, photographs, diary data), 
or as otherwise specified in the Protocol. 
• Verifying that data entries are accurate and correct by physically or electronically 
signing the eCRF. 


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• Maintaining accurate documentation (source data) that supports the information 
entered in the eCRF, or sent to a central vendor designated by the sponsor, or as 
described in other study and data flow manuals. 
− 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 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 applicable medical records must be 
available. 
• May have responsibility for sending participants' data, either as unique samples, or 
copies, or photographs, to be evaluated centrally or analyzed centrally, or both, by a 
qualified vendor designated by the sponsor.  
• Permitting study-related monitoring, sponsor audits, IRB/IEC review, and regulatory 
inspections by providing direct access to source data and other relevant clinical study 
documents. 
− Monitoring:  Qualified representatives of the sponsor or its designee, study 
monitors, will monitor the study according to a predetermined plan.  The 
investigator must allow the study monitors to review any study materials and 
participant records at each monitoring visit. 
− Auditing:  Qualified representatives of the sponsor or its designee may audit the 
clinical study site and study data to evaluate compliance with the Protocol, 
applicable local clinical study regulations, and overall study conduct.  The 
investigator must allow the auditors to review original source records and study 
documentation for all participants. 
− Regulatory inspection:  Regulatory authorities may conduct an inspection of the 
study and the site at any time during the development of an investigational 
product.  The investigator and staff are expected to cooperate with the inspectors 
and allow access to all source documents supporting the eCRFs and other 
study-related documents.  The investigator must immediately notify the sponsor 
when contacted by any regulatory authority for the purposes of conducting an 
inspection. 
11.3. 
Data Privacy and Confidentiality of Study Records 
The investigator and the sponsor or its designee must adhere to applicable data protection laws 
and regulations.  The investigator and the sponsor or its designee are responsible for ensuring 
that sensitive personal information is handled in accordance with local data protection laws 
(including but not limited to HIPAA and GDPR) as applicable.  Appropriate consent for 
collection, use and disclosure and/or transfer (if applicable) of personal information must be 
obtained in accordance with local data protection laws. 


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Participant names will not be supplied to the sponsor or its designee.  Only the participant 
number will be recorded in the eCRF; if the participant's name appears on any other document 
(eg, laboratory report), it must be obliterated on the copy of the document to be supplied to the 
sponsor or its designee.  Study findings stored on a computer will be stored in accordance with 
appropriate technical and organizational measures as required by local data protection laws. 
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the investigator for 10 years after study completion unless local regulations require 
otherwise.  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. 
11.4. 
Financial Disclosure 
Before study initiation, all clinical investigators participating in clinical studies subject to FDA 
Regulation Title 21 CFR Part 54 – Financial Disclosure by Clinical Investigators (ie, "covered 
studies") are required to submit a completed Clinical Investigator Financial Disclosure form that 
sufficiently details any financial interests and arrangements that apply.  For the purpose of this 
regulation, "clinical investigator" is defined as any investigator or subinvestigator who is directly 
involved in the treatment or evaluation of research participants, including the spouse and each 
dependent child of the clinical investigator or subinvestigator.  These requirements apply to both 
US and foreign clinical investigators conducting covered clinical studies. 
Any new clinical investigators added to the covered clinical study during its conduct must also 
submit a completed Investigator Financial Disclosure Form.  During a covered clinical study, 
any changes to the financial information previously reported by a clinical investigator must be 
reported to the sponsor or its designee.  At the conclusion of the covered clinical study, the 
clinical investigators will be reminded of their obligations.  In the event that the clinical 
investigator is not reminded, they nevertheless will remain obligated to report to the sponsor or 
its designee any changes to the financial information previously reported, as well as any changes 
in their financial information for a period of 1 year after completion of the covered clinical study. 
11.5. 
Publication Policy 
By signing the study Protocol, the investigator and his/her institution agree that the results of the 
study may be used by the sponsor, Incyte Corporation, for the purposes of national and 
international registration, publication, and information for medical and pharmaceutical 
professionals.  Study results will be published in accordance with applicable local and national 
regulations.  If necessary, the authorities will be notified of the investigator's name, address, 
qualifications, and extent of involvement.  The terms regarding the publication of study results 
are contained in the agreement signed with the sponsor or its designee.  A signed agreement will 
be retained by the sponsor or its designee. 
The results of this study may be published or presented at scientific meetings.  If this is foreseen, 
the investigator agrees to submit all manuscripts or abstracts to the sponsor before submission.  
This allows the sponsor to protect proprietary information and to provide comments. 
The sponsor will comply with the requirements for publication of study results.  In accordance 
with standard editorial and ethical practice, the sponsor will generally support publication of 


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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 will be determined in line with International Committee of Medical Journal Editors 
authorship requirements. 
11.6. 
Study and Site Closure 
The sponsor or 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, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator 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. 
• Discontinuation of further study treatment development. 


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12. 
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Lipson E, Tawbi HA, Schadendorf D, et al. Relatlimab (RELA) plus nivolumab (NIVO) versus 
NIVO in first-line advanced melanoma: primary phase III results from RELATIVITY-047 
(CA224-047). J Clin Oncol 2021;39(suppl):Abstract 9503. 
Liu K, Zhao K, Wang L, Sun E. The prognostic values of tumor-infiltrating neutrophils, 
lymphocytes and neutrophil/lymphocyte rates in bladder urothelial cancer. Pathol Res Pract 
2018;214:1074-1080. 
Long GV, Dummer R, Hamid O, et al. Epacadostat plus pembrolizumab versus placebo plus 
pembrolizumab in patients with unresectable or metastatic melanoma 
(ECHO-301/KEYNOTE-252): a Phase 3, randomised, double-blind study. Lancet Oncol 
2019;20:1083-1097. 
Magers MJ, Lopez‐Beltran A, Montironi R, Williamson SR, Kaimakliotis HZ, Cheng L. Staging 
of bladder cancer. Histopathology 2019;74:112-134. 
Maio M, Schenker M, Medioni J, et al. Phase 2 study of retifanlimab (INCMGA00012) in 
patients (pts) with selected solid tumors (POD1UM-203). J Clin Oncol 
2021;39(suppl):Abstract 2571. 
Mehnert J, Joshua A, Lakhani N, et al. First-in-human Phase 1 study of INCMGA00012 in 
patients with advanced solid tumors: interim results of the cohort expansion phase. J Immunother 
Cancer 2018;6(suppl 1):357 [abstr P669]. 


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Mellor AL, Baban B, Chandler P, et al. Cutting edge: induced indoleamine 2,3 dioxygenase 
expression in dendritic cell subsets suppresses T cell clonal expansion. J Immunol 
2003;171:1652-1655. 
Mitropoulos D, Artibani W, Graefen M, Remzi M, Rouprêt M, Truss M; European Association 
of Urology Guidelines Panel. Reporting and grading of complications after urologic surgical 
procedures: an ad hoc EAU guidelines panel assessment and recommendations. Eur Urol 
2012;61:341-349. 
National Comprehensive Cancer Network. National Comprehensive Cancer Network Guidelines 
in Oncology: Bladder Cancer Version 3.2020. 2020. 
Necchi A, Anichini A, Raggi D, et al. Pembrolizumab as neoadjuvant therapy before radical 
cystectomy in patients with muscle-invasive urothelial bladder carcinoma (PURE-01): an 
open-label, single-arm, Phase II study. J Clin Oncol 2018;36:3353-3360. 
Ngiow SF, von Scheidt B, Akiba H, Yagita H, Teng MW, Smyth MJ. Anti-TIM3 antibody 
promotes T cell IFN-γ-mediated antitumor immunity and suppresses established tumors. Cancer 
Res 2011;71:3540-3551. 
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol 1982;5:649-655. 
Park JC, Gandhi NM, Carducci MA, et al. A retrospective analysis of the effect on survival of 
time from diagnosis to neoadjuvant chemotherapy to cystectomy for muscle invasive bladder 
cancer. J Urol 2016;195:880-885. 
Peguero JA, Bajaj P, Carcereny E, et al. A multicenter, phase II study of soluble LAG-3 
(Eftilagimod alpha) in combination with pembrolizumab (TACTI-002) in patients with advanced 
non-small cell lung cancer (NSCLC) or head and neck squamous cell carcinoma (HNSCC). J 
Clin Oncol 2019;37(suppl 15):TPS2667 [abstr]. 
Poletajew S, Lisiński J, Moskal K, et al. The time from diagnosis of bladder cancer to radical 
cystectomy in Polish urological centres- results of CysTiming Poland study. Cent European J 
Urol 2014;67:329-332. 
Retifanlimab Investigator's Brochure. Wilmington, DE: Incyte Corporation.  
Rosenblatt R, Sherif A, Rintala E, et al. Pathologic downstaging is a surrogate marker for 
efficacy and increased survival following neoadjuvant chemotherapy and radical cystectomy for 
muscle-invasive urothelial bladder cancer. Eur Urol 2012;61:1229-1238. 
Sakuishi K, Apetoh L, Sullivan JM, Blazar BR, Kuchroo VK, Anderson AC. Targeting Tim-3 
and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J Exp Med 
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Sharma P, Shen Y, Wen S, et al. CD8 tumor-infiltrating lymphocytes are predictive of survival 
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Smith M, Newton R, Owens S, et al. Retrospective pooled analysis of epacadostat clinical 
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Spranger S, Koblish HK, Horton B, Scherle PA, Newton B, Gajewski TF. Mechanism of tumor 
rejection with doublets of CTLA-4, PD-1/PD-L1, or IDO blockade involves restored IL-2 
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comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin 
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APPENDIX A. INFORMATION REGARDING EFFECTIVENESS OF 
CONTRACEPTIVE METHODS 
For male participants in the study: 
All male participants must use a condom from screening through 100 days (in the US) and 190 days (in 
Europe) after the end of systemic exposure.  If a male participant has a partner that is of childbearing 
potential, the partner should also use contraception through 100 days (in the US) and 190 days (in 
Europe) after the end of relevant systemic exposure.  In addition, male participants must refrain from 
donating sperm from screening through 100 days (in the US) and 190 days (in Europe) after the end of 
relevant systemic exposure.  Male participants who have had a vasectomy and have received medical 
assessment of the surgical success qualify as having met the requirement for a highly effective birth 
control method. 
For female participants in the study: 
From screening through 100 days (in the US) and 190 days (in Europe) after the last dose of study 
treatment, women of childbearing potential must have a negative pregnancy test at screening and 
before the first dose of study treatment on Day 1, must agree to take appropriate precautions to avoid 
pregnancy (with at least 99% certainty), and refrain from oocyte donation.   
The following methods that can achieve a failure rate of < 1% per year when used consistently and 
correctly are considered as highly effective birth control methods: 
• 
Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation 
− 
oral 
− 
intravaginal 
− 
transdermal 
• 
Progestogen-only hormonal contraception associated with inhibition of ovulation 
− 
oral 
− 
injectable 
− 
implantablea 
• 
Intrauterine devicea 
• 
Intrauterine hormone-releasing systema 
• 
Bilateral tubal occlusiona 
• 
Vasectomized partnerb 
• 
Sexual abstinencec 
Note: Hormonal contraception may be susceptible to interaction with study drugs, which may 
render hormonal contraception ineffective, and hormonal methods are not methods that can 
achieve in this study a failure rate of < 1% per year. 
Note:  Female participants should also refrain from oocyte donation through 100 days (in US) and 190 days (in 
Europe) after the last dose of study treatment. 
a Contraception methods that in the context of this guidance are considered to have low user dependency. 
b Vasectomized partner is a highly effective method of avoiding pregnancy provided that partner is the sole sexual 
partner of the woman of childbearing potential study participant and that the vasectomized partner has received 
medical assessment of the surgical success. 
c In the context of this guidance, 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 treatments.  The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the 
preferred and usual lifestyle of the participant. 
Source:  Clinical Trials Facilitation and Coordination Group 2020. 


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APPENDIX B. THE AMERICAN JOINT COMMITTEE ON CANCER 
STAGING SYSTEM 8TH EDITION, 2017 
Primary tumour (T) 
TX 
Primary tumour cannot be assessed 
T0 
No evidence of primary tumour 
Ta 
Non‐invasive papillary carcinoma 
Tis 
Carcinoma in situ: 'flat tumour'  
T1 
Tumour invades subepithelial connective tissue 
T2 
Tumour invades muscularis propria 
pT2a Tumour invades superficial muscularis propria (inner half) 
pT2b Tumour invades deep muscularis propria (outer half) 
T3 
Tumour invades perivesical tissue 
pT3a Microscopically 
pT3b Macroscopically (extravesical mass) 
T4 
Tumour invades any of the following:  prostatic stroma, seminal vesicles, uterus, vagina, 
pelvic wall, abdominal wall 
T4a 
Tumour invades prostatic stroma, uterus, vagina 
T4b 
Tumour invades pelvic wall, abdominal wall 
Regional lymph nodes (N) 
NX 
Lymph nodes cannot be assessed 
N0 
No lymph node metastasis 
N1 
Single regional lymph node metastasis in the true pelvis (hypogastric, obturator, external 
iliac or presacral lymph node) 
N2 
Multiple regional lymph node metastasis in the true pelvis (hypogastric, obturator, external 
iliac or presacral lymph node metastasis) 
N3 
Lymph node metastasis to the common iliac lymph nodes 
Distant metastasis (M) 
M0 
No distant metastasis 
M1 
Distant metastasis 
 


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APPENDIX C. CRITERIA DEFINING CISPLATIN INELIGIBILITY 
Proposed Working Group Eligibility Criteria for Clinical Trials Enrolling Patients With 
Metastatic Urothelial Carcinoma "Unfit" for Cisplatin-Based Chemotherapy 
Eligibility Criteria (at least 1 of the following): 
WHO or ECOG PS of 2 or Karnofsky PS of 60%-70% 
Creatinine clearance (calculated or measured) < 60 mL/min 
CTCAE v4 ≥ Grade 2 audiometric hearing loss 
CTCAE v4 ≥ Grade 2 peripheral neuropathy 
NYHA Class III heart failure 
Source:  Galsky et al 2011. 


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APPENDIX D. CLAVIEN-DINDO GRADING SYSTEM FOR THE 
CLASSIFICATION OF SURGICAL COMPLICATIONS 
Grades 
Definitions 
I 
Any deviation from the normal postoperative course without the need for pharmacologic 
treatment or surgical, endoscopic, and radiologic interventions.  Acceptable therapeutic 
regimens are drugs such as antiemetics, antipyretics, analgesics, diuretics, and 
electrolytes, and physiotherapy.  This grade also includes would infections opened at the 
bedside.  
II 
Requiring pharmacologic treatment with drugs other than those allowed for Grade 1 
complications.  Blood transfusions and total parental nutrition are also included.  
III 
Requiring surgical, endoscopic, or radiologic intervention. 
IIIa 
Intervention not under general anaesthesia. 
IIIb 
Intervention under general anaesthesia. 
IV 
Life-threatening complication (including central nervous system complications; brain 
haemorrhage, ischaemic stroke, subarachnoid bleeding but excluding transient ischaemic 
attacks) requiring intermediate care/intensive care unit management.  
IVa 
Single-organ dysfunction (including dialysis).  
IVb 
Multiorgan dysfunction. 
V 
Death of a patient. 
Suffix "d" 
If the patient suffers from a complication at the time of discharge, the suffix "d" (for 
disability) is added to the respective grade of complication.  This label indicates the need 
for a follow-up to evaluation the complication fully.  
Source:  Dindo et al 2004. 
 


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APPENDIX E. STUDIES AND PARTICIPANT GROUPS INCLUDED IN SAFETY ANALYSIS 
Below is a brief overview of the studies and treatment groups included for the analysis of safety in support of Protocol 
INCB 24360-901. 
Study Drug 
Study Number 
Title 
Treatment Groups Included 
Participant Groups 
Epacadostat 
INCB 24360-101 
A Phase I, Open-Label, Dose-Escalation Study to Determine the 
Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of 
INCB024360 in Patients with Advanced Malignancies 
1) INCB024360 50 mg QD 
2) INCB024360 50 mg BID 
3) INCB024360 100 mg BID 
4) INCB024360 300 mg BID 
All participants who 
received at least 1 dose of 
INCB024360 
INCB 24360-210 
A Randomized, Open-Label, Phase 2 Study of the IDO inhibitor 
INCB024360 versus Tamoxifen for Subjects with 
Biochemical-Recurrent-Only Epithelial Ovarian Cancer, Primary 
Peritoneal Carcinoma, or Fallopian Tube Cancer Following 
Complete Remission with First-Line Chemotherapy 
1) INCB024360 600 mg BID 
All participants who 
received at least 1 dose of 
INCB024360 
INCB 24360-303 
A Phase 3 Randomized, Double-Blind Clinical Study of 
Pembrolizumab + Epacadostat vs Pembrolizumab + Placebo as a 
Treatment for Recurrent or Progressive Metastatic Urothelial 
Carcinoma in Patients who have Failed a First-Line 
Platinum-containing Chemotherapy Regimen for 
Advanced/Metastatic Disease 
1) INCB024360 100 mg BID + 
pembrolizumab 200 mg IV Q3W 
All participants who 
received at least 1 dose of 
INCB024360 as a 
monotherapy or in 
combination with  
pembrolizumab 
INCB 24360-307 
A Phase 3 Randomized, Double- blind Trial of Pembrolizumab 
(MK-3475) in Combination with Epacadostat (INCB024360) or 
Placebo in Participants with Cisplatin ineligible Urothelial 
Carcinoma 
1) INCB024360 100 mg BID + 
pembrolizumab 200 mg IV Q3W 
All participants who 
received at least 1 dose of 
INCB024360 as a 
monotherapy or in 
combination with 
pembrolizumab 
Retifanlimab 
INCMGA 0012-101 
A Phase 1 Study of the Safety, Tolerability, and Pharmacokinetics 
of INCMGA00012 (Formerly MGA012) in Patients With 
Advanced Solid Tumors 
1) INCMGA00012 3 mg/kg Q2W 
2) INCMGA00012 3 mg/kg Q4W 
3) INCMGA00012 10 mg/kg Q2W 
4) INCMGA00012 10 mg/kg Q4W 
5) INCMGA00012 375 mg Q3W 
4) INCMGA00012 500 mg Q4W 
4) INCMGA00012 750 mg Q4W 
All participant who 
received at least 1 dose of 
INCMGA00012 
underweight-based dosing 
or flat-dosing schemes 


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Study Drug 
Study Number 
Title 
Treatment Groups Included 
Participant Groups 
INCMGA 0012-102 
A Phase 1b Study of INCMGA00012 in Combination With Other 
Therapies in Patients With Advanced Solid Tumors 
1) INCMGA00012 500 mg Q4W + 
INCB24360 50 mg BID 
2) INCMGA00012 500 mg Q4W + 
INCB24360 100 mg BID 
3) INCMGA00012 500 mg Q4W + 
INCB24360 300 mg BID 
4) INCMGA00012 500 mg Q4W + 
INCB24360 400 mg BID 
5) INCMGA00012 500 mg Q4W + 
INCB24360 600 mg BID 
6) INCMGA00012 500 mg Q4W + 
INCB24360 900 mg BID 
7) INCMGA00012 500 mg Q4W + 
INCB24360 1200 mg BID 
All participants who 
received at least 1 dose of 
INCMGA00012 as a 
monotherapy or in 
combination with 
INCB24360 
INCMGA 0012-201 
A Phase 2 Study of INCMGA00012 in Participants With Metastatic 
Merkel Cell Carcinoma 
1) INCMGA00012 500 mg Q4W 
All participants who 
received at least 1 dose of 
INCMGA00012 
INCMGA 0012-202 
A Phase 2 Study of INCMGA00012 in Participants With Squamous 
Carcinoma of the Anal Canal Who Have Progressed Following 
Platinum-Based Chemotherapy 
1) INCMGA00012 500 mg Q4W 
All participants who 
received at least 1 dose of 
INCMGA00012 
INCMGA 0012-203 
A Phase 2 Study of INCMGA00012 (PD-1 Inhibitor) in Participants 
With Selected Solid Tumors (POD1UM-203) 
1) INCMGA00012 500 mg Q4W 
All participants who 
received at least 1 dose of 
INCMGA00012 
INCAGN02385 INCAGN 2385-101 
A Safety and Tolerability Study of INCAGN02385 in Select 
Advanced Malignancies 
INCAGN02385 25 mg Q2W 
INCAGN02385 75 mg Q2W 
INCAGN02385 250 mg Q2W 
INCAGN02385 350 mg Q2W 
INCAGN02385 750 mg Q2W 
All participants who 
received at least 1 dose of 
INCAGN02385 
INCAGN02390 INCAGN 2390-101 
A Safety and Tolerability Study of INCAGN02390 in Select 
Advanced Malignancies 
INCAGN02390 10 mg Q2W 
INCAGN02390 30 mg Q2W 
INCAGN02390 100 mg Q2W 
INCAGN02390 200 mg Q2W 
INCAGN02390 400 mg Q2W 
INCAGN02390 800 mg Q2W 
INCAGN02390 1600 mg Q2W 
All participants who 
received at least 1 dose of 
INCAGN02390 


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Study Drug 
Study Number 
Title 
Treatment Groups Included 
Participant Groups 
Retifanlimab 
INCAGN02385 
INCAGN02390 
INCAGN 2385-201 
Study of Combination Therapy With INCMGA00012 (Anti-PD-1), 
INCAGN02385 (Anti-LAG-3), and INCAGN02390 (Anti-TIM-3) 
in Participants With Select Advanced Malignancies 
Part 1:  INCAGN02385 Q2W plus 
INCAGN02390 Q2W 
Part 2:  INCAGN02385 Q2W plus 
INCAGN02390 Q2W plus 
retifanlimab 500 mg Q4W 
All participants who 
received at least 1 dose of 
INCAGN02385 and 
INCAGN02390 in Part 1 
and all participants who 
received at least 1 dose of 
INCAGN02385, 
INCAGN02390, and 
retifanlimab in Part 2 
QD = once daily; BID = twice daily; IV = intravenous; Q3W = every 3 weeks; Q4W = every 4 weeks. 


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APPENDIX F. CYP1A2, CYP2C8, AND CYP2C19 SUBSTRATES OR 
OATP1B1 AND OATP1B3 TRANSPORTERS  
The medications listed below are prohibited for participants receiving doses of epacadostat 
≥ 600 mg BID, and alternatives should be sought.  If alternatives cannot be found, the medical 
monitor should be contacted to discuss whether enrollment is appropriate. 
OATP1B1 and 
OATP1B3 Transporters 
CYP1A2 Substrates 
CYP2C8 Substrates 
CYP2C19 Substrates 
• 
Atorvastatin 
• 
Bosentan 
• 
Cerivastatin 
• 
Danoprevir 
• 
Docetaxel 
• 
Fexofenadine 
• 
Glyburide 
• 
Nateglinide 
• 
Paclitaxel 
• 
Repaglinide 
• 
Pitavastatin 
• 
Pravastatin 
• 
Rosuvastatin 
• 
Simvastatin acid 
• 
Fimasartan 
• 
Glecaprevir 
• 
Maraviroc 
• 
Tacrolimus 
• 
Voxilaprevir 
Sensitive: 
• Alosetron 
• Caffeine 
• Duloxetine 
• Melatonin 
• Pirfenidone 
• Ramelteon 
• Selegiline 
• Tacrine 
• Tasimelteon 
• Theophylline 
• Tizanidine 
Sensitive: 
• Repaglinide 
• Daprodustat 
• Dasabuvir 
• Montelukast 
• Pioglitazone 
• Rosiglitazone 
Sensitive: 
• S-mephenytoin 
• Lansoprazole 
• Omeprazole 
• Tilidine 
• Pantoprazole 
• Hexobarbital 
• Diazepam 
• Gliclazide 
• Rabeprazole 
• Voriconazole 
• Proguanil 
 
 


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APPENDIX G. COVID-19 PANDEMIC MITIGATION STRATEGIES AND 
INSTRUCTION 
The COVID-19 global pandemic presents challenges to the ongoing conduct of clinical trials.  In 
line with regulatory guidance regarding clinical trial execution during the pandemic, the sponsor 
has issued the following Protocol considerations to ensure participant safety is maintained and 
adequate benefit/risk analyses are applied relative to the completion of study procedures and 
maintaining the investigational product supply chain. 
Recognizing the dynamic nature and flexibility required to manage the impact of the pandemic 
on this clinical trial, additional details will be incorporated into respective study manuals and 
site-specific monitoring plans as applicable, with institutional requirements as warranted, and 
communicated to the investigative sites as needed.  Relevant test results will be documented in 
the eCRF, and applicable changes to the ICF will be made and monitored.  
Study Site Visits 
If local travel restrictions, isolation requirements, or the investigator's benefit/risk assessment 
determines it to be unsafe for participants to attend study visits at the investigational site, the site 
staff may elect to pursue the following: 
• In order to minimize participant risk, study visits may be conducted via telemedicine 
modalities (phone or video) or as per site institutional guidelines.  At a minimum, a 
review of AEs and concomitant medications must be completed.  On-site visits 
should be conducted whenever feasible and are required for administration of study 
treatment.  The participant may also be asked to undergo additional safety laboratory 
assessments. 
• In order to support investigator oversight of participant safety and disease 
management, the participant may be asked to undergo some laboratory tests or study 
procedures at a local laboratory or facility closer to the participant's residence rather 
than at the investigational site.  In this case, the study physician will provide the 
participant with the list of parameters to be checked.  These tests should be performed 
in certified laboratories. 
• Some tests, such as ECG or CT scan assessments, may require longer windows due to 
the COVID-19 pandemic and may be performed outside the regularly scheduled visit 
window or may be conducted at the next scheduled visit.  It is the investigator's 
responsibility to check with the facility (if performed at a different facility) that the 
data will be obtained and available for evaluation.  General procedures performed 
outside of protocol parameters will be captured as protocol deviations due to 
COVID-19 in the eCRF.    
Participant SARS-CoV-2 Infection and Study Treatment 
An event of active SARS-CoV-2 infection by a participant in the study should be reported as an 
AE or SAE and appropriate medical intervention provided.  For participants with active 
SARS-CoV-2 infection, study treatment should be delayed until the resolution of symptoms and 
until it is allowable for the participant to return to the clinic per institutional guidelines.  Prior to 
restarting treatment, the participant should be afebrile for 72 hours and the treating physician 


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should determine that the participant's condition is stable enough to resume study treatment.  The 
study physician should also consider if the participant is SARS-CoV-2 negative (by test) before 
restarting study treatment if COVID-19 was diagnosed during the trial.  The study team should 
be notified when the study treatment is restarted.  Safety monitoring following COVID-19 
should be implemented as per institutional guidance or clinical judgment (eg, coagulation 
factors).   
COVID-19 Vaccination 
Participants may receive the COVID-19 vaccine as long as it is not a live vaccine, which is 
prohibited per protocol (see Section 5.2, Exclusion Criterion 20).  COVID-19 vaccination will be 
captured in the eCRF as a concomitant medication.  Administration of study treatment may be 
delayed to ensure vaccination is completed.   
Clinical Trial Monitoring 
Study monitoring visits could be postponed; however, the site monitor and sponsor will continue 
to employ off-site monitoring practices such as routine communication methods (eg, phone calls, 
emails, video visits) with the sites to get information on trial progress, participant status, and 
information on issue resolution.  The study monitor may remotely review data entered into the 
EDC for accuracy and completeness if allowed by the national regulatory body, investigational 
site, and/or in compliance with local authorities.   
Reimbursement of Additional Expenses 
The sponsor will reimburse for any extraordinary expenses, keeping appropriate documentation 
as evidence (eg, travel expenses for the local laboratory visit(s), the costs of local [proximate] 
laboratory tests). 


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APPENDIX H. PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Document 
Date 
Amendment 1: 
04 SEP 2020 
Amendment 2:  
02 FEB 2021 
Amendment 3: 
10 MAY 2021 
Amendment 2-IT: 
14 JUL 2021 
Amendment 4: 
01 MAR 2022 
Amendment 4 (01 MAR 2022) 
 
Overall Rationale for the Amendment: 
 
The primary purpose of this amendment is to add 2 new treatment groups to the Protocol 
(retifanlimab plus INCAGN02385 as well as retifanlimab plus INCAGN02385 plus 
INCAGN02390) and to clarify the radiologic tools used for tumor imaging. 
1. Section 1, Protocol Summary (Table 2:  Key Study Design Elements) 
Description of change:  Revised the number of evaluable participants, the number of 
treatment groups, and the number of participants in each treatment group. 
Rationale for change:  To provide updated information based on the addition of 2 new 
treatment groups. 
2. Section 1, Protocol Summary (Table 2:  Key Study Design Elements; Figure 1:  
Study Design Schema; Table 6:  Schedule of Activities for Participants Receiving 
Retifanlimab Plus INCAGN02385 [Treatment Group D]; Table 7:  Schedule of 
Activities for Participants Receiving Retifanlimab Plus INCAGN02385 Plus 
INCAGN02390 [Treatment Group E]; Section 2.1.1, Scientific Rationale for Study 
Design; Section 2.1.2, Treatment Group Rationale; Section 2.1.6, INCAGN02385; 
Section 2.1.6.1, Rationale for INCAGN02385 Dose; Section 2.1.7, INCAGN02390;  
Section 2.1.7.1, Rationale for INCAGN02390 Dose; Section 2.1.8, Combination of 
Retifanlimab Plus INCAGN02385; Section 2.1.9, Combination of Retifanlimab Plus 
INCAGN02385 Plus INCAGN02390; Section 2.1.10, Combination of Retifanlimab 
Plus INCAGN02385 and Combination of Retifanlimab Plus INCAGN02385 Plus 
INCAGN02390; Section 2.2.1, Monotherapy Risks; Section 2.2.2, Combination 
Therapy Risks; Section 2.2.3.1.2, INCAGN02385 and INCAGN02390 Monotherapy 
and in Combination With Retifanlimab (Table 10:  Grade 2 or Higher 
Immune-Related TEAEs for Studies With INCAGN02385, INCAGN02390, and 
Retifanlimab); Section 2.2.4, Benefits; Section 3, Objectives and Endpoints 
(Table 10:  Objectives and Endpoints); Section 4.1, Overall Design; Section 5.2, 
Exclusion Criteria; Section 5.5, Replacement of Participants; Section 6.1, Study 
Treatment Administered (Table 13:  Study Treatment and Treatment Group 
Information); Section 6.2, Handling, Preparation, and Accountability; Section 6.3, 
Measures to Minimize Bias:  Randomization and Blinding; Section 6.4, Study 
Treatment Compliance; Section 6.5, Dose Modifications; Section 8.4, 


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 Immunogenicity Assessments; Section 8.4.1.1, 
Immunogenicity (Antidrug Antibody) Assessments; Section 9.4, Reporting of Serious 
Adverse Events; Section 9.8, Warnings and Precautions; Section 10.1, Sample Size 
Determination; Appendix E, Studies and Participant Groups Included in Safety 
Analysis 
Description of change:  Added information on retifanlimab, INCAGN02385, and 
INCAGN02390. 
Rationale for change:  To incorporate the 2 new treatment groups into the Protocol.   
3. Section 1, Protocol Summary (Table 3:  Schedule of Activities for Participants 
Receiving Epacadostat Plus Retifanlimab [Treatment Group A]; Table 4:  Schedule 
of Activities for Participants Receiving Retifanlimab Monotherapy [Treatment 
Group B]; Table 5:  Schedule of Activities for Participants Receiving Epacadostat 
Monotherapy [Treatment Group C]) 
Description of change:  Added that treatment cycle is Q4W, revised radiologic tumor 
assessments to remove PET/CT and change wording to "CT/MRI of the abdomen and 
pelvis and CT scan of the thorax (RECIST v1.1)," 
 
 
Rationale for change:  To clarify the duration of a treatment cycle, update the criteria 
for imaging for MIBC, 
  
4. Section 1, Protocol Summary (Table 3:  Schedule of Activities for Participants 
Receiving Epacadostat Plus Retifanlimab [Treatment Group A]; Table 4:  Schedule 
of Activities for Participants Receiving Retifanlimab Monotherapy [Treatment 
Group B]; Table 5:  Schedule of Activities for Participants Receiving Epacadostat 
Monotherapy [Treatment Group C]; Section 8.3.5, Laboratory Assessments 
(Table 18:  Required Laboratory Analytes); Section 8.3.5.1, Pregnancy Testing 
Description of change:  Revised pregnancy testing so women of childbearing potential 
only require a serum test at screening and at precystectomy.  A urine or serum pregnancy 
test is required before cystectomy, before the first dose on D1 of every cycle, and at the 
30-day safety follow-up visit; in Europe, a urine or serum pregnancy test is also required 
190 days after the last dose of study treatment.  Pregnancy tests (serum or urine) should 
be repeated if required by local regulations.   
Rationale for change:  Discrepancy in the language for pregnancy testing requirements 
within the sections and pregnancy testing requirement in Europe. 
5. Section 1, Protocol Summary (Table 4:  Schedule of Activities for Participants 
Receiving Retifanlimab Monotherapy [Treatment Group B]; Section 8.1.4, 
Distribution of Reminder Cards 
Description of change:  Added information on distribution of reminder cards.  
Rationale for change:  Clarification. 


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6. Section 2.1.3, Retifanlimab; Section 2.1.3.1, Rationale for Retifanlimab Dose; 
Section 2.1.4, Epacadostat; Section 2.1.4.1, Rationale for Epacadostat Dose; 
Section 2.1.5, Combination of Epacadostat Plus Retifanlimab; 2.2.1.1, Retifanlimab; 
Section 2.2.1.2, Epacadostat; Section 2.2.2.1, Epacadostat and Retifanlimab  
Description of change:  Updated rationale for treatment as well as dose finding for 
retifanlimab, epacadostat, and the combination of retifanlimab and epacadostat. 
Rationale for change:  To provide updated information from the IB and simplify the 
information in the Protocol. 
7. Section 2.1.1, Scientific Rationale for Study Design; Section 8.5.1, Timing of 
Assessments  
Description of change:  Removed PanCK as part of the description of the multiplex IHC 
assay utilized in this study. 
Rationale for change:  To correct information on the multiplex assay utilized. 
8. Section 2.2.3, Risks of Delayed Cystectomy; Section 2.2.3.1, Treatment-Emergent 
Adverse Events of Special Interest; Section 2.2.3.1.2, INCAGN02385 and 
INCAGN02390 Monotherapy and in Combination With Retifanlimab; Section 6.5.6, 
Criteria for Permanent Discontinuation of Study Drug 
Description of change:  Timeline for delay in radical cystectomy changed from 
> 12 weeks from TURBT to > 11 weeks from end of neoadjuvant chemotherapy.   
Rationale for change:  Supportive data demonstrate that a compromise in patient 
outcome occurs if those with no neoadjuvant treatment have delays > 12 weeks from 
TURBT and those with neoadjuvant treatment have delays > 11 weeks from end of 
treatment. 
9. Section 4.1, Overall Design  
Description of change:  Clarified that PD-L1 testing will be done centrally and not 
locally. 
Rationale for change:  Administrative correction. 
10. Section 4.1, Overall Design; Section 6.3, Measures to Minimize Bias:  
Randomization and Blinding 
Description of change:  Changed randomization to 2:2:1:2:2. 
Rationale for change:  Addition of treatment groups. 
11. Section 5.1, Inclusion Criteria (Criteria 5 and 7) 
Description of change:  Revised Criterion 5 to include "refuse cisplatin therapy (does 
not apply in France)" and removed Criterion 7 (residual disease after TURBT [eg, 
surgical opinion, cystoscopy or radiologic presence]).  
Rationale for change:  Clarification and the presence of residual disease will be 
documented but not as a mandatory inclusion criterion.  


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12. Section 5.1, Inclusion Criteria (Criterion 10); Appendix A, Information Regarding 
Effectiveness of Contraceptive Methods 
Description of change:  Clarified that pregnancy/fathering children should be avoided 
through 100 days after the last dose of study drug in the US and 190 days after the last 
dose in Europe. 
Rationale for change:  Updated CTFG requirements. 
13. Section 5.2, Exclusion Criteria (Table 12:  Exclusionary Laboratory Values) 
Description of change:  Removed neutrophil lymphocyte ratio from exclusionary 
laboratory values, modified the hemoglobin exclusion criterion from < 9 to < 8 g/dL, and 
incorporated the monoclonal antibody as well as the epacadostat exclusion criteria to 
apply to the entire study population. 
Rationale for change:  Neutrophil lymphocyte ratio was deemed unnecessary, the 
criteria for hemoglobin exclusion was changed to < 8 g/dL per advice from investigators, 
and incorporating the exclusion criteria was deemed a safer option for participants and 
allows for streamlined screening.   
14. Section 5.2, Exclusion Criteria (Table 12:  Exclusionary Laboratory Values); 
Section 6.5.3, Procedures for Participants Exhibiting Immune-Related Adverse 
Events (Table 15:  Dose Modification and Toxicity Management Guidelines for 
Immune-Related Adverse Events); Section 8.3.5, Laboratory Assessments (Table 18:   
Required Laboratory Analytes) 
Description of change:  Added troponin I and T exclusionary values and management. 
Rationale for change:  Monitoring and management of troponin I and T values with 
INCAGN02385 and INCAGN02390. 
15. Section 5.6, Data Safety Monitoring Board 
Description of change:  Added language on DSMB evaluation for all treatment groups 
and specific information for epacadostat-containing arms. 
Rationale for change:  Clarification. 
16. Section 6.5, Dose Modifications; Section 6.5.1.2, Epacadostat  
Description of change:  Revised dose modification parameters for the epacadostat 
treatment groups. 
Rationale for change:  Clarification on starting dose options and dose modification with 
epacadostat alone or in combination with retifanlimab. 
17. Section 6.5.2, Management of Suspected Infusion Reactions (Table 14:  Guidelines 
for Management of Suspected Infusion Reactions) 
Description of change:  Revised description of Grade 1 reaction and added option to not 
discontinue study treatment permanently in a participant with Grade 3 or 4 reaction if the 
participant responds to symptomatic therapy or brief interruption of infusion. 
Rationale for change:  Clarification and to provide an option to not permanently 
discontinue therapy in some participants with infusion reactions. 


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18. Section 6.5.3, Procedures for Participants Exhibiting Immune-Related Adverse 
Events (Table 15:  Dose Modification and Toxicity Management Guidelines for 
Immune-Related Adverse Events) 
Description of change:  Updated Table 15 to reflect updated guidelines. 
Rationale for change:  To update guidelines on management of irAEs. 
19. Section 6.5.4, Procedures for Participants Exhibiting Drug-Related, 
Non–Immune-Related Adverse Events (Table 16:  Management Guidelines for 
Drug-Related, Non–Immune-Related Adverse Events) 
Description of change:  Added information on non-irAEs for all treatment groups. 
Rationale for change:  Clarification on management of non-irAEs. 
20. Section 6.6.2, Restricted Medications and Procedures; Section 6.6.3, Prohibited 
Medications and Procedures; Appendix F, CYP1A2, CYP2C8, and CYP2C19 
Substrates or OATP1B1 and OATP1B3 Transporters 
Description of change:  Added restricted and prohibited medications for epacadostat 
treatment groups. 
Rationale for change:  To update restricted and prohibited medications. 
21. Section 6.6.3, Prohibited Medications and Procedures; Appendix F, CYP1A2, 
CYP2C8, and CYP2C19 Substrates or OATP1B1 and OATP1B3 Transporters 
Description of change:  Removed reference to CYP3A4 inhibitors and inducers and 
moderate CYP3A4 inducers. 
Rationale for change:  Current treatments in the protocol do not have an effect on 
CYP3A4. 
22. Section 8.1.1, Informed Consent Process 
Description of change:  Changed the consent to a prescreen consent and a screen 
consent for all treatment arms. 
Rationale for change:  To simplify the informed consent and screening process. 
23. Section 8.1.3, Interactive Response Technology Procedure 
Description of change:  Added text that site staff will enter PD-L1 CPS status into the 
IRT during screening and that participants who do not meet inclusion/exclusion criteria 
will fail screening. 
Rationale for change:  Clarification on when entry of PD-L1 CPS status needs to take 
place.  


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24. Section 8.3.5, Laboratory Assessments (Table 18:  Required Laboratory Analytes) 
Description of change:  Removed amino acid panel, removed the phrase "only 
applicable for participants known to be HIV-positive" for HIV screening and 
management, clarified use of either blood urea nitrogen or urea, added HCO3 if clinically 
indicated, and added microscopic examination under urinalysis if blood or protein is 
abnormal. 
Rationale for change:  To remove unnecessary amino acid panel, correct an 
administrative error, and clarify additional laboratory analytes needed.   
25. Section 8.4, 
 Immunogenicity Assessments 
Description of change:  Added clear liquids to be acceptable for fasting state. 
Rationale for change:  To clarify what can be consumed if a participant is fasting. 
26. 
  
  
 
 
27. Section 8.5.2, Tissue Biopsy Collection Requirements  
Description of change:  Added information on biopsy collection for cystectomy.  
Rationale for change:  Clarification.  
28. Section 8.7, End of Treatment and/or Early Termination 
Description of change:  Changed EOT visit to precystectomy visit and stated that if the 
treatment visit is same as the precystectomy visit due to cystectomy being performed 
within 2 weeks of the treatment visit, then evaluations for both the treatment visit and the 
precystectomy visit should be conducted.     
Rationale for change:  Clarified that the precystectomy visit can act as the EOT and 
associated evaluations for both the treatment visit and the precystectomy visit can be 
performed at the same time if cystectomy is within 2 weeks of the treatment visit.     
29. Section 10, Statistics 
Description of change:  Deleted sections on 
 immunogenicity analysis. 
Rationale for change:  Sample collection and details on both 
/pharmacodynamics 
and immunogenicity are described in Section 8.4.  They are not part of secondary or 
formal 
 analyses, and description of statistics is not required. 
30. Section 10.1, Sample Size Determination 
Description of change:  Added the 2 new treatment groups, updated the total number of 
participants, and added that the power calculation is > 95% at a 2-sided alpha level of 
0.01. 
Rationale for change:  Addition of the 2 new treatment groups and clarity. 


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31. Section 10.2, Populations for Analysis (Table 23:  Populations for Analysis) 
Description of change:  Separated pharmacodynamic analysis from 
. 
Rationale for change:  To clarify that both 
 pharmacodynamic analyses will be 
conducted.   
32. Appendix B, CYP Inhibitors and Inducers 
Description of change:  Deleted appendix. 
Rationale for change:  No longer needed. 
33. Incorporation of administrative changes.  Other minor, administrative changes have 
been incorporated throughout the Protocol and are noted in the redline version of the 
amendment. 


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Amendment 2-IT (14 JUL 2021) 
Overall Rationale for the Amendment:  
The primary purpose of this amendment is to address Health Authority comments.   
1. Section 5.1, Inclusion Criteria; Section 8.3.5, Laboratory Assessments (Table 15:  
Required Laboratory Analytes); Appendix A, Information Regarding Effectiveness 
of Contraceptive Methods 
Description of change:  Extended contraceptive treatment to 5 half-lives in men and 
women, corresponding to 190 days. 
Rationale for change:  Modification in accordance with 2020 Clinical Trials Facilitation 
and Coordination Group guidance. 
2. Section 6.5.3, Procedures for Participants Exhibiting Immune-Related Adverse 
Events (Table 13:  Dose Modification and Toxicity Management Guidelines for 
Immune-Related Adverse Events) 
Description of change:  Removed mention of participants with liver metastasis. 
Rationale for change:  Participants with metastatic disease are ineligible to participate in 
the study.  
3. Section 6.6.3, Prohibited Medications and Procedures; Appendix B, CYP3A4 
Inhibitors and Inducers 
Description of change:  Removed text and appendix regarding CYP3A4 inhibitors and 
inducers and moderate CYP3A4 inducers. 
Rationale for change:  Not required with current protocol study drugs. 
4. Incorporation of administrative changes.  Other minor, administrative changes have 
been incorporated throughout the Protocol and are noted in the redline version of the 
amendment. 


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Amendment 3 (10 MAY 2021) 
Overall Rationale for the Amendment: 
The primary purpose of this amendment is to address requested comments and changes from the 
French Health Authority Review. 
1. Section 5.1, Inclusion Criteria 
Description of change:  Modified inclusion criteria to remove "Participants who refuse 
cisplatin-based therapy." 
Rationale for change:  This type of criterion is not acceptable for France, as there are 
standard treatments whose efficacy and safety are known. 
2. Section 5.2, Exclusion Criteria 
Description of change:  Added exclusion of participants with a history of allogenic 
tissue/solid organ transplant. 
Rationale for change:  Immunotherapy may be administered to participants on 
immunosuppressants as part of transplant treatment regimen. 
3. Section 6.5.3, Procedures for Participants Exhibiting Immune-Related Adverse 
Events (Table 13, Dose Modification and Toxicity Management Guidelines for 
Immune-Related Adverse Events) 
Description of change:  Modified a more stringent criteria for Grade 2 and Grade 3 or 4 
toxicities for hypophysitis (adrenal insufficiency). 
Rationale for change:  Updates based on recent ESMO guidelines on management of 
hypophysitis or adrenal insufficiency from immunotherapy. 
4. Section 5.1 Inclusion Criteria, Appendix A 
Description of change:  Modified to extend contraceptive treatment to 5 half-lives in 
men and women, corresponding to 190 days. 
Rationale for change:  Modification in accordance with recent recommendations of the 
CTFG 2020 (Clinical Trial Facilitation Group). 
5. Section 5.6, Data Monitoring Committee 
Description of change:  Changed DSMB from independent DSMB to internal DSMB. 
Rationale for change:  Clarification to align with the DSMB charter. 
6. Section 7.1.1, Reasons for Discontinuation 
Description of change:  Added the following as reasons for discontinuation of treatment:  
"Participants with disease progression or not responding to treatment must discontinue 
the trial." 
Rationale for change:  Clarification that participants who have suspected or confirmed 
disease progression or not responding to therapy should discontinue from the study 
treatment. 


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Amendment 2 (02 FEB 2021) 
Overall Rationale for the Amendment: 
The sponsor evaluated its strategy in bladder cancer and made a decision to remove pemigatinib 
from this study.  As such, this amendment removes the 3 treatment groups that contain 
pemigatinib (pemigatinib monotherapy, pemigatinib plus retifanlimab, and pemigatinib followed 
by retifanlimab).  The removal of information on FGFR is reflected throughout the protocol as 
detailed below.  
1. Section 1, Protocol Summary; Section 2.1.1, Scientific Rationale for Study Design; 
Section 3, Objectives and Endpoints; Section 6.3, Measures to Minimize Bias:  
Randomization and Blinding; Section 8.2, Efficacy Assessments; Section 8.5, 
Pharmacodynamic and Translational Assessments; Section 10.1, Sample Size 
Determination; Section 10.4.1, Primary Analysis 
Description of change:  Amended the primary endpoint to change from baseline in 
CD8+ lymphocytes within resected tumor.  
Rationale for change:  There is evidence in the literature (Sharma et al 2007) that 
changes in CD8+ TILs is associated with favorable survival for patients with 
muscle-invasive bladder cancer.  As such, the study will use a multiplex 
CD8/FoxP3/granzyme B/panCK IHC assay to monitor the overall influx and activation 
state of these populations into the tumor.   
2. Section 1, Protocol Summary; Section 2, Introduction; Section 3, Objectives and 
Endpoints; Section 4, Study Design; Section 5, Study Population; Section 6, Study 
Treatment; Section 8, Study Assessments and Procedures; Section 10, Statistics; 
Appendices  
Description of change:  Removed the 3 treatment groups that included pemigatinib as 
well as information on FGFR and revised the estimated number of participants in this 
study. 
Rationale for change:  The sponsor evaluated its strategy in bladder cancer and made a 
decision to remove pemigatinib from this study. 
3. Section 1, Protocol Summary (Table 3:  Schedule of Activities for Participants 
Receiving Epacadostat + Retifanlimab [Treatment Group A]; Table 4:  Schedule of 
Activities for Participants Receiving Retifanlimab Monotherapy [Treatment Group 
B]; Table 5:  Schedule of Activities for Participants Receiving Epacadostat 
Monotherapy [Treatment Group C]; Section 8.1.2, Screening Procedures; Section 
8.5.2, Tissue Biopsy Collection Requirements 
Description of change:  Clarified that all pretreatment biopsies for PD-L1 testing 
 
s will be from the initial TURBT procedure only and not a mix of 
archival biopsies or those from the TURBT procedure. 
 
 
 


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4. Section 1, Protocol Summary (Table 3:  Schedule of Activities for Participants 
Receiving Epacadostat + Retifanlimab [Treatment Group A]; Table 4:  Schedule of 
Activities for Participants Receiving Retifanlimab Monotherapy [Treatment Group 
B]; Table 5:  Schedule of Activities for Participants Receiving Epacadostat 
Monotherapy [Treatment Group C]; Section 8.5.2, Tissue Biopsy Collection 
Requirements 
Description of change:  Removed the need for flash-frozen biopsy from pretreatment 
tissue biopsy samples and made it optional for sites.  
Rationale for change:  In discussion with clinicians, it appeared to be not feasible to 
obtain a fresh biopsy pretreatment when TURBT had recently been conducted.  As such, 
this requirement was removed.   
4. Section 1, Protocol Summary (Table 3:  Schedule of Activities for Participants 
Receiving Epacadostat + Retifanlimab [Treatment Group A]; Table 4:  Schedule of 
Activities for Participants Receiving Retifanlimab Monotherapy [Treatment Group 
B]; Table 5:  Schedule of Activities for Participants Receiving Epacadostat 
Monotherapy [Treatment Group C]); Section 8.3.5, Laboratory Assessments (Table 
15:  Required Laboratory Analytes) 
Description of change:  Added lipid panel, changed "Endocrine panel" to "Thyroid 
panel," and removed PD-L1 testing. 
Rationale for change:  Lipid panel was added to the SoA for consistency with other 
epacadostat trials.  Endocrine panel was reworded to be more specific to thyroid function 
tests.  The PD-L1 CPS score will be measured centrally and thus does not need to be 
included in the laboratory assessments because it does not require collection of a specific 
specimen.  
 
 
 
 
 
 
 
 
 
 
 


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8. Section 1, Protocol Summary (Table 3:  Schedule of Activities for Participants 
Receiving Epacadostat + Retifanlimab [Treatment Group A]; Table 4:  Schedule of 
Activities for Participants Receiving Retifanlimab Monotherapy [Treatment Group 
B]; Table 5:  Schedule of Activities for Participants Receiving Epacadostat 
Monotherapy [Treatment Group C]) 
Description of change:  Removed collection of a whole blood sample at screening for 
translational analyses. 
Rationale for change:  A whole blood sample is no longer needed because sufficient 
analyses can be conducted on plasma samples.   
9. Section 2.1.1, Scientific Rationale for Study Design; Section 8.5.1, Timing of 
Assessments 
Description of change:  Revised the text to indicate that this study will use a multiplex 
CD8/FoxP3/granzyme B/panCK IHC assay to monitor the overall influx and activation 
state of these populations into the tumor. 
Rationale for change:  The revision of the primary endpoint to change from baseline in 
CD8+ lymphocytes necessitated a change in the panel to be used to measure the primary 
endpoint as well as other translational endpoints.     
10. 
 
 
 
 
 
    


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7. Section 2.1.6, Rationale for Epacadostat Dose; Section 8.5.2, Tissue Biopsy 
Collection Requirements 
Description of change:  Clarified that flash-frozen biopsy samples will be obtained at 
some sites during TURBT and at all sites during radical cystectomy. 
Rationale for change:  Several centers will have participants who undergo TURBT at a 
different institution and thus will not be able to obtain a flash-frozen biopsy, only 
formalin-fixed, paraffin-embedded slides.  Therefore, obtaining a pretreatment 
flash-frozen biopsy will be optional from sites that perform both TURBT and radical 
cystectomy. 
8. Section 2.2.1.1, Retifanlimab; Section 2.2.2.1, Epacadostat and Retifanlimab 
Description of change:  Updated information on exposure to epacadostat and 
retifanlimab. 
Rationale for change:  Updated information in the Investigator's Brochure of each 
compound from current ongoing trials.   
9. Section 2.2.3.1, Treatment-Emergent Adverse Events of Special Interest (Table 6:  
Summary of TEAOSI for Select Studies With Retifanlimab and Epacadostat That 
Occurred Within the First 12 Weeks of Treatment; Table 7:  Grade 2 or Higher 
Immune-Related TEAEs for Studies With Retifanlimab and Epacadostat [Multiple 
Tumor Types]) 
Description of change:  Updated background information on TEAOSI with retifanlimab 
and epacadostat. 
Rationale for change:  Updated analysis conducted based on data from the latest 
Investigator's Brochure for each compound.  The original analysis was conducted based 
on the previous version of each Investigator's Brochure.   
10. Section 2.2.5, Benefit/Risk Assessment During the COVID-19 Pandemic; Appendix 
H, COVID-19 Pandemic Mitigation Strategies and Instruction 
Description of change:  Added text to address the risk/benefit of participating in this 
study during the COVID-19 pandemic.  Appendix H outlines guidance to sites for 
potential disruptions that may occur during the COVID-19 pandemic. 
Rationale for change:  To provide guidance and instruction to investigators and 
participants for disruptions to the conduct of the study that may occur as a result of the 
COVID-19 pandemic. 
11. Section 4.1, Overall Design; Section 8.5.2, Tissue Biopsy Collection Requirements  
Description of change:  Amended PD-L1 testing to be central testing as opposed to local 
or central testing. 
Rationale for change:  The sponsor wanted to accurately reflect the PD-L1 CPS score 
and minimize potential discordance due to local testing; therefore, all samples will be 
centrally tested for PD-L1 CPS score.    


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14. Section 5.2, Exclusion Criteria (Criterion 14) 
Description of change:  Added criterion to exclude participants with known or suspected 
COVID-19 infection. 
Rationale for change:  Recommendation from clinical advisors to clarify that active or 
suspected infection with COVID-19 should be an exclusion criteria.   
 
 
 
 
.   
16. Incorporation of administrative changes.  Other minor, administrative changes have 
been incorporated throughout the Protocol and are noted in the redline version of the 
amendment. 


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Amendment 1 (04 SEP 2020) 
Overall Rationale for the Amendment: 
The primary purpose of this amendment is to address regulatory comments regarding eligibility 
criteria, secondary objective and endpoints, withdrawal criteria, and study conduct and additional 
feedback from investigators to clarify several error and omissions. 
1. Title Page; Section 1, Protocol Summary (Table 1:  Primary and Secondary 
Objectives and Endpoints; Table 2:  Key Study Design Elements); Section 2.1, Study 
Rationale; Section 3, Objectives and Endpoints (Table 3:  Objectives and 
Endpoints); Section 4.1, Overall Design 
Description of change:  Removed "Cisplatin-Ineligible" from and added "…Who Are 
Cisplatin-Ineligible or Refuse Cisplatin Therapy and…" and added "(Optimus)" to study 
title.  Edited study participants to include those refusing cisplatin therapy. 
Rationale for change:  Clarification that participants who refuse cisplatin therapy are 
also included. 
2. Section 1, Protocol Summary (Table 1:  Primary and Secondary Objectives and 
Endpoints); Section 3, Objectives and Endpoints (Table 11:  Objectives and 
Endpoints); 
 
Description of change:  Added preliminary efficacy as a secondary objective and the 
following as secondary endpoints to Table 1 and Table 11: 
• pCR rate, defined as percentage of participants with ypT0N0 in each treatment group. 
• Major pathological response, defined as residual ypT0/1/a/isN0M0. 
 
 
 
 
 
  


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2. Section 1, Protocol Summary (Table 3:  Schedule of Activities for Participants 
Receiving Pemigatinib Monotherapy [Group A]; Table 4:  Schedule of Activities for 
Participants Receiving Pemigatinib + Retifanlimab [Group B]; Table 5:  Schedule of 
Activities for Participants Receiving Pemigatinib Monotherapy × 2 Weeks Followed 
by Retifanlimab [Group C]; Table 6:  Schedule of Activities for Participants 
Receiving Epacadostat + Retifanlimab [Group D]; Table 7:  Schedule of Activities 
for Participants Receiving Retifanlimab Monotherapy [Group E]; Table 8:  
Schedule of Activities for Participants Receiving Epacadostat Monotherapy 
[Group F]); Section 10.4.2, Secondary Analysis 
Description of change:  Added that major pathological response rates at the time of 
radical cystectomy will be assessed as a secondary endpoint in addition to pathological 
CR rates.  
 
 
 
  Moved Tumor Tissue Sampling from "Other Assessments" 
to "Efficacy Assessments."  Also clarified the tumor tissue requirements in that there will 
be 3 tissue requirements (TURBT archival, screening period, and radical cystectomy) for 
all the treatment groups.   
Rationale for change:  To clarify the analysis of major pathological response.  
3. Section 8.2.1, Pathological Complete Response, Major Pathological Response, 
 
 
Description of change:  Added that major pathological response is defined as residual 
ypT0/1/a/isN0M0 on the basis of histological evaluation of the TURBT and cystectomy 
samples.   
 
Rational for change:  To clarify the definition of major pathological response. 
4. Section 1, Protocol Summary (Table 3:  Schedule of Activities for Participants 
Receiving Pemigatinib Monotherapy [Group A]; Table 4:  Schedule of Activities for 
Participants Receiving Pemigatinib + Retifanlimab [Group B]; Table 5:  Schedule of 
Activities for Participants Receiving Pemigatinib Monotherapy × 2 Weeks Followed 
by Retifanlimab [Group C]; Table 6:  Schedule of Activities for Participants 
Receiving Epacadostat + Retifanlimab [Group D]; Table 7:  Schedule of Activities 
for Participants Receiving Retifanlimab Monotherapy [Group E]; Table 8:  
Schedule of Activities for Participants Receiving Epacadostat Monotherapy [Group 
F]) 
Description of change:  For Treatment Groups A, B, D, E, and F: 
• Added Cycle 3 Day 1, because study treatment is 4 to 10 weeks, allowing for Cycle 3 
to start but not complete a cycle (maximum 2 weeks). 
• Cycle 3 Day 1 assessments are similar to Cycle 2 Day 1 assessments for each 
treatment group.  Also clarified Cycle 3 is a maximum of 2 weeks of therapy.  
• Clarified corresponding 
/ADA draws. 
For Treatment Groups A, B, and C:  Removed pre-cystectomy ophthalmology eye exam. 


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For treatment groups D, F:  Removed column C1D15 as no tests will be performed then 
For Treatment Group C:  Clarified that retifanlimab is dispensed in Cycle 1 Day 15 and 
Cycle 2 Day 15 as well as clarified corresponding 
/ADA draws. 
For all treatment groups:  Added PD-L1 testing in addition to the FGFR testing.  Also 
added pathological tumor assessment under efficacy assessments. 
For all treatment groups:  Clarified that 30-day follow-up is for 30 days after cystectomy 
or after last dose of drug if cystectomy is not performed. 
For all treatment groups:  Limited postsurgical safety assessments to be performed 
30 days after cystectomy and removed 90-day post-cystectomy assessment. 
Rationale for change:  Clarification based on medical feedback. 
5. Section 8.3.8, Postsurgical Criteria for Adverse Events; Section 8.8.1, Safety 
Follow-Up 
Description of change:  Removed 90-day post-surgical complications assessment and 
limited it to 30-day.  Overall safety assessment remains at 30 days post cystectomy and at 
90 days post last dose.   
Rationale for change:  Most publications support a 30-day follow-up and not 90-day 
follow-up after cystectomy. 
6. Section 8.4, 
 Immunogenicity Assessments (Table 21:  Timing 
of 
 Antidrug Antibody Serum Sample Collection for 
Retifanlimab; 
 
 
 
 
 
Description of change:  Clarified 
ADA draws, and clarified plasma collection time 
and plasma draws for oral drugs pemigatinib or epacadostat in all treatment groups. 
Rationale for change:  For clarification and to decrease participant burden. 
7. 
 
 
 
 
 
 
8. Section 2.1.1, Scientific Rationale for Study Design  
Description of change:  Added surgical extirpation and cystectomy data from 
SEER-Medicare analysis. 
Rationale for change:  To add a reference detailing the typical time to schedule 
cystectomies. 


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9. Section 5.2, Exclusion Criteria (Criteria 24); Section 6.6.3, Prohibited Medications; 
Appendix H, CYP1A2, CYP2C8, and CYP2C19 Substrates 
Description of change:  For participants who will receive epacadostat, added the 
following criteria: 
a. Concomitant use of medications that are known to be substrates of CYP1A2, 
CYP2C8, or CYP2C19 with narrow therapeutic window are prohibited.   
b. Patients who are receiving or required to receive medications that are known to be 
UGT1A9 inhibitor. 
Added Appendix H CYP1A2, CYP2C8 and CYP2C19 substrates listing prohibited 
medications for participants receiving doses of epacadostat greater than 300 mg BID. 
Also, participants should avoid caffeine consumption.  
Rationale for change:  To exclude participants who are receiving medications that may 
cause potential drug-drug interactions. 
10. Section 6, Study Treatment (Table 13:  Study Treatment Information) 
Description of change:  Clarified that for Treatment Group C, retifanlimab is first 
administered on Cycle 1 Day 15 to correspond with the schedule of assessment Table 5. 
Rationale for change:  Clarification of retifanlimab administration for Treatment 
Group C. 
11. Section 6.5.1, Criteria and Procedures for Dose Interruptions and Adjustments of 
Study Drugs (Table 14:  Guidelines for Dose Modification) 
Description of change:  Clarified for handling of TEAEs that if treatment is withheld for 
more than 2 weeks in any treatment arm, the participant will discontinue from study 
treatment.  Added clarification that if TEAE is not resolved within 2 weeks, then 
retifanlimab will be discontinued for Treatment Groups B, C, D, and E. 
Rationale for change:  To reduce the risk of potential delays in radical cystectomy due 
to TEAEs.  
12. Section 8.5.2, Tissue Biopsy Collection Requirements 
Description of change:  Added that only one commercial assay 22C3 is acceptable for 
PD-L1 CPS testing and that FGFR testing can be performed using commercially 
available assays.  Portion of the tissue sample will be flash frozen to allow for amino acid 
analyses.  This was implemented on all samples.  Also, clarified the number of tissues 
samples that are required as well as the requirement for flash-frozen biopsy to be over dry 
ice. 
Rational for change:  To clarify acceptable PD-L1 and FGFR testing, and to clarify the 
requirement for flash frozen biopsy.  Participants are not yet randomized into treatment 
arms during TURBT and the procedure of flash freezing tissue sample needs to be done 
during/right after the procedure.  Therefore, this procedure cannot be selectively done on 
samples for participants randomized to a treatment arm and will be performed on all 
samples. 


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13. Section 10.2, Population for Analysis (Table 24:  Populations for Analysis) 
Description of change:  Added the efficacy evaluable population will include 
participants with efficacy endpoint data available. 
• For endpoints that are change from baseline, participants with assessments both at 
baseline and at the time of cystectomy will be included. 
• For endpoints that are evaluated at the time of cystectomy, participants with 
assessments at cystectomy will be included. 
Rationale for change:  To clarify the definition of the efficacy evaluable population. 
 
 
 
 
 
 
 
 
16. Section 1, Protocol Summary (Table 3:  Schedule of Activities for Participants 
Receiving Pemigatinib Monotherapy [Group A]; Table 4:  Schedule of Activities for 
Participants Receiving Pemigatinib + Retifanlimab [Group B]; Table 5:  Schedule of 
Activities for Participants Receiving Pemigatinib Monotherapy × 2 Weeks Followed 
by Retifanlimab [Group C]; Table 6:  Schedule of Activities for Participants 
Receiving Epacadostat + Retifanlimab [Group D]; Table 7:  Schedule of Activities 
for Participants Receiving Retifanlimab Monotherapy [Group E]; Table 8:  
Schedule of Activities for Participants Receiving Epacadostat Monotherapy 
[Group F]); Section 4.3 Study Termination; Section 5.2, Exclusion Criteria; 
Section 7.1.2, Discontinuation Procedures; Section 8.4, 
 
Immunogenicity Assessments; Section 9, Adverse Events:  Definitions and 
Procedures for Recording, Evaluating, Follow-Up, and Reporting 
Description of change:  Added "Blood" before chemistries in schedules of assessments; 
added "/DSMB" to "DMC"; added pathologic tumor assessments to cystectomy; added 
Exclusion Criteria 24 regarding participants enrolled in France; added "The status of the 
participant should be updated to EOT in the IRT." to discontinuation procedures; added 
"Any changes in the timing or addition of timepoints for any planned study assessments 
must be documented and approved by the relevant study team member and then archived 
in the sponsor and site study files but will not constitute a Protocol Amendment.  The 
IRB/IEC will be informed of any safety issues that require alteration of the safety 
monitoring scheme or amendment of the ICF."; and updated adverse events definitions 
and procedures to current template. 
Rationale for change:  Changes made based on updated protocol template dated 
JUL 2020. 


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17. Incorporation of administrative changes.  Other minor, administrative changes have 
been incorporated throughout the Protocol and are noted in the redline version of the 
amendment.  "INCMGA00012" has been updated throughout the document with the 
generic name "retifanlimab." 


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SAP_001.pdf: 
Official Title: 
An Open-Label, Randomized, Phase 2, Umbrella Study of Various 
Neoadjuvant Therapies for Participants With Muscle-Invasive 
Urothelial Carcinoma of the Bladder Who Are Cisplatin-Ineligible or 
Refuse Cisplatin Therapy and Undergoing Radical Cystectomy 
(Optimus) 
NCT Number: 
NCT04586244 
Document Date:    Statistical Analysis Plan: 27 MAR 2024 


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Statistical Analysis Plan 
TITLE PAGE 
 
 
INCB 24360-901 
An Open-Label, Randomized, Phase 2, Umbrella Study of Various 
Neoadjuvant Therapies for Participants With Muscle-Invasive Urothelial 
Carcinoma of the Bladder Who Are Cisplatin-Ineligible or Refuse 
Cisplatin Therapy and Undergoing Radical Cystectomy (Optimus) 
 
 
 
IND Number: 
146,743 
EudraCT Number: 
2020-002244-23 
Sponsor: 
Incyte Corporation 
1801 Augustine Cut-Off 
Wilmington, DE 19803 
United States 
Protocol Version: 
Protocol Amendment 4 dated 01 MAR 2022 
CRF Approval Date: 
14 DEC 2023 
SAP Version: 
Original 
SAP Author:  
 
 
Date of Plan: 
27 MAR 2024 
 
 
This study is being conducted in compliance with Good Clinical Practice, 
including the archiving of essential documents. 


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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
TABLE OF CONTENTS .................................................................................................................2 
LIST OF ABBREVIATIONS ..........................................................................................................5 
1. 
INTRODUCTION ........................................................................................................7 
2. 
STUDY INFORMATION, OBJECTIVES, AND ENDPOINTS.................................8 
2.1. 
Protocol and Case Report Form Version ......................................................................8 
2.2. 
Study Objectives and Endpoints ...................................................................................8 
3. 
STUDY DESIGN .......................................................................................................10 
3.1. 
Randomization ............................................................................................................11 
3.2. 
Control of Type I Error ...............................................................................................11 
3.3. 
Sample Size Considerations .......................................................................................12 
3.4. 
Schedule of Assessments ............................................................................................12 
4. 
DATA HANDLING DEFINITIONS AND CONVENTIONS ..................................13 
4.1. 
Scheduled Study Evaluations and Study Periods .......................................................13 
4.1.1. 
Day 1 ...........................................................................................................................13 
4.1.2. 
Study Day ...................................................................................................................13 
4.1.3. 
Baseline Value ............................................................................................................13 
4.1.4. 
Handling of Missing and Incomplete Dates ...............................................................13 
4.1.5. 
Cycle Length and Duration .........................................................................................15 
4.2. 
Variable Definitions ....................................................................................................15 
4.2.1. 
Body Mass Index ........................................................................................................15 
4.2.2. 
Prior and Concomitant Medication .............................................................................15 
5. 
STATISTICAL METHODOLOGY ...........................................................................16 
5.1. 
General Methodology .................................................................................................16 
5.2. 
Treatment Groups .......................................................................................................16 
5.3. 
Analysis Populations ..................................................................................................16 
5.3.1. 
All-Screened Population .............................................................................................16 
5.3.2. 
Full Analysis Set .........................................................................................................16 
5.3.3. 
Per-Protocol Population ..............................................................................................16 
5.3.4. 
Enrolled Population ....................................................................................................16 
5.3.5. 
Translational-Evaluable Population ............................................................................17 


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5.3.6. 
Safety Population ........................................................................................................17 
5.3.7. 
Efficacy Population ....................................................................................................17 
6. 
BASELINE, EXPOSURE, AND DISPOSITION ......................................................18 
6.1. 
Demographics, Baseline Characteristics, and Disease History ..................................18 
6.1.1. 
Demographics and Baseline Characteristics ...............................................................18 
6.1.2. 
Baseline Disease Characteristics ................................................................................18 
6.1.3. 
Disease History ...........................................................................................................18 
6.1.4. 
Prior Therapy ..............................................................................................................18 
6.1.5. 
Medical History ..........................................................................................................19 
6.2. 
Disposition of Participant ...........................................................................................19 
6.3. 
Protocol Deviations ....................................................................................................19 
6.4. 
Exposure .....................................................................................................................19 
6.5. 
Study Treatment Compliance .....................................................................................20 
6.6. 
Prior and Concomitant Medication .............................................................................20 
7. 
EFFICACY .................................................................................................................21 
7.1. 
Efficacy Hypotheses ...................................................................................................21 
7.2. 
Analysis of the Primary Efficacy Parameter ..............................................................21 
7.2.1. 
Primary Efficacy Analysis ..........................................................................................21 
7.2.2. 
Subgroup Analyses for Primary Endpoint ..................................................................21 
7.2.3. 
Sensitivity and Supportive Analyses for Primary Endpoint .......................................21 
7.3. 
Analysis of the Secondary Efficacy Parameters .........................................................21 
7.3.1. 
Pathological Complete Response Rate .......................................................................21 
7.3.2. 
Major Pathological Response Rate .............................................................................22 
8. 
SAFETY AND TOLERABILITY ..............................................................................22 
8.1. 
General Considerations ...............................................................................................22 
8.2. 
Adverse Events ...........................................................................................................22 
8.2.1. 
Adverse Event Definitions ..........................................................................................22 
8.2.2. 
Adverse Events of Special Interest .............................................................................22 
8.2.3. 
Adverse Event Summaries ..........................................................................................23 
8.3. 
Clinical Laboratory Tests ...........................................................................................24 
8.3.1. 
Laboratory Value Definitions .....................................................................................24 
8.3.2. 
Laboratory Value Summaries .....................................................................................24 
8.3.3. 
Potential Hy's Law Events ..........................................................................................25 


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8.4. 
Vital Signs ..................................................................................................................25 
8.5. 
Electrocardiograms .....................................................................................................25 
9. 
INTERIM ANALYSES ..............................................................................................27 
10. 
CHANGES AND MODIFICATIONS TO THE ANALYSIS PLAN ........................27 
10.1. 
Changes to Protocol-Defined Analyses ......................................................................27 
10.2. 
Changes to the Statistical Analysis Plan .....................................................................27 
11. 
REFERENCES ...........................................................................................................28 
APPENDIX A. PLANNED TABLES AND LISTINGS ............................................................29 
 
LIST OF TABLES 
Table 1: 
Objectives and Endpoints .............................................................................................8 
Table 2: 
Sample Size Determination ........................................................................................12 
Table 3: 
Identification of Records for Postbaseline By-Visit Summaries ................................24 
Table 4: 
Normal Ranges for Electrocardiogram Intervals ........................................................26 
Table 5: 
Statistical Analysis Plan Versions ..............................................................................27 
 
LIST OF FIGURES 
Figure 1: 
Study Design Schema .................................................................................................11 
 


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LIST OF ABBREVIATIONS 
Abbreviations and 
Special Terms  
Definition  
AE 
adverse event 
ALT 
alanine aminotransferase  
AST 
aspartate aminotransferase  
BCG 
Bacillus Calmette-Guérin  
BID 
twice daily  
CI 
confidence interval  
COVID-19 
coronavirus disease 2019  
CPS 
combined positive score  
CR 
complete response  
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events  
DSMB 
Data Safety Monitoring Board  
ECG 
electrocardiogram  
ECOG 
Eastern Cooperative Oncology Group  
eCRF 
electronic case report form  
FAS 
Full Analysis Set 
HIV 
human immunodeficiency virus  
IRT 
interactive response technology 
IV 
intravenous(ly) 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIBC 
muscle-invasive bladder cancer 
miUBC 
muscle-invasive urothelial bladder cancer 
NCI 
National Cancer Institute 
pCR 
pathological complete response 
PD-1 
programmed cell death protein 1 
PD-L1 
programmed cell death-ligand 1 
PS 
performance status 
PT 
preferred term 
Q2W 
every 2 weeks 
  
  
QTcB 
QT interval corrected using Bazett's formula 
QTcF 
QT interval corrected using Fridericia's formula 
SAP  
Statistical Analysis Plan  


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Abbreviations and 
Special Terms  
Definition  
TEAE  
treatment-emergent adverse event  
TNM 
tumor, node, metastasis 
TURBT  
transurethral resection of bladder tumor  
ULN  
upper limit of normal  
ypT0/1/a/isN0M0 
pathologic partial responses post therapy 
ypT0N0 
complete pathologic response post therapy 


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1. 
INTRODUCTION 
This is an open-label, randomized, umbrella study to investigate the biological rationale and 
outcomes for selected monotherapy and combination therapies in order to inform of potential 
neoadjuvant treatment combinations to be further tested in miUBC in participants who are 
cisplatin-ineligible or those refusing cisplatin therapy and awaiting radical cystectomy. 
The purpose of this SAP is to provide details of the statistical analyses that have been outlined in 
the INCB 24360-901 Protocol. 
 
 
The details of the analysis methodology of 
 pharmacodynamics and results will 
appear in a separate report. 


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2. 
STUDY INFORMATION, OBJECTIVES, AND ENDPOINTS 
2.1. 
Protocol and Case Report Form Version 
This SAP is based on INCB 24360-901 Protocol Amendment 4 dated 01 MAR 2022 and CRFs 
approved 14 DEC 2023. Unless superseded by an amendment, this SAP will be effective for all 
subsequent Protocol amendments and eCRF versions. 
2.2. 
Study Objectives and Endpoints 
Table 1 presents the objectives and endpoints. 
Table 1: 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
To determine biologic response in participants 
with muscle-invasive cisplatin-ineligible or those 
refusing cisplatin therapy, urothelial carcinoma of 
the bladder. 
For each treatment group, the primary endpoint is 
the change from baseline in CD8+ lymphocytes 
within resected tumor. 
Secondary 
To evaluate the safety and tolerability of each of 
the treatment groups. 
Safety and tolerability assessed by monitoring the 
frequency and severity of AEs, including delay in 
cystectomy due to AEs. 
To evaluate the preliminary efficacy of each of 
the treatment groups. 
• pCR rate, defined as percentage of participants 
with ypT0N0 in each treatment group. 
• Major pathological response, defined as residual 
ypT0/1/a/isN0M0. 


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Table 1: 
Objectives and Endpoints (Continued) 
Objectives 
Endpoints 


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3. 
STUDY DESIGN 
This is an open-label, randomized, Phase 2, umbrella study of various neoadjuvant therapies for 
miUBC (ie, Galsky et al 2011) undergoing radical cystectomy. 
This study will test the biological rationale for the use of targeted and immuno-oncology agents 
for neoadjuvant treatment of cisplatin-ineligible, or participants refusing cisplatin therapy for, 
miUBC and the potential for subsequent efficacy benefit, as shown with other anti–PD-1 
inhibitors, and at doses shown to add minimal/acceptable risk from side effects (ie, positive 
benefit/risk). The translational endpoints will inform which therapies are viable candidates for 
further investigation in miUBC. This study is an umbrella design in which future treatment arms 
may be added or removed at the discretion of the sponsor. 
Participants will be randomized into 1 of the following treatment groups: 
• Treatment Group A: Epacadostat plus retifanlimab 
• Treatment Group B: Retifanlimab monotherapy 
• Treatment Group C: Epacadostat monotherapy 
• Treatment Group D: Retifanlimab plus INCAGN02385 
• Treatment Group E: Retifanlimab plus INCAGN02385 plus INCAGN02390 
Tumor tissue will be tested centrally to determine PD-L1 CPS score before enrollment. 
Participants will be randomized into treatment groups according to the schema in Figure 1. 
Participants with PD-L1 CPS < 10 or PD-L1 CPS ≥ 10 will be randomized at a 2:2:1:2:2 ratio 
into Groups A, B, C, D, and E, respectively. Participants who pass screening for PD-L1 
CPS < 10 will not be randomized into a group once that group has reached the allowed number 
of participants with PD-L1 CPS < 10. Similarly, participants with PD-L1 CPS ≥ 10 will not be 
randomized into a group once that group has reached the allowed number of participants with 
PD-L1 CPS ≥ 10. This will ensure that the desired proportion of participants who have PD-L1 
CPS < 10 and PD-L1 CPS ≥ 10 within each group will be enrolled. 
For Treatment Group C, the subgroup of participants with PD-L1 CPS < 10 or PD-L1 CPS ≥ 10 
that reaches 5 participants will hold enrolling participants to that particular subgroup and will 
continue to enroll until 4 participants in the other subgroup are enrolled. 
Screening assessments may be completed over a period of up to 28 days. Treatment cycles are 
28 days unless otherwise noted. Each participant enrolled in the study will receive a minimum of 
1 treatment cycle if, in the judgment of the investigator, the participant has not met any criteria 
for study withdrawal. The treatment duration will be approximately 4 to 10 weeks. Radical 
cystectomy is typically scheduled for approximately 8 to 10 weeks with an average of 8 weeks 
from the TURBT (ie, approximately Day 56; Poletajew et al 2014). 
Precystectomy assessments will be performed within 2 weeks before surgery. Participants will be 
followed for safety as well as radiographic imaging for 90 days after cystectomy or the last dose 
of study treatment in the event cystectomy is not performed. 


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Figure 1: 
Study Design Schema 
 
1 Treatment duration is based on date of radical cystectomy. Participants should receive a minimum of 4 weeks and 
maximum of 10 weeks of treatment. 
The current sample size represents an estimated number of participants per treatment group in 
order to attain the necessary evaluable paired biopsies. Additional participants will be enrolled in 
treatment groups to ensure the number of evaluable paired biopsies are obtained. This is a 
platform design, and additional treatment arms may be added or prematurely stopped for 
enrollment. 
3.1. 
Randomization 
This is an open-label, stratified, randomized study with a translational primary endpoint of 
change in CD8+ cells within the resected tumor tissue. If eligible for Treatments D and E based 
on exclusionary criteria, participants will be randomized to Treatment Group A, B, C, D, or E 
based on PD-L1 CPS values (see Figure 1) at a 2:2:1:2:2 ratio, respectively. If ineligible for 
Treatments D and E based on exclusionary criteria, participants will be randomized to Treatment 
Group A, B, or C based on PD-L1 CPS values (see Figure 1) at a 2:2:1 ratio. This will ensure 
that the planned number of participants will be enrolled into each treatment group with PD-L1 
CPS balanced within each treatment group. 
3.2. 
Control of Type I Error 
For the primary endpoint, the overall 2-sided Type I error is 0.10. 
No adjustment for alpha spending is considered as there are no plans to stop the study early for 
overwhelming efficacy. A DSMB will be assembled to monitor safety data and study conduct on 
a regular and ongoing basis during the study. No multiplicity control will be applied to the 
assessments. 
/ 
\. 
Stagell-lllA: 
T2-3b, NO, MO 
muscle-Invasive 
cisplatin-
ineligible or 
refuse clsplatln 
therapy mlUBC 
after (TURBT) 
that are 
undergoing 
radical 
cystectomy 
Enroll to 
study 
treatment 
Stratified by PD-ll 
CPS::_ lOand 
PD-ll CPS < 10 
Window of treatment until radical cystectomy1 
C 
Treatment Group A: 
Epacadostat + relifanlimab 
IN = 18 
R 
y 
s 
Treatment Group 8: 
Retlfanlimab monotherapy 
a 
t 
IN = 18 
d e 
Treatment Group C: 
Epacadostat monotherapy 
IN=9 
C 
C 
t 
a 
Treatment Group D: 
Retifanlimab + INCAGN0238S 
(LAG-3 inhibitor) 
0 
IN = 18 
m 
y 
Treatment Group E: 
Retifanlimab + INCAGN02385 
+ INCAGN02390 
IN = 18 
(TIM-3 inhibitor) 


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3.3. 
Sample Size Considerations 
Approximately 81 participants will be enrolled in this study. Per treatment group, the evaluable 
paired biopsies in Table 2 are needed. 
Table 2: 
Sample Size Determination 
Treatment Group 
Number of 
Participants 
Estimated Number 
of Paired Biopsies 
A: Epacadostat plus retifanlimab 
18 
16 
B: Retifanlimab monotherapy 
18 
16 
C: Epacadostat monotherapy 
9 
8 
D: Retifanlimab plus INCAGN02385 
18  
16 
E: Retifanlimab plus INCAGN02385 plus INCAGN02390  
18  
16 
Total 
81 
72 
For each group, the power consideration is based on the fold change from baseline in CD8+ 
T effector cells. Eight evaluable paired biopsies in Treatment Group C will provide 80% power 
to detect a mean fold change from baseline in the degree of 1 standard deviation of the change 
variable at 2-sided alpha = 0.10 level. 
For Treatment Groups A and B, the 16 evaluable paired biopsies will provide > 95% power to 
detect the same degree of the mean change for the entire group and 80% power at 2-sided 
alpha = 0.10 level for both PD-L1 subgroups combined (PD-L1 CPS < 10 and PD-L1 CPS ≥ 10). 
3.4. 
Schedule of Assessments 
Refer to Protocol Amendment 4 dated 01 MAR 2022 for a full description of all study 
procedures and assessment schedules for this study. 


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4. 
DATA HANDLING DEFINITIONS AND CONVENTIONS 
4.1. 
Scheduled Study Evaluations and Study Periods 
4.1.1. 
Day 1 
Day 1 is the date that the first dose of any study treatment is administered to the participants. 
For randomized participants not treated with any study treatment, Day 1 is defined as the date of 
randomization. 
4.1.2. 
Study Day 
If a visit/reporting date is on or after Day 1, then the study day at the visit/reporting date will be 
calculated as 
Day # = (visit/reporting date – Day 1 date + 1). 
If the visit/reporting date is before Day 1, then the study day at the visit/reporting date will be 
calculated as 
Day # = (visit/reporting date – Day 1 date). 
A study day of –1 indicates 1 day before Day 1. 
4.1.3. 
Baseline Value 
Baseline is the last nonmissing measurement obtained before the first administration of any study 
treatment, unless otherwise defined. 
For randomized participants not treated with any study treatment, baseline is defined as the last 
nonmissing assessment before randomization for all parameters. 
When scheduled assessments and unscheduled assessments occur on the same day and the time 
of the assessment or time of first dose is not available, use the following convention to determine 
baseline: 
• If both a scheduled and an unscheduled visit are available on the day of the first dose 
and the time is missing, use the scheduled assessment as baseline. 
• If all scheduled assessments are missing on the day of the first dose and an 
unscheduled assessment is available, use the unscheduled assessment as baseline. 
4.1.4. 
Handling of Missing and Incomplete Dates 
In general, values for missing dates will not be handled unless methods for handling missing 
dates are specified in this section or relevant sections. The original reported dates collected on 
the eCRF should be used in all relevant listings. The following rules will be used for handling 
partial dates for analyses requiring dates. 


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When calculating the time since diagnosis of cancer, a partial cancer diagnosis date will be 
handled as follows in the calculation: 
• If only the day is missing, then the first day of the month will be used. 
• If both the month and day are missing, then 01 JAN of the year will be used. 
• If the diagnosis date is completely missing, then the time since diagnosis will not be 
calculated. 
For AEs, an unsolved missing onset date will be imputed by the date of Day 1, which will force 
the AE to be treatment emergent, with the following exceptions: 
• If the stop/resolution date is prior to the Day 1 date, then the AE will be considered as 
non–treatment emergent. 
• If both the month and day are missing, and the last day of the year is prior to the 
Day 1 date, then the AE will be considered as non–treatment emergent. 
• If only the day is missing, and the last day of the month is prior the Day 1 date, then 
the AE will be considered as non–treatment emergent. 
Imputation of start dates for AEs will be handled as follows: 
• If only the day is missing, and the first day of the month is after the Day 1 date, then 
the AE will be considered as treatment emergent, and the incomplete date will be 
imputed by the first of the month. 
• If both the month and day are missing, and the year is after the Day 1 date, then the 
AE will be considered as treatment emergent, and the incomplete date will be set to 
01 JAN. 
Imputation of end dates for AEs will be handled as follows: 
• If only the day is missing for the AE stop date, the incomplete date will be imputed as 
the last day of the month. 
• If the participant discontinued treatment or died before the last day of that month, the 
end of treatment or death date should be used for imputation. 
When the date of the last dose is used in deriving variables such as duration of treatment or 
TEAE flag, a missing or partial date of the last dose will be handled as follows: 
• If only the day is missing, then the earlier date of the last day of the month or the date 
that the participant discontinued treatment will be used. 
• If both the month and day are missing, then the earlier date of 31 DEC of the year or 
the date that the participant discontinued treatment will be used. 
• Otherwise, the date that the participant discontinued treatment will be used as the date 
of the last dose. 


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4.1.5. 
Cycle Length and Duration 
Cycle 1 Day 1 is the day that the first dose of study treatment is administered. The scheduled 
cycle length is 28 days. The actual Day 1 of subsequent cycles will correspond with the first day 
of administration of epacadostat, retifanlimab, INCAGN02385, INCAGN02390 in that cycle; 
thus, treatment cycles may become out of sync with the originally planned schedule, and the 
cycle length may be different from 28 days. The date of the Day 1 of subsequent cycles recorded 
on the eCRF will be used as the Day 1 of the subsequent cycles. 
Treatment Group A will receive retifanlimab 500 mg (25 mg/mL liquid formulation) IV over 
30 (+ 15) minutes on Day 1 of each 28-day cycle and epacadostat 600 or 400 mg BID. 
Treatment Group B will receive retifanlimab 500 mg (25 mg/mL liquid formulation) IV over 
30 (+ 15) minutes on Day 1 of each 28-day cycle. Treatment Group C will receive epacadostat 
600 or 400 mg BID. Treatment Group D will receive retifanlimab 500 mg (25 mg/mL liquid 
formulation) IV over 30 (+ 15) minutes on Day 1 of each 28-day cycle followed by a 10-minute 
flush and INCAGN02385 350 mg Q2W IV over 30 (−5/+10) minutes followed by a 10-minute 
flush. Treatment Group E will receive retifanlimab 500 mg (25 mg/mL liquid formulation) IV 
over 30 (+ 15) minutes on Day 1 of each 28-day cycle followed by a 10-minute flush, 
INCAGN02385 350 mg Q2W IV over 30 (−5/+10) minutes followed by a 10-minute flush, and 
INCAGN02390 400 mg Q2W IV over 30 (−5/+10) minutes followed by a 10-minute flush. 
4.2. 
Variable Definitions 
4.2.1. 
Body Mass Index 
Body mass index will be calculated as follows: 
Body mass index (kg/m2) = [weight (kg)] / [height (m)]2. 
4.2.2. 
Prior and Concomitant Medication 
Prior medication is defined as any nonstudy medication started before the first dose of study 
treatment. 
Concomitant medication is defined as any nonstudy medication that is started accordingly: 
• Before the date of first administration of epacadostat, retifanlimab, INCAGN02385, 
or INCAGN02390 and is ongoing or ends on/after the date of first study treatment 
administration. 
• On/after the date of first administration of epacadostat, retifanlimab, INCAGN02385, 
or INCAGN02390 and is ongoing or ends during the course of study. 
A prior medication could also be classified as "both prior and concomitant medication" if the 
start date is prior the first dose of study treatment and the end date is on or after first dose of 
study treatment. In the listing, it will be indicated whether a medication is only prior, only 
concomitant, or both prior and concomitant. 
For the purposes of analysis, all medications will be considered concomitant medications unless 
the medications can unequivocally be defined as not concomitant. 


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5. 
STATISTICAL METHODOLOGY 
5.1. 
General Methodology 
Unless otherwise noted, SAS software (SAS Institute Inc, Cary, NC; v9.4 or later) will be used 
for the generation of all tables, graphs, and statistical analyses. Descriptive summaries for 
continuous variables will include but not be limited to the number of observations, mean, 
standard deviation, median, minimum, and maximum. Descriptive summaries for categorical 
variables will include the number and percentage of participants in each category. 
5.2. 
Treatment Groups 
This a randomized, open-label, umbrella study with 5 treatment groups. Participants will be 
randomized to receive retifanlimab monotherapy, retifanlimab plus epacadostat, epacadostat 
monotherapy, retifanlimab plus INCAGN02385, or retifanlimab plus INCAGN02385 plus 
INCAGN02390. Participant data will be summarized by treatment group. 
5.3. 
Analysis Populations 
5.3.1. 
All-Screened Population 
The All-Screened Population will include all participants who signed the informed consent form. 
The All-Screened Population will be used for summarizing the analysis populations. 
5.3.2. 
Full Analysis Set 
The FAS will include all participants who were randomized. Participants will be analyzed 
according to the treatment to which they were assigned at the time of randomization regardless 
of the actual study treatment that the participant might take during the study. 
The FAS will be used to summarize participant disposition, demographics, baseline 
characteristics, Protocol deviations, prior and concomitant medications, general medical history, 
disease history, prior systemic therapy, and prior radiotherapy. 
5.3.3. 
Per-Protocol Population 
Not applicable. 
5.3.4. 
Enrolled Population 
The Enrolled Population will include all participants who were defined as "Completed" on the 
Screening Disposition eCRF. 


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5.3.5. 
Translational-Evaluable Population 
The Translational-Evaluable Population will include all participants enrolled in the study who 
meet the following criteria: 
• Completed a baseline scan and has a minimal residual disease. 
• Received at least 4 weeks of neoadjuvant study treatment. 
− Treatment Groups A and C: last dose of epacadostat should be within 2 days prior 
to day of surgery. 
− Treatment Groups A, B, D, and E: last dose of retifanlimab and/or 
INCAGN02385 and/or INCAGN02390 should be within the 2 weeks prior to day 
of surgery. 
• Provided evaluable paired biopsies (pretreatment core biopsy and surgical resection 
biopsy). 
The Translational-Evaluable Population will be used for the primary efficacy endpoint analysis. 
5.3.6. 
Safety Population 
The Safety Population will include all participants who received at least 1 dose of study 
treatment. Treatment groups for this population will be determined according to the actual 
treatment the participant received regardless of assigned study treatment. 
All safety analyses will be conducted using the Safety Population. 
5.3.7. 
Efficacy Population 
The Efficacy Population will include all participants with secondary efficacy endpoint data 
available for both baseline and postbaseline measurements, and this will be used for the analysis 
of all secondary efficacy endpoints. 


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6. 
BASELINE, EXPOSURE, AND DISPOSITION 
Appendix A provides a list of data displays. Sample data displays are included in a separate 
document. 
6.1. 
Demographics, Baseline Characteristics, and Disease History 
6.1.1. 
Demographics and Baseline Characteristics 
The following demographics and baseline characteristics will be summarized for the FAS: age, 
sex, race, ethnicity. Categorical parameters (sex, race, ethnicity) will be summarized by number 
and percentage. Continuous parameters (age) will be summarized by descriptive statistics (N, 
mean, standard deviation, median, minimum, and maximum). Age will also be summarized in 
categories < 65 years and ≥ 65 years by number and percentage. 
All demographic and baseline characteristic data will be listed. 
6.1.2. 
Baseline Disease Characteristics 
The following baseline disease characteristics will be summarized by number and percentage for 
the FAS: ECOG performance status. 
6.1.3. 
Disease History 
The type of urothelial cancer, stage at diagnosis, current stage, disease histology at diagnosis, 
current disease histology, TNM staging at diagnosis, current TNM staging, time since MIBC 
diagnosis, cisplatin therapy use, smoking status, history of hydronephrosis, and history of 
BCG-intravesical installations will be summarized. Categorical parameters will be summarized 
by number and percentage. Continuous parameters will be summarized by descriptive statistics 
(N, mean, standard deviation, median, minimum, and maximum) for the FAS. 
The TURBT procedure for diagnosis will be summarized using number and percentage for all 
categorical values including if a radical TURBT procedure was performed and the PD-L1 CPS 
score category. 
Time since diagnosis will be calculated as follows: 
Time since diagnosis (years) = (date of randomization – date of diagnosis + 1) / 365.25. 
All disease history data will be listed. 
6.1.4. 
Prior Therapy 
The number of prior systemic cancer therapy regimens will be summarized for all participants in 
the FAS. The component drugs of prior systemic therapy regimens will be coded using the WHO 
Drug Dictionary. The number and percentage of participants who received each drug will be 
summarized by WHO drug class and WHO drug PT. The regimen name, component drugs, start 
and stop dates, route, purpose of the regimen, best response, reason for discontinuation, and date 
of relapse/progression will be listed. 
The number of participants who received prior radiation will be summarized for the FAS. The 
radiotherapy type, body site, start and stop dates, reason for the regimen, number of fractions 
received, total dose, and best response will be listed. 


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The number of participants who had prior surgery or surgical procedure for the malignancies 
under study will be summarized for the FAS. The date and description of the surgery/procedure 
will be listed. 
6.1.5. 
Medical History 
For participants in the FAS, medical history will be summarized by assigned treatment group. 
This summation will include the number and percentage of participants with a medical history 
event for each body system/organ class as documented on the eCRF and coded using MedDRA. 
All available medical history data will be listed. 
6.2. 
Disposition of Participant 
The number and percentage of participants who were randomized, who were treated, who were 
ongoing with study treatment, who completed study treatment, who discontinued study treatment 
with a primary reason for discontinuation, who underwent radical cystectomy, who were still in 
the study, who completed the study, and who withdrew from the study with a primary reason for 
withdrawal will be summarized for the FAS. The number of participants randomized by country 
and site will also be provided by treatment group. All disposition information will be listed. 
6.3. 
Protocol Deviations 
Protocol deviations and adjudications will be summarized and listed. 
6.4. 
Exposure 
For participants in the safety population, exposure to epacadostat, retifanlimab, INCAGN02385, 
and INCAGN02390 will be summarized descriptively as the following: 
• Number of cycles of epacadostat: number of cycles with a nonzero dose of 
epacadostat. 
• Number of cycles of retifanlimab: number of cycles with a nonzero dose of 
retifanlimab. 
• Number of cycles of INCAGN02385: number of cycles with a nonzero dose of 
INCAGN02385. 
• Number of cycles of INCAGN02390: number of cycles with a nonzero dose of 
INCAGN02390. 
• Duration of treatment with epacadostat (days): date of last dose of epacadostat – 
date of first dose of epacadostat + 1 – days of interruption. 
• Duration of treatment with retifanlimab (days): date of last dose of retifanlimab – 
date of first dose of retifanlimab + 1. 
• Duration of treatment with INCAGN02385 (days): date of last dose of 
INCAGN02385 – date of first dose of INCAGN02385 + 1. 
• Duration of treatment with INCAGN02390 (days): date of last dose of 
INCAGN02390 – date of first dose of INCAGN02390 + 1. 


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• Average daily dose of epacadostat (mg/day): total actual epacadostat dose taken 
(mg) / duration of treatment with epacadostat (days). 
Total actual dose taken will be calculated based on the information entered in the 
Drug Accountability Epacadostat eCRF. 
• Average dose of retifanlimab (mg): total actual retifanlimab dose taken (mg) / 
number of treatments with retifanlimab. 
Total actual dose taken will be calculated based on the information entered in the 
Dose Retifanlimab eCRF. 
• Average dose of INCAGN02385 (mg): total actual INCAGN02385 dose taken (mg) 
/ number of treatments with INCAGN02385. 
Total actual dose taken will be calculated based on the information entered in the 
Dose INCAGN02385 eCRF. 
• Average dose of INCAGN02390 (mg): total actual INCAGN02390 dose taken (mg) 
/ number of treatments with INCAGN02390. 
Total actual dose taken will be calculated based on the information entered in the 
Dose INCAGN02390 eCRF. 
• Epacadostat dose modifications: number of participants who had epacadostat dose 
reduction and interruption. 
• Dose delays and dose interruptions: number of participants with dose delays and 
dose interruptions. 
All exposure data will be listed. 
6.5. 
Study Treatment Compliance 
For participants in the safety population, overall compliance (%) for epacadostat will be 
calculated for all participants as follows: 
Compliance (%) = 100  [total dose actually taken] / [total prescribed dose]. 
The total prescribed dose is defined as the sum of the doses prescribed by the investigator 
accounting for dose modifications. 
The total actual dose taken will be calculated based on information entered on the Drug 
Accountability Epacadostat eCRF. If there are dispensed drugs that have not been returned yet, 
the actual dose taken starting from the dispense date of the unreturned drugs will be imputed by 
the dose taken as reported on the Dose Epacadostat eCRF. 
For participants treated with retifanlimab, INCAGN02385, or INCAGN02390, compliance will 
be calculated based on infusion records documented by the site staff and monitored by the 
sponsor/designee. 
6.6. 
Prior and Concomitant Medication 
Prior medications and concomitant medications will be coded using the WHO Drug Dictionary. 
The number and percentage of participants in the FAS for each prior and concomitant medication 
will be summarized by WHO drug class and WHO drug PT. All medications will be listed. 


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7. 
EFFICACY 
Appendix A provides a list of data displays. Sample data displays are included in a separate 
document. 
7.1. 
Efficacy Hypotheses 
The primary hypothesis is that each study treatment assigned in each treatment group given prior 
to a cystectomy will change the amount of immune cells (CD8+ lymphocytes) within the 
resected tumor in participants with bladder cancer. Assuming Si(t) is the log 2 of fold change 
from baseline function in regard to CD8+ lymphocyte counts, the testing hypothesis is as 
follows: 
• H0 (null hypothesis): Si(t) = 0 
• HA (alternative hypothesis): Si(t) ≠ 0 
7.2. 
Analysis of the Primary Efficacy Parameter 
7.2.1. 
Primary Efficacy Analysis 
The primary efficacy variable is the fold change from baseline in number of CD8+ lymphocytes 
in the resected tumor tissue. This will be derived as follows: 
Fold change from baseline = number of CD8+ lymphocytes at cystectomy / number of CD8+ 
lymphocytes at screening 
Values of fold change from baseline of CD8+ lymphocytes are transformed to log 2 of fold 
change and will be summarized by descriptive statistics (N, mean, standard deviation, standard 
error, median, minimum, and maximum). For each treatment group, a paired t-test will be 
provided using n – 1 degrees of freedom, where n is the number of evaluable paired samples. An 
80% CI with a 2-sided alpha of 0.10 will be included with the test statistic and p-value. 
Participants in the Translational-Evaluable Population who had tumor samples both at baseline 
and at the time of cystectomy will be included. 
7.2.2. 
Subgroup Analyses for Primary Endpoint 
Not applicable. 
7.2.3. 
Sensitivity and Supportive Analyses for Primary Endpoint 
Not applicable. 
7.3. 
Analysis of the Secondary Efficacy Parameters 
7.3.1. 
Pathological Complete Response Rate 
Pathological CR rates at the time of radical cystectomy will be assessed as a secondary endpoint. 
Pathological CR is defined as ypT0N0 and in situ cancer on the basis of histology evaluation of 
the TURBT and cystectomy samples by local institutional analysis. The number and percentage 
of participants with ypT0N0 in each treatment group will be calculated, and 80% CIs will be 


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estimated using the Clopper-Pearson method. The Efficacy Population will be used for this 
analysis. All response data will be listed. 
7.3.2. 
Major Pathological Response Rate 
Major pathological response rates at the time of radical cystectomy will be assessed as a 
secondary endpoint. The number and percentage of participants with ypT0/1/a/isN0M0 in each 
treatment group will be calculated, and 80% CIs will be estimated using the Clopper-Pearson 
method. The Efficacy Population will be used for this analysis. All response data will be listed. 
8. 
SAFETY AND TOLERABILITY 
Appendix A provides a list of data displays. Sample data displays are included in a separate 
document. 
8.1. 
General Considerations 
Summary tables may be replaced with listings when appropriate. For instance, an AE frequency 
table may be replaced with a listing if it only contains a few unique PTs reported on relatively 
few participants. 
8.2. 
Adverse Events 
8.2.1. 
Adverse Event Definitions 
A TEAE is any AE, either reported for the first time or the worsening of a pre-existing event, 
occurring after the first dose of study treatment. Analysis of AEs (as discussed below) will be 
limited to TEAEs, but data listings will include all AEs regardless of their timing in relation to 
study treatment administration. For purposes of analysis, all AEs will be considered TEAEs 
unless the AE can unequivocally be defined as not treatment-emergent. 
Adverse events will be tabulated by MedDRA SOC and PT. Severity of AEs will be graded 
using the NCI CTCAE v5. The CTCAE reporting guidelines and grading details are available on 
the Cancer Therapy Evaluation Program website. 
The subset of AEs considered by the investigator to be related to study treatment will be 
considered to be treatment-related AEs. If the investigator does not specify the relationship of the 
AE to study treatment, the AE will be considered to be treatment-related. The incidence of 
TEAEs and treatment-related TEAEs will be tabulated. In addition, serious TEAEs will also be 
tabulated. 
All AE data will be listed. 
8.2.2. 
Adverse Events of Special Interest 
Adverse events reported as post–radical cystectomy complications as well as those assessed as 
immune-related will be coded according to the MedDRA 26.0. Postsurgery complications will be 
further classified according to the Clavien-Dindo Grading System (Dindo et al 2004). 


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8.2.3. 
Adverse Event Summaries 
An overall summary of AEs by treatment group will include the following: 
• Number (%) of participants who had any TEAEs 
• Number (%) of participants who had any serious TEAEs 
• Number (%) of participants who had any Grade 3 or higher TEAEs 
• Number (%) of participants who had any TEAEs related to study treatment 
• Number (%) of participants who had any immune-related TEAEs 
• Number (%) of participants who had any immune-related TEAEs of Grade 3 or 
higher 
• Number (%) of participants who permanently discontinued study treatment because 
of a TEAE 
• Number (%) of participants who temporarily interrupted study treatment because of a 
TEAE 
• Number (%) of participants who had any fatal TEAEs 
• Number (%) of participants who had a delay in radical cystectomy due to a TEAE 
• Number (%) of participants who had a TEAE leading to hospitalization 
The following summaries will be produced by MedDRA term: 
• Summary of TEAEs by MedDRA SOC and PT 
• Summary of TEAEs by MedDRA PT in decreasing order of frequency 
• Summary of TEAEs by MedDRA SOC, PT, and maximum severity 
• Summary of Grade 3 or higher TEAEs by MedDRA SOC and PT 
• Summary of Grade 3 or higher TEAEs by MedDRA PT in decreasing order of 
frequency 
• Summary of serious TEAEs by MedDRA SOC and PT 
• Summary of serious TEAEs by MedDRA PT in decreasing order of frequency 
• Summary of treatment-related TEAEs by MedDRA SOC and PT 
• Summary of treatment-related TEAEs by MedDRA PT in decreasing order of 
frequency 
• Summary of immune-related TEAEs by MedDRA SOC and PT 
• Summary of immune-related TEAEs of Grade 3 or higher by MedDRA SOC and PT 
• Summary of treatment-related serious TEAEs by MedDRA SOC and PT 
• Summary of treatment-related serious TEAEs by MedDRA PT in decreasing order of 
frequency 


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• Summary of nonserious TEAEs by MedDRA SOC and PT 
• Summary of TEAEs leading to dose interruption by MedDRA SOC and PT 
• Summary of TEAEs leading to discontinuation of study treatment by MedDRA SOC 
and PT 
• Summary of TEAEs with a fatal outcome by MedDRA SOC and PT 
• Summary of TEAEs by MedDRA SOC and PT leading to delay in radical cystectomy 
• Summary of TEAEs considered as post–radical cystectomy complications by 
MedDRA SOC and PT 
8.3. 
Clinical Laboratory Tests 
8.3.1. 
Laboratory Value Definitions 
Laboratory values, change from baseline values, and percent change from baseline values will be 
summarized descriptively by visit. Change from baseline will be defined as: 
Change from baseline = observed value at timepoint – baseline value 
Percent change from baseline will defined as: 
Percent change from baseline = 100 × (observed value at timepoint – baseline value) / 
baseline value 
Baseline will be determined according to Section 4.1.3. 
The baseline value will be determined using the nonmissing values collected before the first 
dose, prioritizing scheduled assessments for baseline identification over unscheduled visits. The 
last record before administration in the highest priority will be considered the baseline record. 
Laboratory test values will be assessed for severity based on the numerical component of 
CTCAE v5. 
8.3.2. 
Laboratory Value Summaries 
Any laboratory test results and associated normal ranges from local laboratories will be 
converted to SI units, if needed. 
When there are multiple nonmissing laboratory values for a participant's particular test within a 
visit window, the convention described in Table 3 will be used to determine the record used for 
by-visit tabulations and summaries. 
Table 3: 
Identification of Records for Postbaseline By-Visit Summaries 
Priority 
Laboratory Visit 
Proximity to Visit Window 
Tiebreaker 
1 
Scheduled 
In-window 
Use smallest laboratory 
sequence number 
2 
Unscheduled 
In-window 
3 
Scheduled 
Out-of-window 


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Shift tables based on the worst postbaseline value recorded will use all postbaseline values. The 
denominator for the percentage calculation will use the number of participants in the baseline 
category as the denominator for the percentage in each of the categories during the study. 
Numeric laboratory values will be summarized descriptively in SI units, and non-numeric test 
values will be tabulated when necessary. 
Severity grades will be assigned to laboratory test values based on the numerical component of 
CTCAE v5. Shift tables will be presented showing change in CTCAE grade from baseline to 
worst grade postbaseline. Separate summaries for abnormally high and abnormally low 
laboratory values will be provided when the laboratory parameter has both high and low grading 
criteria. The denominator for the percentage calculation will be the number of participants in the 
baseline category. The number of participants who had worsening of laboratory abnormalities 
will be summarized by maximum severity. 
All clinical laboratory data will be listed. 
8.3.3. 
Potential Hy's Law Events 
Participants with elevated ALT or AST > 3 × ULN range and alkaline phosphatase < 2 × ULN 
range accompanied by total bilirubin > 2 × ULN range will be listed by treatment group. 
8.4. 
Vital Signs 
Values at each scheduled visit, change, and percentage change from baseline for vital signs, 
including pulse, respiratory rate, and temperature, will be summarized descriptively. Change 
from baseline will be defined as: 
Change from baseline = observed value at timepoint – baseline value 
Percent change from baseline will defined as: 
Percent change from baseline = 100 × (observed value at timepoint – baseline value) / 
baseline value 
For vital signs including systolic blood pressure, diastolic blood pressure, and body weight, shift 
tables will be presented showing change in CTCAE grade from baseline to worst grade 
postbaseline. Severity grades will be assigned to these values based on the numerical component 
of CTCAE v5. 
For participants exhibiting vital sign abnormalities, the abnormal values will be listed along with 
their assigned treatment group. 
8.5. 
Electrocardiograms 
Twelve-lead ECGs including heart rate and PR, RR, QT, QRS, QT, QTcB, and QTcF intervals 
will be obtained for each participant during the study. Values at each scheduled visit, change, 
and percentage change from baseline will be summarized for each ECG parameter. Baseline will 
be the last value collected before the first dose of study treatment. Change from baseline will be 
defined as: 
Change from baseline = observed value at timepoint – baseline value 


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Percent change from baseline will defined as: 
Percent change from baseline = 100 × (observed value at timepoint – baseline value) / 
baseline value 
Normal ranges for ECG values are defined in Table 4. ECG values will also be considered 
abnormal if the absolute percentage change from baseline is more than 25% (30% for QRS 
interval). Participants exhibiting ECG abnormalities will be listed with study visit and assigned 
treatment group. Abnormal values for participants with alert ECG values, defined as both the 
absolute value and the percentage change from baseline being outside normal ranges, will be 
identified and listed. Outliers of QT, QTcB, and QTcF values, defined as absolute values 
> 450 milliseconds, > 470 milliseconds, > 500 milliseconds, respectively, or change from 
baseline > 30 milliseconds, will be summarized. 
Table 4: 
Normal Ranges for Electrocardiogram Intervals 
Parameter 
High Threshold 
Low Threshold 
PR 
≤ 200 ms 
≥ 120 ms 
RR 
≤ 1200 ms 
≥ 600 ms 
QT (male) 
≤ 450 ms 
≥ 350 ms 
QT (female) 
≤ 460 ms 
≥ 360 ms 
QRS 
≤ 100 ms 
≥ 60 ms 
QTcB, QTcF 
≤ 450 ms 
≥ 295 ms 
Interpretation of ECGs will be summarized by number and percentage. Clinically significant 
abnormalities will be summarized by count and percentage by visit. Specific abnormalities will 
be listed. 


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9. 
INTERIM ANALYSES 
There are no planned, formal interim analyses for this study. Periodic review of accrued clinical 
data will be conducted in accordance with the DSMB charter. 
10. 
CHANGES AND MODIFICATIONS TO THE ANALYSIS PLAN 
All versions of the SAP are listed in Table 5. 
Table 5: 
Statistical Analysis Plan Versions 
SAP Version 
Date 
Original 
27 MAR 2024 
10.1. 
Changes to Protocol-Defined Analyses 
The following differ from those described in the Protocol: 
• The primary efficacy endpoint will be fold change from baseline instead of change 
from baseline in the number of CD8+ lymphocytes. 
• The SAP changed CD8+ T effector cells to CD8+ lymphocytes for consistency. 
 
 
• The definitions of the Translational-Evaluable and Efficacy Populations were 
updated. 
10.2. 
Changes to the Statistical Analysis Plan 
Not applicable. 


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11. 
REFERENCES 
Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal 
with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 2004;240:205-213. 
Galsky MD, Hahn NM, Rosenberg J, et al. Treatment of patients with metastatic urothelial 
cancer "unfit" for cisplatin-based chemotherapy. J Clin Oncol 2011;29:2432-2438. 
Poletajew S, Lisiński J, Moskal K, et al. The time from diagnosis of bladder cancer to radical 
cystectomy in Polish urological centres - results of CysTiming Poland study. Cent European J 
Urol 2014;67:329-332. 
Voskuilen CS, Oo HZ, Genitsch V, et al. Multicenter validation of histopathologic tumor 
regression grade after neoadjuvant chemotherapy in muscle-invasive bladder cancer. Am J Surg 
Pathol 2019;43:1600-1610. 


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APPENDIX A. PLANNED TABLES AND LISTINGS 
This appendix provides a list of the planned tables and listings for the Clinical Study Report. 
Shells are provided in a separate document. 
The lists of tables and listings are to be used as guidelines. Modifications of the lists that do not 
otherwise affect the nature of the analysis will not warrant an amendment to the SAP. 
Tables 
Table No. 
Title 
Population 
Baseline and Demographic Characteristics 
1.1.1 
Analysis Populations 
All-Screened 
1.1.2 
Summary of Participant Disposition 
FAS 
1.1.3 
Summary of Number of Participants Enrolled by Country and Site 
FAS 
1.1.4 
Summary of Protocol Deviations 
FAS 
1.2.1 
Summary of Demographics and Baseline Characteristics 
FAS 
1.3.1 
Summary of Cancer History and Baseline Disease Characteristics 
FAS 
1.4.1 
Summary of Prior Medications 
FAS 
1.4.2 
Summary of Concomitant Medications 
FAS 
1.5.1 
Summary of General Medical History 
FAS 
1.5.2 
Summary of Prior Systemic Cancer Therapy 
FAS 
1.5.3 
Summary of Prior Radiotherapy and Procedures 
FAS 
Efficacy 
2.1 
Summary of Fold Change From Baseline in the Number of CD8+ Lymphocytes 
Translational-
Evaluable 
2.2 
Summary of Pathological Complete Response Rate 
Efficacy 
2.3 
Summary of Major Pathological Response 
Efficacy 
Safety 
3.1.1.1 
Summary of Exposure and Duration of Exposure to Epacadostat 
Safety 
3.1.1.2 
Summary of Exposure and Duration of Exposure to Retifanlimab 
Safety 
3.1.1.3 
Summary of Exposure and Duration of Exposure to INCAGN02385 
Safety 
3.1.1.4 
Summary of Exposure and Duration of Exposure to INCAGN02390 
Safety 
3.1.2 
Summary of Epacadostat Compliance 
Safety 
3.2.1 
Overall Summary of Treatment-Emergent Adverse Events 
Safety 
3.2.2 
Summary of Treatment-Emergent Adverse Events by MedDRA System Organ 
Class and Preferred Term 
Safety 
3.2.3 
Summary of Treatment-Emergent Adverse Events by MedDRA Preferred Term in 
Decreasing Order of Frequency 
Safety 
3.2.4 
Summary of Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, and Maximum Severity 
Safety 
3.2.5 
Summary of Grade 3 or Higher Treatment-Emergent Adverse Events by 
MedDRA System Organ Class and Preferred Term 
Safety 
3.2.6 
Summary of Grade 3 or Higher Treatment-Emergent Adverse Events by 
MedDRA Preferred Term in Decreasing Order of Frequency 
Safety 
3.2.7 
Summary of Serious Treatment-Emergent Adverse Events by MedDRA System 
Organ Class and Preferred Term 
Safety 
3.2.8 
Summary of Treatment-Emergent Serious Adverse Events by MedDRA Preferred 
Term in Decreasing Order of Frequency 
Safety 


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Table No. 
Title 
Population 
3.2.9 
Summary of Treatment-Related Treatment-Emergent Adverse Events by 
MedDRA System Organ Class and Preferred Term 
Safety 
3.2.10 
Summary of Treatment-Related Treatment-Emergent Adverse Events by 
MedDRA Preferred Term in Decreasing Order of Frequency 
Safety 
3.2.11 
Summary of Investigator Assessed Immune-Related Treatment-Emergent 
Adverse Events by MedDRA System Organ Class and Preferred Term 
Safety 
3.2.12 
Summary of Investigator Assessed Immune-Related Treatment-Emergent 
Adverse Events of Grade 3 or Higher by MedDRA System Organ Class and 
Preferred Term 
Safety 
3.2.13 
Summary of Treatment-Related Serious Treatment-Emergent Adverse Events by 
MedDRA System Organ Class and Preferred Term 
Safety 
3.2.14 
Summary of Treatment-Related Serious Treatment-Emergent Adverse Events by 
MedDRA Preferred Term in Decreasing Order of Frequency 
Safety 
3.2.15 
Summary of Treatment-Emergent Adverse Events With a Fatal Outcome by 
MedDRA System Organ Class and Preferred Term 
Safety 
3.2.16 
Summary of Nonserious Treatment-Emergent Adverse Events by MedDRA 
System Organ Class and Preferred Term 
Safety 
3.2.17 
Summary of Treatment-Emergent Adverse Events Leading to Dose Interruption 
by MedDRA System Organ Class and Preferred Term 
Safety 
3.2.18 
Summary of Treatment-Emergent Adverse Events Leading to Discontinuation of 
Study Treatment by MedDRA System Organ Class and Preferred Term 
Safety 
3.2.19 
Summary of Treatment-Emergent Adverse Events That Caused Delay in Radical 
Cystectomy by MedDRA System Organ Class and Preferred Term  
Safety 
3.2.20 
Summary of Treatment-Emergent Adverse Events Considered as Post-Radical 
Cystectomy Complications by MedDRA System Organ Class and Preferred Term 
Safety 
3.3.1.1 
Summary of Laboratory Values - Hematology 
Safety 
3.3.1.2 
Summary of Laboratory Values - Chemistry 
Safety 
3.3.1.3 
Summary of Laboratory Values - Coagulation 
Safety 
3.3.1.4 
Summary of Laboratory Values - Thyroid Panel 
Safety 
3.3.1.5 
Summary of Laboratory Values - Lipids 
Safety 
3.3.2.1 
Shift Summary of Hematology Laboratory Values in CTCAE Grade - To the 
Worst Abnormal Value 
Safety 
3.3.2.2 
Shift Summary of Chemistry Laboratory Values in CTCAE Grade - To the Worst 
Abnormal Value 
Safety 
3.4.1 
Shift Summary of Systolic Blood Pressure in CTCAE Grade - To the Worst 
Abnormal Value 
Safety 
3.4.2 
Shift Summary of Diastolic Blood Pressure in CTCAE Grade - To the Worst 
Abnormal Value 
Safety 
3.4.3 
Summary of Pulse 
Safety 
3.4.4 
Summary of Respiratory Rate 
Safety 
3.4.5 
Summary of Body Temperature 
Safety 
3.4.6 
Shift Summary of Body Weight in CTCAE Grade - To the Worst Abnormal 
Value 
Safety 
3.5.1 
Summary of PR Interval (ms) From 12-Lead ECG 
Safety 
3.5.2 
Summary of RR Interval (ms) From 12-Lead ECG 
Safety 
3.5.3 
Summary of QRS Interval (ms) From 12-Lead ECG 
Safety 
3.5.4 
Summary of QT Interval (ms) From 12-Lead ECG 
Safety 
3.5.5 
Summary of QTcB Interval (ms) From 12-Lead ECG 
Safety 


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Table No. 
Title 
Population 
3.5.6 
Summary of QTcF Interval (ms) From 12-Lead ECG 
Safety 
3.5.7 
Summary of Heart Rate (bpm) From 12-Lead ECG 
Safety 
3.5.8 
Summary of Outliers of QT, QTcB, and QTcF Interval Values (ms) From 
12-Lead ECG 
Safety 
3.5.8 
Summary of Clinically Significant ECG Abnormality 
Safety 
3.5.9 
Summary of ECG Interpretation 
Safety 
3.6.1 
Summary of Delay Time in Planned Radical Cystectomy  
Safety 
3.6.2 
Summary of Reasons for Delay in Planned Radical Cystectomy 
Safety 
Listings 
Listing No. 
Title 
2.1.1 
Informed Consent 
2.1.2 
Disposition 
2.1.3 
Radical Cystectomy 
2.1.4 
Delay in Cystectomy 
2.1.5 
Last Dose Administration and Radical Cystectomy Delay 
2.1.6 
Staging of Bladder Cancer Pre- and Post-Radical Cystectomy 
2.1.7 
End of Study Details 
2.1.8 
Post-Therapy 
2.2.1 
Inclusion/Exclusion Criteria 
2.2.2 
Protocol Deviations 
2.3.1 
Analysis Populations 
2.4.1 
Demographics and Baseline Characteristics 
2.4.2.1 
Urothelial Cancer History: Previous Urothelial Cancer History 
2.4.2.2 
Urothelial Cancer History: MIBC Current Diagnosis 
2.4.2.3 
Urothelial Cancer History: TURBT Diagnosis Method 
2.4.3 
Prior Radiation Treatment 
2.4.4 
Prior Systemic Therapy 
2.4.5 
Prior Surgery or Surgical Procedure for Disease Under Study 
2.4.6 
Procedures and Nondrug Therapy 
2.4.7 
Medical History 
2.4.8 
Prior and Concomitant Medications 
2.5.1 
Study Drug Compliance 
2.5.2 
Study Drug Administration - Epacadostat 
2.5.3 
Study Drug Administration - Retifanlimab 
2.5.4 
Study Drug Administration - INCAGN02385 
2.5.5 
Study Drug Administration - INCAGN02390 
2.6.1 
Deaths 
2.6.2 
Overall Response Assessment by Visit 
2.6.3 
Response Assessment 
2.6.4 
Pathological Complete Response 
2.6.5 
Major Pathological Response 
2.6.6 
ECOG Status 
2.7.1 
Adverse Events 
2.7.2 
Serious Adverse Events 


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Listing No. 
Title 
2.7.3 
Grade 3 and Higher Adverse Events 
2.7.4 
Fatal Adverse Events 
2.7.5.1 
Adverse Events Leading to Study Treatment Discontinuation 
2.7.5.2 
Adverse Events Leading to Delay of Radical Cystectomy  
2.7.5.3 
Adverse Events Leading to Hospitalization 
2.7.6 
Adverse Events Related to Post-Radical Cystectomy  
2.7.7.1 
Epacadostat-Related Adverse Events 
2.7.7.2 
Retifanlimab-Related Adverse Events 
2.7.7.3 
INCAGN02385-Related Adverse Events 
2.7.7.4 
INCAGN02390-Related Adverse Events 
2.7.8 
Infusion-Related Reactions 
2.7.9 
Postsurgical Complications Associated With Bladder Surgery 
2.8.1 
Clinical Laboratory Values - Hematology 
2.8.2 
Clinical Laboratory Values - Chemistry 
2.8.3 
Clinical Laboratory Values - Urinalysis 
2.8.4 
Clinical Laboratory Values - Coagulation 
2.8.5 
Clinical Laboratory Values - Thyroid Panel 
2.8.6 
Clinical Laboratory Values - Lipids 
2.8.7 
Clinical Laboratory Values - Serology 
2.8.8 
Abnormal Clinical Laboratory Values 
2.8.9 
Potential Hy's Law Events 
2.8.10 
Pregnancy Test 
2.9.1 
Vital Signs 
2.9.2 
Abnormal Vital Signs Values 
2.10.1 
12-Lead ECG Values 
2.10.2 
Abnormal 12-Lead ECG Values 
2.11 
Physical Examinations 
2.12.1 
Translational Assessments 
2.12.2 
RBC/Platelet Transfusions 
2.12.3 
Tissue Biopsies 
2.12.4 
HIV Management 
2.12.5 
COVID-19 Comments 
2.12.6 
Imaging